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.     

Women's response to fetal choroid plexus cysts detected by prenatal ultrasound.

OBJECTIVES: To determine maternal responses to detection of a minor structural variant, the choroid plexus cyst (CPC), in their fetus on prenatal ultrasound. STUDY DESIGN: We interviewed 34 pregnant women with an isolated CPC detected on mid-pregnancy ultrasound about their objective experience at diagnosis, emotional response and subsequent reactions. Audiotaped, transcribed responses were evaluated by two independent raters and analyzed qualitatively and quantitatively. RESULTS: All women reported negative emotional responses including shock, distress, fear and decreased attachment, despite counseling by 82% of providers that the CPC was probably benign. Three women underwent amniocentesis purely for reassurance after CPC detection. Most (79%) sought information beyond what their physician provided, frequently on the internet. One half of women reported that intense negative responses were temporary. However, weeks after diagnosis, 62% continued to believe that the CPC presented some danger to their baby. CONCLUSIONS: Detection of CPC prenatally can evoke profound, negative maternal emotional responses despite accurate provider counseling. Practitioners should consider these responses when counseling parents about these and other structural variants of unclear functional significance.     

Differential Cellular Gene Expression in Ganglioglioma

Summary:  Purpose:  Gangliogliomas (GGs) are neuronal-glial tumors highly associated with epilepsy. We hypothesized that the expression of select gene families including neurotransmitter receptor subunits and growth factors would be distinct in neurons and astrocytes within GG compared with adjacent cortex and that these changes would yield insights into seizure onset and lesion formation.
Methods:  Candidate gene expression was defined in single immunohistochemically labeled neurons and astrocytes microdissected from GG specimens compared with neurons and astrocytes microdissected from morphologically intact cortex adjacent to the GG or normal control cortex.
Results:  Differential expression of 16 genes including glutamate transporter (EAAC1) and receptor (NMDA2C, mGluR5), growth factor (hepatocyte growth factor), and receptor (platelet derived growth factor receptor β, fibroblast growth factor receptor 3) mRNAs was detected in GG neurons compared with control neurons. In astrocytes, altered expression of p75NGF, mGluR3, TGFβ3 and Glt-1 mRNAs was detected. Nestin mRNA, a gene that exhibits enhanced expression in balloon cell cortical dysplasia, was increased in GG neurons. Because of the morphological similarities between GG and cortical dysplasia, we show that there is activation of the mTOR cascade in GG as evidenced by enhanced expression of phospho-p70S6kinase and phosphoribosomal S6 proteins.
Conclusion:  We find differential candidate gene expression in neurons and astrocytes in GG compared with adjacent cortex and show that there is activation of the mTOR pathway. These changes highlight pathways that may be pivotal for epileptogenesis and lesion growth.     

Stimulation of glutamate receptor protein synthesis and membrane insertion within isolated neuronal dendrites

The selective subcellular localization of mRNAs to dendrites and the recent demonstration of local protein synthesis have highlighted the potential role of postsynaptic sites in modulation of cell-cell communication. We show that epitope-tagged subunit 2 of the ionotopic glutamate receptor, GluR2, mRNA transfected into isolated hippocampal neuronal dendrites is translated in response to pharmacologic stimulation. Further, confocal imaging of N-terminally labeled GluR2 reveals that the newly synthesized GluR2 protein can integrate into the dendritic membrane with the N terminus externally localized. These data demonstrate that integral membrane proteins can be synthesized in dendrites and can locally integrate into the cell membrane.     

Induction chemotherapy plus high-dose radiotherapy versus radiotherapy alone in locally advanced unresectable non-small-cell lung cancer

Background: High-dose radiation therapy is generally recommendedas standard treatment in regionally advanced unresectable non-small-celllung cancer (NSCLC), but medianand long-term survival remainpoor. Some reports have recently shown an improvement of resultsin advanced NSCLC when cisplatin was included in the chemotherapyregimens. Therefore, we designed a randomized trial to determinewhether induction chemotherapy before high-dose radiotherapyimproves response rate and survival in stage HI NSCLC over thatachieved with radiotherapy alone. Patients and methods: From March, 1984 to December, 1988, 66consecutive patients with stage HI unresectable NSCLC were randomizedto one of two treatment arms; 61 were evaluable for survivaland 58 for response and toxicity. Patients randomly assignedto arm A received cisplatin (CDDP 100 mg/m² on day 1) and etoposide(VP 16 120 mg/ m² on days 1, 2, 3) every 3 wks for 3 coursesfollowed by radiotherapy 56 Gy on pre-treatment tumor volumeand 40 Gy on mediastinum and bilateral supraclavicular nodes.Patients assigned to arm B received only the same radiotherapy.The 61 eligible patients were comparable in terms of age, performancestatus, histology and treatment. Results: Response rate was 53% in arm A and 32% in arm B. Themedian survival was 52 wks for the combined treatment arm and36 wks for the radiation therapy arm. At six years of follow-upall the patients were dead. Toxicity was mild and no treatment-relateddeaths were recorded. Conclusion: Induction chemotherapy produced a better responserate and a trend of improved survival (4 months) but a significantsurvival advantage was not achieved (p < 0.11), probablybecause of the small number of patients enrolled in the trial. chemotherapy, non-small-cell lung cancer, radiotherapy, combined treatment