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1. Evolution of Major Amputation Risk in Patients Hospitalized in France for Critical Limb Ischemia: The COPART Registry

Author

Alessandra Bura-Rivière, Emmanuel Messas, Victor Aboyans, François-Xavier Lapébie, Ileana Desormais, Marion Mangin, Carine Boulon, P. Lacroix, Alice Coudene, Joël Constans, Valerie Aurillac, Service des Maladies Cardiaques et Vasculaires [CHU Bordeaux], CHU Bordeaux [Bordeaux], Service de Médecine Vasculaire [CHU Toulouse], Centre Hospitalier Régional Universitaire de Toulouse (CHRU Toulouse), Service de Chirurgie Thoracique et Vasculaire - Médecine vasculaire [CHU Limoges], CHU Limoges, Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Département d'endocrinologie - Bordeaux 2, Université Bordeaux Segalen - Bordeaux 2, Service de cardiologie [CHU Limoges], Service d'hypertension artérielle et médecine vasculaire, Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
Male, critical limb ischemia, medicine.medical_specialty, Time Factors, Multivariate analysis, Statin, medicine.drug_class, Critical Illness, medicine.medical_treatment, Disease, 030204 cardiovascular system & hematology, peripheral artery disease, Revascularization, Risk Assessment, Amputation, Surgical, Peripheral Arterial Disease, 03 medical and health sciences, Cohorte des Patients ARTeriopathes, 0302 clinical medicine, Ischemia, Risk Factors, Internal medicine, Angioplasty, medicine, Humans, Registries, 030212 general & internal medicine, major amputation, Aged, Aged, 80 and over, business.industry, Endovascular Procedures, Critical limb ischemia, Odds ratio, Middle Aged, Limb Salvage, 3. Good health, Hospitalization, Treatment Outcome, Cohort, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, prognosis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Vascular Surgical Procedures
Abstract

International audience; Over the past decade, improvements in medical treatment and revascularization techniques have been beneficial for patients with peripheral artery disease in the late stage of critical limb ischemia (CLI). We evaluated the putative reduction in the number of major amputees in the Cohorte des Patients ARTeriopathes (COPART) cohort over time. Patients were selected from this multicenter cohort, from 2006 to 2016, for CLI according to Trans-Atlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease II criteria. Patients included before and after 2011 were compared. Patients were followed for 1 year. Primary outcome was the rate of major amputations. Secondary outcomes were minor amputations, deaths from all causes, cardiovascular deaths; 989 patients were included, 489 before 2011 and 450 after 2011. There was a significant decrease in rates of major amputation after 2011 (17% vs 25%), confirmed in multivariate analysis (odds ratio [OR]: 1.5 [1.1-2.2]), an increase in revascularization, particularly distal angioplasty (OR: 2.7 [1.7-4.4]) and increased statin intake (OR: 1.6 [1.1-2.1]). For secondary outcomes, there was no significant difference. Limb prognosis of CLI patients has improved over the past decade, possibly due to more revascularizations, particularly distal ones, and increased statin use.

Published
2020

2. High‐dose chemotherapy followed by autologous stem cell rescue in Wilms tumors: French report on toxicity and efficacy

Author

Isabelle Pellier, Hélène Sudour-Bonnange, Marie-Dominique Tabone, Claudia Pasqualini, Christophe Bergeron, Gudrun Scheleirmacher, Frédérique Dijoud, Aurore Coulomb-L'Hermine, Xavier Muracciole, Anne Notz-Carrere, Claire Freycon, Magali Morelle, Cécile Boulanger, Manon Delafoy, Arnauld Verschuur, Sabine Irtan, Estelle Thebaud, Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut Curie [Paris], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de radiothérapie - [Hôpital de la Timone - Hôpital Nord - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE)- Hôpital Nord [CHU - APHM], Hospices Civils de Lyon (HCL), Centre Léon Bérard [Lyon], Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Département d'oncologie pédiatrique [Institut Curie, Paris], Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité d'oncologie pédiatrique [Centre Oscar Lambret, Lille], Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, Service d'oncologie pédiatrique [CHU Nantes], Service d'Onco-Hématologie Pédiatrique [CHU Grenoble], Service d'Hémato-oncologie Pédiatrique [CHU Bordeaux], CHU Bordeaux [Bordeaux]-Hôpital Pellegrin, Service d'Hématologie et Oncologie pédiatriques [CHRU Toulouse], Centre Hospitalier Régional Universitaire de Toulouse (CHRU Toulouse), Service d'Immunologie Hématologie et Oncologie pédiatriques [CHU Angers], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de chirurgie viscérale pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Service de pathologie [CHU Trousseau], Unité de Biostatistiques [Lyon], Centre Léon-Bérard : Centre de lutte contre le cancer de Lyon et Rhône-Alpes, and Département d'oncologie pédiatrique [Centre Léon Bérard, Lyon]

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Autologous Stem Cell Rescue, Adolescent, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Transplantation, Autologous, Wilms Tumor, Young Adult, 03 medical and health sciences, High dose chemotherapy, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Young adult, Child, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Chemotherapy, business.industry, Stem Cells, Hematopoietic Stem Cell Transplantation, Wilms' tumor, Hematology, medicine.disease, Combined Modality Therapy, Kidney Neoplasms, 3. Good health, Respiratory failure, Child, Preschool, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, Toxicity, Cohort, Female, business, 030215 immunology
Abstract

International audience; BackgroundHeterogeneous data have been reported on high-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) in Wilms tumors (WTs). We aimed to define its safety and efficacy in the French cohort, and to compare this management to current international recommendations.MethodsData prospectively collected from children, adolescents, and young adults with WT treated with HDCT/ASCR between 2000 and 2016 in French centers were retrospectively analyzed. Toxicity was reported according to CTCAE v4.03.ResultsFifty-four patients received HDCT/ASCR (first line, n = 13; recurrence, n = 41). Their median age at the time of ASCR was 5.3 years (range 2.2–21.6). Main nonhematological acute grades 3–4 toxicities were digestive and renal. No significant difference of toxicity rate was observed among HDCT regimens and schedules. Two patients died shortly after ASCR (renal and multiorgan failure), and one heavily pretreated patient died of late respiratory failure. The selection criteria applied to define those patients eligible for HDCT/ASCR retrospectively matched to those currently used in the International Society of Pediatric Oncology (SIOP) UMBRELLA protocol for 38 patients, with encouraging survival rates compared to published data. The objective response rate to HDCT was 21%, with a disease control rate after HDCT of 85%. After a median follow-up of 7 years, the 5-year event-free survival (EFS) and overall survival (OS) were 54% (95% CI: 32%–76%) and 62% (95% CI: 31%–82%) for frontline patients, and 57% (95% CI: 39%–71%) and 69% (95% CI: 52%–81%) at recurrence.ConclusionHDCT was feasible and showed encouraging results in well-defined settings. Data from the current prospective protocol will help to better evaluate HDCT impact on survival.

Published
2021

3. ISAba1-dependent overexpression of eptA in clinical strains of Acinetobacter baumannii resistant to colistin

Author

Anaïs Potron, Marlène Amara, Laurent Cavalié, Benoît Valot, Rémy A. Bonnin, Laurent Dortet, Florence Reibel, Christine Bernard, Patrick Plésiat, Gerald Larrouy-Maumus, Laurence Parmeland, Jean-Baptiste Vuillemenot, Maxime Bour, Pauline Triponney, Hélène Puja, Laboratoire Chrono-environnement - UFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier de Versailles (CHV), Centre Hospitalier Régional Universitaire de Toulouse (CHRU Toulouse), Grand Hôpital de l'Est Parisien, Centre hospitalier Saint Joseph - Saint Luc [Lyon], Groupe Hospitalier Nord Essonne [Longjumeau], Imperial College London, Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), and Centre Hospitalier de Versailles André Mignot (CHV)

Subjects
Acinetobacter baumannii, Male, Microbiology (medical), Operon, Biology, law.invention, Microbiology, 03 medical and health sciences, Bacterial Proteins, Start codon, law, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Drug Resistance, Bacterial, medicine, Humans, Pharmacology (medical), Gene, ComputingMilieux_MISCELLANEOUS, Polymerase chain reaction, Aged, 030304 developmental biology, Aged, 80 and over, Pharmacology, Whole genome sequencing, 0303 health sciences, Whole Genome Sequencing, Colistin, 030306 microbiology, Middle Aged, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Anti-Bacterial Agents, Infectious Diseases, Multilocus sequence typing, Female, Acinetobacter Infections, Transcription Factors, medicine.drug
Abstract

BackgroundColistin resistance in Acinetobacter baumannii often results from mutational activation of the two-component system PmrAB and subsequent addition of phospho-ethanolamine (pEtN) to lipooligosaccharide by up-regulated pEtN transferase PmrC.ObjectivesTo characterize mechanisms of colistin resistance independent of PmrCAB in A. baumannii.MethodsTwenty-seven colistin-resistant A. baumannii were collected from 2012 to 2018. Analysis of operon pmrCAB was performed by PCR and sequencing. Seven strains were investigated further by WGS and whole-genome MLST (wgMLST).ResultsSeven out of the 27 selected isolates were found to overexpress eptA, a gene homologous to pmrC, likely as a consequence of upstream insertion of an ISAba1 element. Insertion sites of ISAba1 were mapped 13, 18 and 156 bp ahead of the start codon of eptA in five strains, one strain and one strain, respectively. The finding that the isolates did not cluster together when compared by wgMLST analysis supports the notion that distinct insertion events occurred in close, but different, genetic backgrounds.ConclusionsActivation of eptA and subsequent addition of pEtN to the cell surface represents a novel mechanism of resistance to colistin in A. baumannii.

Published
2019

4. Defining the risk of first intravenous immunoglobulin unresponsiveness in non-Asian patients with Kawasaki disease

Author

Fouad Madhi, Isabelle Koné-Paut, Stéphanie Tellier, Martha Darce Bello, Ulrich Meinzer, Maryam Piram, Franck Boralevi, Rolando Cimaz, Celine Piedvache, Sylvie Di Filippo, Pediatric Rheumatology [Le Kremlin-Bicêtre], Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses [Le Kremlin-Bicêtre] (CeRéMAIA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Paediatric Rheumatology, Nephrology and Internal medicine [Toulouse], Centre Hospitalier Régional Universitaire de Toulouse (CHRU Toulouse), Hospices Civils de Lyon (HCL), Dermatology [Bordeaux], CHU Bordeaux [Bordeaux], Paediatrics [Créteil], Centre Hospitalier Intercommunal de Créteil (CHIC), Paediatrics, Paediatric Internal Medicine, Rheumatology and Infectious Diseases [Paris], Centre de référence des rhumatismes inflammatoires et maladies autoimmunes systémiques rares de l'enfant [Paris] (RAISE), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Milan, Clinical Research Unit [Le Kremlin-Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, The sponsor was Assistance Publique-Hôpitaux de Paris (Département de la Recherche Clinique et du Développement). The study was funded by a grant from Programme Hospitalier de Recherche Clinique-PHRC 2009 (French Ministry of Health) and the French Society of Rheumatology (SFR)., Bodescot, Myriam, Service Néphrologie, médecine interne et hypertension pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Università degli Studi di Milano = University of Milan (UNIMI)

Subjects
Male, Multivariate analysis, Vasculitis syndromes, Drug Resistance, lcsh:Medicine, Drug resistance, 030204 cardiovascular system & hematology, Pediatrics, Severity of Illness Index, 0302 clinical medicine, Risk Factors, Ethnicity, Medicine, Prospective Studies, Prospective cohort study, lcsh:Science, Child, education.field_of_study, Paediatric rheumatic diseases, Multidisciplinary, Immunoglobulins, Intravenous, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Child, Preschool, Female, France, Risk assessment, medicine.medical_specialty, Population, Mucocutaneous Lymph Node Syndrome, Risk Assessment, Sensitivity and Specificity, Article, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 030225 pediatrics, Internal medicine, Severity of illness, Humans, education, Retrospective Studies, business.industry, lcsh:R, Infant, Reproducibility of Results, Retrospective cohort study, medicine.disease, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Multivariate Analysis, Kawasaki disease, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract

About 10–20% of patients with Kawasaki disease (KD) are unresponsive to intravenous immunoglobulin (IVIg) and are at increased risk of coronary artery abnormalities (CAAs). Early identification is critical to initiate aggressive therapies, but available scoring systems lack sensitivity in non-Japanese populations. We investigated the accuracy of 3 Japanese scoring systems and studied factors associated with IVIg unresponsiveness in a large multiethnic French population of children with KD to build a new scoring system. Children admitted for KD between 2011–2014 in 65 centers were enrolled. Factors associated with second line-treatment; i.e. unresponsiveness to initial IVIg treatment, were analyzed by multivariate regression analysis. The performance of our score and the Kobayashi, Egami and Sano scores were compared in our population and in ethnic subgroups. Overall, 465 children were reported by 84 physicians; 425 were classified with KD (55% European Caucasian, 12% North African/Middle Eastern, 10% African/Afro-Caribbean, 3% Asian and 11% mixed). Eighty patients (23%) needed second-line treatment. Japanese scores had poor performance in our whole population (sensitivity 14–61%). On multivariate regression analysis, predictors of secondary treatment after initial IVIG were hepatomegaly, ALT level ≥30 IU/L, lymphocyte count 3 and time to treatment

Published
2020

5. Restoring Endothelial Function by Targeting Desert Hedgehog Downstream of Klf2 Improves Critical Limb Ischemia in Adults

Author

Marie-Ange Renault, Caroline Caradu, Candice Chapouly, Pierre-Louis Hollier, Sarah Guimbal, Alessandra Bura-Rivière, Thierry Couffinhal, Mathilde Dubois, Eric Ducasse, Alain-Pierre Gadeau, Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Service de Médecine Vasculaire [CHU Toulouse], Centre Hospitalier Régional Universitaire de Toulouse (CHRU Toulouse), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), This study was sponsored by the Toulouse University Hospital Centre and supported by a grant from the French Ministry of Health (Interregional Clinical Research Hospital Program PHRC-I 2009 N°RCB: 2009-A00889-48), the Société de Chirurgie Vasculaire et Endovasculaire de langue française, and the Fondation de France, Appels d’Offre Recherche sur les maladies Cardiovasculaires 2013 and 2018. Additionally, this study was co-funded by the Institut National de la Santé et de la Recherche Médicale and by the University of Bordeaux., Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Boullé, Christelle

Subjects
Male, 0301 basic medicine, Physiology, 030204 cardiovascular system & hematology, 0302 clinical medicine, Ischemia, therapeutics, Medicine, Cells, Cultured, Mice, Knockout, Cyclohexylamines, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Hindlimb, 3. Good health, Cell biology, Autocrine Communication, KLF2, Cytokines, Inflammation Mediators, medicine.symptom, Cardiology and Cardiovascular Medicine, Signal Transduction, Critical Illness, Upstream and downstream (transduction), Kruppel-Like Transcription Factors, Neovascularization, Physiologic, Inflammation, Thiophenes, Capillary Permeability, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Downstream (manufacturing), peripheral arterial disease, Human Umbilical Vein Endothelial Cells, Animals, Humans, Hedgehog Proteins, Muscle, Skeletal, Desert hedgehog, business.industry, hedgehogs, Endothelial Cells, Critical limb ischemia, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Gene Expression Regulation, Article RECHERCHE, inflammation, Regional Blood Flow, Stress, Mechanical, business, Function (biology)
Abstract

Rationale: Klf (kruppel-like factor) 2 is critical to establish and maintain endothelial integrity. Objective: Therefore, determining upstream and downstream mediators of Klf2 would lead to alternative therapeutic targets in cardiovascular disease management. Methods and Results: Here we identify Dhh (desert hedgehog) as a downstream effector of Klf2, whose expression in endothelial cells (ECs) is upregulated by shear stress and decreased by inflammatory cytokines. Consequently, we show that Dhh knockdown in ECs promotes endothelial permeability and EC activation and that Dhh agonist prevents TNF-α (tumor necrosis factor alpha) or glucose-induced EC dysfunction. Moreover, we demonstrate that human critical limb ischemia, a pathological condition linked to diabetes mellitus and inflammation, is associated to major EC dysfunction. By recreating a complex model of critical limb ischemia in diabetic mice, we found that Dhh-signaling agonist significantly improved EC function without promoting angiogenesis, which subsequently improved muscle perfusion. Conclusion: Restoring EC function leads to significant critical limb ischemia recovery. Dhh appears to be a promising target, downstream of Klf2, to prevent the endothelial dysfunction involved in ischemic vascular diseases.

Published
2018

6. Functional muscle impairment in facioscapulohumeral muscular dystrophy is correlated with oxidative stress and mitochondrial dysfunction

Author

Sébastien Bommart, Emilie Passerieux, Ahmed Turki, Raul Juntas Morales, Gilles Carnac, Alexandra Belayew, Dalila Laoudj-Chenivesse, Sylvia Pietri, Karen Lambert, Joël Pincemail, Fabien Pillard, Gérald Hugon, Maurice Hayot, Eric Raynaud de Mauverger, Jacques Mercier, Yegor S. Vassetzky, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire de Toulouse (CHRU Toulouse), CHU, Liège, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service de Biologie Moléculaire, Université de Mons, Belgique, Interactions moléculaires et cancer (IMC (UMR 8126)), Signalisation, noyaux et innovations en cancérologie (UMR8126), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Pietri, Sylvia

Subjects
Male, MnSOD, Cu-SOD, DUX4, [SDV]Life Sciences [q-bio], Glutathione reductase, Mitochondria dysfunction, thiobarbituric acid-reactive substances, medicine.disease_cause, Biochemistry, Antioxidants, chemistry.chemical_compound, 0302 clinical medicine, Facioscapulohumeral muscular dystrophy, endurance limit time, double homebox 4 gene, Muscular dystrophy, ComputingMilieux_MISCELLANEOUS, 2 minute walking test n Correspondence to: INSERM, reactive oxygen species, 0303 health sciences, 2-MWT, Chemistry, T Lim, Autosomal dominant trait, ROS, oxidized glutathione, Muscular Dystrophy, Facioscapulohumeral, Mitochondria, [SDV] Life Sciences [q-bio], GR, medicine.anatomical_structure, Radical oxygen species, MVC, copper-zinc-dependent superoxide dismutase, Female, GSSG, musculoskeletal diseases, Adult, medicine.medical_specialty, 4-hydroxy-2-nonenal, TBARS, Lipofuscin, Facioscapulohumeral muscular dystrophy (FSHD), 03 medical and health sciences, Physiology (medical), Internal medicine, medicine, GSH, Humans, Facioscapulohumeral muscular dystrophy (FSHD) 4-Hydroxy-2-nonenal Thiobarbituric acid-reactive substances Lipofuscin Oxidative stress Protein oxidation Radical oxygen species Mitochondria dysfunction Antioxidants Abbreviations: FSHD, reduced glutathione, glutathione reductase, 030304 developmental biology, manganese-dependent superoxide dismutase, Skeletal muscle, facioscapulohumeral dystrophy, Glutathione, Bâtiment Crastes de Paulet, medicine.disease, Endocrinology, HNE, Oxidative stress, maximal voluntary contraction, Protein oxidation, 030217 neurology & neurosurgery, U1046
Abstract

Facioscapulohumeral muscular dystrophy (FSHD), the most frequent muscular dystrophy, is an autosomal dominant disease. In most individuals with FSHD, symptoms are restricted to muscles of the face, arms, legs, and trunk. FSHD is genetically linked to contractions of the D4Z4 repeat array causing activation of several genes. One of these maps in the repeat itself and expresses the DUX4 (the double homeobox 4) transcription factor causing a gene deregulation cascade. In addition, analyses of the RNA or protein expression profiles in muscle have indicated deregulations in the oxidative stress response. Since oxidative stress affects peripheral muscle function, we investigated mitochondrial function and oxidative stress in skeletal muscle biopsies and blood samples from patients with FSHD and age-matched healthy controls, and evaluated their association with physical performances. We show that specifically, oxidative stress (lipid peroxidation and protein carbonylation), oxidative damage (lipofuscin accumulation), and antioxidant enzymes (catalase, copper-zinc-dependent superoxide dismutase, and glutathione reductase) were higher in FSHD than in control muscles. FSHD muscles also presented abnormal mitochondrial function (decreased cytochrome c oxidase activity and reduced ATP synthesis). In addition, the ratio between reduced (GSH) and oxidized glutathione (GSSG) was strongly decreased in all FSHD blood samples as a consequence of GSSG accumulation. Patients with FSHD also had reduced systemic antioxidative response molecules, such as low levels of zinc (a SOD cofactor), selenium (a GPx cofactor involved in the elimination of lipid peroxides), and vitamin C. Half of them had a low ratio of gamma/alpha tocopherol and higher ferritin concentrations. Both systemic oxidative stress and mitochondrial dysfunction were correlated with functional muscle impairment. Mitochondrial ATP production was significantly correlated with both quadriceps endurance (T(LimQ)) and maximal voluntary contraction (MVC(Q)) values (rho=0.79, P=0.003; rho=0.62, P=0.05, respectively). The plasma concentration of oxidized glutathione was negatively correlated with the T(LimQ), MVC(Q) values, and the 2-min walk distance (MWT) values (rho=-0.60, P=0.03; rho=-0.56, P=0.04; rho=-0.93, P0.0001, respectively). Our data characterized oxidative stress in patients with FSHD and demonstrated a correlation with their peripheral skeletal muscle dysfunction. They suggest that antioxidants that might modulate or delay oxidative insult may be useful in maintaining FSHD muscle functions.

Published
2012

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