Background: MRI offers quantification of proton density fat fraction (PDFF) and tissue characteristics with T1 mapping. The influence of age, sex, and the potential confounding effects of fat on T1 values in skeletal muscle in healthy adults are insufficiently known.
Purpose: To determine the accuracy and repeatability of a saturation-recovery chemical-shift encoded multiparametric approach (SR-CSE) for quantification of T1 and muscle fat content, and establish normative values (age, sex) from a healthy cohort.
Introduction: Short-term clinical outcomes from SARS-CoV-2 infection are generally favorable. However, 15-20% of patients report persistent symptoms of at least 12 weeks duration, often referred to as long COVID. Population studies have also demonstrated an increased risk of incident diabetes and cardiovascular disease at 12 months following infection.
View Article and Find Full Text PDFBackground And Purpose: Inhibitors of voltage-gated sodium channels (Nas) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are non-selective. We aimed to create novel, isoform selective inhibitors of Na channels as a means of informing the development of improved antiseizure drugs.
Experimental Approach: We created a series of compounds with diverse selectivity profiles enabling block of Na1.
The aim of this study was to investigate the comparative antiseizure activity of the -enantiomers of ,-fenfluramine and ,-norfenfluramine and to evaluate the relationship between their concentration in plasma and brain and anticonvulsant activity. ,-Fenfluramine, ,-norfenfluramine and their individual enantiomers were evaluated in the mouse maximal electroshock seizure (MES) test. ,-Fenfluramine, ,-norfenfluramine and their individual -enantiomers were also assessed in the DBA/2 mouse audiogenic seizure model.
View Article and Find Full Text PDFBackground: T1 mapping of the liver is confounded by the presence of fat. Multiparametric T1 mapping combines fat-water separation with T1-weighting to enable imaging of water-specific T1 (T1), proton density fat fraction (PDFF), and T2* values. However, normative T1 values in the liver and its dependence on age/sex is unknown.
View Article and Find Full Text PDFNBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target Na1.6 channels. Such a molecule provides a precision-medicine approach to target -related epilepsy syndromes (-RES), where gain-of-function (GoF) mutations lead to excess Na1.
View Article and Find Full Text PDFObjective: The objective was to evaluate the safety and efficacy of TV-45070 ointment, as a treatment for postherpetic neuralgia, and to explore the response in patients with the Nav1.7 R1150W gain-of-function polymorphism.
Materials And Methods: This was a randomized, placebo-controlled, 2-period, 2-treatment crossover trial.
Chronic obstructive pulmonary disease (COPD) is a long-term lung disease characterised by breathlessness, cough and sputum production. Progressively worsening breathlessness for the patient with COPD limits everyday activity, reduces quality of life and increases the risk of premature death. Beyond reducing symptoms and the rate and severity of exacerbations, the aim of treatment is to increase exercise capacity and improve overall health and wellbeing.
View Article and Find Full Text PDFWhile genetic determinants strongly influence HDL cholesterol (HDLc) levels, most genetic causes underlying variation in HDLc remain unknown. We aimed to identify novel rare mutations with large effects in candidate genes contributing to extreme HDLc in humans, utilizing family-based Mendelian genetics. We performed next-generation sequencing of 456 candidate HDLc-regulating genes in 200 unrelated probands with extremely low (≤10th percentile) or high (≥90th percentile) HDLc.
View Article and Find Full Text PDFHuman visual area V6, in the parieto-occipital sulcus, is thought to have an important role in the extraction of optic flow for the monitoring and guidance of self-motion (egomotion) because it responds differentially to egomotion-compatible optic flow when compared to: (a) coherent but egomotion-incompatible flow (Cardin & Smith, 2010), and (b) incoherent motion (Pitzalis et al., 2010). It is not clear, however, whether V6 responds more strongly to egomotion-incompatible global motion than to incoherent motion.
View Article and Find Full Text PDFWe have utilized a novel application of human genetics, illuminating the important role that rare genetic disorders can play in the development of novel drugs that may be of relevance for the treatment of both rare and common diseases. By studying a very rare Mendelian disorder of absent pain perception, congenital indifference to pain, we have defined Nav1.7 (endocded by SCN9A) as a critical and novel target for analgesic development.
View Article and Find Full Text PDFMutations in the SCN9A gene leading to deficiency of its protein product, Na(v)1.7, cause congenital indifference to pain (CIP). CIP is characterized by the absence of the ability to sense pain associated with noxious stimuli.
View Article and Find Full Text PDFCongenital indifference to pain (CIP) is a rare condition in which patients have severely impaired pain perception, but are otherwise essentially normal. We identified and collected DNA from individuals from nine families of seven different nationalities in which the affected individuals meet the diagnostic criteria for CIP. Using homozygosity mapping and haplotype sharing methods, we narrowed the CIP locus to chromosome 2q24-q31, a region known to contain a cluster of voltage-gated sodium channel genes.
View Article and Find Full Text PDFOur previous results pointed to a putative gene for susceptibility to bipolar affective disorder located on the chromosomal region 12q23-q24 that segregated in the Saguenay-Lac-St-Jean population of Quebec. We report here results from a second genome-wide scan based on the analysis of 380 polymorphic microsatellite markers. For the purpose of this analysis, an additional 18 families were recruited from the Saguenay-Lac-St-Jean region and pooled to our previous sample to improve its statistical power, giving a total of 394 sampled individuals.
View Article and Find Full Text PDFHereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder characterized by impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons. We identified two large pedigrees segregating the disorder in an isolated population living in Newfoundland and performed a 5-cM genome scan. Linkage analysis identified a locus mapping to 12p13.
View Article and Find Full Text PDFSchizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans.
View Article and Find Full Text PDFGenetic isolates have been useful cohorts in which to search for genes underlying disorders of unknown pathology. One such cohort is thought to exist in the Central Valley of Costa Rica surrounding the city of San Jose. Previous investigators identified a rare dominant gene for hereditary deafness in this population, and a suggestive linkage of severe bipolar psychosis has been reported in another study.
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