Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein

Owing to the frequent incidence of blast-induced traumatic brain injury (bTBI) in recent military conflicts, there is an urgent need to develop effective therapies for bTBI-related pathologies. Blood-brain barrier (BBB) breakdown has been reported to occur after primary blast exposure, making restoration of BBB function and integrity a promising therapeutic target. We tested the hypothesis that treatment with dexamethasone (DEX) after primary blast injury potentiates recovery of an in vitro BBB model consisting of mouse brain endothelial cells (bEnd.3). DEX treatment resulted in complete recovery of transendothelial electrical resistance and hydraulic conductivity 1 day after injury, compared with 3 days for vehicle-treated injured cultures. Administration of RU486 (mifepristone) inhibited effects of DEX, confirming that barrier restoration was mediated by glucocorticoid receptor signaling. Potentiated recovery with DEX treatment was accompanied by stronger zonula occludens (ZO)-1 tight junction immunostaining and expression, suggesting that increased ZO-1 expression was a structural correlate to BBB recovery after blast. Interestingly, augmented ZO-1 protein expression was associated with specific upregulation of the α⁺ isoform but not the α⁻ isoform. This is the first study to provide a mechanistic basis for potentiated functional recovery of an in vitro BBB model because of glucocorticoid treatment after primary blast injury.     

Angiotensin Converting Enzyme Inhibitors: Animal Experiments Suggest a New Pharmacological Treatment for Alcohol Abuse in Humans

The prevalence of heavy alcohol consumption is a major problem of increasing proportions throughout the world. Although alcohol sensitizing drugs and more recently serotonin uptake inhibitors are drug interventions with some following, their long term beneficial consequences have yet to be demonstrated. In recent years, we have demonstrated that manipulating activity in the renin-angiotensin system will dramatically alter voluntary alcohol consumption in rats. Based on these findings, the present study evaluated the ability of a class of drugs known as the angiotensin converting enzyme inhibitors to reduce voluntary alcohol drinking in laboratory animals. These drugs prevent the conversion of angiotensin I to angiotensin II. They have been licensed for use in Europe and North America and are indicated in the treatment of hypertension. Our experiments showed that both captopril (Capoten, Squibb) and enalapril (Vasotec, Merck Sharpe & Dohme) can reduce alcohol drinking in both normotensive and hypertensive animals regardless of whether the pattern of intake is in a bout or of a less exaggerated nature. Furthermore, this change in alcohol intake can occur without concomitant changes in blood pressure, plasma renin activity, overall fluid balance, or the distribution and metabolism of alcohol. Taken together these findings suggest that the angiotensin converting enzyme inhibitors should be evaluated in a clinical setting for they may prove to be a useful new treatment or treatment adjunct for alcohol abuse in humans.     

Isolation impairs place preference conditioning to morphine but not aversive learning in mice

Morphine (8–100 mg/kg IP) induces place preference conditioning in mice. The effect of two different periods of isolation (15 and 30 days) was examined. Mice isolated for 15 days but not 30 days exhibited place preference conditioning to morphine (8 mg/kg). After 30 days of isolation morphine could not induce place preference conditioning with the following doses (8, 16, 64, 100 mg/kg). Social regrouping of male mice previously isolated for 30 days with naive female mice for 15 or 30 days resulted in a reappearance of the conditioned place preference to morphine (16 mg/kg). The specificity of this associative deficit was examined by testing learning in isolated compared to non-isolated mice in two distinct settings: escape learning in the Morris water maze and passive avoidance acquisition and retention. On the Morris water maze isolated mice did not differ from non-isolated mice regarding place learning, the probe trial or extinction. Isolated mice were unimpaired in passive avoidance acquisition and retention. It was concluded that the deficits in place preference conditioning were not the result of a global learning impairment in isolated mice. Received: 10 April 1996 /Final version: 20 September 1996     

Probable gas embolism during operative hysteroscopy caused by products of combustion

PURPOSE: Gas embolism is a rare but well documented entity during operative hysteroscopy, with an incidence of 10-50%. Catastrophic outcomes occur at a rate of three in 17,000 procedures. The purpose of this report is to present a non-fatal case of gas embolism probably caused by the gaseous products of combustion. CLINICAL FEATURES: A 50-yr-old woman with a history of menorrhagia was scheduled for hysteroscopy and endometrial ablation and polypectomy. Fifteen minutes into the procedure, with the patient in lithotomy position, 20 degree head down tilt, and breathing spontaneously, a sudden oxygen desaturation occurred from 97% to 87%. The patient's end-tidal carbon dioxide dropped from 46 mmHg to 27 mmHg. The patient's breathing pattern remained normal, respiratory rate remained 11-12 breaths x min(-1) but amplitude of the reservoir bag movement was increased. Cardiovascular variables remained stable. She responded rapidly to 100% oxygen and made an uneventful recovery. Having ruled out other possible causes, we concluded gas embolism was responsible for the fall in oxygen saturation and end-tidal CO(2). CONCLUSION: With all the precautions in place to minimize the likelihood of fluid overload and ambient air embolism occurring, we surmised that products of combustion were the cause of the gas embolism. During endometrial ablation, gaseous products of combustion, mainly carbon dioxide, accumulate. The gases may then contribute to the rise in uterine pressure that occurs as irrigation fluid enters the uterus and this rise in pressure in turn encourages passage of gas into the open venous sinuses.     

Cognitive-behavioral therapy for panic: an open study

This paper reports results of an open prospective study of 26 patients who met DSM-III criteria for panic disorder or agoraphobia with panic attacks. Cognitive-behavioral treatment alone produced clinically and statistically significant improvement in panic symptoms, including both full-blown and limited symptom episodes. In addition, the treatment produced improvement in associated symptoms of phobic avoidance and generalized anxiety. This work provides further preliminary indication of the usefulness of cognitive-behavioral strategies as an alternative to medication in symptom-oriented treatments.     

Genetics of epilepsy: epilepsy research foundation workshop report.

The Sixth Epilepsy Research Foundation workshop, held in Oxford in March 2006, brought together basic scientists, geneticists, epidemiologists, statisticians, pharmacologists and clinicians to consider progress, issues and strategies for harnessing genetics to improve the understanding and treatment of the epilepsies. General principles were considered, including the fundamental importance of clear study design, adequate patient numbers, defi ned phenotypes, robust statistical data handling, and follow-up of genetic discoveries. Topics where some progress had been made were considered including chromosomal abnormalities, neurodevelopment, hippocampal sclerosis, juvenile myoclonic epilepsy, focal cortical dysplasia and pharmacogenetics. The ethical aspects of epilepsy genetics were reviewed. Principles and limitations of collaboration were discussed. Presentations and their matched discussions are produced here. There was optimism that further genetic research in epilepsy was not only feasible, but might lead to improvements in the lives of people with epilepsy.