SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We ...investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5.
We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls.
Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS.
About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
Background & Aims: Tobacco smoking has a complex effect on intestinal inflammation, being protective in ulcerative colitis, whereas it aggravates Crohn's disease. The beneficial effect of smoking has ...been attributed to nicotine, but the mechanisms underlying the adverse effect are still under investigation. The aim of this study was to examine the effect of cigarette smoking on experimental colitis in rats and to investigate the underlying mechanism.
Methods: Rats were exposed daily to cigarette smoke by means of a specialized smoking chamber. Control rats were placed in the same chamber without introducing smoke. In parallel experiments, rats received the ganglionic blocker hexamethonium before smoke exposure. After 2 weeks, colitis was induced by dinitrobenzenesulfonic acid (DNBS), and inflammation was assessed 3 days later.
Results: Exposure to cigarette smoke significantly increased macroscopic and histological damages as well as myeloperoxidase activity compared with sham-treated controls. Treatment with hexamethonium before smoking reversed the effect of the smoke on the colitis, improving all parameters.
Conclusions: Exposure to cigarette smoke aggravates DNBS-induced colitis in the rat. This effect is reversed by hexamethonium, suggesting that a neural pathway is involved.
GASTROENTEROLOGY 1999;117:877-883
The Argo-YBJ experiment has now reached its final design configuration. The detector system consists of a full coverage array (about 5800 square meters) of resistive plate chambers (RPCs). The ...throughput depends on the trigger rate and threshold. The DAQ system must be able to sustain a maximum transfer rate of the order of 15 MB/s and a high peak data flow. Data are read out using a typical front-end acquisition chain built around a custom bus. Specialized electronics have been designed and dedicated software has been written to perform this task. Data are sent to the online farm through a switch exploiting a gigabit ethernet protocol. A solution to transfer data from the YBJ laboratory to the laboratories belonging to the Argo-YBJ collaboration exploiting the GRID middleware has also been implemented. In this paper we describe the daq and the data mover main characteristics and performance.
ATLAS data are distributed centrally to Tier-1 and Tier-2 sites. The first stages of data selection and analysis take place mainly at Tier-2 centres, with the final, iterative and interactive, stages ...taking place mostly at Tier-3 clusters. The Italian ATLAS cloud consists of a Tier-1, four Tier-2s, and Tier-3 sites at each institute. Tier-3s that are grid-enabled are used to test code that will then be run on a larger scale at Tier-2s. All Tier-3s offer interactive data access to their users and the possibility to run PROOF. This paper describes the hardware and software infrastructure choices taken, the operational experience after 10 months of LHC data, and discusses site performances.
The authors analyze the impact of the rotation law on equilibrium sequences of relativistic differentially-rotating neutron stars in axisymmetry. The maximum allowed mass for each model is strongly ...affected by the distribution of the angular velocity in the radial direction and by the consequent degree of differential rotation. To study the wide parameter space implied by the choice of the rotation law, we introduce a functional form that generalizes the so-called "j-const. law" adopted in all previous work. They compute equilibrium sequences of differentially rotating stars with a polytropic equation of state starting from the spherically symmetric static case. By analyzing the sequences with decreasing degrees of differential rotation, they find that the maximum value of the ratio T/|W| of rotational kinetic energy to gravitational binding energy, is substantially limited in these cases to a value of 0.128.
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