Abuso sexual como preditivo de extrema vulnerabilidade na adolescência / Sexual abuse as a predictor of extreme vulnerability in adolescence

Introdução: A atividade sexual precoce na adolescência pode relacionar-se à abuso sexual intrafamiliar, estupro por agressor identificável ou desconhecido. Aspecto que revela uma das preocupações consideradas fatores de risco, associados à extrema vulnerabilidade. Este estudo demonstra a complexidade no conceito “ser vulnerável” e a intrínseca rede de causalidade a partir de três casos de adolescentes vítimas de violência sexual, atendidas em serviço de referência. Pautado em revisão da literatura, com busca no PubMed, cujas palavras-chave foram: “vulnerabilidade sexual”; “precocidade sexual”; “abuso sexual na infância”; “infecções sexualmente transmissíveis”, nos últimos 5 anos, obteve-se 132 artigos, e foram selecionados 20 artigos, sobre o tema. Relato de casos: As adolescentes menores de 16 anos, são as vítimas mais frequentes de abuso sexual. O risco pode ocorrer, por parentes próximos, como observado no caso de T.C.S (17 anos no momento do atendimento), mas desde 11 anos foi vítima de abuso sexual e sofria ameaças pelo avôdrasto (parceiro da avó). No caso da E.C.W. (15 anos), devido questões psicossociais, como bullying e depressão, a vulnerabilidade incidiu com abuso perpetrado por "amigo" que conheceu na internet. Enquanto que no caso de F.C. (11 anos), a ausência dos pais e transtorno de desenvolvimento, possivelmente a levaram a exposições e à comportamentos de riscos. Discussão: Adolescentes com histórico de abuso físico e/ou sexual são mais propensas a início sexual precoce e comportamentos sexuais de risco, incluindo múltiplos parceiros sexuais e não uso de preservativos. Adolescentes submetidas a situações de vulnerabilidade e pobreza extrema tendem a ter outras questões associadas como depressão, ideação suicida, desafios familiares, traumas, falta de apoio psicossocial, bullying e transtornos de desenvolvimento. Conclusão: Os dados apresentados destacam a importância de desenvolver estratégias preventivas focadas nas adolescentes mais suscetíveis, com comportamentos sexuais de risco e com base nos fatores causais vinculados, em especial a partir da identificação do abuso sexual

Persistent Organic Pollutant Exposure Leads to Insulin Resistance Syndrome

International audienceBackground: the incidence of the insulin resistance syndrome has increased at an alarming rate worldwide, creating a serious challenge to public health care in the 21st century. Recently, epide-miological studies have associated the prevalence of type 2 diabetes with elevated body burdens of persistent organic pollutants (POPs). However, experimental evidence demonstrating a causal link between POPs and the development of insulin resistance is lacking. Objective: We investigated whether exposure to POPs contributes to insulin resistance and meta-bolic disorders. Methods: Sprague-Dawley rats were exposed for 28 days to lipophilic POPs through the con-sumption of a high-fat diet containing either refined or crude fish oil obtained from farmed Atlantic salmon. In addition, differentiated adipocytes were exposed to several POP mixtures that mimicked the relative abundance of organic pollutants present in crude salmon oil. We measured body weight, whole-body insulin sensitivity, POP accumulation, lipid and glucose homeostasis, and gene expres-sion and we performed micro array analysis. Results: Adult male rats exposed to crude, but not refined, salmon oil developed insulin resis-tance, abdominal obesity, and hepatosteatosis. The contribution of POPs to insulin resistance was confirmed in cultured adipocytes where POPs, especially organochlorine pesticides, led to robust inhibition of insulin action. Moreover, POPs induced down-regulation of insulin-induced gene-1 (Insig-1) and Lpin1, two master regulators of lipid homeostasis. Conclusion: Our findings provide evidence that exposure to POPs commonly present in food chains leads to insulin resistance and associated metabolic disorder

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Detailed stratified GWAS analysis for severe COVID-19 in four European populations

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.S.E.H. and C.A.S. partially supported genotyping through a philanthropic donation. A.F. and D.E. were supported by a grant from the German Federal Ministry of Education and COVID-19 grant Research (BMBF; ID:01KI20197); A.F., D.E. and F.D. were supported by the Deutsche Forschungsgemeinschaft Cluster of Excellence ‘Precision Medicine in Chronic Inflammation’ (EXC2167). D.E. was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Computational Life Sciences funding concept (CompLS grant 031L0165). D.E., K.B. and S.B. acknowledge the Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594). T.L.L., A.T. and O.Ö. were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project numbers 279645989; 433116033; 437857095. M.W. and H.E. are supported by the German Research Foundation (DFG) through the Research Training Group 1743, ‘Genes, Environment and Inflammation’. L.V. received funding from: Ricerca Finalizzata Ministero della Salute (RF-2016-02364358), Italian Ministry of Health ‘CV PREVITAL’—strategie di prevenzione primaria cardiovascolare primaria nella popolazione italiana; The European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- and for the project ‘REVEAL’; Fondazione IRCCS Ca’ Granda ‘Ricerca corrente’, Fondazione Sviluppo Ca’ Granda ‘Liver-BIBLE’ (PR-0391), Fondazione IRCCS Ca’ Granda ‘5permille’ ‘COVID-19 Biobank’ (RC100017A). A.B. was supported by a grant from Fondazione Cariplo to Fondazione Tettamanti: ‘Bio-banking of Covid-19 patient samples to support national and international research (Covid-Bank). This research was partly funded by an MIUR grant to the Department of Medical Sciences, under the program ‘Dipartimenti di Eccellenza 2018–2022’. This study makes use of data generated by the GCAT-Genomes for Life. Cohort study of the Genomes of Catalonia, Fundació IGTP (The Institute for Health Science Research Germans Trias i Pujol) IGTP is part of the CERCA Program/Generalitat de Catalunya. GCAT is supported by Acción de Dinamización del ISCIII-MINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026); the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR 529). M.M. received research funding from grant PI19/00335 Acción Estratégica en Salud, integrated in the Spanish National RDI Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (European Regional Development Fund (FEDER)-Una manera de hacer Europa’). B.C. is supported by national grants PI18/01512. X.F. is supported by the VEIS project (001-P-001647) (co-funded by the European Regional Development Fund (ERDF), ‘A way to build Europe’). Additional data included in this study were obtained in part by the COVICAT Study Group (Cohort Covid de Catalunya) supported by IsGlobal and IGTP, European Institute of Innovation & Technology (EIT), a body of the European Union, COVID-19 Rapid Response activity 73A and SR20-01024 La Caixa Foundation. A.J. and S.M. were supported by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36). A.J. was also supported by national grant PI17/00019 from the Acción Estratégica en Salud (ISCIII) and the European Regional Development Fund (FEDER). The Basque Biobank, a hospital-related platform that also involves all Osakidetza health centres, the Basque government’s Department of Health and Onkologikoa, is operated by the Basque Foundation for Health Innovation and Research-BIOEF. M.C. received Grants BFU2016-77244-R and PID2019-107836RB-I00 funded by the Agencia Estatal de Investigación (AEI, Spain) and the European Regional Development Fund (FEDER, EU). M.R.G., J.A.H., R.G.D. and D.M.M. are supported by the ‘Spanish Ministry of Economy, Innovation and Competition, the Instituto de Salud Carlos III’ (PI19/01404, PI16/01842, PI19/00589, PI17/00535 and GLD19/00100) and by the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018, COVID-Premed, COVID GWAs). The position held by Itziar de Rojas Salarich is funded by grant FI20/00215, PFIS Contratos Predoctorales de Formación en Investigación en Salud. Enrique Calderón’s team is supported by CIBER of Epidemiology and Public Health (CIBERESP), ‘Instituto de Salud Carlos III’. J.C.H. reports grants from Research Council of Norway grant no 312780 during the conduct of the study. E.S. reports grants from Research Council of Norway grant no. 312769. The BioMaterialBank Nord is supported by the German Center for Lung Research (DZL), Airway Research Center North (ARCN). The BioMaterialBank Nord is member of popgen 2.0 network (P2N). P.K. Bergisch Gladbach, Germany and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. He is supported by the German Federal Ministry of Education and Research (BMBF). O.A.C. is supported by the German Federal Ministry of Research and Education and is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—CECAD, EXC 2030–390661388. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. This work was supported by grants of the Rolf M. Schwiete Stiftung, the Saarland University, BMBF and The States of Saarland and Lower Saxony. K.U.L. is supported by the German Research Foundation (DFG, LU-1944/3-1). Genotyping for the BoSCO study is funded by the Institute of Human Genetics, University Hospital Bonn. F.H. was supported by the Bavarian State Ministry for Science and Arts. Part of the genotyping was supported by a grant to A.R. from the German Federal Ministry of Education and Research (BMBF, grant: 01ED1619A, European Alzheimer DNA BioBank, EADB) within the context of the EU Joint Programme—Neurodegenerative Disease Research (JPND). Additional funding was derived from the German Research Foundation (DFG) grant: RA 1971/6-1 to A.R. P.R. is supported by the DFG (CCGA Sequencing Centre and DFG ExC2167 PMI and by SH state funds for COVID19 research). F.T. is supported by the Clinician Scientist Program of the Deutsche Forschungsgemeinschaft Cluster of Excellence ‘Precision Medicine in Chronic Inflammation’ (EXC2167). C.L. and J.H. are supported by the German Center for Infection Research (DZIF). T.B., M.M.B., O.W. und A.H. are supported by the Stiftung Universitätsmedizin Essen. M.A.-H. was supported by Juan de la Cierva Incorporacion program, grant IJC2018-035131-I funded by MCIN/AEI/10.13039/501100011033. E.C.S. is supported by the Deutsche Forschungsgemeinschaft (DFG; SCHU 2419/2-1).Peer reviewe

Detailed stratified GWAS analysis for severe COVID-19 in four European populations

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic ∼0.9-Mb inversion polymorphism and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.Andre Franke and David Ellinghaus were supported by a grant from the German Federal Ministry of Education and Research (01KI20197), Andre Franke, David Ellinghaus and Frauke Degenhardt were supported by the Deutsche Forschungsgemeinschaft Cluster of Excellence “Precision Medicine in Chronic Inflammation” (EXC2167). David Ellinghaus was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Computational Life Sciences funding concept (CompLS grant 031L0165). David Ellinghaus, Karina Banasik and Søren Brunak acknowledge the Novo Nordisk Foundation (grant NNF14CC0001 and NNF17OC0027594). Tobias L. Lenz, Ana Teles and Onur Özer were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project numbers 279645989; 433116033; 437857095. Mareike Wendorff and Hesham ElAbd are supported by the German Research Foundation (DFG) through the Research Training Group 1743, "Genes, Environment and Inflammation". This project was supported by a Covid-19 grant from the German Federal Ministry of Education and Research (BMBF; ID: 01KI20197). Luca Valenti received funding from: Ricerca Finalizzata Ministero della Salute RF2016-02364358, Italian Ministry of Health ""CV PREVITAL – strategie di prevenzione primaria cardiovascolare primaria nella popolazione italiana; The European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- and for the project ""REVEAL""; Fondazione IRCCS Ca' Granda ""Ricerca corrente"", Fondazione Sviluppo Ca' Granda ""Liver-BIBLE"" (PR-0391), Fondazione IRCCS Ca' Granda ""5permille"" ""COVID-19 Biobank"" (RC100017A). Andrea Biondi was supported by the grant from Fondazione Cariplo to Fondazione Tettamanti: "Biobanking of Covid-19 patient samples to support national and international research (Covid-Bank). This research was partly funded by a MIUR grant to the Department of Medical Sciences, under the program "Dipartimenti di Eccellenza 2018–2022". This study makes use of data generated by the GCAT-Genomes for Life. Cohort study of the Genomes of Catalonia, Fundació IGTP. IGTP is part of the CERCA Program / Generalitat de Catalunya. GCAT is supported by Acción de Dinamización del ISCIIIMINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026); the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR 529). Marta Marquié received research funding from ant PI19/00335 Acción Estratégica en Salud, integrated in the Spanish National RDI Plan and financed by ISCIIISubdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de hacer Europa").Beatriz Cortes is supported by national grants PI18/01512. Xavier Farre is supported by VEIS project (001-P-001647) (cofunded by European Regional Development Fund (ERDF), “A way to build Europe”). Additional data included in this study was obtained in part by the COVICAT Study Group (Cohort Covid de Catalunya) supported by IsGlobal and IGTP, EIT COVID-19 Rapid Response activity 73A and SR20-01024 La Caixa Foundation. Antonio Julià and Sara Marsal were supported by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36). Antonio Julià was also supported the by national grant PI17/00019 from the Acción Estratégica en Salud (ISCIII) and the FEDER. The Basque Biobank is a hospitalrelated platform that also involves all Osakidetza health centres, the Basque government's Department of Health and Onkologikoa, is operated by the Basque Foundation for Health Innovation and Research-BIOEF. Mario Cáceres received Grants BFU2016-77244-R and PID2019-107836RB-I00 funded by the Agencia Estatal de Investigación (AEI, Spain) and the European Regional Development Fund (FEDER, EU). Manuel Romero Gómez, Javier Ampuero Herrojo, Rocío Gallego Durán and Douglas Maya Miles are supported by the “Spanish Ministry of Economy, Innovation and Competition, the Instituto de Salud Carlos III” (PI19/01404, PI16/01842, PI19/00589, PI17/00535 and GLD19/00100), and by the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018, COVID-Premed, COVID GWAs). The position held by Itziar de Rojas Salarich is funded by grant FI20/00215, PFIS Contratos Predoctorales de Formación en Investigación en Salud. Enrique Calderón's team is supported by CIBER of Epidemiology and Public Health (CIBERESP), "Instituto de Salud Carlos III". Jan Cato Holter reports grants from Research Council of Norway grant no 312780 during the conduct of the study. Dr. Solligård: reports grants from Research Council of Norway grant no 312769. The BioMaterialBank Nord is supported by the German Center for Lung Research (DZL), Airway Research Center North (ARCN). The BioMaterialBank Nord is member of popgen 2.0 network (P2N). Philipp Koehler has received non-financial scientific grants from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany, and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. He is supported by the German Federal Ministry of Education and Research (BMBF).Oliver A. Cornely is supported by the German Federal Ministry of Research and Education and is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy – CECAD, EXC 2030 – 390661388. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. Genotyping was performed by the Genotyping laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki. This work was supported by grants of the Rolf M. Schwiete Stiftung, the Saarland University, BMBF and The States of Saarland and Lower Saxony. Kerstin U. Ludwig is supported by the German Research Foundation (DFG, LU-1944/3-1). Genotyping for the BoSCO study is funded by the Institute of Human Genetics, University Hospital Bonn. Frank Hanses was supported by the Bavarian State Ministry for Science and Arts. Part of the genotyping was supported by a grant to Alfredo Ramirez from the German Federal Ministry of Education and Research (BMBF, grant: 01ED1619A, European Alzheimer DNA BioBank, EADB) within the context of the EU Joint Programme – Neurodegenerative Disease Research (JPND). Additional funding was derived from the German Research Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. Philip Rosenstiel is supported by the DFG (CCGA Sequencing Centre and DFG ExC2167 PMI and by SH state funds for COVID19 research). Florian Tran is supported by the Clinician Scientist Program of the Deutsche Forschungsgemeinschaft Cluster of Excellence “Precision Medicine in Chronic Inflammation” (EXC2167). Christoph Lange and Jan Heyckendorf are supported by the German Center for Infection Research (DZIF). Thorsen Brenner, Marc M Berger, Oliver Witzke und Anke Hinney are supported by the Stiftung Universitätsmedizin Essen. Marialbert Acosta-Herrera was supported by Juan de la Cierva Incorporacion program, grant IJC2018-035131-I funded by MCIN/AEI/10.13039/501100011033. Eva C Schulte is supported by the Deutsche Forschungsgemeinschaft (DFG; SCHU 2419/2-1).N

La bétaïne, un élément régulateur des points de contacts entre la mitochondrie et le réticulum endoplasmique (MAMs) de l’hépatocyte

International audienceLes points de contact entre les mitochondries et le réticulum endoplasmique (RE), appelés MAMs pour Mitochondria-Associated Membranes, ont un rôle crucial dans le contrôle de l'homéostasie glucido-lipidique de l’hépatocyte. Des données récentes montrent que les MAMs sont altérées dans le foie de modèles murins de résistance à l’insuline et de stéatose, faisant des MAMs une cible thérapeutique privilégiée pour la prévention ou le traitement des pathologies métaboliques. Ces plateformes dynamiques peuvent être régulées par différents facteurs, notamment les nutriments. Nous avons fait l’hypothèse que la bétaïne (un acide aminé dérivé de la glycine), de par sa structure et ses propriétés, pourrait moduler la structure et la fonction des MAMs de l’hépatocyte. Des hépatocytes primaires de rats Wistar, mâles, âgés de 3 mois ont été isolés par une méthode de perfusion à la collagénase et cultivés dans du DMEM (3 g/l de glucose) complet. Les cellules ont été incubées pendant 18h dans le milieu de culture avec BSA (Bovine serum albumine, 200µM), supplémenté ou non avec de la bétaïne (5mM). La structure des MAMs a été explorée par microscopie électronique à transmission (MET) et par in situ proximity ligation assay (PLA) pour l’unité fonctionnelle formée par le récepteur IP3R1 (inositol 1,4,5-trisphosphate receptor) du RE et le canal VDAC1 (voltage dependent anion channel) de la mitochondrie. La respiration mitochondriale a été mesurée par oxygraphie sur cellules perméabilisées avec les substrats glutamate (5 mM)/malate (2,5 mM) et succinate (5 mM)/roténone (5 µM). L’expression génique et le contenu en protéines clés des MAMs (VDAC1, mitofusine 2 : Mfn2 et la chaperonne Grp75) ont également été analysés.Les résultats montrent que la bétaïne favorise l’intégrité des MAMs par rapport au contrôle :•La longueur des MAMs mesurée par MET par rapport à la circonférence mitochondriale est augmentée de 41% sous bétaïne par rapport au contrôle (bétaïne 16,2% vs. contrôle 11,5%, p<0,05). Les contacts de 20 à 30nm de largeur, responsables des transferts calciques du RE vers la mitochondrie, sont particulièrement augmentés suite au traitement à la bétaïne (bétaïne 3,5% vs. contrôle 2,0%, p<0,01 soit +75%).•Le nombre d’interaction VDAC1/IP3R1 par noyau analysé par in situ PLA est augmenté de 16,7% sous bétaïne par rapport au contrôle (p<0,05).Ces adaptations sont associées à une modification de la respiration cellulaire en glutamate/malate (+48%, p<0,01). Par ailleurs, l’expression génique de Mfn2, la protéine la plus retrouvée aux MAMs, est augmentée de 26,2% par rapport au contrôle (p<0,001) et son contenu protéique est augmenté de 15,2% (p=0.052). Nos résultats confirment notre hypothèse selon laquelle la bétaïne régule l’intégrité des MAMs. Ceci pourrait s’expliquer par un effet spécifique sur l’expression de la protéine de structure Mfn2. L'augmentation de la respiration cellulaire témoigne d'un effet bénéfique de l'amélioration de l'intégrité de la MAM sur la fonction oxydative mitochondriale

Betaine, a regulator of mitochondrial-endoplasmic reticulum (MAM) interactions in the hepatocyte

International audienceBackground and objectives : Interactions between mitochondria and the endoplasmic reticulum (ER), called MAMs, are impaired in the liver of obese mice, with insulin resistance (IR) and steatosis. As certain nutrients can regulate MAMs, we tested whether betaine (a methylated amino acid derived from glycine) could modulate the structure and function of hepatocyte MAMs. Methods : Primary hepatocytes from Wistar rats (male, 3 months, n=5) were incubated in the presence or absence of betaine (5mM). The structure of MAMs was explored by electron microscopy (TEM) and by in situ proximity ligation assay (PLA) for the functional unit formed by IP3R1 (inositol 1,4,5-trisphosphate receptor) at the ER and VDAC1 (voltage dependent anion channel) at the mitochondrion. Mitochondrial respiration was measured by oxygraphy in permeabilised cells. Gene expression and protein content of key actor at the MAMs (VDAC1, mitofusin 2: Mfn2, chaperone Grp75) were analysed. The results were analysed with Student's t-test.Results : Betaine promoted MAM integrity vs. control. The length of MAMs measured by TEM relative to the mitochondrial circumference was increased by 4.7 points under betaine vs. control (16.2 vs. 11.5%, p<0.05). The number of VDAC1/IP3R1 interactions per nucleus analysed by in situ PLA was increased by 16.7% under betaine vs. control (p<0.05). These adaptations were associated with an increase in glutamate (5mM)/malate (2.5mM) cellular respiration (+48%, p<0.01). Furthermore, the gene expression and protein content of Mfn2, the protein most commonly found at MAMs, were increased by 26.2 and 15.2% vs. control (p<0.001 and p=0.052), respectively. Conclusions : Our results evidenced that betaine regulates the integrity of MAMs. This could be explained by a specific effect on the expression of the structural protein Mfn2. The increase in cellular respiration indicates a beneficial effect of improved MAM integrity on mitochondrial oxidative function

La bétaïne, un élément régulateur des points de contacts entre la mitochondrie et le réticulum endoplasmique (MAMs) de l’hépatocyte

International audienceLes points de contact entre les mitochondries et le réticulum endoplasmique (RE), appelés MAMs pour Mitochondria-Associated Membranes, ont un rôle crucial dans le contrôle de l'homéostasie glucido-lipidique de l’hépatocyte. Des données récentes montrent que les MAMs sont altérées dans le foie de modèles murins de résistance à l’insuline et de stéatose, faisant des MAMs une cible thérapeutique privilégiée pour la prévention ou le traitement des pathologies métaboliques. Ces plateformes dynamiques peuvent être régulées par différents facteurs, notamment les nutriments. Nous avons fait l’hypothèse que la bétaïne (un acide aminé dérivé de la glycine), de par sa structure et ses propriétés, pourrait moduler la structure et la fonction des MAMs de l’hépatocyte. Des hépatocytes primaires de rats Wistar, mâles, âgés de 3 mois ont été isolés par une méthode de perfusion à la collagénase et cultivés dans du DMEM (3 g/l de glucose) complet. Les cellules ont été incubées pendant 18h dans le milieu de culture avec BSA (Bovine serum albumine, 200µM), supplémenté ou non avec de la bétaïne (5mM). La structure des MAMs a été explorée par microscopie électronique à transmission (MET) et par in situ proximity ligation assay (PLA) pour l’unité fonctionnelle formée par le récepteur IP3R1 (inositol 1,4,5-trisphosphate receptor) du RE et le canal VDAC1 (voltage dependent anion channel) de la mitochondrie. La respiration mitochondriale a été mesurée par oxygraphie sur cellules perméabilisées avec les substrats glutamate (5 mM)/malate (2,5 mM) et succinate (5 mM)/roténone (5 µM). L’expression génique et le contenu en protéines clés des MAMs (VDAC1, mitofusine 2 : Mfn2 et la chaperonne Grp75) ont également été analysés.Les résultats montrent que la bétaïne favorise l’intégrité des MAMs par rapport au contrôle :•La longueur des MAMs mesurée par MET par rapport à la circonférence mitochondriale est augmentée de 41% sous bétaïne par rapport au contrôle (bétaïne 16,2% vs. contrôle 11,5%, p<0,05). Les contacts de 20 à 30nm de largeur, responsables des transferts calciques du RE vers la mitochondrie, sont particulièrement augmentés suite au traitement à la bétaïne (bétaïne 3,5% vs. contrôle 2,0%, p<0,01 soit +75%).•Le nombre d’interaction VDAC1/IP3R1 par noyau analysé par in situ PLA est augmenté de 16,7% sous bétaïne par rapport au contrôle (p<0,05).Ces adaptations sont associées à une modification de la respiration cellulaire en glutamate/malate (+48%, p<0,01). Par ailleurs, l’expression génique de Mfn2, la protéine la plus retrouvée aux MAMs, est augmentée de 26,2% par rapport au contrôle (p<0,001) et son contenu protéique est augmenté de 15,2% (p=0.052). Nos résultats confirment notre hypothèse selon laquelle la bétaïne régule l’intégrité des MAMs. Ceci pourrait s’expliquer par un effet spécifique sur l’expression de la protéine de structure Mfn2. L'augmentation de la respiration cellulaire témoigne d'un effet bénéfique de l'amélioration de l'intégrité de la MAM sur la fonction oxydative mitochondriale

La bétaïne, un élément régulateur des interactions entre la mitochondrie et le réticulum endoplasmique (MAMs) dans l’hépatocyte

International audienceLes interactions entre mitochondries et réticulum endoplasmique (RE), appelés MAMs, sont altérés dans le foie de souris obèses, avec insulino-résistance (IR) et stéatose. Certains nutriments pouvant réguler les MAMs, nous avons testé si la bétaïne (un acide aminé dérivé de la glycine) pourrait moduler la structure et la fonction des MAMs de l’hépatocyte. Des hépatocytes primaires de rats Wistar (mâles, 3 mois, n=5) ont été incubés en présence ou non de bétaïne (5mM). La structure des MAMs a été explorée par microscopie électronique (MET) et par in situ proximity ligation assay (PLA) pour l’unité fonctionnelle formée par IP3R1 (inositol 1,4,5-trisphosphate receptor) au RE et VDAC1 (voltage dependent anion channel) à la mitochondrie. La respiration mitochondriale a été mesurée par oxygraphie sur cellules perméabilisées. L’expression génique et le contenu en protéines des MAMs (VDAC1, mitofusine 2 : Mfn2, chaperonne Grp75) ont été analysés. Les résultats ont été analysés avec le test t de Student.La bétaïne favorise l’intégrité des MAMs vs. contrôle. La longueur des MAMs mesurée par MET par rapport à la circonférence mitochondriale est augmentée de 4,7 points sous bétaïne vs. contrôle (16,2 vs. 11,5%, p<0,05). Le nombre d’interaction VDAC1/IP3R1 par noyau analysé par in situ PLA est augmenté de 16,7% sous bétaïne vs. contrôle (p<0,05). Ces adaptations sont associées à une augmentation de la respiration cellulaire en glutamate (5mM)/malate (2,5mM) (+48%, p<0,01). Par ailleurs, l’expression génique et le contenu protéique de Mfn2, la protéine la plus retrouvée aux MAMs, sont augmentés de 26,2 et 15,2% vs. contrôle (p<0,001 et p=0.052), respectivement. Nos résultats montrent que la bétaïne régule l’intégrité des MAMs. Ceci pourrait s’expliquer par un effet spécifique sur l’expression de la protéine de structure Mfn2. L'augmentation de la respiration cellulaire témoigne d'un effet bénéfique de l'amélioration de l'intégrité des MAMs sur la fonction oxydative mitochondriale