Effects of Bariatric Surgery on Cardiac Ectopic Fat Lesser Decrease in Epicardial Fat Compared to Visceral Fat Loss and No Change in Myocardial Triglyceride Content

ObjectivesThis study investigated the effect of bariatric surgery (BS)–induced weight loss on cardiac ectopic fat using 3T magnetic resonance imaging in morbid obesity.BackgroundHeart disease is one of the leading causes of mortality and morbidity in obese patients. Deposition of cardiac ectopic fat has been related to increased heart risk. Whether sustained weight loss can modulate epicardial fat or myocardial fat is unknown.MethodsTwenty-three morbidly obese patients underwent 1H-magnetic resonance spectroscopy to determine myocardial triglyceride content (MTGC), magnetic resonance imaging to assess epicardial fat volume (EFV), cardiac function, and computed tomography visceral abdominal fat (VAF) measurements at baseline and 6 months after BS.ResultsThe BS reduced body mass index significantly, from 43.1 ± 4.5 kg/m2 to 32.3 ± 4.0 kg/m2, subcutaneous fat from 649 ± 162 cm2 to 442 ± 127 cm2, VAF from 190 ± 83 cm2 to 107 ± 44 cm2, and EFV from 137 ± 37 ml to 98 ± 25 ml (all p < 0.0001). There was no significant change in MTGC: 1.03 ± 0.2% versus 1.1 ± 0.2% (p = 0.85). A significant reduction in left ventricular mass (118 ± 24 g vs. 101 ± 18 g) and cardiac output (7.1 ± 1.6 l/min vs. 5.4 ± 1.0 l/min) was observed and was statistically associated with weight loss (p < 0.05). The loss in EFV was limited (−27 ± 11%) compared to VAF diminution (−40 ± 19%). The EFV variation was not correlated with percentage of body mass index or VAF loss (p = 0.007). The ratio of %EFV to %VAF loss decreased with sleep apnea syndrome (1.34 ± 0.3 vs. 0.52 ± 0.08, p < 0.05).ConclusionsSix-month BS modulates differently cardiac ectopic fat deposition, with a significant decrease in epicardial fat and no change in myocardial fat. Epicardial fat volume loss was limited in patients with sleep apnea. (Impact of Bariatric Surgery on Epicardial Adipose Tissue and on Myocardial Function; NCT01284816

Rabconnectin-3α is required for the morphological maturation of GnRH neurons and kisspeptin responsiveness

A few hundred hypothalamic neurons form a complex network that controls reproduction in mammals by secreting gonadotropin-releasing hormone (GnRH). Timely postnatal changes in GnRH secretion are essential for pubertal onset. During the juvenile period, GnRH neurons undergo morphological remodeling, concomitantly achieving an increased responsiveness to kisspeptin, the main secretagogue of GnRH. However, the link between GnRH neuron activity and their morphology remains unknown. Here, we show that brain expression levels of Dmxl2, which encodes the vesicular protein rabconnectin-3α, determine the capacity of GnRH neurons to be activated by kisspeptin and estradiol. We also demonstrate that Dmxl2 expression levels control the pruning of GnRH dendrites, highlighting an unexpected role for a vesicular protein in the maturation of GnRH neuronal network. This effect is mediated by rabconnectin-3α in neurons or glial cells afferent to GnRH neurons. The widespread expression of Dmxl2 in several brain areas raises the intriguing hypothesis that rabconnectin-3α could be involved in the maturation of other neuronal populations

Haploinsufficiency of Dmxl2, Encoding a Synaptic Protein, Causes Infertility Associated with a Loss of GnRH Neurons in Mouse

International audienceCharacterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3a, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3a was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH) axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3a controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a complex neurological phenotype, with abnormal glucose metabolism and gonadotropic axis deficiency due to a loss of GnRH neurons. Our findings identify rabconectin-3a as a key controller of neuronal and endocrine homeostatic processes

Recent Laborian of the Peyrazet cave-rock shelter (Creysse, Lot, France). New data for the end of Lateglacial in Quercy

Découverte en 1990, la grotte-abri de Peyrazet (Creysse, Lot, France) se situe dans le Haut-Quercy en bordure du causse de Martel, à quelques centaines de mètres du cours actuel de la Dordogne. Les fouilles menées depuis 2008 livrent une archéoséquence du Tardiglaciaire qui permet de combler certaines lacunes documentaires régionales et plus largement du Sud-Ouest de la France. Au Magdalénien supérieur succède un niveau ayant donné des indices d’un Azilien sensu lato stratigraphiquement séparé du Laborien, ensemble supérieur qui fait l’objet de cet article. Jusqu’alors ce technocomplexe de la fin du Pléistocène et des débuts de l’Holocène demeurait mal connu dans la région. En effet, seuls des travaux anciens menés dans deux gisements permettaient de noter sa présence en Quercy. La découverte d’un ensemble laborien récent (ou Épilaborien) à Peyrazet est l’occasion de conduire une étude collective des divers vestiges dans un cadre archéostratigraphique mieux maîtrisé. L’analyse géoarchéologique met en évidence l’action conjointe du ruissellement et de l’éboulisation comme principaux responsables de la mise en place des dépôts. Dans la partie S-O du site, un lithofaciès de remaniement indique une bioturbation importante en lien avec le creusement de terriers. Bien que leur origine ne soit pas liée aux activités humaines, les rongeurs, les oiseaux, les poissons et les mésomammifères (excepté le lièvre) apportent des données concernant l’environnement des chasseurs-cueilleurs. La grande faune est dominée par le cerf dont les carcasses pourraient avoir été introduites incomplètes sur le site puis traitées pour en extraire la viande et la moelle. Nous avons bénéficié d’une analyse fonctionnelle croisée à l’étude typo-technologique des vestiges lithiques composés pour l’essentiel de silex locaux et régionaux. Ce double regard a permis de mettre en évidence une diversité d’activités mise en œuvre dans la cavité. Une pièce d’ocre rouge, quelques vestiges d’industrie osseuse et des éléments de parure participent également à la description d’une large gamme de tâches effectuées lors d’un séjour prolongé ou de plusieurs occupations successives. La comparaison des pointes de chasse microlithiques avec d’autres gisements sur une vaste échelle géographique conduit à discuter l’attribution de cet ensemble supérieur à différentes phases du Laborien. L’hypothèse d’un Laborien récent (ou Épilaborien) conduit à réfléchir à une perduration de morphotypes ancestraux parallèlement à de nouveaux types d’armatures, observation déjà réalisée notamment à La Borie del Rey dans le Haut-Agenais mais qui demande encore des précisions et de nouvelles découvertes.Discovered in 1990, Peyrazet cave-rock shelter (Creysse, Lot) lies in the Haut-Quercy region at the limits of the Martel limestone plateau, several hundred meters from the current Dordogne River valley. Excavations begun in 2008 produced a Late Glacial archaeo-sequence that sheds new light on several still poorly understood aspects of the archeological record in both the Haut-Quercy region and southwestern France in general. The level overlying the Late Magdalenian occupation produced limited evidence for the Azilian and is stratigraphically separated from the Laborian. This latter techno-complex, dated to the end of the Pleistocene and early Holocene, remains poorly documented in the region, having only been previously identified from two sites in the Quercy. The discovery of a recent Laborian (Epilaborian) occupation at Peyrazet presented the ideal occasion for a collaborative study of the diverse archaeological material recovered from this well-understood archaeo-stratigraphic context. A geoarchaeological analysis produced evidence for both surface runoff and the accumulation of coarse deposits (éboulis) as the principal site formation processes. In the southwest area of the site, a reworked lithofacies demonstrates substantial bioturbation in connection with animal burrowing. Although the presence of rodent, bird, fish, and medium-sized mammals (except hare) cannot be definitively connected to human activity, they nevertheless provide important information concerning the environments exploited by hunter-gatherer groups. Larger species are dominated by red deer whose carcasses were partially processed before being introduced to the site, where meat was subsequently removed and marrow consumed. A functional analysis combined with a typo-technological study of the primarily locally- and regionally-procured lithic material revealed evidence for diverse activities having taken place on-site. An ochre fragment, several bone tools and ornaments equally indicate a large variety of tasks to have been carried out during a single, long occupation or several successive visits. A typo-technological comparison of hunting weaponry (microliths) from sites across a substantial area suggests the assemblage to represent either a Laborian/Epilaborian mix or a unique Epilaborian occupation. This latter case would indicate the persistence of older morphotypes alongside the development of new tools forms, a situation already identified at Borie del Rey in the Haut-Agenais but which requires more detailed study supported by new discoveries

DLK1 Is a Somato-Dendritic Protein Expressed in Hypothalamic Arginine-Vasopressin and Oxytocin Neurons

Delta-Like 1 Homolog, Dlk1, is a paternally imprinted gene encoding a transmembrane protein involved in the differentiation of several cell types. After birth, Dlk1 expression decreases substantially in all tissues except endocrine glands. Dlk1 deletion in mice results in pre-natal and post-natal growth deficiency, mild obesity, facial abnormalities, and abnormal skeletal development, suggesting involvement of Dlk1 in perinatal survival, normal growth and homeostasis of fat deposition. A neuroendocrine function has also been suggested for DLK1 but never characterised. To evaluate the neuroendocrine function of DLK1, we first characterised Dlk1 expression in mouse hypothalamus and then studied post-natal variations of the hypothalamic expression. Western Blot analysis of adult mouse hypothalamus protein extracts showed that Dlk1 was expressed almost exclusively as a soluble protein produced by cleavage of the extracellular domain. Immunohistochemistry showed neuronal DLK1 expression in the suprachiasmatic (SCN), supraoptic (SON), paraventricular (PVN), arcuate (ARC), dorsomedial (DMN) and lateral hypothalamic (LH) nuclei. DLK1 was expressed in the dendrites and perikarya of arginine-vasopressin neurons in PVN, SCN and SON and in oxytocin neurons in PVN and SON. These findings suggest a role for DLK1 in the post-natal development of hypothalamic functions, most notably those regulated by the arginine-vasopressin and oxytocin systems

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Altitude shapes the environmental drivers of large‐scale variation in abundance of a widespread mammal species

International audienc

Estimation of Bait Uptake by Badgers, Using Non-invasive Methods, in the Perspective of Oral Vaccination Against Bovine Tuberculosis in a French Infected Area

International audienceAlthough France is officially declared free of bovine tuberculosis (TB), Mycobacterium bovis infection is still observed in several regions in cattle and wildlife, including badgers ( Meles meles ). In this context, vaccinating badgers should be considered as a promising strategy for the reduction in M. bovis transmission between badgers and other species, and cattle in particular. An oral vaccine consisting of live Bacille Calmette–Guérin (BCG) contained in bait is currently under assessment for badgers, for which testing bait deployment in the field and assessing bait uptake by badgers are required. This study aimed to evaluate the bait uptake by badgers and determine the main factors influencing uptake in a TB-infected area in Burgundy, north-eastern France. The baits were delivered at 15 different setts located in the vicinity of 13 pastures within a TB-infected area, which has been subject to intense badger culling over the last decade. Pre-baits followed by baits containing a biomarker (Rhodamine B; no BCG vaccine) were delivered down sett entrances in the spring (8 days of pre-baiting and 4 days of baiting) and summer (2 days of pre-baiting and 2 days of baiting) of 2018. The consumption of the marked baits was assessed by detecting fluorescence, produced by Rhodamine B, in hair collected in hair traps positioned at the setts and on the margins of the targeted pastures. Collected hairs were also genotyped to differentiate individuals using 24 microsatellites markers and one sex marker. Bait uptake was estimated as the proportion of badgers consuming baits marked by the biomarker over all the sampled animals (individual level), per badger social group, and per targeted pasture. We found a bait uptake of 52.4% (43 marked individuals of 82 genetically identified) at the individual level and a mean of 48.9 and 50.6% at the social group and pasture levels, respectively. The bait uptake was positively associated with the presence of cubs (social group level) and negatively influenced by the intensity of previous trapping (social group and pasture levels). This study is the first conducted in France on bait deployment in a badger population of intermediate density after several years of intensive culling. The results are expected to provide valuable information toward a realistic deployment of oral vaccine baits to control TB in badger populations

<i>Dlk1</i> expression increases in the hypothalamus between birth and adulthood.

<p>A) Total hypothalamic RNA was extracted on post-natal days 6, 20 and 60 (P6, P20, P60). mRNA levels were quantified using real-time RT-PCR as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036134#s2" target="_blank">materials and methods</a> section. The graphs show fold increases in expression at P20 and P60 compared to P6. <i>Kiss1</i> expression was quantified using real-time RT-PCR as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036134#s2" target="_blank">materials and methods</a> section. The graphs represent pooled data (mean ± SEM) from three different experiments with 4 mice per group. *indicates a significant increase (<i>p</i><0.01) relative to P6. B) DLK1 protein levels on P6, P20 and P60 were evaluated using western blot on total cellular extracts with the H-118 antibody.</p