High-altitude population neonatal and maternal phenotypes associated with birthweight protection.

BACKGROUND: States which reduce foetal oxygen delivery are associated with impaired intrauterine growth. Hypoxia results when barometric pressure falls with ascent to altitude, and with it the partial pressure of inspired oxygen ('hypobaric hypoxia'). birthweight is reduced when native lowlanders gestate at such high altitude (HA)-an effect mitigated in native (millennia) HA populations. Studying HA populations offer a route to explore the mechanisms by which hypoxia impacts foetal growth. METHODS: Between February 2017 and January 2019, we prospectively studied 316 pregnant women, in Leh, Ladakh (altitude 3524 m, where oxygen partial pressure is reduced by 1/3) and 101 pregnant women living in Delhi (low altitude, 216 m above sea level). RESULTS: Of Ladakhi HA newborns, 14% were small for gestational age (10th weight centile. CONCLUSIONS: This study showed that Ladakhi offspring birthweight is relatively spared from the expected adverse HA effects. Furthermore, maternal body composition and greater UtA size may be physiological HA adaptations and warrant further study, as they offer potential mechanisms to overcome hypoxia-related growth issues. IMPACT: Reduced foetal oxygen delivery seen in native lowlanders who gestate at HA causes foetal growth restriction-an effect thought to be mitigated in native HA populations. We found that greater maternal body mass and UtA diameter were associated with increased offspring birthweight in a (Ladakh) HA population. This supports a role for them as physiological mediators of adaptation and provides insights into potential mechanisms that may treat hypoxia-related growth issues

The characteristics, dynamics and risk of death in COVID-19 positive dialysis patients in London, UK

Background: Dialysis patients, with frequent co-morbidities, advanced age and frailty, visiting treatment facilities frequently are perhaps more prone to SARS-Cov-2 infection and related death - the risk-factors and dynamics of which are unknown. The aim of this study was to investigate the hospital outcomes in SARS-CoV-2 infected dialysis patients. Methods: Data on 224 hemodialysis patients between 02/29/2020 and 05/15/2020 with confirmed SARS-CoV-2 were analyzed for outcomes and potential risk factors for death, using competing risk regression model assessed by sub-distribution hazards ratio (SHR). Results: Crude data analyses suggest an overall case fatality ratio of 22.7(95%CI(17.3-28.3)%) overall but that varies across age groups from 11.4(95%CI(0.9-9.2)) in 80 years; with 60% of deaths occurring in the first 15 days and 80% within 21 days indicating a rapid deterioration towards death after admission. Almost 90% of surviving patients were discharged within 28 days. Death was more likely than hospital discharge in more frail (WHO performance status 3-4) [SHR=2.16(1.25-3.74);p=0.006)], ischemic heart disease [SHR=2.28(1.32-3.94),p=0.003], cerebrovascular disease [SHR=2.11(1.20-3.72),p=0.010], smoking history [SHR=2.69(1.33-5.45),p=0.006], and (completely or partially) hospitalized patients [SHR=10.26.(3.10-33.94),p<.001]; and in patients with high CRP [SHR=1.35(1.10-1.67)] and high neutrophil:lymphocyte ratio [SHR=1.03(1.01-1.04),p<0.001]. Our data did not support differences in the risk of death associated with gender, ethnicity, dialysis vintage or other comorbidities. However, comparison with the entire dialysis population attending these hospitals, and 12.9% being affected, revealed that non-Caucasians (62% vs. 52% in all patients, p=0.001) and diabetic patients (54% vs. 22%, p<0.001) were disproportionately affected. Conclusion: This report discusses the outcomes of a large cohort of dialysis patients with SARS-CoV-2, infection affecting more diabetics and non-Caucasians; with a high case fatality ratio, which increased significantly with age, frailty, smoking, increasing CRP and neutrophil:lymphocyte ratio at presentation

Autophagy is Involved in Cardiac Remodeling in Response to Environmental Temperature Change

Objectives: To study the reversibility of cold-induced cardiac hypertrophy and the role of autophagy in this process. Background: Chronic exposure to cold is known to cause cardiac hypertrophy independent of blood pressure elevation. The reversibility of this process and the molecular mechanisms involved are unknown. Methods: Studies were performed in two-month-old mice exposed to cold (4°C) for 24 h or 10 days. After exposure, the animals were returned to room temperature (21°C) for 24 h or 1 week. Results: We found that chronic cold exposure significantly increased the heart weight/tibia length (HW/TL) ratio, the mean area of cardiomyocytes, and the expression of hypertrophy markers, but significantly decreased the expression of genes involved in fatty acid oxidation. Echocardiographic measurements confirmed hypertrophy development after chronic cold exposure. One week of deacclimation for cold-exposed mice fully reverted the morphological, functional, and gene expression indicators of cardiac hypertrophy. Experiments involving injection of leupeptin at 1 h before sacrifice (to block autophagic flux) indicated that cardiac autophagy was repressed under cold exposure and re-activated during the first 24 h after mice were returned to room temperature. Pharmacological blockage of autophagy for 1 week using chloroquine in mice subjected to deacclimation from cold significantly inhibited the reversion of cardiac hypertrophy. Conclusion: Our data indicate that mice exposed to cold develop a marked cardiac hypertrophy that is reversed after 1 week of deacclimation. We propose that autophagy is a major mechanism underlying the heart remodeling seen in response to cold exposure and its posterior reversion after deacclimation

Cpd-1 Null Mice Display a Subtle Neurological Phenotype

CPD1 (also known as ANP32-E) belongs to a family of evolutionarily conserved acidic proteins with leucine rich repeats implicated in a variety of cellular processes regulating gene expression, vesicular trafficking, intracellular signaling and apoptosis. Because of its spatiotemporal expression pattern, CPD1 has been proposed to play an important role in brain morphogenesis and synaptic development.We have generated CPD1 knock-out mice that we have subsequently characterized. These mice are viable and fertile. However, they display a subtle neurological clasping phenotype and mild motor deficits.CPD1 is not essential for normal development; however, it appears to play a role in the regulation of fine motor functions. The minimal phenotype suggests compensatory biological mechanisms

Neuronal methylome reveals CREB-associated neuro-axonal impairment in multiple sclerosis

BACKGROUND: Due to limited access to brain tissue, the precise mechanisms underlying neuro-axonal dysfunction in neurological disorders such as multiple sclerosis (MS) are largely unknown. In that context, profiling DNA methylation, which is a stable and cell type-specific regulatory epigenetic mark of genome activity, offers a unique opportunity to characterize the molecular mechanisms underpinning brain pathology in situ. We examined DNA methylation patterns of neuronal nuclei isolated from post-mortem brain tissue to infer processes that occur in neurons of MS patients. RESULTS: We isolated subcortical neuronal nuclei from post-mortem white matter tissue of MS patients and non-neurological controls using flow cytometry. We examined bulk DNA methylation changes (total n = 29) and further disentangled true DNA methylation (5mC) from neuron-specific DNA hydroxymethylation (5hmC) (n = 17), using Illumina Infinium 450K arrays. We performed neuronal sub-type deconvolution using glutamate and GABA methylation profiles to further reduce neuronal sample heterogeneity. In total, we identified 2811 and 1534 significant (genome-wide adjusted P value < 0.05) differentially methylated and hydroxymethylated positions between MS patients and controls. We found striking hypo-5mC and hyper-5hmC changes occurring mainly within gene bodies, which correlated with reduced transcriptional activity, assessed using published RNAseq data from bulk brain tissue of MS patients and controls. Pathway analyses of the two cohorts implicated dysregulation of genes involved in axonal guidance and synaptic plasticity, with meta-analysis confirming CREB signalling as the most highly enriched pathway underlying these processes. We functionally investigated DNA methylation changes of CREB signalling-related genes by immunohistofluoresence of phosphorylated CREB in neurons from brain sections of a subcohort of MS patients and controls (n = 15). Notably, DNA methylation changes associated with a reduction of CREB activity in white matter neurons of MS patients compared to controls. CONCLUSIONS: Our data demonstrate that investigating 5mC and 5hmC modifications separately allows the discovery of a substantial fraction of changes occurring in neurons, which can escape traditional bisulfite-based DNA methylation analysis. Collectively, our findings indicate that neurons of MS patients acquire sustained hypo-5mC and hyper-5hmC, which may impair CREB-mediated neuro-axonal integrity, in turn relating to clinical symptoms

Patient Selection in One Anastomosis/Mini Gastric Bypass—an Expert Modified Delphi Consensus

Purpose: One anastomosis/mini gastric bypass (OAGB/MGB) is up to date the third most performed obesity and metabolic procedure worldwide, which recently has been endorsed by ASMBS. The main criticisms are the risk of bile reflux, esophageal cancer, and malnutrition. Although IFSO has recognized this procedure, guidance is needed regarding selection criteria. To give clinicians a daily support in performing the right patient selection in OAGB/MGB, the aim of this paper is to generate clinical guidelines based on an expert modified Delphi consensus. Methods: A committee of 57 recognized bariatric surgeons from 24 countries created 69 statements. Modified Delphi consensus voting was performed in two rounds. An agreement/disagreement among ≥ 70.0% of the experts was considered to indicate a consensus. Results: Consensus was achieved for 56 statements. Remarkably, ≥ 90.0% of the experts felt that OAGB/MGB is an acceptable and suitable option "in patients with Body mass index (BMI) > 70, BMI > 60, BMI > 50 kg/m2 as a one-stage procedure," "as the second stage of a two-stage bariatric surgery after Sleeve Gastrectomy for BMI > 50 kg/m2 (instead of BPD/DS)," and "in patients with weight regain after restrictive procedures. No consensus was reached on the statement that OAGB/MGB is a suitable option in case of resistant Helicobacter pylori. This is likely as there is a concern that this procedure is associated with reflux and its related long-term complications including risk of cancer in the esophagus or stomach. Also no consensus reached on OAGB/MGB as conversional surgery in patients with GERD after restrictive procedures. Consensus for disagreement was predominantly achieved "in case of intestinal metaplasia of the stomach" (74.55%), "in patients with severe Gastro Esophageal Reflux Disease (GERD)(C,D)" (75.44%), "in patients with Barrett's metaplasia" (89.29%), and "in documented insulinoma" (89.47%). Conclusion: Patient selection in OAGB/MGB is still a point of discussion among experts. There was consensus that OAGB/MGB is a suitable option in elderly patients, patients with low BMI (30-35 kg/m2) with associated metabolic problems, and patients with BMIs more than 50 kg/m2 as one-stage procedure. OAGB/MGB can also be a safe procedure in vegetarian and vegan patients. Although OAGB/MGB can be a suitable procedure in patients with large hiatal hernia with concurrent hiatal hernia, it should not be offered to patients with grade C or D esophagitis or Barrett's metaplasia.info:eu-repo/semantics/publishedVersio

IFSO (International Federation for Surgery of Obesity and Metabolic Disorders) Consensus Conference Statement on One-Anastomosis Gastric Bypass (OAGB-MGB): Results of a Modified Delphi Study

Background: One-anastomosis gastric bypass (OAGB-MGB) is currently the third performed primary bariatric surgical procedure worldwide. However, the procedure is hampered by numerous controversies and there is considerable variability in surgical technique, patient selection, and pre- and postoperative care among the surgeons performing this procedure. This paper reports the results of a modified Delphi consensus study organized by the International Federation for Surgery of Obesity and Metabolic Disorders (IFSO). Methods: Fifty-two internationally recognized bariatric experts from 28 countries convened for voting on 90 consensus statements over two rounds to identify those on which consensus could be reached. Inter-voter agreement of ≥ 70% was considered consensus, with voting participation ≥ 80% considered a robust vote. Results: At least 70% consensus was achieved for 65 of the 90 questions (72.2% of the items), 61 during the first round of voting and an additional four in the second round. Where consensus was reached on a binary agree/disagree or yes/no item, there was agreement with the statement presented in 53 of 56 instances (94.6%). Where consensus was reached on a statement where options favorable versus unfavorable to OAGB-MGB were provided, including statements in which OAGB-MGB was compared to another procedure, the response option favorable to OAGB-MGB was selected in 13 of 23 instances (56.5%). Conclusion: Although there is general agreement that the OAGB-MGB is an effective and usually safe option for the management of patients with obesity or severe obesity, numerous areas of non-consensus remain in its use. Further empirical data are needed