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.     

Transjugular intrahepatic cavoportal shunt for Budd–Chiari syndrome

Budd–Chiari syndrome (BCS) is characterized by obstruction of the hepatic venous outflow tract. Therapeutic options for BCS are limited. We report a case of a 21-year-old woman with protein S and C deficiency with gross ascites. Treatment with transjugular intrahepatic portosystemic shunt (TIPS) was attempted, which revealed occluded hepatic veins, so transcaval TIPS was performed. No serious procedure-related complication occurred. After successful shunt creation, the patient's symptoms subsided and she was discharged and followed up for 6 months.     

Prodrugs for Improved Oral β-Estradiol Bioavailability

Prodrugs of -estradiol (1) were prepared with the objective of improving its oral bioavailability. -Estradiol-3-acetylsalicylate (2), -estradiol-3-salicylate (3), and -estradiol-3-anthranilate (4) were synthesized. With these prodrugs the 3-phenolic hydroxy group of estradiol was protected, so that first-pass conjugative metabolism could be reduced. Prodrug hydrolysis rates in dog and human plasma in vitro were determined. Deacetylation of estradiol-3-acetylsalicylate was much more rapid than its hydrolysis to estradiol. In dogs, oral estradiol bioavailability after administration of 2 and 4 was 17-fold and 5-fold higher, respectively, than after oral 1.     

Naltrexone-3-salicylate (a Prodrug of Naltrexone): Synthesis and Pharmacokinetics in Dogs

Naltrexone-3-salicylate (3), a prodrug of naltrexone (1), was prepared by a simple procedure from naltrexone-3-acetylsalicylate (2). The plasma (dog and human) hydrolysis half-life of 3 was found to be approximately 30 min. Compound 2 was previously shown to hydrolyze in dog and human plasma with a fast deacetylation step to 3, followed by slower hydrolysis of 3 to 1 (t _1/2, 30 min). Oral naltrexone bioavailability was greatly improved (30-fold) after oral administration of 3 to dogs, similar to the improvement observed after oral administration of 2. The half-life of naltrexone in dogs after oral administration of 3 was similar to that observed after oral administration of 2 (1 hr).     

Does the MMR vaccine and secretin or its receptor share an antigenic epitope?

In a subgroup of children with autism-spectrum like conditions symptoms seem to appear as a 'regression' (in normal development). It has been postulated that the onset of such autistic symptoms may involve an autoimmune response against the central nervous system and that the antigenic determinant could possibly be gastrointestinal in origin. It has been suggested that the presence of the measles virus and 'autistic enterocolitis' demonstrates the possibility that the MMR triple vaccine may be mediating the inflammation with possible production of antibodies against the virus containing vaccine. Such an antibody may share antigenic determinant to molecules found in the gut. We propose that this may be secretin or its receptor, found in the gut as well as in the central nervous system. The antibody response to the gut may also conceivably occur in the brain at a critical time in development. The modulation of development by secretin may be a static event possibly occurring at a specific time in early childhood development and if it involves an autoimmune response then a disruption in development may result. These hypothesized events can only occur if the MMR vaccine shares antigenic determinants that resemble secretin or any of its receptor types and remains to be studied.     

Effects of caffeine on potassium currents in isolated rat ventricular myocytes

Rapid exposure of cardiac muscle to high concentrations of caffeine releases Ca(2+) from the sarcoplasmic reticulum (SR). This Ca(2+) is then extruded from the cell by the Na(+)/Ca(2+) exchanger. Measurement of the current carried by the exchanger (I(Na/Ca)) can therefore be used to estimate of the Ca(2+) content of the SR. Previous studies have shown that caffeine, however, can also inhibit K(+) currents. We therefore investigated whether the inhibitory effects of caffeine on these currents could contaminate measurements of I(Na/Ca). Caffeine caused partial inhibition of the inward rectifier K(+) current (I(K1)): the outward current at -40 mV was 1.15+/-0.24 pA/pF in control and decreased to 0.34+/-0.15 pA/pF in the presence of 10 mmol/l caffeine (P<0.05, n=15). This was similar to the effect of caffeine on the holding current observed at -40 mV in the absence of K(+) channel block and could therefore account for the contaminating effects of caffeine observed during measurements of I(Na/Ca). Moreover, caffeine also partially inhibited the transient outward ( I(to)) and the delayed rectifier (I(K)) K(+) currents.     

Use of antidepressant medications and the possible association with breast cancer risk. A review

BACKGROUND: Antidepressant medication use has dramatically increased over the past decade, particularly for the newer classes such as selective serotonin reuptake inhibitors. While there is no question about the usefulness of these medications, it is important to review animal and epidemiologic studies that have evaluated the association between antidepressant medication use and the risk of breast cancer. METHODS: This paper reviews the scientific literature pertaining to the prevalence of and indications for antidepressant medication use, and the possible association between antidepressant medication use and breast cancer risk. RESULTS: Antidepressant medications are most commonly indicated for depressive disorders, and are also used for other conditions (e.g., anxiety disorders, personality disorders, and pain). In addition, antidepressants may be an effective alternative to estrogen therapy for the alleviation of hot flashes among peri-/postmenopausal women. Several epidemiologic studies have reported that certain antidepressants may be associated with a slightly increased breast cancer risk; however, the literature remains inconsistent. CONCLUSIONS: The possibility of an association between certain antidepressant medications and breast cancer risk has not been excluded, although further studies are needed before the body of scientific evidence can be conclusive. Evidence to date does not support a change in the current use of antidepressant medications.     

Telepathology for routine light microscopic and frozen section diagnosis

Telepathology (TP) uses telecommunication linkages to electronically capture, store, retrieve, and transmit images to distant sites. We assessed the feasibility of a dynamic real-time TP system for light microscopic (LM) diagnosis of anatomic pathology specimens, including frozen sections. Six pathologists, in 2 separate periods, read a set of 160 retrospectively retrieved slides (80 of which were frozen sections) by TP and LM. Reading times were recorded. Diagnoses were compared with the reference diagnosis (established by a group of 5 independent pathologists) and graded on a scale of 0 to 2 (2, correct; 1, incorrect but no clinical impact; 0, incorrect with clinical impact). Overall, LM was more accurate than TP compared with the reference diagnosis (score, 1.68 vs 1.54). There was no difference in accuracy between frozen section and paraffin-embedded tissue. Intraobserver agreement ranged from 82.5% to 88.2%. The average reading time was 6.0 minutes for TP and 1.4 minutes for LM. During the study, reading time decreased for TP but not for LM. These results show that despite marginally lower accuracy and longer reading times, TP isfeasible for routine light microscopic diagnosis, including frozen sections.