Results Of A Genome-wide Genetic Screen For Panic Disorder

Panic disorder is characterized by spontaneous and recurrent panic attacks, often accompanied by agoraphobia. The results of family, twin, and segregation studies suggest a genetic role in the etiology of the illness. We have genotyped up to 23 families that have a high density of panic disorder with 540 microsatellite DNA markers in a first-pass genomic screen. The thirteen best families (ELOD > 6.0 under the dominant genetic model) have been genotyped with an ordered set of markers encompassing all the autosomes, at an average marker density of 11 cM. Over 110,000 genotypes have been generated on the whole set of families, and the data have been analyzed under both a dominant and a recessive model, and with the program SIBPAIR. No lod scores exceed 2.0 for either parametric model. Two markers give lod scores over 1.0 under the dominant model (chromosomes 1p and 20p), and four do under the recessive model (7p, 17p, 20q, and X/Y). One of these (20p) may be particularly promising. Analysis with SIBPAIR yielded P values equivalent to a lod score of 1.0 or greater (i.e., P < .016, one-sided, uncorrected for multiple tests) for 11 marker loci (2, 7p, 8p, 8q, 9p, 11q, 12q, 16p, 20p and 20q)

Integration of multiscale dendritic spine structure and function data into systems biology models

Comprising 1011 neurons with 1014 synaptic connections the human brain is the ultimate systems biology puzzle. An increasing body of evidence highlights the observation that changes in brain function, both normal and pathological, consistently correlate with dynamic changes in neuronal anatomy. Anatomical changes occur on a full range of scales from the trafficking of individual proteins, to alterations in synaptic morphology both individually and on a systems level, to reductions in long distance connectivity and brain volume. The major sites of contact for synapsing neurons are dendritic spines, which provide an excellent metric for the number and strength of signaling connections between elements of functional neuronal circuits. A comprehensive model of anatomical changes and their functional consequences would be a holy grail for the field of systems neuroscience but its realization appears far on the horizon. Various imaging technologies have advanced to allow for multi-scale visualization of brain plasticity and pathology, but computational analysis of the massive big data sets involved forms the bottleneck toward the creation of multiscale models of brain structure and function. While a full accounting of techniques and progress toward a comprehensive model of brain anatomy and function is beyond the scope of this or any other single paper, this review serves to highlight the opportunities for analysis of neuronal spine anatomy and function provided by new imaging technologies and the high-throughput application of older technologies while surveying the strengths and weaknesses of currently available computational analytical tools and room for future improvement

Four new families with autosomal dominant partial epilepsy with auditory features: clinical description and linkage to chromosome 10q24

Purpose: Autosomal dominant partial epilepsy with auditory features (ADPEAF) is a rare form of nonprogressive lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances. The gene predisposing to this syndrome was localized to a 10-cM region on chromosome 10q24. We assessed clinical features and linkage evidence in four newly ascertained families with ADPEAF, to refine the clinical phenotype and confirm the genetic localization. Methods: We genotyped 41 individuals at seven microsatellite markers spanning the previously defined 10-cM minimal genetic region. We conducted two-point linkage analysis with the ANALYZE computer package, and multipoint parametric and nonparametric linkage analyses as implemented in GENEHUNTER2. Results: In the four families, the number of individuals with idiopathic epilepsy ranged from three to nine. Epilepsy was focal in all of those with idiopathic epilepsy who could be classified. The proportion with auditory symptoms ranged from 67 to 100%. Other ictal symptoms also were reported; of these, sensory symptoms were most common. Linkage analysis showed a maximum 2-point LOD score of 1.86 at (theta = 0.0 for marker DIOS603, and a maximum multipoint LOD score of 2.93. Conclusions: These findings provide strong confirmation of link-age of a gene causing ADPEAF to chromosome 10q24. The results suggest that the susceptibility gene has a differential effect on the lateral temporal lobe, thereby producing the characteristic clinical features described here. Molecular studies aimed at the identification of the causative gene are underway

Severity and burden of partial-onset seizures in a phase III trial of eslicarbazepine acetate.

OBJECTIVE: The objective of this study was to compare posttreatment seizure severity in a phase III clinical trial of eslicarbazepine acetate (ESL) as adjunctive treatment of refractory partial-onset seizures. METHODS: The Seizure Severity Questionnaire (SSQ) was administered at baseline and posttreatment. The SSQ total score (TS) and component scores (frequency and helpfulness of warning signs before seizures [BS]; severity and bothersomeness of ictal movement and altered consciousness during seizures [DS]; cognitive, emotional, and physical aspects of postictal recovery after seizures [AS]; and overall severity and bothersomeness [SB]) were calculated for the per-protocol population. Analysis of covariance, adjusted for baseline scores, estimated differences in posttreatment least square means between treatment arms. RESULTS: Out of 547 per-protocol patients, 441 had valid SSQ TS both at baseline and posttreatment. Mean posttreatment TS for ESL 1200mg/day was significantly lower than that for placebo (2.68 vs 3.20, p&lt;0.001), exceeding the minimal clinically important difference (MCID: 0.48). Mean DS, AS, and SB were also significantly lower with ESL 1200mg/day; differences in AS and SB exceeded the MCIDs. The TS, DS, AS, and SB were lower for ESL 800mg/day than for placebo; only SB was significant (p=0.013). For both ESL arms combined versus placebo, mean scores differed significantly for TS (p=0.006), DS (p=0.031), and SB (p=0.001). CONCLUSIONS: Therapeutic ESL doses led to clinically meaningful, dose-dependent reductions in seizure severity, as measured by SSQ scores. CLASSIFICATION OF EVIDENCE: This study presents Class I evidence that adjunctive ESL (800 and 1200mg/day) led to clinically meaningful, dose-dependent seizure severity reductions, measured by the SSQ

Gastric and enteric phytobezoars caused by ingestion of persimmon in equids

Case Description—13 equids (10 horses, 2 donkeys, and 1 pony) were examined for signs of colic (n = 7), weight loss (6), anorexia (3), and diarrhea (2). Ten equids were evaluated in the fall (September to November). Seven equids had a history of persimmon ingestion. Clinical Findings—A diagnosis of phytobezoar caused by persimmon ingestion was made for all equids. Eight equids had gastric persimmon phytobezoars; 5 had enteric persimmon phytobezoars. Gastroscopy or gastroduodenoscopy revealed evidence of persimmon ingestion in 8 of 10 equids in which these procedures were performed. Treatment and Outcome—2 of 13 equids were euthanatized prior to treatment. Supportive care was instituted in 11 of 13 equids, including IV administration of fluids (n = 8) and treatment with antimicrobials (5), NSAIDs (5), and gastric acid suppressants (4). Persimmon phytobezoar–specific treatments included dietary modification to a pelleted feed (n = 8); oral or nasogastric administration of cola or diet cola (4), cellulase (2), or mineral oil (2); surgery (4); and intrapersimmon phytobezoar injections with acetylcysteine (1). Medical treatment in 5 of 7 equids resulted in resolution of gastric persimmon phytobezoars. Seven of 8 equids with gastric persimmon phytobezoars and 1 of 5 equids with enteric persimmon phytobezoars survived > 1 year after hospital discharge. Clinical Relevance—Historical knowledge of persimmon ingestion in equids with gastrointestinal disease warrants gastroduodenoscopy for evaluation of the presence of persimmon phytobezoars. In equids with gastric persimmon phytobezoars, medical management (including administration of cola or diet cola and dietary modification to a pelleted feed) may allow for persimmon phytobezoar dissolution.Heidi E. Banse, Lyndi L. Gilliam, Amanda M. House, Harold C. McKenzie, Philip J. Johnson, Marco A. F. Lopes, Robert J. Carmichael, Erin S. Groover, Alison M. LaCarrubba, Melanie A. Breshears, Margaret M. Brosnahan, Rebecca Funk, Todd C. Holbroo

Interspecific divergence in foliar nutrient dynamics and stem growth in a temperate forest in response to chronic nitrogen inputs

We studied the effects of excessive nitrogen (N) fertilization on foliar nutrient dynamics and stem growth in three important tree species in a mixed-deciduous forest. Stem diameter growth, foliar N concentrations, nitrogen–phosphorus (N/P) ratios, and nutrient resorption were determined for Acer rubrum L. (ACRU), Liriodendron tulipifera L. (LITU), and Prunus serotina Ehrh. (PRSE) on two 30-year-old watersheds at the Fernow Experimental Forest, West Virginia, USA: WS3, fertilized annually with 35 kg ammonium sulfate·ha-1 since 1989, and WS7, an untreated control watershed. In an earlier (1992) study, foliar N concentrations of all three species averaged 11% higher in WS3 than in WS7. By 2000, that was no longer the case for any species; indeed N in ACRU leaves was 13% lower in WS3 that year. N/P ratios were elevated in WS3 only in PRSE in 1992 and in both ACRU and PRSE in 1997, but by 2001, mean N/P for all three species was lower in WS3. N resorption efficiencies were 30% lower in WS3 in ACRU and PRSE, but not in LITU. Stem diameter growth in WS3 was 55% lower in ACRU and 30% lower in LITU and PRSE compared with that in WS7. Results may indicate declining growth vigor in ACRU and, to a lesser extent, PRSE and LITU in the fertilized watershed. Observed interspecific differences in growth and plant nutrition responses suggest eventual changes in species composition under increasing N saturation

Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features

The epilepsies are a common, clinically heterogeneous group of disorders defined by recurrent unprovoked seizures1. Here we describe identification of the causative gene in autosomal-dominant partial epilepsy with auditory features (ADPEAF, MIM 600512), a rare form of idiopathic lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances2, 3. We constructed a complete, 4.2-Mb physical map across the genetically implicated disease-gene region, identified 28 putative genes (Fig. 1) and resequenced all or part of 21 genes before identifying presumptive mutations in one copy of the leucine-rich, glioma-inactivated 1 gene (LGI1) in each of five families with ADPEAF. Previous studies have indicated that loss of both copies of LGI1 promotes glial tumor progression. We show that the expression pattern of mouse Lgil is predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy. Discovery of LGI1 as a cause of ADPEAF suggests new avenues for research on pathogenic mechanisms of idiopathic epilepsies