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.     

Herpetic croup: two case reports and a review of the literature

Croup is an acute infectious illness usually occurring in children; it is characterized by brassy cough and stridor. The main pathogens include mainly parainfluenza and influenza viruses. Recently there have been reports of prolonged croup caused by the herpes simplex viruses. We report two cases of prolonged croup due to herpes simplex types 1 and 2. We also review and summarize the reported pediatric cases of herpetic croup.     

Primitive Neuroectodermal Tumors of the Central Nervous System

Controversial issues relating to the pathobiology and classification of central nervous system primitive neuroectodermal tumors (PNETs) have plagued neuropathologists for more than 70 years. Hypotheses advanced in the mid-1920's have remained as fixed concepts in contemporary literature, largely consequent to repetitious support by a small number of neuropathologists despite a growing body of information discrediting these ideas from neuroembryologists, oncologists, neuroscien-tists and pathologists.
Attention has largely focused upon PNETs arising in the cerebellum (commonly known as medul-loblastomas [MBs]), because about 80% of central nervous system (CNS) PNETs originate in this site. It has been asserted that the 20% which do not are biologically different, although most individuals agree that the histological features of PNETs that occur in different sites throughout the CNS are indistinguishable from those growing in the cerebellum.
The historical aspects of this controversy are examined in the face of evidence that there is, in fact, a unique class of CNS tumors which should appropriately be regarded as primitive neuroectodermal in nature. Specifically, a number of different approaches to the problem have yielded data supporting this hypothesis. These approaches include the identification of patterns of expression among a variety of cellular antigens (demonstrated by the use of immunopathological techniques), molecular analyses of cell lines derived from these tumors, experimental production of PNETs and molecular genetic analyses.
Differences of opinion among surgeons, oncologists and radiotherapists are typically resolved by conducting cooperative studies of patients with these tumors who are diagnosed and treated at multiple centers.     

Temporal prominence of auditory evoked potentials (N1 wave) in 4-8-year-old children

Cortical auditory evoked potentials (N1 wave) were studied in 24 adults (12 men, 12 women) and 20 children (12 boys, 8 girls; age: 4-8 years). In adults, this wave was recorded with maximal amplitude at frontocentral sites, peaking at about 100 ms poststimulation, whereas in children the auditory response displayed maximal amplitude at the midtemporal sites, with a positive wave at about 100 ms and a large negative wave at approximately 170 ms. Moreover, the modulatory effects of intensity on N1 amplitude were prominent at frontocentral sites in adults and at temporal sites in children. Frontocentral negative response was also recorded in children but was smaller in amplitude and longer in peak latency (around 140 ms) than in adults; responses were of greater amplitude at the frontal site than at the vertex before 6 years of age, whereas the reverse was more often found after this age. These data suggest great differences with age in the neural generators contributing to auditory evoked potentials recorded in the N1 latency range.     

The three-dimensional scintillation dosimetry method: test for a 106Ru eye plaque applicator

The need for fast, accurate and high resolution dosimetric quality assurance in radiation therapy has been outpacing the development of new and improved 2D and 3D dosimetry techniques. This paper summarizes the efforts to create a novel and potentially very fast, 3D dosimetry method based on the observation of scintillation light from an irradiated liquid scintillator volume serving simultaneously as a phantom material and as a dose detector medium. The method, named three-dimensional scintillation dosimetry (3DSD), uses visible light images of the liquid scintillator volume at multiple angles and applies a tomographic algorithm to a series of these images to reconstruct the scintillation light emission density in each voxel of the volume. It is based on the hypothesis that with careful design and data processing, one can achieve acceptable proportionality between the local light emission density and the locally absorbed dose. The method is applied to a Ru-106 eye plaque immersed in a 16.4 cm3 liquid scintillator volume and the reconstructed 3D dose map is compared along selected profiles and planes with radiochromic film and diode measurements. The comparison indicates that the 3DSD method agrees, within 25% for most points or within approximately 2 mm distance to agreement, with the relative radiochromic film and diode dose distributions in a small (approximately 4.5 mm high and approximately 12 mm diameter) volume in the unobstructed, high gradient dose region outside the edge of the plaque. For a comparison, the reproducibility of the radiochromic film results for our measurements ranges from 10 to 15% within this volume. At present, the 3DSD method is not accurate close to the edge of the plaque, and further than approximately 10 mm (<10% central axis depth dose) from the plaque surface. Improvement strategies, considered important to provide a more accurate quick check of the dose profiles in 3D for brachytherapy applicators, are discussed.     

Distinct sleep-wake stages in rats depend differentially on age

The objective was to study age-related changes in sleep-wake stages in the rat by using precise polyphysiograph criteria for stage identification. Cortical and hippocampal electroencephalogram, and ocular and myographic activities were recorded in young, middle-aged, and old male Wistar rats to define 6 stages: active and quiet wake (AW, QW); light and deep slow wave sleep (SWS: S1, S2); intermediate stage of sleep (IS); and paradoxical sleep (PS). The old rats displayed a decrease in S1, S2, and IS, accompanied by an enhancement of AW. No age changes were found for QW and PS. It is suggested that the consolidation of SWS is primarily disturbed in the old rats, which may lead to a facilitation of wake.     

Family-based association studies of bipolar disorder with candidate genes involved in dopamine neurotransmission: DBH, DAT1, COMT, DRD2, DRD3 and DRD5

The dopaminergic system has been implicated in the aetiology of mood disorders. We conducted family-based association studies for polymorphisms at three genes involved in the metabolism of dopamine: dopamine transporter (DAT1), dopamine-beta-hydroxylase (DBH) and catechol-O-methyl transferase (COMT); and three dopamine receptors: DRD2, DRD3 and DRD5. We used a sample of 122 parent-offspring trios of British Caucasian origin where the proband had bipolar disorder I (BPI), and analysed the results with the transmission/disequilibrium test (TDT) which is robust to hidden population stratification. No statistically significant differences were found between transmitted and not transmitted alleles for any of the polymorphisms studied.     

Comparing sulindac with indomethacin for closure of ductus arteriosus in preterm infants

Objectives: A prospective study comparing the efficiacy and side-effects of oral sulindac with intravenous indomethacin in clinically stable preterm infants (<1750 g) requiring non-invasive closure of haemodynamically significant patent ductus arteriosus.
Methodology: As maturity and birthweight are the two major determinants of ductal closure, infants were matched as closely as possible for these parameters. An eligible patient was first assigned to the sulindac group and a subsequent patient with similar gestational age (± 1 week) and birthweight (±100 g) to the previously recruited infant would automatically receive indomethacin. A total of eight infants were enrolled in each group.
Results: The ductus arteriosus was successfully closed in all eight infants receiving indomethacin, and in seven of eight infants receiving sulindac. No significant differences were found with regards to the ductal size between the two groups at diagnosis or on each of the consecutive days of treatment ( P >0.25). More renal adverse effects were encountered in the indomethacin group. Significant differences in changes from baseline value for urine output, plasma sodium, urea and creatinine concentrations were noted at 24, 48 and 72 h after commencement of treatment between the two groups ( P <0.05). All the parameters returned to normal or pre-treatment levels 48 h after stopping therapy. Unexpectedly, severe gastrointestinal complications were encountered in the sulindac group.
Conclusions: Sulindac is capable of promoting ductal constriction in clinically stable preterm infants without compromising the renal function. The spectrum of gastrointestinal complications observed in sulindac treated infants were similar to those described for indomethacin. The use of sulindac for ductal closure in the preterm infant should remain experimental.     

Automated whole‐brain N‐acetylaspartate proton MRS quantification

Concentration of the neuronal marker, N‐acetylaspartate (NAA), a quantitative metric for the health and density of neurons, is currently obtained by integration of the manually defined peak in whole‐head proton (¹H)‐MRS. Our goal was to develop a full spectral modeling approach for the automatic estimation of the whole‐brain NAA concentration (WBNAA) and to compare the performance of this approach with a manual frequency‐range peak integration approach previously employed. MRI and whole‐head ¹H‐MRS from 18 healthy young adults were examined. Non‐localized, whole‐head ¹H‐MRS obtained at 3 T yielded the NAA peak area through both manually defined frequency‐range integration and the new, full spectral simulation. The NAA peak area was converted into an absolute amount with phantom replacement and normalized for brain volume (segmented from T₁‐weighted MRI) to yield WBNAA. A paired‐sample t test was used to compare the means of the WBNAA paradigms and a likelihood ratio test used to compare their coefficients of variation. While the between‐subject WBNAA means were nearly identical (12.8 ± 2.5 mm for integration, 12.8 ± 1.4 mm for spectral modeling), the latter's standard deviation was significantly smaller (by ~50%, p = 0.026). The within‐subject variability was 11.7% (±1.3 mm ) for integration versus 7.0% (±0.8 mm ) for spectral modeling, i.e., a 40% improvement. The (quantifiable) quality of the modeling approach was high, as reflected by Cramer–Rao lower bounds below 0.1% and vanishingly small (experimental ‐ fitted) residuals. Modeling of the whole‐head ¹H‐MRS increases WBNAA quantification reliability by reducing its variability, its susceptibility to operator bias and baseline roll, and by providing quality‐control feedback. Together, these enhance the usefulness of the technique for monitoring the diffuse progression and treatment response of neurological disorders. Copyright © 2014 John Wiley & Sons, Ltd.