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1. Tranexamic acid dose–response relationship for antifibrinolysis in postpartum haemorrhage during Caesarean delivery: TRACES, a double-blind, placebo-controlled, multicentre, dose-ranging biomarker study

Author

Anne-Sophie Ducloy-Bouthors, Sixtine Gilliot, Maeva Kyheng, David Faraoni, Alexandre Turbelin, Hawa Keita-Meyer, Agnès Rigouzzo, Gabriela Moyanotidou, Benjamin Constant, Francoise Broisin, Agnès L. Gouez, Rémi Favier, Edith Peynaud, Louise Ghesquiere, Gilles Lebuffe, Alain Duhamel, Delphine Allorge, Sophie Susen, Benjamin Hennart, Emmanuelle Jeanpierre, Pascal Odou, Cyril Huissoud, Charles Garabedian, Fanny Lassalle, Frederic J. Mercier, Catherine Barre-Drouard, Max Gonzalez Estevez, Julien Corouge, Anne-Sophie Baptiste, Anne-Frédérique Dalmas, Pierre Richart, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Jeanne de Flandre [Lille], Service de Biostatistiques [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Toxicologie et Génopathies [CHRU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, CHU Lille, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA], Evaluation des technologies de santé et des pratiques médicales - ULR 2694 [METRICS], Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA) - ULR 7365, Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], and Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD]

Subjects
Anesthesiology and Pain Medicine, Tranexamic Acid, Double-Blind Method, Pregnancy, Cesarean Section, [SDV]Life Sciences [q-bio], Postpartum Hemorrhage, Humans, Female, Fibrinolysin, Blood Coagulation Disorders, Antifibrinolytic Agents, Biomarkers
Abstract

International audience; BackgroundThe optimal dose of tranexamic acid to inhibit hyperfibrinolysis in postpartum haemorrhage is unclear. Tranexamic Acid to Reduce Blood Loss in Hemorrhagic Cesarean Delivery (TRACES) was a double-blind, placebo-controlled, randomised, multicentre dose-ranging study to determine the dose–effect relationship for two regimens of intravenous tranexamic acid vs placebo.MethodsWomen experiencing postpartum haemorrhage during Caesarean delivery were randomised to receive placebo (n=60), tranexamic acid 0.5 g (n=57), or tranexamic acid 1 g i.v. (n=58). Biomarkers of fibrinolytic activation were assayed at five time points, with inhibition of hyperfibrinolysis defined as reductions in the increase over baseline in D-dimer and plasmin–antiplasmin levels and in the plasmin peak time.ResultsIn the placebo group, hyperfibrinolysis was evidenced by a mean increase over baseline [95% confidence interval] of 93% [68–118] for D-dimer level at 120 min and 56% [25–87] for the plasmin–antiplasmin level at 30 min. A dose of tranexamic acid 1 g was associated with smaller increases over baseline (D-dimers: 38% [13–63] [P=0.003 vs placebo]; plasmin–antiplasmin: –2% [–32 to 28] [P=0.009 vs placebo]). A dose of tranexamic acid 0.5 g was less potent, with non-significant reductions (D-dimers: 58% [32–84] [P=0.06 vs placebo]; plasmin–antiplasmin: 13% [18–43] [P=0.051]). Although both tranexamic acid doses reduced the plasmin peak, reduction in plasmin peak time was significant only for the 1 g dose of tranexamic acid.ConclusionsFibrinolytic activation was significantly inhibited by a dose of intravenous tranexamic acid 1 g but not 0.5 g. Pharmacokinetic–pharmacodynamic modelling of these data might identify the best pharmacodynamic monitoring criteria and the optimal tranexamic acid dosing regimen for treatment of postpartum haemorrhage.

Published
2022
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2. Safe and Efficient Sigma1 Ligand: A Potential Drug Candidate for Multiple Sclerosis

Author

Bénédicte Oxombre, Fahima Madouri, Anne-Sophie Journé, Séverine Ravez, Eloise Woitrain, Pascal Odou, Nathalie Duhal, Sandro Ninni, David Montaigne, Nadira Delhem, Patrick Vermersch, Patricia Melnyk, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Lille Nord (France), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Lille Neurosciences & Cognition - U 1172 [LilNCog], Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires [RNMCD - U1011], Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA], Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 [ONCO-THAI], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc], Université de Lille, CHU Lille, Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA) - ULR 7365, Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, and Lille Neurosciences & Cognition (LilNCog) - U 1172

Subjects
sigma1 receptor, benzamide, [SDV]Life Sciences [q-bio], Organic Chemistry, Neurodegenerative Diseases, General Medicine, Ligands, multiple sclerosis, Catalysis, Computer Science Applications, Inorganic Chemistry, Central Nervous System Diseases, Benzamides, CNS, Humans, Receptors, sigma, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract

International audience; Multiple Sclerosis (MS) is an autoimmune demyelinating and neurodegenerative disease of the central nervous system (CNS). Current management strategies suppress or modulate immune function, all with consequences and known side effects. They demonstrate a high level of success in limiting new relapses. However, the neurodegenerative process still affects both grey and white matter in the central nervous system. The sigma1 (S1R) ligand-regulated chaperone is implicated in many biological processes in various CNS-targeted diseases, acting on neural plasticity, myelination and neuroinflammation. Among the proteins involved in MS, S1R has therefore emerged as a promising new target. Standard and robust methods have been adopted to analyze the adsorption, distribution, metabolism, excretion (ADME) properties, safety pharmacology and toxicology of a previously synthetized simple benzamide-derived compound with nanomolar affinity for S1R, high selectivity, no cytotoxicity and good metabolic stability. The compound was also characterized as an agonist based on well-validated assays prior to in vivo investigations. Interestingly, we found that the oral administration of this compound resulted in an overall significant reduction in clinical progression in an MS experimental model. This effect is mediated through S1R action. Our results further suggest the potential use of this compound in the treatment of MS.

Published
2022
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3. Metabolic hormones in human breast milk are preserved by high hydrostatic pressure processing but reduced by Holder pasteurization

Author

Lucie Marousez, Léa Tran, Edwina Micours, Marie De Lamballerie, Frédéric Gottrand, Véronique Pierrat, Delphine Eberlé, Delphine Ley, Jean Lesage, Université de Lille, Inserm, CHU Lille, Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)], Laboratoire de génie des procédés - environnement - agroalimentaire [GEPEA], Lille Inflammation Research International Center (LIRIC) - U995, Hôpital Jeanne de Flandres, Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de génie des procédés - environnement - agroalimentaire (GEPEA), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Nantes université - UFR des Sciences et des Techniques (Nantes univ - UFR ST), Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - Institut Universitaire de Technologie Saint-Nazaire (Nantes Univ - IUT Saint-Nazaire), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), ANR-18-CE21-0005,HHP-humanmilk,Le traitement du lait maternel par haute pression hydrostatique augmente ses qualités biologiques et intestinotrophiques : études expérimentales ex-vivo et chez le nouveau-né prématuré.(2018), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), lesage, jean, and APPEL À PROJETS GÉNÉRIQUE 2018 - Le traitement du lait maternel par haute pression hydrostatique augmente ses qualités biologiques et intestinotrophiques : études expérimentales ex-vivo et chez le nouveau-né prématuré. - - HHP-humanmilk2018 - ANR-18-CE21-0005 - AAPG2018 - VALID

Subjects
hormones, Milk, Human, Human milk, high hydrostatic pressure holder pasteurization human milk hormones, General Medicine, [SDV.IDA] Life Sciences [q-bio]/Food engineering, Analytical Chemistry, High hydrostatic pressure, Milk Banks, [CHIM.OTHE] Chemical Sciences/Other, [SDV.IDA]Life Sciences [q-bio]/Food engineering, Holder pasteurization, Hydrostatic Pressure, Humans, Insulin, Pasteurization, Female, [CHIM.OTHE]Chemical Sciences/Other, Food Science
Abstract

International audience; In human milk banks (HMBs), donor milk (DM) is commonly sterilized by Holder pasteurization (HoP). High hydrostatic pressure (HHP) processing is an innovative, alternative method for DM sterilization. We evaluated the impact of HHP processing on the concentration of seven metabolic milk hormones. Eight samples of raw DM were aliquoted. One aliquot was sterilized by HoP (62 • C for 30 min), and another was processed by HHP (350 MPa at 38 • C). Compared with raw DM, HoP milk displayed reduced concentrations of insulin, nesfatin-1, cortisol, leptin, apelin and GLP-1, though adiponectin levels were unchanged. HHP processing maintained the levels of insulin, nesfatin-1, cortisol and leptin at their initial levels in raw DM, reduced apelin and adiponectin levels, but increased GLP-1 level. Sterilization of DM by HHP thus preserves the main metabolic hormones in human milk, underlining the interest of this method for use in HMBs.

Published
2022
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4. Influence of nocturnal hypoxemia on follow-up course after type B acute aortic syndrome

Author

Delsart, P. (Pascal), Soquet, J. (Jerome), Pierache, A. (Adeline), Dedeken, M. (Maxime), Fry, S. (Stephanie), Mallart, A. (Anne), Pontana, F. (Francois), Azzaoui, R. (Richard), Juthier, F. (Francis), Sobocinski, J. (Jonathan), Mounier Vehier, C. (Claire), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Coeur Poumon [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Médicaments et biomatériaux à libération contrôlée: mécanismes et optimisation - Advanced Drug Delivery Systems - U 1008 (MBLC - ADDS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Inserm, CHU Lille, Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires [RNMCD - U1011], Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017, Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, Advanced Drug Delivery Systems (ADDS) - U1008, and Evaluation des technologies de santé et des pratiques médicales - ULR 2694 [METRICS]

Subjects
Pulmonary and Respiratory Medicine, Adult, Male, RC705-779, Research, [SDV]Life Sciences [q-bio], Nocturnal hypoxemia, Sleep apnea, Aortic dissection, Middle Aged, Prognosis, Respiration, Artificial, Diseases of the respiratory system, Sleep Apnea Syndromes, cardiovascular system, Humans, Female, Stents, France, Prospective Studies, Hypoxia, Aged
Abstract

Introduction Association between sleep nocturnal breathing disorders and acute aortic syndrome (AAS) has been described but mid-term data are scarce. Objectives We assessed the prognostic value of sleep apnea parameters and their relationship with aortic morphology after the onset of a type B AAS. Methods Between January 2010 and January 2018, sleep apnea screening in post type B AAS was prospectively performed. The association of sleep apnea parameters with aortic morphology and aortic expansion during follow-up was studied. Results Over the 8-year-study period, 103 patients were included, with a mean age of 57.8 ± 12.1 years old. Median follow-up was 25.0 months (11.0–51.0). Thirty-two patients (31%) required aortic stenting during the acute phase. In patients treated by aortic stenting, the descending thoracic aortic diameter was positively associated with a higher percentage of nocturnal time of saturation ≤ 90% after adjustment (p = 0.016). During follow-up, the nocturnal time of saturation ≤ 90% in patients treated by medical therapy was the only parameter associated with significant aortic expansion rate (r = 0.26, p = 0.04). Thirty-eight patients started and sustained nocturnal ventilation during follow-up. The association between aortic expansion rate and nocturnal time of saturation ≤ 90% did not persist during follow-up after adjustment on nocturnal ventilation initiation (r = 0.25, p = 0.056). Conclusions Nocturnal hypoxemia parameters are positively associated with the max onset aortic diameter and significant aortic growth after type B AAS. Nocturnal ventilation seems to mitigate aortic expansion during follow-up.

Published
2021
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5. Day-time declamping is associated with better outcomes in kidney transplantation: the circarein study

Author

Sébastien Bouyé, Marie Frimat, Mathilde Jacquelinet, Nasser Alhawajri, Gilles Lebuffe, Christian Jacquelinet, Marc Hazzan, Bart Staels, David Montaigne, Amandine Coppin, Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Agence de la biomédecine [Saint-Denis la Plaine], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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, No funding was required for this study which falls within the missions of the agence de la biomédecine. BS and DM are supported by grants from Agence Nationale pour la Recherche (ANR-16-RHUS-0006-PreciNASH, ANR-10-LABX-0046, ANR TOMIS-Leukocyte: ANR-CE14-0003-01 and ANR CALMOS: ANR-18-CE17-0003-02), the Leducq Foundation LEAN Network 16CVD01 and the National Center for Precision Diabetic Medicine–PreciDIAB (ANR-18-IBHU-0001, 20001891/NP0025517, 2019_ESR_11). BS is a recipient of an Advanced ERC Grant (694717)., ANR-16-RHUS-0006,PreciNASH,PreciNASH(2016), ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), ANR-19-CE14-0003,TOMIS-leukocyte,Impact du moment de la journée sur la réaction inflammatoire péri-opératoire et le remodelage cardiaque inverse après remplacement valvulaire aortique(2019), ANR-18-CE17-0003,CALMOS,Homéostasie calcique mitochondriale dans le contrôle des troubles du rythme associés à la cardiomyopathie métabolique(2018), ANR-18-IBHU-0001,PreciDIAB,PreciDIAB Institute, the holistic approach of personal diabets care(2018), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), CHU Lille, Inserm, Université de Lille, Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires [RNMCD - U1011], Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) - U1167, CIC CHU ( Lille)/inserm, Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA) - ULR 7365, Épidémiologie et recherches translationnelles sur les maladies rénales et cardiovasculaires (EPREC) [U1018 (Équipe 5)], Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Université de Lille, LillOA, PreciNASH - - PreciNASH2016 - ANR-16-RHUS-0006 - RHUS - VALID, EGID Diabetes Pole - - EGID2010 - ANR-10-LABX-0046 - LABX - VALID, Impact du moment de la journée sur la réaction inflammatoire péri-opératoire et le remodelage cardiaque inverse après remplacement valvulaire aortique - - TOMIS-leukocyte2019 - ANR-19-CE14-0003 - AAPG2019 - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Homéostasie calcique mitochondriale dans le contrôle des troubles du rythme associés à la cardiomyopathie métabolique - - CALMOS2018 - ANR-18-CE17-0003 - AAPG2018 - VALID, PreciDIAB Institute, the holistic approach of personal diabets care - - PreciDIAB2018 - ANR-18-IBHU-0001 - IBHU - VALID, and Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID

Subjects
medicine.medical_specialty, [SDV]Life Sciences [q-bio], Ischemia, Ischemic time, kidney transplantation, 030204 cardiovascular system & hematology, 030230 surgery, time-of-the day, Graft function, Article, ischemia-reperfusion, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Kidney transplantation, Kidney, business.industry, transplant survival, Patient survival, Graft Tolerance, General Medicine, medicine.disease, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Cohort, Cardiology, Medicine, business
Abstract

Despite improvements in organ preservation techniques and efforts to minimize the duration of cold ischemia, ischemia–reperfusion (IR) injury remains associated with poor graft function and long-term survival in kidney transplantation. We recently demonstrated a clinically significant day-time variation in myocardial tolerance to IR, transcriptionally orchestrated by the circadian clock. Patient and graft post-transplant survival were studied in a cohort of 10,291 patients first transplanted between 2006 and 2017 to test whether kidney graft tolerance to IR depends on the time-of-the-day of clamping/declamping, and thus impacts graft and patient survival. Post-transplant 1- and 3-year survival decreased with increasing ischemia duration. Time-of-the-day of clamping did not influence outcomes. However, night-time (vs. day-time) declamping was associated with a significantly worse post-transplant survival. After adjustment for other predictors, night-time (vs. day-time) declamping remained associated with a worse 1-year (HR= 1.26 (1.08–1.47), p = 0.0028 by Cox multivariable analysis) and 3-year (HR= 1.14 (1.02–1.27), p = 0.021) outcome. Interestingly, the deleterious impact of prolonged ischemia time (&gt, 15 h) was partially compensated by day-time (vs. night-time) declamping. Compared to night-time declamping, day-time declamping was associated with a better prognosis of kidney transplantation despite a longer duration of cold ischemia.

Published
2021
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6. Severe SARS‐CoV‐2 patients develop a higher specific T‐cell response

Author

Enagnon Kazali Alidjinou, Karine Faure, Isabelle Top, Alain Duhamel, Jacques Trauet, Emmanuelle Jeanpierre, Julien Poissy, Bertrand Meresse, Benoit Gachet, Fanny Vuotto, Pauline Varlet, Guillaume Lefèvre, Sarah Stabler, Jules Bauer, C. Yelnik, François Maggiotto, Vincent Elsermans, Arnaud Dendooven, Julien Labreuche, Sophie Susen, Mohamed Bou Saleh, David Launay, Thierry Brousseau, Sylvain Dubucquoi, Brigitte Prevost, Eloise Woitrain, Laurence Bocket, Marc Lambert, Julie Demaret, David Montaigne, Annabelle Dupont, Myriam Labalette, Laurent Dubuquoy, Institut d'Immunologie [CHRU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Pathogenèse virale du diabète de type 1 - ULR 3610 (Laboratoire de Virologie), Centre de référence des maladies auto-immunes systémiques rares du Nord et Nord Ouest [CHRU Lille], Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), I-SITE ULNE. Grant Number: ANR-16-IDEX-0004 ULNE, ANR-16-IDEX-0004,ULNE,ULNE(2016), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Lille, LillOA, ULNE - - ULNE2016 - ANR-16-IDEX-0004 - IDEX - VALID, Université de Lille, CNRS, Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)], Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL], Pathogenèse virale du diabète de type 1 - ULR 3610, Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) - U1167, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE], Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576, Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017, and Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD)

Subjects
0301 basic medicine, lcsh:Immunologic diseases. Allergy, Immunology, ELISpot, T cells, SARS‐CoV‐2, 03 medical and health sciences, 0302 clinical medicine, Antigen, Immunity, Interquartile range, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immunology and Allergy, Medicine, 030212 general & internal medicine, General Nursing, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, biology, business.industry, SARS-CoV-2, ELISPOT, Outbreak, Original Articles, Acquired immune system, 3. Good health, Vaccination, 030104 developmental biology, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, biology.protein, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Original Article, Antibody, business, lcsh:RC581-607
Abstract

Objectives Assessment of the adaptive immune response against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is crucial for studying long‐term immunity and vaccine strategies. We quantified IFNγ‐secreting T cells reactive against the main viral SARS‐CoV‐2 antigens using a standardised enzyme‐linked immunospot assay (ELISpot). Methods Overlapping peptide pools built from the sequences of M, N and S viral proteins and a mix (MNS) were used as antigens. Using IFNγ T‐CoV‐Spot assay, we assessed T‐cell and antibody responses in mild, moderate and severe SARS‐CoV‐2 patients and in control samples collected before the outbreak. Results Specific T cells were assessed in 60 consecutive patients (mild, n = 26; moderate, n = 10; and severe patients, n = 24) during their follow‐up (median time from symptom onset [interquartile range]: 36 days [28;53]). T cells against M, N and S peptide pools were detected in n = 60 (100%), n = 56 (93.3%), n = 55 patients (91.7%), respectively. Using the MNS mix, IFNγ T‐CoV‐Spot assay showed a specificity of 96.7% (95% CI, 88.5–99.6%) and a specificity of 90.3% (75.2–98.0%). The frequency of reactive T cells observed with M, S and MNS mix pools correlated with severity and with levels of anti‐S1 and anti‐RBD serum antibodies. Conclusion IFNγ T‐CoV‐Spot assay is a reliable method to explore specific T cells in large cohorts of patients. This test may become a useful tool to assess the long‐lived memory T‐cell response after vaccination. Our study demonstrates that SARS‐CoV‐2 patients developing a severe disease achieve a higher adaptive immune response., We quantified IFNg‐secreting T cells reactive against the M, N and S viral SARS‐CoV‐2 proteins using a standardized enzyme‐linked immunospot assay in 60 patients. The frequency of reactive T cells correlated with severity, and with levels of anti‐S1 and anti‐RBD (receptor binding domain) serum antibodies, demonstrating a higher adaptive immune response after developing a more severe disease. IFNg T‐CoV‐Spot assay may also become a useful tool to assess the long‐lived memory T cell response after vaccination.

Published
2020
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7. Prognostic value of aerobic capacity and exercise oxygen pulse in postaortic dissection patients

Author

Olivia Domanski, Mohamed Koussa, Antoine Bical, Natacha Rousse, Valentin Loobuyck, Jonathan Sobocinski, David Montaigne, Bruno Jegou, Olivier Fabre, Agnes Mugnier, Francis Juthier, André Vincentelli, Claire Mounier-Vehier, Jerome Soquet, Richard Azzaoui, Patrick Devos, Ilir Hysi, Camille Delahaye, Pascal Delsart, Régis Matran, François Pontana, Thomas Modine, Institut Coeur Poumon [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Médicaments et biomatériaux à libération contrôlée: mécanismes et optimisation - Advanced Drug Delivery Systems - U 1008 (MBLC - ADDS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre Hospitalier de Lens, Impact de l'environnement chimique sur la santé humaine - ULR 4483 (IMPECS), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), Université de Lille, LillOA, CHU Lille, Inserm, Université de Lille, METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694, Advanced Drug Delivery Systems (ADDS) - U1008, Evaluation des technologies de santé et des pratiques médicales - ULR 2694 [METRICS], Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, Médicaments et biomatériaux à libération contrôlée: mécanismes et optimisation - Advanced Drug Delivery Systems - U 1008 [MBLC - ADDS], Lille Neurosciences & Cognition (LilNCog) - U 1172, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], IMPact de l'Environnement Chimique sur la Santé humaine (IMPECS) - ULR 4483, Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires [RNMCD - U1011], and Impact de l'environnement chimique sur la santé humaine - ULR 4483 [IMPECS]

Subjects
medicine.medical_specialty, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Population, Oxygen pulse, Clinical Investigations, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Oxygen Consumption, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine.artery, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], cardiopulmonary exercise testing, Humans, 030212 general & internal medicine, Prospective Studies, aortic dissection, prognosis, Adverse effect, Prospective cohort study, education, Aortic dissection, education.field_of_study, Aorta, Exercise Tolerance, business.industry, Dissection, VO2 max, General Medicine, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Oxygen, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cohort, Cardiology, cardiovascular system, Exercise Test, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cardiology and Cardiovascular Medicine, business
Abstract

International audience; BACKGROUND: Although recommendations encourage daily moderate activities in post aortic dissection, very little data exists regarding cardiopulmonary exercise testing (CPET) to personalize those patient's physical rehabilitation and assess their cardiovascular prognosis.METHODS: We aimed at testing the prognostic insight of CPET regarding aortic and cardiovascular events by exploring a prospective cohort of patients followed-up after acute aortic dissection.METHODS: Patients referred to our department after an acute (type A or B) aortic dissection were prospectively included in a cohort between September 2012 and October 2017. CPET was performed once optimal blood pressure control was obtained. Clinical follow-up was done after CPET for new aortic event and major cardio-vascular events (MCE) not directly related to the aorta.RESULTS: Among the 165 patients who underwent CPET, no adverse event was observed during exercise testing. Peak oxygen pulse was 1.46(1.22-1.84) mlO2/beat, that is, 97 (83-113) % of its predicted value, suggesting cardiac exercise limitation in a population under beta blockers (92% of the population). During a follow-up of 39(20-51) months from CPET, 42 aortic event recurrences and 22 MCE not related to aorta occurred. Low peak oxygen pulse (

Published
2020
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8. Clinical characteristics and outcome of patients with infective endocarditis diagnosed in a department of internal medicine

Author

Vincent Sobanski, Sandrine Morell-Dubois, Hélène Maillard, Marc Lambert, Louis Kreitmann, David Launay, Eric Hachulla, D. Montaigne, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Lille Inflammation Research International Center - U 995 (LIRIC), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), CHU Lille, Inserm, Université de Lille, Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) - U1167, Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, and Lille Inflammation Research International Center (LIRIC) - U995

Subjects
medicine.medical_specialty, Adult patients, echocardiography, diagnosis, infective endocarditis, internal medicine, business.industry, [SDV]Life Sciences [q-bio], lcsh:R, lcsh:Medicine, General Medicine, 030204 cardiovascular system & hematology, medicine.disease, University hospital, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Infective endocarditis, medicine, 030212 general & internal medicine, Transthoracic echocardiogram, Sign or Symptom, business
Abstract

Clinical manifestations of infective endocarditis (IE) can be highly non-specific. Our objective was to describe the clinical characteristics of patients initially referred to a department of internal medicine for a diagnostic work-up, and eventually diagnosed with IE. We retrospectively retrieved adult patients admitted to the department of internal medicine at Lille University Hospital between 2004 and 2015 who fulfilled Duke Classification criteria for definite IE. Thirty-five patients were included. The most frequently involved bacteria were non-hemolytic streptococci. Most patients presented with various systemic, cardiac, embolic, rheumatic, and immunological findings, with no sign or symptom displaying high sensitivity. The first transthoracic echocardiogram was negative in 42% of patients. Furthermore, definite diagnosis required performing at least 2 transesophageal examinations in 24% of patients. We observed a trend towards decreased survival in the subgroup of patients in whom the delay between onset of symptoms and diagnosis was &gt, 30 days. In conclusion, patients who are initially referred to internal medicine for a diagnosis work-up and who are ultimately diagnosed with IE have non-specific symptoms and a high percentage of initial normal echocardiography. Those patients require prolonged echocardiographic monitoring as a prolonged delay in diagnosis is associated with poorer outcomes such as death.

Published
2020
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9. Erratum. Ten-Year Outcome of Islet Alone or Islet After Kidney Transplantation in Type 1 Diabetes: A Prospective Parallel-Arm Cohort Study. Diabetes Care 2019;42:2042-2049

Author

Eric Van Belle, François Machuron, Marc Hazzan, Marie-Christine Vantyghem, Christian Noel, Thomas Hubert, Robert Caiazzo, Stéphanie Espiard, Julie Kerr-Conte, Arnaud Jannin, Violeta Raverdy, Pascal Pigny, François Pattou, Nathalie Delalleau, Valery Gmyr, Kristell Le Mapihan, Marie Frimat, Mikael Chetboun, Université de Lille, LillOA, Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 (MSAP), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - USR 3290 (MSAP), Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Inserm, CHU Lille, Recherche translationnelle sur le diabète (RTD) - U1190, Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE], Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP], Lille Inflammation Research International Center - U 995 [LIRIC], and Recherche translationnelle sur le diabète - U 1190 [RTD]

Subjects
Advanced and Specialized Nursing, Type 1 diabetes, medicine.medical_specialty, geography, geography.geographical_feature_category, business.industry, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], MEDLINE, 030209 endocrinology & metabolism, medicine.disease, Islet, 3. Good health, Islet after kidney, Transplantation, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, 030212 general & internal medicine, business, Cohort study
Abstract

The names of the working groups that collaborated in the study reported in this article were inadvertently omitted from the byline. The corrected byline should … 2019;42

Published
2020
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10. Targeting Oxidative Stress and Mitochondrial Dysfunction in the Treatment of Impaired Wound Healing: A Systematic Review

Author

Mariola, Cano Sanchez, Steve, Lancel, Eric, Boulanger, Remi, Neviere, Inserm, Université de Lille, CHU Lille, Institut Pasteur de Lille, Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, Lille Inflammation Research International Center (LIRIC) - U995, Vulnérabilité cardiovasculaire, pathologie métabolique et endocrinienne [VCPME], Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], and Lille Inflammation Research International Center - U 995 [LIRIC]

Subjects
reactive oxygen species, mitochondria, antioxidants, lcsh:Therapeutics. Pharmacology, diabetes, inflammation, advanced glycation end products, lcsh:RM1-950, wound healing, Review
Abstract

Wound healing is a well-tuned biological process, which is achieved via consecutive and overlapping phases including hemostasis, inflammatory-related events, cell proliferation and tissue remodeling. Several factors can impair wound healing such as oxygenation defects, aging, and stress as well as deleterious health conditions such as infection, diabetes, alcohol overuse, smoking and impaired nutritional status. Growing evidence suggests that reactive oxygen species (ROS) are crucial regulators of several phases of healing processes. ROS are centrally involved in all wound healing processes as low concentrations of ROS generation are required for the fight against invading microorganisms and cell survival signaling. Excessive production of ROS or impaired ROS detoxification causes oxidative damage, which is the main cause of non-healing chronic wounds. In this context, experimental and clinical studies have revealed that antioxidant and anti-inflammatory strategies have proven beneficial in the non-healing state. Among available antioxidant strategies, treatments using mitochondrial-targeted antioxidants are of particular interest. Specifically, mitochondrial-targeted peptides such as elamipretide have the potential to mitigate mitochondrial dysfunction and aberrant inflammatory response through activation of nucleotide-binding oligomerization domain (NOD)-like family receptors, such as the pyrin domain containing 3 (NLRP3) inflammasome, nuclear factor-kappa B (NF-κB) signaling pathway inhibition, and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). 7;8

Published
2018

11. The logic of transcriptional regulator recruitment architecture at cis-regulatory modules controlling liver functions

Author

Jason S. Carroll, Nathalie Hennuyer, Bruno Derudas, Eric Baugé, Parisa Mazrooei, Aurélien A. Sérandour, Julie Dubois-Chevalier, Jérôme Eeckhoute, Bart Staels, Guillemette Marot, Philippe Lefebvre, Mathieu Lupien, Céline Gheeraert, Vanessa Dubois, Penderia Guillaume, Hélène Dehondt, Réjane Paumelle, Claire Mazuy, Université de Lille, Droit et Santé, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Medical Biophysics (MBP), University of Toronto, University of Cambridge [UK] (CAM), MOdel for Data Analysis and Learning (MODAL), Laboratoire Paul Painlevé (LPP), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies-Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-École polytechnique universitaire de Lille (Polytech Lille), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Carroll, Jason [0000-0003-3643-0080], Apollo - University of Cambridge Repository, Marot, Guillemette, Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID, CHU Lille, INSERM, Inserm, Université de Lille, Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694, Department of Medical Biophysics [MBP], University of Cambridge [UK] [CAM], Evaluation des technologies de santé et des pratiques médicales - ULR 2694 [METRICS], Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Paul Painlevé - UMR 8524 (LPP), and Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-École polytechnique universitaire de Lille (Polytech Lille)

Subjects
0301 basic medicine, Transcription, Genetic, Cytoplasmic and Nuclear/deficiency, [SDV]Life Sciences [q-bio], Receptors, Cytoplasmic and Nuclear, Mice, 0302 clinical medicine, [STAT.ML]Statistics [stat]/Machine Learning [stat.ML], Receptors, Transcriptional regulation, Regulatory Elements, Transcriptional, Genetics (clinical), Epigenomics, Cis-regulatory module, Regulation of gene expression, Mice, Knockout, PPAR alpha/deficiency, [STAT.ME] Statistics [stat]/Methodology [stat.ME], [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Genome, Genomics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV] Life Sciences [q-bio], Liver, Transcriptional, Transcription, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Algorithms, Liver/metabolism, Knockout, Computational biology, PPAR alpha/genetics, Biology, 03 medical and health sciences, Genetic, Genetics, Animals, PPAR alpha, Enhancer, Gene, Gene Expression Profiling, fungi, Regulatory Elements, [STAT.ML] Statistics [stat]/Machine Learning [stat.ML], Genomics/methods, Gene expression profiling, 030104 developmental biology, Gene Expression Regulation, Cytoplasmic and Nuclear/genetics, 030217 neurology & neurosurgery
Abstract

Control of gene transcription relies on concomitant regulation by multiple transcriptional regulators (TRs). However, how recruitment of a myriad of TRs is orchestrated at cis-regulatory modules (CRMs) to account for coregulation of specific biological pathways is only partially understood. Here, we have used mouse liver CRMs involved in regulatory activities of the hepatic TR, NR1H4 (FXR; farnesoid X receptor), as our model system to tackle this question. Using integrative cistromic, epigenomic, transcriptomic, and interactomic analyses, we reveal a logical organization where trans-regulatory modules (TRMs), which consist of subsets of preferentially and coordinately corecruited TRs, assemble into hierarchical combinations at hepatic CRMs. Different combinations of TRMs add to a core TRM, broadly found across the whole landscape of CRMs, to discriminate promoters from enhancers. These combinations also specify distinct sets of CRM differentially organized along the genome and involved in regulation of either housekeeping/cellular maintenance genes or liver-specific functions. In addition to these TRMs which we define as obligatory, we show that facultative TRMs, such as one comprising core circadian TRs, are further recruited to selective subsets of CRMs to modulate their activities. TRMs transcend TR classification into ubiquitous versus liver-identity factors, as well as TR grouping into functional families. Hence, hierarchical superimpositions of obligatory and facultative TRMs bring about independent transcriptional regulatory inputs defining different sets of CRMs with logical connection to regulation of specific gene sets and biological pathways. Altogether, our study reveals novel principles of concerted transcriptional regulation by multiple TRs at CRMs.

Published
2017
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12. The Effect of Lactobacillus fermentum ME‐3 Treatment on Glycation and Diabetes Complications

Author

Eric Boulanger, Axel Guilbaud, Brigitte Onraed, Céline Niquet-Léridon, Patrice Maboudou, Mike Howsam, Susanna Schraen, Sophie Lestavel, Frédéric J. Tessier, Anne Garat, Marc Fremont, Florian Delguste, Benoît Foligné, CHU Lille, Inserm, Institut Pasteur de Lille, Université de Lille, Lille Inflammation Research International Center (LIRIC) - U995, Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) - U1167, Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, Lille Inflammation Research International Center - U 995 [LIRIC], IMPact de l'Environnement Chimique sur la Santé humaine (IMPECS) - ULR 4483, UniLaSalle, Lille Neurosciences & Cognition (LilNCog) - U 1172, Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE], Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Impact de l'environnement chimique sur la santé humaine - ULR 4483 [IMPECS], Service de pathologie [CHU Lille], Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Lille Inflammation Research International Center - U 995 (LIRIC), Transformations et Agro-ressources (UT&A), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Impact de l'environnement chimique sur la santé humaine - ULR 4483 (IMPECS), and Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
Glycation End Products, Advanced, Male, 0301 basic medicine, Limosilactobacillus fermentum, Lactobacillus fermentum, [SDV]Life Sciences [q-bio], Type 2 diabetes, carboxymethyllysine, Pharmacology, Gut flora, Kidney, Weight Gain, Diabetes Mellitus, Experimental, law.invention, Diabetes Complications, 03 medical and health sciences, Probiotic, law, Glycation, Diabetes mellitus, medicine, Animals, furosine, Glycated Hemoglobin, 030109 nutrition & dietetics, diabetes, biology, business.industry, Lysine, Probiotics, Diabetic mouse, biology.organism_classification, medicine.disease, Lipids, Gastrointestinal Microbiome, 030104 developmental biology, glycation, probiotics, Liver, Receptors, Leptin, Steatosis, business, Food Science, Biotechnology
Abstract

International audience; ScopeType 2 diabetes (T2D) induces organ damage associated with glycation, among other metabolic pathways. While therapeutic strategies have been tested to reduce the formation and impact of glycation products, results remain equivocal. Anti-diabetic therapies using probiotics have been proposed, but their effect upon glycation has not been reported. Here, the effects of the bacterial strain Lactobacillus fermentum ME-3 on glycation and T2D-related complications in a mouse model of T2D are investigated.Methods & ResultsWild-type LepRdb and diabetic LepRdb littermates receive a daily gavage of either water or the probiotic ME-3 strain (1010 CFU). Glycation markers, fructoselysine-derived furosine (FL-furosine) and carboxymethyllysine (CML), are quantified in four major organs and plasma using stable-isotope dilution LC–MS/MS. After 12 weeks of ME-3 treatment, diabetic mice gain less weight and exhibit an apparently improved glucose tolerance. The ME-3 treatment reduces median renal levels of FL-furosine in both genotypes by 12–15%, and renal and pulmonary free-CML in diabetic mice by 30% and 18%, respectively. Attenuated hepatic steatosis and an improved plasma lipid profile are also observed with treatment in both genotypes, while the gut microbiota profile is unchanged.ConclusionL. fermentum ME-3 has therapeutic potential for reducing the formation/accumulation of some glycation products in kidneys and attenuating some common diabetes-related complications.

Published
2020
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13. Central venous-to-arterial carbon dioxide difference as a prognostic tool in high-risk surgical patients

Author

Gilles Lebuffe, Benoît Tavernier, Emmanuel Robin, Oscar Pires, Maher Fleyfel, Emmanuel Futier, Benoit Vallet, Université de Lille, LillOA, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Clermont-Ferrand, CHU Lille, Inserm, Institut Pasteur de Lille, Université de Lille, Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Evaluation des technologies de santé et des pratiques médicales - ULR 2694 [METRICS], Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA], Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA) - EA 7365, and CHU Estaing [Clermont-Ferrand]

Subjects
Male, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, medicine.medical_treatment, MESH: Thoracic Surgical Procedures/adverse effects, Hemodynamics, Critical Care and Intensive Care Medicine, Postoperative Complications, Risk Factors, MESH: Risk Factors, Lactate Level, Prospective Studies, Simplified Acute Physiology Score, 10. No inequality, Prospective cohort study, MESH: Catheterization, Central Venous/methods, MESH: Aged, MESH: Middle Aged, MESH: Carbon Dioxide/blood, Middle Aged, Prognosis, Simplify Acute Physiology Score, MESH: Postoperative Complications/etiology, MESH: Postoperative Complications/blood, Female, Perfusion, medicine.medical_specialty, Catheterization, Central Venous, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, MESH: Prognosis, medicine, Humans, Sequential Organ Failure Assessment Score, Clinical significance, Aged, Mechanical ventilation, MESH: Humans, Receiver operating characteristic, business.industry, Research, Postoperative complication, Carbon Dioxide, Thoracic Surgical Procedures, MESH: Prospective Studies, MESH: Male, Surgery, MESH: Blood Gas Analysis/methods, MESH: Postoperative Complications/diagnosis, Postoperative Complication, Blood Gas Analysis, business, Central Venous Oxygen Saturation, MESH: Female
Abstract

IntroductionThe purpose of this study was to evaluate the clinical relevance of high values of central venous-to-arterial carbon dioxide difference (PCO2gap) in high-risk surgical patients admitted to a postoperative ICU. We hypothesized that PCO2gap could serve as a useful tool to identify patients still requiring hemodynamic optimization at ICU admission.MethodsOne hundred and fifteen patients were included in this prospective single-center observational study during a 1-year period. High-risk surgical inclusion criteria were adapted from Schoemaker and colleagues. Demographic and biological data, PCO2gap, central venous oxygen saturation, lactate level and postoperative complications were recorded for all patients at ICU admission, and 6 hours and 12 hours after admission.ResultsA total of 78 (68%) patients developed postoperative complications, of whom 54 (47%) developed organ failure. From admission to 12 hours after admission, there was a significant difference in mean PCO2gap (8.7 ± 2.8 mmHg versus 5.1 ± 2.6 mmHg;P = 0.001) and median lactate values (1.54 (1.1-3.2) mmol/l versus 1.06 (0.8-1.8) mmol/l;P = 0.003) between patients who developed postoperative complications and those who did not. These differences were maximal at admission to the ICU. At ICU admission, the area under the receiver operating characteristic curve for occurrence of postoperative complications was 0.86 for the PCO2gap compared to Sequential Organ Failure Assessment score (0.82), Simplified Acute Physiology Score II score (0.67), and lactate level (0.67). The threshold value for PCO2gap was 5.8 mmHg. Multivariate analysis showed that only a high PCO2gap and a high Sequential Organ Failure Assessment score were independently associated with the occurrence of postoperative complications. A high PCO2gap (≥6 mmHg) was associated with more organ failure, an increase in duration of mechanical ventilation and length of hospital stay.ConclusionA high PCO2gap at admission in the postoperative ICU was significantly associated with increased postoperative complications in high-risk surgical patients. If the increase in PCO2gap is secondary to tissue hypoperfusion then the PCO2gap might be a useful tool complementary to central venous oxygen saturation as a therapeutic target.

Published
2015
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