Disruption of tumor necrosis factor alpha receptor 1 signaling accelerates NAFLD progression in mice upon a high-fat diet

Obesity is accompanied by a low-grade inflammation state, characterized by increased proinflammatory cytokines levels such as tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1β). In this regard, there exists a lack of studies in hepatic tissue about the role of TNFα receptor 1 (TNFR1) in the context of obesity and insulin resistance during the progression of nonalcoholic fatty liver disease (NAFLD). The aim of this work was to evaluate the effects of high-caloric feeding (HFD) (40% fat, for 16 weeks) on liver inflammation-induced apoptosis, insulin resistance, hepatic lipid accumulation and its progression toward nonalcoholic steatohepatitis (NASH) in TNFR1 knock-out and wild-type mice. Mechanisms involved in HFD-derived IL-1β release and impairment of insulin signaling are still unknown, so we determined whether IL-1β affects liver insulin sensitivity and apoptosis through TNFα receptor 1 (TNFR1)-dependent pathways. We showed that knocking out TNFR1 induces an enhanced IL-1β plasmatic release upon HFD feed. This was correlated with higher hepatic and epididymal white adipose tissue mRNA levels. In vivo and in vitro assays confirmed an impairment in hepatic insulin signaling, in part due to IL-1β-induced decrease of AKT activation and diminution of IRS1 levels, followed by an increase in inflammation, macrophage (resident and recruited) accumulation, hepatocyte apoptotic process and finally hepatic damage. In addition, TNFR1 KO mice displayed higher levels of pro-fibrogenic markers. TNFR1 signaling disruption upon an HFD leads to an accelerated progression from simple steatosis to a more severe phenotype with many NASH features, pointing out a key role of TNFR1 in NAFLD progression.This work was supported by research grants from Consejo Nacional de Investigaciones Científicas y Técnicas (PIP-CONICET 112201500508, to C.E.C.) and SAF2016-75004-R and SAF2015-70270-REDT (MINECO, Spain)to P.M.S. and O.M.Peer reviewe

ADGRL3 (LPHN3) variants predict substance use disorder

Genetic factors are strongly implicated in the susceptibility to develop externalizing syndromes such as attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder, and substance use disorder (SUD). Variants in the ADGRL3 (LPHN3) gene predispose to ADHD and predict ADHD severity, disruptive behaviors comorbidity, long-term outcome, and response to treatment. In this study, we investigated whether variants within ADGRL3 are associated with SUD, a disorder that is frequently co-morbid with ADHD. Using family-based, case-control, and longitudinal samples from disparate regions of the world (n = 2698), recruited either for clinical, genetic epidemiological or pharmacogenomic studies of ADHD, we assembled recursive-partitioning frameworks (classification tree analyses) with clinical, demographic, and ADGRL3 genetic information to predict SUD susceptibility. Our results indicate that SUD can be efficiently and robustly predicted in ADHD participants. The genetic models used remained highly efficient in predicting SUD in a large sample of individuals with severe SUD from a psychiatric institution that were not ascertained on the basis of ADHD diagnosis, thus identifying ADGRL3 as a risk gene for SUD. Recursive-partitioning analyses revealed that rs4860437 was the predominant predictive variant. This new methodological approach offers novel insights into higher order predictive interactions and offers a unique opportunity for translational application in the clinical assessment of patients at high risk for SUD

Novel Textbook Outcomes following emergency laparotomy:Delphi exercise

Background: Textbook outcomes are composite outcome measures that reflect the ideal overall experience for patients. There are many of these in the elective surgery literature but no textbook outcomes have been proposed for patients following emergency laparotomy. The aim was to achieve international consensus amongst experts and patients for the best Textbook Outcomes for non-trauma and trauma emergency laparotomy. Methods: A modified Delphi exercise was undertaken with three planned rounds to achieve consensus regarding the best Textbook Outcomes based on the category, number and importance (Likert scale of 1–5) of individual outcome measures. There were separate questions for non-trauma and trauma. A patient engagement exercise was undertaken after round 2 to inform the final round. Results: A total of 337 participants from 53 countries participated in all three rounds of the exercise. The final Textbook Outcomes were divided into ‘early’ and ‘longer-term’. For non-trauma patients the proposed early Textbook Outcome was ‘Discharged from hospital without serious postoperative complications (Clavien–Dindo ≥ grade III; including intra-abdominal sepsis, organ failure, unplanned re-operation or death). For trauma patients it was ‘Discharged from hospital without unexpected transfusion after haemostasis, and no serious postoperative complications (adapted Clavien–Dindo for trauma ≥ grade III; including intra-abdominal sepsis, organ failure, unplanned re-operation on or death)’. The longer-term Textbook Outcome for both non-trauma and trauma was ‘Achieved the early Textbook Outcome, and restoration of baseline quality of life at 1 year’. Conclusion: Early and longer-term Textbook Outcomes have been agreed by an international consensus of experts for non-trauma and trauma emergency laparotomy. These now require clinical validation with patient data.</p

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment

Decreased intestinal TG accumulation and absence of fat malabsorption in <i>Ces1/Es-x^−/−</i> mice.

<p>(A) Uptake of dietary fat along the length of the small intestine. Mice were fasted for 4 h and gavaged with radiolabeled triolein diluted in olive oil. Two hours later, the small intestine was excised, flushed, cut, digested and radioactivity associated with the intestinal segments was determined. N = 3 mice/group. (B) Fat in stools. Sudan III staining of stool fat upon spontaneous defecation in fed mice. (C) Analysis of fat in stools by organic extraction after spontaneous defecation. N = 5–7 mice/group. (D) Fecal lipids analyzed by TLC. N = 5–7 mice/group.</p

Intestinal Ces1/Es-x expression is regulated by nutritional status.

<p>(A) Intestinal Ces1/Es-x protein expression in different nutritional states. Mice were fasted for 24 h and refed for 6 h. Fasted and refed mice were euthanized at 8:00 P.M. TGH is a related carboxylesterase migrating at a lower M_r due to lesser glycosylation and is recognized by the polyclonal anti-Ces1/Es-x antibodies. Two µg intestinal proteins were subjected to analysis. Cnx, calnexin  =  loading control. (B) Quantitation of Ces1/Es-x immunoreactive bands obtained in different nutritional states. **p<0.01 Refed vs Fasted. (C) Ces1/Es-x protein distribution along the small intestine. Small intestine was cut into 12 pieces 2-cm long. Proteins were separated by SDS-PAGE and immunodetected with anti-Ces1/Es-x antibodies. Representative data from 3 different independent experiments are shown. (D) Absence of Ces1/Es-x protein (immunoblot) in the intestine from <i>Ces1/Es-x</i>^−/− mice. (E) H&E staining of small intestine (200×) sections.</p

Primers used for quantitative real time PCR.

<p>Primers used for quantitative real time PCR.</p

Decreased expression of lipid absorption and increased expression of lipid secretion markers in <i>Ces1/Es-x^−/−</i> mice.

<p>(A) Intestinal expression of lipid absorption, synthesis and secretion genes in intestines from 24-week old mice was analyzed by qPCR. Mice were fasted for 4 h. N = 5 mice/group. *p<0.05 vs. wild-types. (B) Immunoblot of intestinal ApoB48. (D) Immunoblot of intestinal MTP. Same animals as in (A) were used. Cnx, calnexin  =  loading control. (D) and (E) quantitation of the immunoreactive ApoB48 and MTP bands, respectively. **p<0.01 vs. wild-type.</p

Lower TG accumulation in enterocytes from <i>Ces1/Es-x^−/−</i> mice.

<p>(A) and (B) Enterocytes from fasted mice were isolated and incubated with micelles containing radiolabeled oleic acid. Cellular radiolabel incorporation into TG and media radiolabeled TG secretion were assessed by lipid extraction, TLC separation, iodine exposure and scintillation counting. Cellular and media TG mass was measured by gas chromatography. N = 4 mice/group, *p<0.05, ***p<0.001. (C) Lipid content in intestinal mucosal scrapings from mice fasted overnight and re-fed for 6 h. Lipid standards in the last two lanes on the right are: DG, diacylglycerol (dioleoylglycerol); OA, oleic acid, TG, triacylglycerol (triolein), CE, cholesteryl ester (cholesteryl oleate). (D) Quantitation of the TG band in (C). (E) Lipid content in intestinal mucosal scrapings from mice fasted overnight. Lipid standards in the last two lanes on the right are as in (C). (F) Quantitation of the TG band in (E). *p<0.05 vs. wild-type.</p