In silico investigation of a KCNQ1 mutation associated with short QT syndrome

Short QT syndrome (SQTS) is a rare condition characterized by abnormally ‘short’ QT intervals on the ECG and increased susceptibility to cardiac arrhythmias and sudden death. This simulation study investigated arrhythmia dynamics in multi-scale human ventricle models associated with the SQT2-related V307L KCNQ1 ‘gain-of-function’ mutation, which increases slow-delayed rectifier potassium current (IKs). A Markov chain (MC) model recapitulating wild type (WT) and V307L mutant IKs kinetics was incorporated into a model of the human ventricular action potential (AP) for investigation of QT interval changes and arrhythmia substrates. In addition, the degree of simulated IKs inhibition necessary to normalize the QT interval and terminate re-entry in SQT2 conditions was quantified. The developed MC model accurately reproduced AP shortening and reduced effective refractory period associated with altered IKs kinetics in homozygous (V307L) and heterozygous (WT-V307L) mutation conditions, which increased the lifespan and dominant frequency of re-entry in 3D human ventricle models. IKs reductions of 58% and 65% were sufficient to terminate re-entry in WT-V307L and V307L conditions, respectively. This study further substantiates a causal link between the V307L KCNQ1 mutation and pro-arrhythmia in human ventricles, and establishes partial inhibition of IKs as a potential anti-arrhythmic strategy in SQT2

Undernourished patients do not have increased risk of severe COVID-19 outcomes

International audienceBackground: Undernutrition has been previously identified as a deleterious factor in acute infections. In covid-19 infection, obesity is a risk-factor of severe evolution, but initial undernutrition has not been evaluated yet.Methods: We retrospectively analyzed correlation between nutritional status at admission and severe outcomes (intensive care unit admission, invasive mechanical ventilation requirement and death) of patients hospitalized for confirmed covid-19 infection.Results: Risk of intensive care unit admission and invasive mechanical ventilation requirement was not significantly different between undernutrition and normoweight sub-groups, but increased in excessive weight sub-group (ODDR (IC 95%) 1.048 (1.011-1.086), p = 0.011). Risk of death was the same in all sub-groups.Conclusion: Undernutrition didn't appear as a factor of severe outcomes in covid-19 infection

Assessment of liver fibrosis by transient elastography (Fibroscan((R))) in patients with A1AT deficiency

BACKGROUND: Alpha-1-antitrypsin deficiency (A1ATD) is a common genetic condition which predisposes to emphysema and liver disorders. It is estimated that 10-15% of homozygous individuals for the Z allele (PiZZ) may develop liver fibrosis. The optimal modalities to detect liver disease in PiZZ adult patients need to be defined. The aim of this prospective study was to perform a systematic non-invasive evaluation of the liver fibrosis by elastometry using Fibroscan((R)) in a cohort of A1ATD patients with emphysema. METHODS: Patients followed in our respiratory unit were enrolled in this prospective study and underwent on the same day a physical examination, a biochemical profiling, an abdominal ultrasound (US) and a Fibroscan((R)). RESULTS: Twenty-nine PiZZ adults (19 male) were included. Median age was 50.4 yrs (21.5-67.2). Median serum A1AT level was 0.20 g/L (0.15-0.33). Liver Function Tests (LFT) were not normal in 2 patients and US was abnormal in 6 patients. Two patients had both abdnormal LFT and US. Fibroscan((R)) was technically feasible in 28/29 (97%) patients. Median liver stiffness was 4.5 kPa (2.8-32.8), and was \\textgreater 7.2 kPa in 5/28 (18%) and \\textgreater 14 kPa in 2/28 (7%) patients. Liver stiffness was increased in 2/2 (100%) patients with abnormal LFT and US, in 1/4 (25%) with abnormal LFT or US and in 2/22 (10%) patients with normal LFT and US. CONCLUSIONS: Fibroscan((R)) is an easy and repeatable tool which can be used in PiZZ patients to screen for the presence of significant liver fibrosis and to identify patients at higher risk to develop liver complications in the future and who may benefit from a closer surveillance

Radiation on Earth or in Space: What Does It Change?

After having been an instrument of the Cold War, space exploration has become a major technological, scientific and societal challenge for a number of countries. With new projects to return to the Moon and go to Mars, radiobiologists have been called upon to better assess the risks linked to exposure to radiation emitted from space (IRS), one of the major hazards for astronauts. To this aim, a major task is to identify the specificities of the different sources of IRS that concern astronauts. By considering the probabilities of the impact of IRS against spacecraft shielding, three conclusions can be drawn: (1) The impacts of heavy ions are rare and their contribution to radiation dose may be low during low Earth orbit; (2) secondary particles, including neutrons emitted at low energy from the spacecraft shielding, may be common in deep space and may preferentially target surface tissues such as the eyes and skin; (3) a “bath of radiation” composed of residual rays and fast neutrons inside the spacecraft may present a concern for deep tissues such as bones and the cardiovascular system. Hence, skin melanoma, cataracts, loss of bone mass, and aging of the cardiovascular system are possible, dependent on the dose, dose-rate, and individual factors. This suggests that both radiosusceptibility and radiodegeneration may be concerns related to space exploration. In addition, in the particular case of extreme solar events, radiosensitivity reactions—such as those observed in acute radiation syndrome—may occur and affect blood composition, gastrointestinal and neurologic systems. This review summarizes the specificities of space radiobiology and opens the debate as regards refinements of current radiation protection concepts that will be useful for the better estimation of risks

Cohorte DEFI-ALPHA et projet hospitalier de recherche clinique POLYGEN DEFI-ALPHA. Étude des facteurs cliniques, biologiques et génétiques associés à l’apparition et à l’évolution de complications hépatiques chez les enfants présentant un déficit en alpha-1 antitrypsine

International audienc

Dramatic increase of central venous catheter-related infections associated with a high turnover of the nursing team

International audienceBACKGROUND & AIMS: This retrospective study evaluated the impact of new organization during the moving to a new university pediatric hospital on the incidence of central catheter-related blood stream infections (CRBSIs) among children on long-term parenteral nutrition. METHODS: The study ran from April 2007 to March 2014, starting a year prior to reorganisation of the department of pediatric Hepato-Gastroenterology and Nutrition associated to moving the children to a new hospital in April 2008, and continuing for 6 years following the move. During this time, data from all children hospitalized in this department who received parenteral nutrition (PN) for more than 15 days were analysed. RESULTS: During this 7-years study, 183 children aged 4.6 +/- 0.5 years received prolonged PN. Intestinal diseases were the main aetiologies (89%), primarily short bowel syndrome (18.4%), Hirschsprung disease and CIPO (13.5%) and inflammatory bowel disease (13.8%). The mean durations of hospitalization and of PN during hospitalization were, respectively, 70 +/- 2.1 and 55.7 +/- 3.6 days. During the study period, 151 CRBSIs occurred in 77 children (42% of all patients), i.e. 14.8 septic episodes/1000 PN days and 12.0 septic episodes/1000 CVC days. No patient died of a central venous catheter-related infection. However, following the move from the older hospital to the newer one, the rate of CRBSIs significantly doubled, from 3.9/1000 to 8.8/1000 CVC days (p = 0.02). During the following 4 years, the incidence of CRBSIs tended to increase between the 2nd and the 5th year after the move: 11.3 (p = NS); 21.4 (p = 0.01); 17.3 (p = NS), 20.3/1000 (p = NS) CVC days. We also observed that after evaluations by the Department of Infection Control, nurse training and stabilization of the nursing team, the incidence decreased significantly from 20.3 to 11.1/1000 CVC days during the 6th year after the move (p = 0.01). CONCLUSION: Our results reveal the deleterious impact of the reorganization during the hospital moving on the CRBSI incidence rate, and the possible implication of inexperienced team of nurses

Childhood/adult-onset lysosomal acid lipase deficiency: A serious metabolic and vascular phenotype beyond liver disease-four new pediatric cases

International audienceBACKGROUND: The childhood/adult-onset lysosomal acid lipase deficiency (LALD; late-onset LALD) is a rare genetic disease. Children present severe fatty liver disease with early cirrhosis. Before enzyme replacement therapy, statins were the standard treatment to improve the severe dyslipidemia. However, late-onset LALD should be considered as a systemic metabolic disease: chronic hyper-low density lipoprotein and hypo-high-density lipoprotein cholesterolemia induces early atherosclerosis in addition to the liver morbidity. OBJECTIVE: To assess 4 new pediatric cases of late-onset LALD with an evaluation of hepatic, metabolic, and vascular evolution under statin. METHODS: Four patients were retrospectively described. Anthropometric data (weight, height, and body mass index) and laboratory data (LIPA mutations, acid lipase residual activity, liver and lipid profile, and homeostatic model assessment index) were collected. Liver histology was assessed by the noninvasive tests FibroScan and FibroTest and confirmed by liver biopsy. Vascular impact was followed up by carotid intima-media thickness (cIMT) assessment. RESULTS: The 4 cases of late-onset LALD came from 2 families, each with a boy (aged 8.6 and 11 years at diagnosis) and a girl (aged 10.6 and 13 years at diagnosis). Treatment with statins was performed for 8 and 5 years, respectively, from diagnosis. Statins decreased the low-density lipoprotein cholesterol mean value of 40%. All children showed significant liver fibrosis (F3 [n = 3]; F2 [n = 1]). cIMT showed the following for all children: abnormal measures without improvement and atherosclerotic plaques. One child developed a deleterious metabolic phenotype with obesity and insulin resistance (homeostatic model assessment = 3.08) associated with higher mean hepatic transaminases (149 vs 98, 88, and 61 IU/L) and increased mean cIMT values (raising from 0.47 to 0.5 mm vs 0.43 and 0.43 mm). CONCLUSION: Late-onset LALD is a rare metabolic disease with a larger impact than liver disease. Our work shows the importance of having a global metabolic view and to evaluate the cardiovascular impact of the new enzymatic treatment. (C) 2016 National Lipid Association. All rights reserved