Rare BANF1 Alleles and Relatively Frequent EMD Alleles Including `Healthy Lipid' Emerin p.D149H in the ExAC Cohort

Emerin (EMD) and barrier to autointegration factor 1 (BANF1) each bind A-type lamins (LMNA) as fundamental components of nuclear lamina structure. Mutations in LMNA, EMD and BANF1 are genetically linked to many tissue-specific disorders including Emery-Dreifuss muscular dystrophy and cardiomyopathy (LMNA, EMD), lipodystrophy, insulin resistance and type 2 diabetes (LMNA) and progeria (LMNA, BANF1). To explore human genetic variation in these genes, we analyzed EMD and BANF1 alleles in the Exome Aggregation Consortium (ExAC) cohort of 60,706 unrelated individuals. We identified 13 rare heterozygous BANF1 missense variants (p.T2S, p.H7Y, p.D9N, p.S22R, p.G25E, p.D55N, p.D57Y, p.L63P, p.N70T, p.K72R, p.R75W, p.R75Q, p.G79R), and one homozygous variant (p.D9H). Several variants are known (p.G25E) or predicted (e.g., p.D9H, p.D9N, p.L63P) to perturb BANF1 and warrant further study. Analysis of EMD revealed two previously identified variants associated with adult-onset cardiomyopathy (p.K37del, p.E35K) and one deemed `benign' in an Emery-Dreifuss patient (p.D149H). Interestingly p.D149H was the most frequent emerin variant in ExAC, identified in 58 individuals (overall allele frequency 0.06645%), of whom 55 were East Asian (allele frequency 0.8297%). Furthermore, p.D149H associated with four `healthy' traits: reduced triglycerides (-0.336; p = 0.0368), reduced waist circumference (-0.321; p = 0.0486), reduced cholesterol (-0.572; p = 0.000346) and reduced LDL cholesterol (-0.599; p = 0.000272). These traits are distinct from LMNA-associated metabolic disorders and provide the first insight that emerin influences metabolism. We also identified one novel in-frame deletion (p.F39del) and 62 novel emerin missense variants, many of which were relatively frequent and potentially disruptive including p.N91S and p.S143F (0.041% and -0.034% of non-Finnish Europeans, respectively), p.G156S (-0.39% of Africans), p.R204G (-0.18% of Latinx), p.R207P (-0.08% of South Asians) and p.R221L (-0.15% of Latinx). Many novel BANF1 variants are predicted to disrupt dimerization or binding to DNA, histones, emerin or A-type lamins. Many novel emerin variants are predicted to disrupt emerin filament dynamics or binding to BANF1, HDAC3, A-type lamins or other partners. These new human variants provide a foundational resource for future studies to test the molecular mechanisms of BANF1 and emerin function, and to understand the link between emerin variant p.D149H and a `healthy' lipid profile

Ectopic Fat Deposition and Diabetes Mellitus

International audienceDr. Zhu and colleagues also note the different situations in which the vasovagal reflex can occur, and suggest matching work and life environments between the placebo and fludrocortisone groups. Although an interesting and insightful comment, this might not be practical. Rather, given how often in their daily affairs patients are subjected to orthostatic stress, the question might be why the reflex is provoked only occasionally rather than several times daily. Both questions raise the issue of a more individualized approach to patients, and we suspect that just such an approach is the key to the successful treatment of vasovagal syncope (2). We read with interest the paper by Levelt et al. (1) in a recent issue of the Journal, which deciphered the parameters that give rise to ectopic fat deposition in insulin-resistant states, such as type 2 diabetes (T2D). One of the strengths of this study is the use of mul-tiparametric cardiovascular and liver magnetic resonance imaging (MRI), and proton and phosphorus magnetic resonance spectroscopy, allowing a comparison of epicardial adipose tissue (EAT), myocardial and hepatic triglyceride content, hepatic fibroin-flammatory changes, but also cardiac function and energetics between lean healthy and lean and obese subjects with T2D. One of the study limitations is that epicardial fat volume was not measured in lean healthy subjects, so that the increase in EAT was only validated in 33 subjects with T2D without control subjects. However, MRI was performed in all subjects , and one could expect that the authors assessed EAT with MRI. Indeed, MRI offers excellent spatial resolution; it is now recognized to be the gold standard for adipose tissue imaging and superior to computed tomography in separating epicardial from pericardial fat, the latter of which has different vascularization and developmental origin from EAT. Moreover, it is also the only imaging modality in which volumetric quantification of EAT has been validated ex vivo (2). In this setting of body fat distribution, the different ectopic fat depots need to be distinguished, and we tend to disagree with the concept of EAT as a proxy for visceral fat. Visceral fat refers to visceral abdominal adipose tissue and cannot be replaced by EAT, as visceral abdominal adipose tissue flexibility to weight loss, "beiging" (brown in white adipose tissue) molecular features, has been shown to be different from EAT (3,4). Levelt et al. (1) evaluated different ectopic fat depots in lean healthy and lean and obese subjects with T2D. Nevertheless, the presence of a body mass index <25 kg/m 2 at diabetes mellitus diagnosis , with the current obesity epidemic, raises a question regarding the type of diabetes. Do these lean diabetic patients have non-type 2, secondary, or monogenic forms of diabetes? Did the authors eliminate latent autoimmune diabetes in adults, in which the progression of ß cell failure is slow? Among patients with phenotypic type 2 diabetes, latent autoimmune diabetes in adults occurs in 10% of individuals older than age 35 years (5). Further studies are needed to determine to what extent hyperglycemia drives specific ectopic fat deposition

Looking beyond ectopic fat amount: A SMART method to quantify epicardial adipose tissue density

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Liraglutide for patients with non-alcoholic steatohepatitis

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Gut microbiota and non-alcoholic fatty liver disease: new insights

International audienceNon-alcoholic fatty liver disease (NAFLD) is a severe liver disease that is increasing in prevalence with the worldwide epidemic of obesity and its related insulin-resistance state. A two-hit' mechanism has been proposed; however, the complete physiopathogenesis remains incompletely understood. Evidence for the role of the gut microbiota in energy storage and the subsequent development of obesity and some of its related diseases is now well established. More recently, a new role of gut microbiota has emerged in NAFLD. The gut microbiota is involved in gut permeability, low-grade inflammation and immune balance, it modulates dietary choline metabolism, regulates bile acid metabolism and produces endogenous ethanol. All of these factors are molecular mechanisms by which the microbiota can induce NAFLD or its progression toward overt non-alcoholic steatohepatitis

Editorial: Cardiac fat in metabolic and endocrine diseases

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An Experimental Study of Intraluminal Hyperpressure Reproducing a Gastric Leak Following a Sleeve Gastrectomy

International audienceIntroduction A gastric leak (GL) represents the main post-operative complication following a sleeve gastrectomy (SG) and occurs most commonly at the top of the stapling, without any clear explanation. Objective This experimental study evaluates the biomechanical behavior of post-SG gastric specimens using both insufflation and tensile tests. Materials and Methods A total gastrectomy followed by an ex vivo SG was performed in 15 pigs. The Bsleeved^stomachs were subjected to intraluminal hyperpressure until failure. Uniaxial circumferential and longitudinal tensile tests were performed using gastric strips obtained from the Bresected^stomachs. All the deformations and burst pressures were recorded and analyzed. Results A GL appeared in the upper third of the stapling in 73% of cases. The mean burst pressure was 26.3 ± 5.3 mmHg and was significantly correlated with the volume of the Bsleeved^stomachs (p = 0.02). The overall deformation of the Bsleeved^stomachs was comparable in the frontal (38.3%) and profile (40.5%) planes. The greatest displacement was observed at the failure zone (11 mm on average). The biomechanical behavior of the stomach wall differed according to the strip orientation. The circum-ferential strips presented a higher strain-to-failure rate (97%) and a lower Young's modulus (0.99 MPa) when compared to the longitudinal strips (45% and 2.58 MPa, respectively). Conclusion This preliminary study reproduced a GL in the same location as observed during clinical practice. The volume of the SG influenced the burst pressure. Further experimental studies and numerical simulations should evaluate the impact of shape modifications on an SG

Vécu des femmes infertiles atteintes d’un syndrome des ovaires polykystiques : étude qualitative sur les forums de discussion en ligne

International audienceObjectives: To highlight the self-reported experiences and disease perceptions of infertile women with polycystic ovary syndrome (PCOS).Methods: A qualitative study using an inductive method was conducted on infertile women with PCOS who shared their self-reported experiences on French-speaking on-line forums.Results: 785 comments by 211 women on 7 forums were analyzed. Women complained of late diagnosis and lack of information regarding PCOS. PCOS and infertility showed negative psychological impact on daily life. This impact appeared to be alleviated by the sharing of knowledge and experience enabled by these forums.Conclusion: The self-reported experience of infertile women with PCOS is interesting for health practitioners. The psychological impact of PCOS and perceptions of illness appear to be improved by sharing experiences between women with PCOS, suggesting a beneficial support role of online discussion forums.Objectifs: explorer l'expérience personnelle et les perceptions de leur maladie par des femmes infertiles ayant un syndrome des ovaires polykystiques (SOPK).Méthodes: étude qualitative conduite chez des femmes infertiles, ayant un syndrome des ovaires polykystiques, partageant leur expérience personnelle sur des forums Internet francophones.Résultats: A travers 7 forums en ligne, 785 commentaires provenant de 211 femmes ont été analysés. Les femmes se plaignaient d'un retard diagnostique et d'un manque d'informations concernant le syndrome des ovaires polykystiques. Nous avons observé un impact psychologique négatif du SOPK et de l'infertilité sur la vie quotidienne de ces femmes. Cet impact semblait être amélioré par les échanges de connaissances et le partage d'expériences permis par les forums Internet.Conclusion: l'expérience personnelle des femmes infertiles atteintes de SOPK est intéressante pour les professionnels de santé. L'impact psychologique du SOPK et les perceptions de la maladie semblent être améliorés par le partage d'expérience entre les femmes atteintes de SOPK, suggérant un rôle de soutien bénéfique des forums de discussion en ligne

Pharmacologic Venous Thromboprophylaxis After Bariatric Surgery

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