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1. Long- Versus Short-Acting Erythropoiesis-Stimulating Agent Type and Mortality

Author

Bruce M. Robinson, Sophie Liabeuf, Francesco Locatelli, Kosaku Nitta, Aleix Cases, Angelo Karaboyas, Ziad A. Massy, Kitty J Jager, Friedrich K. Port, Medical Informatics, ACS - Pulmonary hypertension & thrombosis, APH - Aging & Later Life, APH - Quality of Care, APH - Global Health, DESSAIVRE, Louise, Arbor Research Collaborative for Health, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service Néphrologie/Dialyse [AP-HP Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], 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, Alessandro Manzoni Hospital, Universitat de Barcelona (UB), Tokyo Women's Medical University (TWMU), CHU Amiens-Picardie, Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, University of Amsterdam [Amsterdam] (UvA), University of Michigan [Ann Arbor], and University of Michigan System

Subjects
[SDV] Life Sciences [q-bio], Nephrology, business.industry, medicine.drug_class, [SDV]Life Sciences [q-bio], MEDLINE, Research Letter, Medicine, Pharmacology, business, Erythropoiesis-stimulating agent, ComputingMilieux_MISCELLANEOUS
Abstract

International audience; No abstract available

Published
2021
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2. Dual Programmed Death Receptor‐1 and Vascular Endothelial Growth Factor Receptor‐2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma

Author

Rakesh R. Ramjiawan, Shuichi Aoki, Hiroto Kikuchi, Rakesh K. Jain, Aya Matsui, Kohei Shigeta, Emilie Mamessier, Nabeel Bardeesy, Ivy X. Chen, Tai Hato, Shuji Kitahara, Dan G. Duda, Mark Cobbold, Peigen Huang, Hiroki Ochiai, Meenal Datta, Andrew X. Zhu, Massachusetts General Hospital [Boston], Keio University School of Medicine [Tokyo, Japan], Saitama Medical Center [Saitama, Japan], Tokyo Women's Medical University (TWMU), Centre de Recherche en Cancérologie de Marseille (CRCM), 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), Tohoku University Graduate School of Medicine, VU University Medical Center [Amsterdam], National Cancer Institute Central Hospital [Tokyo, Japan], Medical oncology laboratory, mamessier, emilie, Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and 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)

Subjects
0301 basic medicine, Chemokine, Carcinoma, Hepatocellular, Programmed Cell Death 1 Receptor, [SDV.CAN]Life Sciences [q-bio]/Cancer, Angiogenesis Inhibitors, Antibodies, Mice, 03 medical and health sciences, Paracrine signalling, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Spheroids, Cellular, Antineoplastic Combined Chemotherapy Protocols, Tumor-Associated Macrophages, medicine, Animals, Cytotoxic T cell, ComputingMilieux_MISCELLANEOUS, Neovascularization, Pathologic, Hepatology, biology, business.industry, Monocyte, Liver Neoplasms, Kinase insert domain receptor, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Neoplasms, Experimental, Vascular Endothelial Growth Factor Receptor-2, 3. Good health, Blockade, Editorial, 030104 developmental biology, medicine.anatomical_structure, biology.protein, Cancer research, 030211 gastroenterology & hepatology, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business, CD8, T-Lymphocytes, Cytotoxic
Abstract

Background and aims Activation of the antitumor immune response using programmed death receptor-1 (PD-1) blockade showed benefit only in a fraction of patients with hepatocellular carcinoma (HCC). Combining PD-1 blockade with antiangiogenesis has shown promise in substantially increasing the fraction of patients with HCC who respond to treatment, but the mechanism of this interaction is unknown. Approach and results We recapitulated these clinical outcomes using orthotopic-grafted or induced-murine models of HCC. Specific blockade of vascular endothelial receptor 2 (VEGFR-2) using a murine antibody significantly delayed primary tumor growth but failed to prolong survival, while anti-PD-1 antibody treatment alone conferred a minor survival advantage in one model. However, dual anti-PD-1/VEGFR-2 therapy significantly inhibited primary tumor growth and doubled survival in both models. Combination therapy reprogrammed the immune microenvironment by increasing cluster of differentiation 8-positive (CD8+ ) cytotoxic T cell infiltration and activation, shifting the M1/M2 ratio of tumor-associated macrophages and reducing T regulatory cell (Treg) and chemokine (C-C motif) receptor 2-positive monocyte infiltration in HCC tissue. In these models, VEGFR-2 was selectively expressed in tumor endothelial cells. Using spheroid cultures of HCC tissue, we found that PD-ligand 1 expression in HCC cells was induced in a paracrine manner upon anti-VEGFR-2 blockade in endothelial cells in part through interferon-gamma expression. Moreover, we found that VEGFR-2 blockade increased PD-1 expression in tumor-infiltrating CD4+ cells. We also found that under anti-PD-1 therapy, CD4+ cells promote normalized vessel formation in the face of antiangiogenic therapy with anti-VEGFR-2 antibody. Conclusions We show that dual anti-PD-1/VEGFR-2 therapy has a durable vessel fortification effect in HCC and can overcome treatment resistance to either treatment alone and increase overall survival in both anti-PD-1 therapy-resistant and anti-PD-1 therapy-responsive HCC models.

Published
2019
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3. Residues of neonicotinoids in soil, water and people's hair: A case study from three agricultural regions of the Philippines

Author

Edward A. D. Mitchell, Maarten Bijleveld van Lexmond, Francisco Sánchez-Bayo, Jean-Marc Bonmatin, Kumiko Taira, Florencia G. Claveria, Gaétan Glauser, Elizabeth Lumawig-Heitzman, Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université de Neuchâtel (UNINE), De La Salle University [Manila] (DLSU), Task force on systemic pesticides, Tokyo Women's Medical University (TWMU), and The University of Sydney

Subjects
Insecticides, Environmental Engineering, 010504 meteorology & atmospheric sciences, Philippines, Systemic insecticides, 010501 environmental sciences, Biology, 01 natural sciences, Acetamiprid, Toxicology, chemistry.chemical_compound, Neonicotinoids, Soil, Imidacloprid, Environmental Chemistry, Humans, Waste Management and Disposal, 0105 earth and related environmental sciences, Human pesticide contamination, 2. Zero hunger, [SDV.EE]Life Sciences [q-bio]/Ecology, environment, Tropical agriculture, Neonicotinoid, Clothianidin, Water, Environmental monitoring, Pesticide, Thiacloprid, Nitro Compounds, Pollution, 6. Clean water, 3. Good health, chemistry, UHPLC-MS-MS, Soil water, Thiamethoxam
Abstract

International audience; Synthetic pesticides such as neonicotinoids are commonly used to treat crops in tropical regions, where data on environmental and human contamination are patchy and make it difficult to assess to what extent pesticides may harm human health, especially in less developed countries.To assess the degree of environmental and human contamination with neonicotinoids we collected soil, water and people's hair in three agricultural regions of the Philippines and analysed them by ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS-MS). Five neonicotinoids, namely acetamiprid, clothianidin, imidacloprid, thiacloprid and thiamethoxam were targeted.Residues of neonicotinoids were found in 78% of 67 soil samples from the three provinces. Total neonicotinoid loads ranged on average between 0.017 and 0.89 μg/kg in soils of rice, banana and vegetable crops, and were 130 times higher (113.5 μg/kg) in soils of a citrus grove. Imidacloprid was the most prevalent compound at an average of 0.56 μg/kg in soil while thiacloprid was below the limit of detection. Half of the eight water samples from a rice field and nearby creek contained residues of imidacloprid (mean 1.29 ng/L) and one contained thiamethoxam (0.15 ng/L). Residues of neonicotinoids were found in 81% of 99 samples of people's hair from the surveyed regions (average total concentrations 0.14 to 1.18 ng/g, maximum 350 ng/g). Hair residue levels correlated well with the concentrations of thiamethoxam and total residues in soils from the same locality (r = 0.98). The presence of thiacloprid in 15% of the hair samples but not in soil samples suggests an additional route of exposure among people, which is most likely to be through ingestion of agricultural food and drinks available in the market.

Published
2021
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4. Sleep and daytime problems during the COVID-19 pandemic and effects of coronavirus infection, confinement and financial suffering: A multinational survey using a harmonised questionnaire

Author

Markku Partinen, Brigitte Holzinger, Charles M Morin, Colin Espie, Frances Chung, Thomas Penzel, Christian Benedict, Courtney J Bolstad, Jonathan Cedernaes, Rachel Ngan Yin Chan, Yves Dauvilliers, Luigi De Gennaro, Fang Han, Yuichi Inoue, Kentaro Matsui, Damien Leger, Ana Suely Cunha, Ilona Merikanto, Sergio Mota-Rolim, Michael Nadorff, Giuseppe Plazzi, Jules Schneider, Mariusz Sieminski, Yun-Kwok Wing, Bjørn Bjorvatn, Department of Neurosciences, Clinicum, HUS Neurocenter, SLEEPWELL Research Program, Research Programs Unit, Herrada, Anthony, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Helsinki Sleep Clinic [Helsinki], Medizinische Universität Wien = Medical University of Vienna, Centre de recherche de l’Institut universitaire en santé mentale de Québec [Canada] (CERVO), Département de réadaptation (Faculté de médecine de l'Université Laval) [Canada], Faculté de médecine de l'Université Laval [Québec] (ULaval), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-Faculté de médecine de l'Université Laval [Québec] (ULaval), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), University of Oxford, University Health Network, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Uppsala University, Mississippi State University [Mississippi], Northwestern University Feinberg School of Medicine, The Chinese University of Hong Kong [Hong Kong], Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Fondazione Santa Lucia [IRCCS], Clinical and Behavioral Neurology [IRCCS Santa Lucia], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Peking University [Beijing], Tokyo Medical University, Tokyo Women's Medical University (TWMU), Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sommeil-Vigilance-Fatigue et Santé Publique (VIFASOM (URP_7330)), Institut de Recherche Biomédicale des Armées (IRBA)-Université Paris Cité (UPCité), Universidade Federal do Rio Grande do Norte [Natal] (UFRN), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Medical University of Gdańsk, Haukeland University Hospital, and University of Bergen (UiB)

Subjects
[SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Epidemiology, insomnia, COVID-19, pandemic, sleep, stress, depression, epidemiology, social medicine, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Surveys and Questionnaires, MESH: COVID-19, 030212 general & internal medicine, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, MESH: Sleep Quality, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, sleep medicine, Public Health, Global Health, Social Medicine and Epidemiology, General Medicine, 3. Good health, Sleep Quality, Neurology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, Adult, MESH: Pandemics, Social medicine, 03 medical and health sciences, anxiety disorders, Anxiety disorders, Sleep medicine, Humans, SARS-CoV-2, Pandemics, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], MESH: SARS-CoV-2, MESH: Surveys and Questionnaires, MESH: Humans, neurology, 3112 Neurosciences, MESH: Adult, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 3121 General medicine, internal medicine and other clinical medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, LOCKDOWN, MESH: Female, 030217 neurology & neurosurgery
Abstract

ObjectivesSleep is important for human health and well-being. No previous study has assessed whether the COVID-19 pandemic impacts sleep and daytime function across the globe.MethodsThis large-scale international survey used a harmonised questionnaire. Fourteen countries participated during the period of May–August 2020. Sleep and daytime problems (poor sleep quality, sleep onset and maintenance problems, nightmares, hypnotic use, fatigue and excessive sleepiness) occurring ‘before’ and ‘during’ the pandemic were investigated. In total, 25 484 people participated and 22 151 (86.9%) responded to the key parameters and were included. Effects of COVID-19, confinement and financial suffering were considered. In the fully adjusted logistic regression models, results (weighted and stratified by country) were adjusted for gender, age, marital status, educational level, ethnicity, presence of sleep problems before COVID-19 and severity of the COVID-19 pandemic in each country at the time of the survey.ResultsThe responders were mostly women (64%) with a mean age 41.8 (SD 15.9) years (median 39, range 18–95). Altogether, 3.0% reported having had COVID-19; 42.2% reported having been in confinement; and 55.9% had suffered financially. All sleep and daytime problems worsened during the pandemic by about 10% or more. Also, some participants reported improvements in sleep and daytime function. For example, sleep quality worsened in about 20% of subjects and improved in about 5%. COVID-19 was particularly associated with poor sleep quality, early morning awakening and daytime sleepiness. Confinement was associated with poor sleep quality, problems falling asleep and decreased use of hypnotics. Financial suffering was associated with all sleep and daytime problems, including nightmares and fatigue, even in the fully adjusted logistic regression models.ConclusionsSleep problems, fatigue and excessive sleepiness increased significantly worldwide during the first phase of the COVID-19 pandemic. Problems were associated with confinement and especially with financial suffering.

Published
2021
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5. Social jetlag changes during the COVID-19 pandemic as a predictor of insomnia - A multi-national survey study

Author

Brandão, Luiz Eduardo Mateus, Martikainen, Teemu, Merikanto, Ilona, Holzinger, Brigitte, Morin, Charles M, Espie, Colin A, Bolstad, Courtney J, Leger, Damien, Chung, Frances, Plazzi, Giuseppe, Dauvilliers, Yves, Matsui, Kentaro, De Gennaro, Luigi, Sieminski, Mariusz, Nadorff, Michael R, Chan, Ngan Yin, Wing, Yun Kwok, Mota-Rolim, Sérgio Arthuro, Inoue, Yuichi, Partinen, Markku, Benedict, Christian, Bjorvatn, Bjorn, Cedernaes, Jonathan, Salvy-Córdoba, Nathalie, Uppsala University Hospital, Finnish Institute for Health and Welfare [Helsinki, Finland] (FIHW), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Orton Orthopaedic Hospital (Orton Ltd), Medizinische Universität Wien = Medical University of Vienna, Université Laval [Québec] (ULaval), Centre de recherche de l’Institut universitaire en santé mentale de Québec [Canada] (CERVO), Département de réadaptation (Faculté de médecine de l'Université Laval) [Canada], Faculté de médecine de l'Université Laval [Québec] (ULaval), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-Faculté de médecine de l'Université Laval [Québec] (ULaval), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Nuffield Department of Primary Care Health Sciences, University of Oxford, University of Oxford, Mississippi State University [Mississippi], Sommeil-Vigilance-Fatigue et Santé Publique (VIFASOM (URP_7330)), Institut de Recherche Biomédicale des Armées (IRBA)-Université Paris Cité (UPCité), Toronto Western Hospital, Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), National Center of Neurology and Psychiatry National Institute of Mental Health, Department of Clinical Laboratory and Department of Sleep-Wake Disorders (NCNP), Tokyo Women's Medical University (TWMU), Department of Psychology [University of Roma 'La Sapienza'], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Fondazione Santa Lucia [IRCCS], Clinical and Behavioral Neurology [IRCCS Santa Lucia], Istituto delle Scienze Neurologiche di Bologna, Partenaires INRAE, Medical University of Gdańsk, Baylor College of Medicine (BCM), Baylor University, City University of Hong Kong [Hong Kong] (CUHK), Federal University of Rio Grande do Norte, Natal, RN, Brazil, Tokyo Medical University, Helsinki Sleep Clinic [Helsinki], Uppsala Universitet [Uppsala], Haukeland University Hospital, University of Bergen (UiB), Feinberg School of Medicine, Northwestern University [Evanston], SLEEPWELL Research Program, Department of Psychology and Logopedics, Department of Neurosciences, Clinicum, and HUS Neurocenter

Subjects
BNSQ, ISI, midsleep, MSFsc, PHQ-4, psychological distress, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Psychological distress, SLEEP HYGIENE, 3124 Neurology and psychiatry, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], ANXIETY, CHRONOTYPE, Original Research, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, 3112 Neurosciences, Public Health, Global Health, Social Medicine and Epidemiology, DEPRESSION, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Midsleep, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, HEALTH, LOCKDOWN
Abstract

Purpose: Lifestyle and work habits have been drastically altered by restrictions due to the COVID-19 pandemic. Whether the associated changes in sleep timing modulate the risk of suffering from symptoms of insomnia, the most prevalent sleep disorder, is however incompletely understood. Here, we evaluate the association between the early pandemic-associated change in 1) the magnitude of social jetlag (SJL) – ie, the difference between sleep timing on working vs free days – and 2) symptoms of insomnia. Patients and Methods: A total of 14,968 anonymous participants (mean age: 40 years; 64% females) responded to a standardized internet-based survey distributed across 14 countries. Using logistic multivariate regression, we examined the association between the degree of social jetlag and symptoms of insomnia, controlling for important confounders like social restriction extension, country specific COVID-19 severity and psychological distress, for example. Results: In response to the pandemic, participants reported later sleep timing, especially during workdays. Most participants (46%) exhibited a reduction in their SJL, whereas 20% increased it; and 34% reported no change in SJL. Notably, we found that both increased and decreased SJL, as a result of the COVID-19 pandemic, were associated with later sleep midpoint (indicating a later chronotype) as well as more recurrent and moderate-to-severe symptoms of insomnia (about 23– 54% higher odds ratio than subjects with unchanged SJL). Primarily those with reduced SJL shifted their bedtimes to a later timepoint, compared with those without changes in SJL. Conclusion: Our findings offer important insights into how self-reported changes to the stability of sleep/wake timing, as reflected by changes in SJL, can be a critical marker of the risk of experiencing insomnia-related symptoms – even when individuals manage to reduce their social jetlag. These findings emphasize the clinical importance of analyzing sleep-wake regularity. publishedVersion

Published
2021
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6. Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction: insights fromBIOSTAT-CHFandASIAN-HFregistries

Author

Wataru Shimizu, Gurpreet Singh Wander, Wan Ting Tay, Leong L. Ng, Wouter Ouwerkerk, Jitendra P. S. Sawhney, Chim C. Lang, Chung-Lieh Hung, Stefan D. Anker, Dirk J. van Veldhuisen, Kenneth Dickstein, Faiez Zannad, A. Mark Richards, Inder S. Anand, John G.F. Cleland, Jasper Tromp, Carolyn S.P. Lam, Adriaan A. Voors, Nobuhisa Hagiwara, Ajay Naik, Tiew-Hwa Katherine Teng, Cardiovascular Centre (CVC), Epidemiology and Data Science, Dermatology, National Heart Centre Singapore (NHCS), Amsterdam UMC - Amsterdam University Medical Center, Duke-National University of Singapore Graduate Medical School, The University of Western Australia (UWA), Glenfield Hospital, Duke-NUS Medical School [Singapore], University Medical Center Groningen [Groningen] (UMCG), National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, University of Bergen (UiB), Stavanger University Hospital, University Hospitals Leicester, University of Leicester, University of Dundee, Ninewells Hospital and Medical School [Dundee], Berlin-Brandenburg Center for Regenerative Therapies [Berlin, Germany], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Charité Campus Virchow-Klinikum (CVK), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Division of Cardiology, Department of Internal Medicine, Mackay Memorial Hospital, Brigham and Women’s Hospital [Boston, MA], Harvard Medical School [Boston] (HMS), Sir Gangaram Hospital, CIMS Hospital, Tokyo Women's Medical University (TWMU), Nippon Medical School [Tokyo, Japon], Dayanand Medical College and Hospital [Ludhiana], Veterans Affairs Medical Center, Cardiovascular Research Institute, National University Heart Centre, University of Otago [Dunedin, Nouvelle-Zélande], Biomedical Research Council Asian neTwork for Translational Research and Cardiovascular Trials (ATTRaCT). Grant Numbers: SPF2014/005, SPF2014/004, SPF2014/003, Boston Scientific Investigator Sponsored Research Program, National Medical Research Council of Singapore. Grant Number: R-172-003-219-511, European Project: 242209,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,BIOSTAT-CHF(2010), and European Project

Subjects
Male, Angiotensin-Converting Enzyme Inhibitors, 030204 cardiovascular system & hematology, Ventricular Function, Left, Renin-Angiotensin System, 0302 clinical medicine, Prospective Studies, Registries, ESC GUIDELINES, Aldosterone, ELDERLY-PATIENTS, Ejection fraction, Hazard ratio, Middle Aged, Europe, VARIABLE SELECTION, ENALAPRIL, Cardiology, Female, TRIAL, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Asia, medicine.drug_class, Heart failure, Outcomes, 03 medical and health sciences, Angiotensin Receptor Antagonists, Reduced ejection fraction, MORBIDITY, Up-titration, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, LEFT-VENTRICULAR FUNCTION, Internal medicine, Renin–angiotensin system, medicine, Humans, In patient, cardiovascular diseases, Beta blocker, Aged, CARVEDILOL, business.industry, MORTALITY, Stroke Volume, medicine.disease, Confidence interval, Target dose, business, SUDDEN CARDIAC DEATH, Evidence-based pharmacotherapy
Abstract

Background Angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and beta-blockers are guideline-recommended first-line therapies in heart failure (HF) with reduced ejection fraction (HFrEF). Previous studies showed that individual drug classes were under-dosed in many parts of Europe and Asia. In this study, we investigated the association of combined up-titration of ACEi/ARBs and beta-blockers with all-cause mortality and its combination with hospitalization for HF. Methods and results A total of 6787 HFrEF patients (mean age 62.6 +/- 13.2 years, 77.7% men, mean left ventricular ejection fraction 27.7 +/- 7.2%) were enrolled in the prospective multinational European (BIOSTAT-CHF;n = 2100) and Asian (ASIAN-HF;n = 4687) studies. Outcomes were analysed according to achieved percentage of guideline-recommended target doses (GRTD) of combination ACEi/ARB and beta-blocker therapy, adjusted for indication bias. Only 14% (n = 981) patients achieved >= 50% GRTD for both ACEi/ARB and beta-blocker. The best outcomes were observed in patients who achieved 100% GRTD of both ACEi/ARB and beta-blocker [hazard ratio (HR) 0.32, 95% confidence interval (CI) 0.26-0.39 vs. none]. Lower dose of combined therapy was associated with better outcomes than 100% GRTD of either monotherapy. Up-titrating beta-blockers was associated with a consistent and greater reduction in hazards of all-cause mortality (HR for 100% GRTD: 0.40, 95% CI 0.25-0.63) than corresponding ACEi/ARB up-titration (HR 0.75, 95% CI 0.53-1.07). Conclusion This study shows that best outcomes were observed in patients attaining GRTD for both ACEi/ARB and beta-blockers, unfortunately this was rarely achieved. Achieving >50% GRTD of both drug classes was associated with better outcome than target dose of monotherapy. Up-titrating beta-blockers to target dose was associated with greater mortality reduction than up-titrating ACEi/ARB.

Published
2020
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7. Thirst for Intention? Grasping a Glass Is a Thirst-Controlled Action

Author

Patrice Revol, Sarah Collette, Zoe Boulot, Alexandre Foncelle, Chiharu Niki, David Thura, Akila Imai, Sophie Jacquin-Courtois, Michel Cabanac, François Osiurak, Yves Rossetti, Integrative Multisensory Perception, Action and Cognition (IMPACT), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Artificial Evolution and Computational Biology (BEAGLE), Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Tokyo Women's Medical University (TWMU), Shinshu University [Nagano], Université Laval [Québec] (ULaval), Laboratoire d'Etude des Mécanismes Cognitifs (EMC), Université Lumière - Lyon 2 (UL2), Integrative, Multisensory, Perception, Action and Cognition Team [Bron] (IMPACT), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École Centrale de Lyon (ECL), Université de Lyon-Université Lumière - Lyon 2 (UL2)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Université Lumière - Lyon 2 (UL2), Service de Médecine Physique et de Réadaptation, Hospices Civils de Lyon (HCL)-Hôpital Henry Gabrielle [CHU - HCL], Hospices Civils de Lyon (HCL), Espace et Action, and Université de Lyon-Université de Lyon-IFR19-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
lcsh:BF1-990, Affect (psychology), 050105 experimental psychology, Thirst, 03 medical and health sciences, 0302 clinical medicine, motivation, medicine, Psychology, 0501 psychology and cognitive sciences, human, Set (psychology), General Psychology, Original Research, [SCCO.NEUR]Cognitive science/Neuroscience, 05 social sciences, Motor control, Cognition, Voluntary action, lcsh:Psychology, Action (philosophy), Covert, intention, kinematics, psychomotor performance, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, 030217 neurology & neurosurgery, Cognitive psychology
Abstract

International audience; Every day and every hour, we feel we perform numerous voluntary actions, i.e., actions under the control of our will. Individual’s ability to initiate goal-directed movement is classically described as a hierarchical motor organization, from an intentional module, mostly considered as a black box, to muscular activity supporting action execution. The general focus is usually set on the triggering of action by intention, which is assumed to be the only entry to the action cascade, rather than on the preceding formation of intentions. If intentions play a key role in the specification of movement kinematic parameters, it remains largely unknown whether unconscious cognitive processes may also affect action preparation and unfolding. Recently, a seemingly irrelevant variable, thirst, was shown to modulate a simple arbitrary action such as key-pressing. Thirsty individuals were shown to produce stronger motor inhibition in no-go trials when a glass of water was present. In the present experiment, we intended to explore whether motor inhibition operates not only upstream from the action cascade but may also affect the unfolding of reaching movements, i.e., at a lower-level control. Thirsty vs. non-thirsty control subjects were asked to reach and grasp green (go trial) or red glasses (no-go trial) filled with either water or transparent gel wax with a central candlewick. Thirsty subjects were faster to initiate actions toward the water glasses. They also exhibited an earlier maximal grip aperture and a global reduction of movement time which was mostly explained by a shortening of deceleration time. The deceleration phase was correlated with individual’s thirst rating. In addition, no-go trial toward a glass of water tended to inhibit the next movement toward a glass filled with gel wax. Thus, our results show that an unintentional influence of an internal state can reorganize voluntary action structure not only at the decision-making level but also at the level of motor control. Although subjects explicitly paid more attention and were more cautious to glasses filled with water, they reported no explicit sensation of an increased urge to grasp it, further suggesting that these effects are controlled by covert mechanisms.

Published
2019
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8. Characteristic findings of skeletal muscle MRI in caveolinopathies

Author

Takatoshi Sato, Terumi Murakami, S. Kajino, M. Yoshioka, Yukiko K. Hayashi, S. Nagata, M. Shichiji, Ichizo Nishino, K. Ishiguro, Naomi Hino-Fukuyo, Mariko Okubo, Keiko Ishigaki, Satoshi Kuru, T. Nakayama, Makiko Osawa, Nobuyuki Murakami, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Tokyo Women's Medical University (TWMU), National Center of Neurology and Psychiatry National Institute of Mental Health (NCNP), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], 030105 genetics & heredity, Biceps, Caveolins, Congenital generalized lipodystrophy, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, PTRF, Muscular Diseases, Caveolin, medicine, Humans, Muscular dystrophy, Myopathy, Child, Muscle, Skeletal, Genetics (clinical), business.industry, Skeletal muscle, medicine.disease, Phenotype, Magnetic Resonance Imaging, medicine.anatomical_structure, Neurology, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Caveolinopathies, caused by CAV3 mutations, can include several phenotypes such as rippling muscle disease, limb-girdle muscular dystrophy type 1C, distal myopathy, familial hypertrophic cardiomyopathy, and idiopathic hyperCKemia. Here we present characteristic skeletal muscle imaging findings in four patients with genetically defined childhood-onset RMD caused by CAV3 mutations and in one patient with congenital generalized lipodystrophy type 4 with muscular dystrophy due to polymerase I and transcript release factor (PTRF) mutations, which may have caused secondary deficiency of caveolin-3. Muscle MRI revealed that the rectus femoris and semitendinosus muscles were most commonly affected in the rippling muscle disease patients. Peripheral changes in the rectus femoris were specific and observed even in one of the younger patients in this study. Furthermore, muscle involvement extended to the semitendinosus muscles, biceps femoris, and gracilis with disease progression or increase in its severity. Similar patterns of involvement were observed on reviewing skeletal muscle images of various previously reported phenotypes of caveolinopathy; interestingly, patients with secondary deficiency of caveolin due to PTRF mutations revealed the same pattern. Thus, primary caveolinopathies and secondary deficiency of caveolin demonstrated specific findings on skeletal muscle imaging, regardless of the broad phenotypic spectrum of these two conditions.

Published
2018
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9. Sex in basic research - Concepts in the cardiovascular field

Author

Anna Maria D'Ursi, Virginia M. Miller, Walter Malorni, Claudine Junien, Gregor Majdic, Elisa Giannetta, Susanna M. Hofmann, Georgios Kararigas, Ute Seeland, Rebecca M. Reynolds, Cara Tannenbaum, Christin Mieth, Thomas C. Carpenter, Renée Ventura-Clapier, Sandra Brunelleschi, Elke Dworatzek, Vera Regitz-Zagrosek, Flavia Franconi, Miyuki Katai, Karolina Kublickiene, Marek Glezerman, Hiroaki Shimokawa, Jeanette Erdmann, Jean-François Arnal, Inke R. König, Signalisation et Physiopathologie Cardiovasculaire, UM-S 1180, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Sud (Paris 11), Université Paris-Saclay, Institute of Gender in Medicine and Center for Cardiovascular Research, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Deutsch Zentrum Herz Kreislauf Forsch DZHK, Faculté de Médecine Toulouse-Rangueil, Université Fédérale Toulouse Midi-Pyrénées, Department of Health Sciences, School of Medicine, University of Eastern Piedmont, College of Medicine and Veterinary Medicine, University of Edinburgh, Institut für Kardiogenetik, Universität zu Lübeck [Lübeck], Department of Biomedical Science, University of Sheffield [Sheffield], Ricercatore TD in Endocrinologia, Dipartimento di Medicina Sperimentale, Sezione di Fisiopatologia Medica, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], International Society for Gender Medicine, Research Center for Medicine, Rabin Medical Center, Tel Aviv University [Tel Aviv], Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München (LMU), German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), Biologie du Développement et Reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Department of General Medicine, Section of Gender Medicine, Tokyo Women's Medical University (TWMU), Centre for Gender Medicine and Departments of Obstetrics and Gynecology and Renal Medicine, Karolinska Institute, Institut für Medizinische Biometrie und Statistik, Institute for Preclinical Sciences, Veterinary Faculty, University of Ljubljana, Institute of Physiology, Medical Faculty, University of Maribor, National Center for Gender-Specific Medicine, Istituto Superiore di Sanità, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Mayo Clinic, Center for Cardiovascular Science, Queen's Medical Researche Institute, University of Edinburgh-University of Edinburgh, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Institute of Gender and Health, Canadian Institutes of Health Research (CIHR), Medicinal Chemistry DIFARMA, Università degli Studi di Salerno (UNISA), EUGenMed project (FP7) and DZHK, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Universität zu Lübeck [Lübeck] - University of Lübeck [Lübeck], Sapienza University of Rome (DIAG), German Center for Diabetes Research, Biologie du développement et reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Max Delbrück Center for Molecular Medicine (MDC), Helmholtz-Gemeinschaft, and Queen's Medical Research Institute

Subjects
0301 basic medicine, Male, Biomedical Research, Physiology, Alternative medicine, sexual differentiation, animal models, basic research, cardiac cell models, chromosomes, hormones, sex, 030204 cardiovascular system & hematology, Cardiovascular System, law.invention, sexe, Toxicology, 0302 clinical medicine, law, Basic research, Pregnancy, Risk Factors, Medicine, Cardiac cell models, Gonadal Steroid Hormones, système cardiovasculaire, Animal Models, Basic Research, Cardiac Cell Models, Chromosomes, Hormones, Sex, Sex Characteristics, Prognosis, Sex specific, 3. Good health, Animal models, Phenotype, Drug development, Cardiovascular Diseases, Research Design, cerveau, Engineering ethics, animal vascular system, Female, Cardiology and Cardiovascular Medicine, différenciation sexuelle, medicine.medical_specialty, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Acknowledgement, sex, basic research, chromosomes, hormones, animal models, cardiac cell models, hormone sexuelle, sex hormones, 03 medical and health sciences, épigénétique, Sex Factors, Physiology (medical), Animals, Humans, Genetic Predisposition to Disease, Healthcare Disparities, Chromosomes, Human, X, Sexual differentiation, Chromosomes, Human, Y, business.industry, Field (Bourdieu), Health Status Disparities, 030104 developmental biology, CLARITY, business, régulation génique
Abstract

Article en libre accès; Women and men, female and male animals and cells are biologically different, and acknowledgement of this fact is critical to advancing medicine. However, incorporating concepts of sex-specific analysis in basic research is largely neglected, introducing bias into translational findings, clinical concepts and drug development. Research funding agencies recently approached these issues but implementation of policy changes in the scientific community is still limited, probably due to deficits in concepts, knowledge and proper methodology. This expert review is based on the EUGenMed project (www.eugenmed.eu) developing a roadmap for implementing sex and gender in biomedical and health research. For sake of clarity and conciseness, examples are mainly taken from the cardiovascular field that may serve as a paradigm for others, since a significant amount of knowledge how sex and oestrogen determine the manifestation of many cardiovascular diseases (CVD) has been accumulated. As main concepts for implementation of sex in basic research, the study of primary cell and animals of both sexes, the study of the influence of genetic vs. hormonal factors and the analysis of sex chromosomes and sex specific statistics in genome wide association studies (GWAS) are discussed. The review also discusses methodological issues, and analyses strength, weaknesses, opportunities and threats in implementing sex-sensitive aspects into basic research.

Published
2017
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10. The Intracranial Distribution of Gliomas in Relation to Exposure From Mobile Phones: Analyses From the INTERPHONE Study

Author

Per Kragh Andersen, Mary L. McBride, Kirsten Frederiksen, Sarah Fleming, Bruce K. Armstrong, Joachim Schüz, Siegal Sadetzki, Maria Blettner, Maria Feychting, Jack Siemiatycki, Christoffer Johansen, Martine Hours, Kathrine Grell, Alistair Woodward, Anthony J. Swerdlow, Susanna Lagorio, Tore Tynes, Daniel Krewski, Anssi Auvinen, Naohito Yamaguchi, Elisabeth Cardis, Section of Biostatistics [Copenhagen], Department of Public Health [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Aarhus University [Aarhus], Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Center for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra [Barcelona] (UPF)-Catalunya ministerio de salud, School of Public Health, University of Sydney, University of Montreal, University of Ottawa [Ottawa], BC Cancer Agency, University of Copenhagen = Københavns Universitet (KU), department of Epidemiology, University of Tampere [Finland], Unité Mixte de Recherche Epidémiologique et de Surveillance Transport Travail Environnement (UMRESTTE UMR T9405), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR), Institute of Medical Biometry, Epidemiology and Informatics (IMBEI), Johannes Gutenberg - Universität Mainz (JGU), Cancer & Radiation Epidemiology Unit, Gertner Institute, Istituto Superiore di Sanità, Tokyo Women's Medical University (TWMU), Epidemiology and Biostatistics, University of Auckland [Auckland], National Institute of Occupational Health (STAMI), National Institute of Occupational Health (STAMI) (STAMI), Institute of Environmental Medicine, Karolinska Institutet [Stockholm], University of Leeds, Epidemiology section, and Institute of Cancer Research in Sutton

Subjects
Adult, Male, medicine.medical_specialty, TELEPHONE, Neoplasms, Radiation-Induced, Time Factors, Epidemiology, Original Contributions, Tumor burden, Brain tumor, Audiology, MOBILE TELEPHONES, 03 medical and health sciences, 0302 clinical medicine, Phone, Risk Factors, Recall bias, EXPOSITION AU RISQUE, CERVEAU, Medicine, Humans, 030212 general & internal medicine, Epidemiologic research, Self report, ONDE, RADIO-FREQUENCY ELECTROMAGNETIC FIELDS, business.industry, Brain Neoplasms, INTERPHONE STUDY, Middle Aged, medicine.disease, Tumor Burden, Mobile phone, 030220 oncology & carcinogenesis, Epidemiologic Research Design, GLIOMA, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, SPATIAL POINT PATTERN, Neoplasm Grading, business, INTRACRANIAL DISTRIBUTION, Cell Phone, TUMEUR
Abstract

When investigating the association between brain tumors and use of mobile telephones, accurate data on tumor position are essential, due to the highly localized absorption of energy in the human brain from the radio-frequency fields emitted. We used a point process model to investigate this association using information that included tumor localization data from the INTERPHONE Study (Australia, Canada, Denmark, Finland, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Sweden, and the United Kingdom). Our main analysis included 792 regular mobile phone users diagnosed with a glioma between 2000 and 2004. Similar to earlier results, we found a statistically significant association between the intracranial distribution of gliomas and the self-reported location of the phone. When we accounted for the preferred side of the head not being exclusively used for all mobile phone calls, the results were similar. The association was independent of the cumulative call time and cumulative number of calls. However, our model used reported side of mobile phone use, which is potentially inuenced by recall bias. The point process method provides an alternative to previously used epidemiologic research designs when one is including localization in the investigation of brain tumors and mobile phone use.; Il s'agit d'explorer la relation entre dose de radiofréquences reçue ds le cerveau lors de l'utilisation de téléphone mobile et la survenue de tumeurs du cerveau.

Published
2016
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11. Worldwide sequence conservation of transmission-blocking vaccine candidate Pvs230 in Plasmodium vivax

Author

Kazuyuki Tanabe, Jetsumon Sattabongkot, Shin-Ichiro Tachibana, Masanori Yagi, Meiko Hamai, Marcelo U. Ferreira, Takafumi Tsuboi, Hiroshi Ohmae, Toshihiro Horii, Masanori Doi, Yaming Cao, Milijaona Randrianarivelojosia, Akira Kaneko, Toshihiro Mita, Motomi Torii, Mayumi Tachibana, Fadile Yildiz Zeyrek, Cell-free Science and Technology Research Center, Ehime University [Matsuyama], Laboratory of Malariology, Research Institute for Microbial Diseases, Osaka University [Osaka], Department of Molecular Parasitology, Ehime University Graduate School of Medicine, Department of International Affairs and Tropical Medicine, Tokyo Women's Medical University (TWMU), Department of Molecular Protozoology, Research Institute for Microbial Diseases, Department of Microbiology, Harran University Medical Faculty, Department of Parasitology [São Paulo] (IBS), Institute of Biomedical Sciences (ICB/USP), Universidade de São Paulo (USP)-Universidade de São Paulo (USP), Department of Parasitology, National Institute of Infectious Diseases, Karolinska Institutet [Stockholm], Global COE, Nagasaki University, Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP), Armed Forces Research Institute of Medical Sciences [Bangkok] (AFRIMS), Department of Immunology, College of Basic Medical Sciences, China Medical University, Ehime Proteo-Medicine Research Center, Venture Business Laboratory, and This research was supported by the Ministry of Education, Culture, Sports, Science and Technology (18073013, 18GS03140013, 20390120, 19406009, 21022034, 22406012), and by the Ministry of Health, Labour, and Welfare, Japan (H20-Shinkou-ippan-013, H21-Chikyukibo-ippan-005) and by Japan Society for the Promotion of Science Fellowship Program (to FYZ). Field work in Brazil was funded by the National Institutes of Health of USA (RO1 AI 075416-01), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, 470570/2006-7), and the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 05/51988-0 and 07/51199-0). This work was also supported by grant from the National Natural Science Foundation of China (30972774)

Subjects
MESH: Sequence Analysis, DNA, [SDV]Life Sciences [q-bio], Plasmodium vivax, Protozoan Proteins, MESH: Amino Acid Sequence, Nucleotide diversity, Conserved sequence, 0302 clinical medicine, MESH: Animals, MESH: Phylogeny, MESH: Protozoan Proteins, Conserved Sequence, Phylogeny, Genetics, 0303 health sciences, education.field_of_study, MESH: Conserved Sequence, biology, MESH: Malaria Vaccines, MESH: Plasmodium vivax, 3. Good health, Infectious Diseases, Molecular Medicine, Sequence analysis, Molecular Sequence Data, 030231 tropical medicine, Population, MESH: Sequence Alignment, MESH: DNA, Protozoan, Antigens, Protozoan, Article, 03 medical and health sciences, Malaria Vaccines, parasitic diseases, Malaria, Vivax, medicine, Gametocyte, Animals, Humans, Amino Acid Sequence, education, 030304 developmental biology, MESH: Humans, MESH: Molecular Sequence Data, General Veterinary, General Immunology and Microbiology, Public Health, Environmental and Occupational Health, MESH: Malaria, Vivax, Plasmodium falciparum, Sequence Analysis, DNA, DNA, Protozoan, biology.organism_classification, medicine.disease, Virology, Sequence Alignment, Malaria, MESH: Antigens, Protozoan
Abstract

International audience; Pfs230, surface protein of gametocyte/gamete of the human malaria parasite, Plasmodium falciparum, is a prime candidate of malaria transmission-blocking vaccine. Plasmodium vivax has an ortholog of Pfs230 (Pvs230), however, there has been no study in any aspects on Pvs230 to date. To investigate whether Pvs230 can be a vivax malaria transmission-blocking vaccine, we performed evolutionary and population genetic analysis of the Pvs230 gene (pvs230: PVX_003905). Our analysis of Pvs230 and its orthologs in eight Plasmodium species revealed two distinctive parts: an interspecies variable part (IVP) containing species-specific oligopeptide repeats at the N-terminus and a 7.5kb interspecies conserved part (ICP) containing 14 cysteine-rich domains. Pvs230 was closely related to its orthologs, Pks230 and Pcys230, in monkey malaria parasites. Analysis of 113 pvs230 sequences obtained from worldwide, showed that nucleotide diversity is remarkably low in the non-repeat 8-kb region of pvs230 (θπ=0.00118) with 77 polymorphic nucleotide sites, 40 of which results in amino acid replacements. A signature of purifying selection but not of balancing selection was seen on pvs230. Functional and/or structural constraints may limit the level of polymorphism in pvs230. The observed limited polymorphism in pvs230 should ground for utilization of Pvs230 as an effective transmission-blocking vaccine.

Published
2011
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12. Electrophysiological and morphological characterization of a case of autosomal recessive congenital myasthenic syndrome with acetylcholine receptor deficiency due to a N88K rapsyn homozygous mutation

Author

Jean-Paul Leroy, Jordi Molgó, Julien Barbier, Michel Fardeau, Daniel Hantaï, F. Andreux, Pascale Richard, Jeanine Koenig, Cassandra Prioleau, Bruno Eymard, Eriko Yasaki, Philippe Dartevelle, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Paediatrics, Tokyo Women's Medical University (TWMU), Laboratoire de neurobiologie cellulaire et moléculaire (NBCM), Centre National de la Recherche Scientifique (CNRS), Institut de Neurobiologie Alfred Fessard (INAF), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Morvan, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de Chirurgie thoracique, Centre chirurgical Marie Lannelongue, Université Bordeaux Segalen - Bordeaux 2, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Centre Chirurgical Marie Lannelongue (CCML)

Subjects
Male, Biopsy, DNA Mutational Analysis, Neuromuscular transmission, Muscle Proteins, Chromosome Disorders, Receptors, Nicotinic, medicine.disease_cause, Synaptic Transmission, MESH: Down-Regulation, Membrane Potentials, MESH: Biopsy, 0302 clinical medicine, Gene Frequency, Medicine, MESH: DNA Mutational Analysis, Genetics (clinical), MESH: Muscle, Skeletal, MESH: Chromosome Disorders, 0303 health sciences, Mutation, MESH: Electrophysiology, medicine.diagnostic_test, Homozygote, Congenital myasthenic syndrome, Pedigree, Electrophysiology, medicine.anatomical_structure, Neurology, MESH: Receptors, Nicotinic, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, MESH: Homozygote, Adult, MESH: Myasthenic Syndromes, Congenital, medicine.medical_specialty, MESH: Mutation, MESH: Pedigree, Neuromuscular Junction, Synaptic Membranes, Down-Regulation, Genes, Recessive, In Vitro Techniques, Neuromuscular junction, MESH: Muscle Proteins, MESH: Receptor Aggregation, 03 medical and health sciences, Internal medicine, MESH: Synaptic Transmission, MESH: Gene Frequency, Humans, MESH: Membrane Potentials, Muscle, Skeletal, MESH: Genes, Recessive, 030304 developmental biology, Acetylcholine receptor, Myasthenic Syndromes, Congenital, MESH: Humans, Muscle biopsy, business.industry, Receptor Aggregation, Fatigable weakness, Muscle weakness, MESH: Adult, MESH: Haplotypes, medicine.disease, MESH: Synaptic Membranes, MESH: Male, Endocrinology, Haplotypes, Pediatrics, Perinatology and Child Health, MESH: Neuromuscular Junction, Neurology (clinical), business, MESH: Female, 030217 neurology & neurosurgery
Abstract

Congenital myasthenic syndromes are rare heterogeneous hereditary disorders, which lead to defective neuromuscular transmission resulting in fatigable muscle weakness. Post-synaptic congenital myasthenic syndromes are caused by acetylcholine receptor kinetic abnormalities or by acetylcholine receptor deficiency. Most of the congenital myasthenic syndromes with acetylcholine receptor deficiency are due to mutations in acetylcholine receptor subunit genes. Some have recently been attributed to mutations in the rapsyn gene. Here, we report the case of a 28-year-old French congenital myasthenic syndrome patient who had mild diplopia and fatigability from the age of 5 years. His muscle biopsy revealed a marked reduction in rapsyn and acetylcholine receptor at neuromuscular junctions together with a simplification of the subneural apparatus structure. In this patient, we excluded mutations in the acetylcholine receptor subunit genes and identified the homozygous N88K rapsyn mutation, which has already been shown by cell expression to impair rapsyn and acetylcholine receptor aggregation at the neuromuscular junction. The detection of the N88K mutation at the heterozygous state in five of 300 unrelated control subjects shows that this mutation is not infrequent in the healthy population. Electrophysiological measurements on biopsied intercostal muscle from this patient showed that his rapsyn mutation-induced fatigable weakness is expressed not only in a diminution in acetylcholine receptor membrane density but also in a decline of endplate potentials evoked at low frequency.

Published
2004
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13. Developmental genetic bases behind the independent origin of the tympanic membrane in mammals and diapsids

Author

Hiroki Kurihara, Tatsuya Hirasawa, Yukiko Kurihara, Tamami Hirai, Taro Kitazawa, Sachiko Miyagawa-Tomita, Kazuhiro Maeda, Jiro Hitomi, Shigeru Kuratani, Masaki Takechi, Noritaka Adachi, Hideaki Kume, Giovanni Levi, Nicolas Narboux-Nême, The University of Tokyo (UTokyo), Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Laboratory for evolutionary morphology, Kobe University, Evolution des régulations endocriniennes (ERE), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Tokyo Women's Medical University (TWMU), Global COE Program (Integrative Life Science based on the Study of Biosignaling Mechanisms), KAKENHI and Platform for Dynamic Approaches to Living System from the MEXT, Japan, grants-in-aid for scientific research from the Ministry of Health, Labour and Welfare, Japan, and CREST from JST, Japan.

Subjects
Embryo, Nonmammalian, Tympanic Membrane, Classical example, Molecular Sequence Data, General Physics and Astronomy, Structural diversity, Mandible, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Evolutionary genetics, Evolution, Molecular, Mice, Gene duplication, Maxilla, medicine, Morphogenesis, Animals, Paired Box Transcription Factors, First pharyngeal pouch, Homeodomain Proteins, Multidisciplinary, Base Sequence, Endothelin-1, Gene Expression Regulation, Developmental, Lizards, [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, General Chemistry, Anatomy, Embryo, Mammalian, Receptor, Endothelin A, biology.organism_classification, Ambystoma mexicanum, Goosecoid Protein, medicine.anatomical_structure, Developmental genetics, Sharks, Middle ear, Amniote, Evolutionary developmental biology, Transcription Factors
Abstract

The amniote middle ear is a classical example of the evolutionary novelty. Although paleontological evidence supports the view that mammals and diapsids (modern reptiles and birds) independently acquired the middle ear after divergence from their common ancestor, the developmental bases of these transformations remain unknown. Here we show that lower-to-upper jaw transformation induced by inactivation of the Endothelin1-Dlx5/6 cascade involving Goosecoid results in loss of the tympanic membrane in mouse, but causes duplication of the tympanic membrane in chicken. Detailed anatomical analysis indicates that the relative positions of the primary jaw joint and first pharyngeal pouch led to the coupling of tympanic membrane formation with the lower jaw in mammals, but with the upper jaw in diapsids. We propose that differences in connection and release by various pharyngeal skeletal elements resulted in structural diversity, leading to the acquisition of the tympanic membrane in two distinct manners during amniote evolution., The evolution of the amniote middle ear remains unclear. Here, the authors show that inactivation of the Edn1-Dlx5/6 cascade during development results in loss of the tympanic membrane in mouse and duplication in chicken, which suggests independent evolution of the tympanic membrane in different amniotes.

Published
2015
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14. Prdm1 functions in the mesoderm of the second heart field, where it interacts genetically with Tbx1, during outflow tract morphogenesis in the mouse embryo

Author

Sachiko Miyagawa-Tomita, Joseph A. Brzezinski, Margaret Buckingham, Alicia Mayeuf-Louchart, Robert G. Kelly, Yusuke Watanabe, Stéphane D. Vincent, Département de Biologie du Développement et Cellules souches - Department of Developmental and Stem Cell Biology, Institut Pasteur [Paris] (IP), Bases Génétiques, Moléculaires et Cellulaires du Développement (BGMCD), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Washington [Seattle], Tokyo Women's Medical University (TWMU), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Institut Pasteur and the CNRS URA 2578 (National Centre for Scientific Research), with grants from the E.U. Integrated Project ‘Heart Repair’ (LHSM-CT2005-018630) and ‘CardioCell’ (LT2009-223372) to M.B. S.M.-T. received a fellowship from the Naito foundation., European Project: 32570,HEARTREPAIR, European Project: 223372,EC:FP7:HEALTH,FP7-HEALTH-2007-B,CARDIOCELL(2009), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Department of Structural Biology [Seattle], Department of Pediatric Cardiology [Tokyo], Aix Marseille Université (AMU)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), VINCENT, Stéphane, Heart Failure and Repair - HEARTREPAIR - 32570 - OLD, and Development of cardiomyocyte replacement strategy for the clinic - CARDIOCELL - - EC:FP7:HEALTH2009-05-01 - 2012-10-31 - 223372 - VALID

Subjects
Male, Pathology, Organogenesis, Gene Expression, Aorta, Thoracic, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Mesoderm, Gene Knockout Techniques, Mice, hemic and lymphatic diseases, Morphogenesis, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Heart development, Stem Cells, Neural crest, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Gene Expression Regulation, Developmental, Heart, General Medicine, Anatomy, Arterial tree, medicine.anatomical_structure, embryonic structures, Female, medicine.medical_specialty, Genotype, Persistent truncus arteriosus, Mice, Transgenic, [SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, medicine.artery, Genetics, medicine, Animals, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Aorta, Lateral plate mesoderm, Epistasis, Genetic, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Embryo, Mammalian, Outflow tract morphogenesis, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Branchial Region, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Mutation, Positive Regulatory Domain I-Binding Factor 1, T-Box Domain Proteins, Pharyngeal arch, Transcription Factors
Abstract

International audience; Congenital heart defects affect at least 0.8% of newborn children and are a major cause of lethality prior to birth. Malformations of the arterial pole are particularly frequent. The myocardium at the base of the pulmonary trunk and aorta and the arterial tree associated with these great arteries are derived from splanchnic mesoderm of the second heart field (SHF), an important source of cardiac progenitor cells. These cells are controlled by a gene regulatory network that includes Fgf8, Fgf10 and Tbx1. Prdm1 encodes a transcriptional repressor that we show is also expressed in the SHF. In mouse embryos, mutation of Prdm1 affects branchial arch development and leads to persistent truncus arteriosus (PTA), indicative of neural crest dysfunction. Using conditional mutants, we show that this is not due to a direct function of Prdm1 in neural crest cells. Mutation of Prdm1 in the SHF does not result in PTA, but leads to arterial pole defects, characterized by mis-alignment or reduction of the aorta and pulmonary trunk, and abnormalities in the arterial tree, defects that are preceded by a reduction in outflow tract size and loss of caudal pharyngeal arch arteries. These defects are associated with a reduction in proliferation of progenitor cells in the SHF. We have investigated genetic interactions with Fgf8 and Tbx1, and show that on a Tbx1 heterozygote background, conditional Prdm1 mutants have more pronounced arterial pole defects, now including PTA. Our results identify PRDM1 as a potential modifier of phenotypic severity in TBX1 haploinsufficient DiGeorge syndrome patients.

Published
2014
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15. Emergence of a BCR-ABL translocation in a patient with the JAK2V617F mutation: evidence for secondary acquisition of BCR-ABL in the JAK2V617F clone

Author

William Vainchenker, Hisashi Yamada, Kohji Ozaki, Isabelle Plo, Mayuka Nakatake, Kiyotaka Kawauchi, Emna Mahfoudhi, Masaharu Akiyama, Osamu Yamada, Medical Research Institute, Tokyo Women's Medical University (TWMU), Laboratoire d'hématologie moléculaire et cellulaire (LR11IPT07), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Hématopoïèse normale et pathologique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Laboratoire d'Excellence du Globule Rouge, Villejuif, France, Institute of DNA Medicine, The Jikei University School of Medicine, Supported by grants from the Ligue Nationale Contre le Cancer (National League Against Cancer, and équipe labelisée 2010-2012), Agence Nationale de la Recherche Blanc 2010, INSERM, INSERM–Direction Générale de la Recherche Scientifique (Tunis), and by a Grant-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (grant No. 22501053).

Subjects
Male, Cancer Research, MESH: Mutation, [SDV]Life Sciences [q-bio], Clone (cell biology), Fusion Proteins, bcr-abl, Chromosomal translocation, MESH: Janus Kinase 2, MESH: Prognosis, Translocation, Genetic, medicine, Humans, Jak2v617f mutation, MESH: Leukemia, Lymphocytic, Chronic, B-Cell, ComputingMilieux_MISCELLANEOUS, Aged, Genetics, MESH: Aged, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, business.industry, MESH: Fusion Proteins, bcr-abl, Janus Kinase 2, medicine.disease, Prognosis, Fusion protein, Virology, Leukemia, Lymphocytic, Chronic, B-Cell, MESH: Male, MESH: Translocation, Genetic, Leukemia, Oncology, Mutation, business
Abstract

International audience

Published
2014
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16. ZFC3H1, a Zinc Finger Protein, Modulates IL-8 Transcription by Binding with Celastramycin A, a Potential Immune Suppressor

Author

Takeshi, Tomita, Katsuaki, Ieguchi, Frédéric, Coin, Fredric, Coin, Yasuhiro, Kato, Haruhisa, Kikuchi, Yoshiteru, Oshima, Shoichiro, Kurata, Yoshiro, Maru, Coin, Frédéric, Tokyo Women's Medical University (TWMU), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Tohoku University [Sendai]

Subjects
RNA Stability, [SDV]Life Sciences [q-bio], Immunofluorescence, Gene Expression, Plasma protein binding, Biochemistry, Nucleic Acids, Molecular Cell Biology, Drug Discovery, Medicine and Health Sciences, RNA, Small Interfering, Zinc finger, Multidisciplinary, DNA-Binding Proteins, [SDV] Life Sciences [q-bio], Cytokines, Medicine, Epigenetics, RNA Interference, Signal transduction, Research Article, Biotechnology, Protein Binding, Signal Transduction, Transcriptional Activation, Drug Research and Development, Ultraviolet Rays, Science, DNA transcription, Immunology, DNA repair, Biology, Research and Analysis Methods, Immune Suppression, DNA-binding protein, Cell Line, Tumor, Chemical Biology, Genetics, Humans, Electrophoretic mobility shift assay, Pyrroles, Immunoassays, Transcription factor, Pharmacology, Reporter gene, Biology and life sciences, Tumor Necrosis Factor-alpha, Binding protein, Interleukin-8, Immunity, Correction, DNA, Cell Biology, Resorcinols, Molecular Development, Endonucleases, Phosphoproteins, Molecular biology, Small Molecules, Immune System, Immunologic Techniques, RNA, Clinical Immunology, Developmental Biology, HeLa Cells, Transcription Factors
Abstract

International audience; Celastramycin A, a small molecule that inhibits the production of antibacterial peptides in an ex vivo culture system of Drosophila, suppresses the TNFα-mediated induction of IL-8 in mammalian cells. To understand its molecular mechanism, we examined Celastramycin A binding proteins and investigated their biological functions. Our screening and subsequent pull-down assay revealed ZFC3H1 (also known as CCDC131 or CSRC2), an uncharacterized zinc finger protein, as a Celastramycin A binding protein. The knockdown of ZFC3H1 reduced IL-8 expression levels in the TNFα-stimulated lung carcinoma cell line, LU99, and UV-irradiated HeLa cells. Based on reporter assay results, we concluded that ZFC3H1 participates in the transcriptional activation of IL-8. The findings of our UV-irradiation experiments implied that ZFC3H1 may indirectly interact with ERCC1 in an activated DNA repair complex. Thus, we designated ZFC3H1 as a mammalian target of Celastramycin A (mTOC).

Published
2014
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17. Extensive morphological and immunohistochemical characterization in myotubular myopathy

Author

Michel Fardeau, Norma B. Romero, Jean-Yves Hogrel, Makiko Osawa, Jocelyn Laporte, Valérie Biancalana, M. Shichiji, HAL UPMC, Gestionnaire, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Tokyo Women's Medical University (TWMU), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Centre de référence des maladies rares neuromusculaires [CHU Pitié-Salpétriêre], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Pathology, medicine.medical_specialty, MTM1, Myotubularin, Morphological pattern, satellite, Biology, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Biopsy, medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Centronuclear myopathy, Centronuclear myopathies, myotubular myopathy, Original Research, 030304 developmental biology, satellite cells, 0303 health sciences, Muscle biopsy, medicine.diagnostic_test, Muscle weakness, Skeletal muscle, medicine.disease, Congenital myopathy, myotubularin, medicine.anatomical_structure, T-tubules, cells, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, 030217 neurology & neurosurgery
Abstract

International audience; The X-linked myotubular myopathy (XLMTM) also called X-linked centronu-clear myopathy is a rare congenital myopathy due to mutations in the MTM1 gene encoding myotubularin. The disease gives rise to a severe muscle weakness in males at birth. The main muscle morphological characteristics (significant number of small muscle fibers with centralized nuclei and type 1 fiber predominance) are usually documented, but the sequence of formation and maintenance of this particular morphological pattern has not been extensively characterized in humans. In this study, we perform a reevaluation of morphological changes in skeletal muscle biopsies in severe XLMTM. We correlate the pathologic features observed in the muscle biopsies of 15 newborns with MTM1-mutations according to the " adjusted-age " at the time of muscle biopsy, focusing on sequential analysis in the early period of the life (from 34 weeks of gestation to 3 months of age). We found a similar morphological pattern throughout the period analyzed; the proportion of myofibers with central nuclei was high in all muscle biopsies, independently of the muscle type, the age of the newborns at time of biopsy and the specific MTM1 mutation. We did not observe a period free of morphological abnormalities in human skeletal muscle as observed in myotubularin-deficient mouse models. In addition, this study demonstrated some features of delayed maturation of the muscle fibers without any increase in the number of satellite cells, associated with a marked disorgani-zation of the muscle T-tubules and cytoskeletal network in the skeletal muscle fibers.

Published
2013
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18. Spontaneous mutations in the Plasmodium falciparum sarcoplasmic/ endoplasmic reticulum Ca2+-ATPase (PfATP6) gene among geographically widespread parasite populations unexposed to artemisinin-based combination therapies

Author

Tanabe, Kazuyuki, Zakeri, Sedigheh, Palacpac, Nirianne Marie Q, Afsharpad, Manada, Randrianarivelojosia, Milijaona, Kaneko, Akira, Marma, Aung Swi Prue, Horii, Toshihiro, Mita, Toshihiro, Laboratory of Malariology, Research Institute for Microbial Diseases, Biotechnology Research Center, Institut Pasteur d'Iran, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Department of Molecular Protozoology, Osaka University [Osaka]-Research Institute for Microbial Diseases, Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP), Karolinska Institutet [Stockholm], Emerging and Re-emerging Diseases, Communicable Disease Control, Directorate General of Health Services, Department of International Affairs and Tropical Medicine, Tokyo Women's Medical University (TWMU), and This work was supported by Grant-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (18073013), from the Japan Society for Promotion of Sciences (18GS03140013, 20390120, 22406012), and from the Ministry of Health, Labor and Welfare (H20-Shinkou-ippan-013).

Subjects
MESH: Mutation, MESH: Polymorphism, Single Nucleotide, [SDV]Life Sciences [q-bio], MESH: Anti-Infective Agents, Plasmodium falciparum, Protozoan Proteins, MESH: Haplotypes, Polymorphism, Single Nucleotide, Artemisinins, Sarcoplasmic Reticulum Calcium-Transporting ATPases, MESH: Sarcoplasmic Reticulum Calcium-Transporting ATPases, Anti-Infective Agents, Gene Frequency, Haplotypes, Mechanisms of Resistance, MESH: Artemisinins, parasitic diseases, Mutation, MESH: Gene Frequency, Animals, MESH: Animals, MESH: Protozoan Proteins, MESH: Plasmodium falciparum
Abstract

International audience; Recent reports on the decline of the efficacy of artemisinin-based combination therapies (ACTs) indicate a serious threat to malaria control. The endoplasmic/sarcoplasmic reticulum Ca(2+)-ATPase ortholog of Plasmodium falciparum (PfSERCA) has been suggested to be the target of artemisinin and its derivatives. It is assumed that continuous artemisinin pressure will affect polymorphism of the PfSERCA gene (serca) if the protein is the target. Here, we investigated the polymorphism of serca in parasite populations unexposed to ACTs to obtain baseline information for the study of potential artemisinin-driven selection of resistant parasites. Analysis of 656 full-length sequences from 13 parasite populations in Africa, Asia, Oceania, and South America revealed 64 single nucleotide polymorphisms (SNPs), of which 43 were newly identified and 38 resulted in amino acid substitutions. No isolates showed L263E and S769N substitutions, which were reportedly associated with artemisinin resistance. Among the four continents, the number of SNPs was highest in Africa. In Africa, Asia, and Oceania, common SNPs, or those with a minor allele frequency of ≥0.05, were less prevalent, with most SNPs noted to be continent specific, whereas in South America, common SNPs were highly prevalent and often shared with those in Africa. Of 50 amino acid haplotypes observed, only one haplotype (3D7 sequence) was seen in all four continents (64%). Forty-eight haplotypes had frequencies of less than 5%, and 40 haplotypes were continent specific. The geographical difference in the diversity and distribution of serca SNPs and haplotypes lays the groundwork for assessing whether some artemisinin resistance-associated mutations and haplotypes are selected by ACTs.

Published
2010
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19. Role of mesodermal FGF8 and FGF10 overlaps in the development of the arterial pole of the heart and pharyngeal arch arteries

Author

Stéphane D. Vincent, Margaret Buckingham, Sachiko Miyagawa-Tomita, Yusuke Watanabe, Anne M. Moon, Robert G. Kelly, Département de Biologie du Développement et Cellules souches - Department of Developmental and Stem Cell Biology, Institut Pasteur [Paris] (IP), Bases Génétiques, Moléculaires et Cellulaires du Développement (BGMCD), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Tokyo Women's Medical University (TWMU), Institut de Biologie du Développement de Marseille-Luminy (IBDML), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), University of Utah, The work performed in the laboratory of M.E.B. was supported by the Institut Pasteur and the Centre National de la Recherche Scientifique, with grants from the European Union Integrated Project 'Heart Repair' LHSM-CT2005-018630 (also to R.G.K.) and the CardioCell LT2009-223372 project. The work performed in the laboratory of A.M.M. was supported by the National Institute of Child Health and Development. Y.W. received a fellowship from the European Union Integrated Project 'Heart Repair.' S.M.-T. received a fellowship from the Naito Foundation to perform work for 6 months in the laboratory of M.E.B., European Project: 32570,HEARTREPAIR, European Project: 223372,EC:FP7:HEALTH,FP7-HEALTH-2007-B,CARDIOCELL(2009), Institut Pasteur [Paris], and Department of Pediatric Cardiology [Tokyo]

Subjects
Heart Defects, Congenital, Mesoderm, animal structures, Fibroblast Growth Factor 8, Genotype, Physiology, Heart Ventricles, Population, Gene Dosage, Ectoderm, Biology, Fibroblast growth factor, Article, Ventricular Outflow Obstruction, 03 medical and health sciences, Mice, 0302 clinical medicine, Fetal Heart, medicine, Animals, education, Crosses, Genetic, 030304 developmental biology, 0303 health sciences, education.field_of_study, FGF10, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Anatomy, second heart field, Mice, Mutant Strains, stomatognathic diseases, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, medicine.anatomical_structure, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Branchial Region, Circulatory system, embryonic structures, pharyngeal arch artery defects, arterial pole defects, Cardiology and Cardiovascular Medicine, Fibroblast Growth Factor 10, 030217 neurology & neurosurgery, Pharyngeal arch, Gene Deletion, Artery
Abstract

Rationale : The genes encoding fibroblast growth factor (FGF) 8 and 10 are expressed in the anterior part of the second heart field that constitutes a population of cardiac progenitor cells contributing to the arterial pole of the heart. Previous studies of hypomorphic and conditional Fgf8 mutants show disrupted outflow tract (OFT) and right ventricle (RV) development, whereas Fgf10 mutants do not have detectable OFT defects. Objectives : Our aim was to investigate functional overlap between Fgf8 and Fgf10 during formation of the arterial pole. Methods and Results : We generated mesodermal Fgf8; Fgf10 compound mutants with MesP1Cre . The OFT/RV morphology in these mutants was affected with variable penetrance; however, the incidence of embryos with severely affected OFT/RV morphology was significantly increased in response to decreasing Fgf8 and Fgf10 gene dosage. Fgf8 expression in the pharyngeal arch ectoderm is important for development of the pharyngeal arch arteries and their derivatives. We now show that Fgf8 deletion in the mesoderm alone leads to pharyngeal arch artery phenotypes and that these vascular phenotypes are exacerbated by loss of Fgf10 function in the mesodermal core of the arches. Conclusions : These results show functional overlap of FGF8 and FGF10 signaling from second heart field mesoderm during development of the OFT/RV, and from pharyngeal arch mesoderm during pharyngeal arch artery formation, highlighting the sensitivity of these key aspects of cardiovascular development to FGF dosage.

Published
2009
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20. POMT2 intragenic deletions and splicing abnormalities causing congenital muscular dystrophy with mental retardation

Author

Pascale Guicheney, Nigel F. Clarke, Taratuto Ana Lia, Akiko Yanagisawa, Susana Quijano-Roy, Norma B. Romero, Sandrine Vuillaumier-Barrot, Diana Rodriguez, C. Bouchet, Makiko Osawa, Nathalie Seta, Sylvie Odent, Tamao Endo, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pediatrics, Tokyo Women's Medical University (TWMU), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pédiatrie, Rééducation et Réanimation Neurorespiratoire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Glycobiology Research Group, Tokyo Metropolitan Institute of Gerontology, Institute for Neurological Research, Department of Neuropathology, Garrahan National Paediatric Hospital, Service de génétique clinique, hôpital Sud, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), De Villemeur, Hervé, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, Microcephaly, DNA, Complementary, Adolescent, RNA Splicing, DNA Mutational Analysis, Molecular Sequence Data, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Mannosyltransferases, Severity of Illness Index, Muscular Dystrophies, 03 medical and health sciences, Exon, 0302 clinical medicine, Intellectual Disability, Genetics, medicine, Humans, Muscular dystrophy, Allele, Dystroglycans, Muscle, Skeletal, Genetics (clinical), Exome sequencing, Alleles, 030304 developmental biology, Sequence Deletion, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, fungi, General Medicine, DNA, Sequence Analysis, DNA, medicine.disease, 3. Good health, genomic DNA, Muscular Dystrophies, Limb-Girdle, Child, Preschool, Congenital muscular dystrophy, Female, 030217 neurology & neurosurgery, Limb-girdle muscular dystrophy
Abstract

Background Alpha-dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) with autosomal recessive inheritance characterized by abnormal glycosylation of alpha-dystroglycan. Although six genetic causes have been identified ( FKTN, POMGNT1, POMT1, POMT2, FKRP , and LARGE ) many alpha-dystroglycanopathy patients remain without a genetic diagnosis after standard exon sequencing. To date POMT2 mutations have been identified in CMD cases with a wide range of clinical severities from Walker–Warburg syndrome to limb girdle muscular dystrophy without structural brain or ocular involvement. Methods We analyzed POMT2 in six CMD patients, who had severe diffuse muscle weakness, generalized joint contractures, microcephaly, severe mental retardation and elevated CK levels. Eye involvement was absent or limited to myopia or strabismus. We sequenced the coding regions of POMT2 using genomic DNA and cDNA generated from blood lymphocytes or B lymphoblastoid cell lines. Quantitative PCR analysis of genomic DNA was used to identify and determine the breakpoints of large deletions. Results We report five novel mutations in POMT2 , four of which were outside of coding exons, two large genomic deletions and two intronic single base substitutions that induced aberrant mRNA splicing. Conclusions Large scale DNA rearrangements (such as large deletions) and cryptic splice mutations, that can be missed on standard sequencing of genomic DNA, may be relatively common in POMT2 . Additional techniques, such as sequencing of cDNA are needed to identify all mutations. These results also confirm that POMT2 mutations are an important cause of the less severe alpha-dystroglycanopathy phenotypes.

Published
2009
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21. Genetics of rheumatoid arthritis contributes to biology and drug discovery

Author

Daniel B. Mirel, Lude Franke, Robert M. Plenge, S. Louis Bridges, Anne E. Eyler, Tsuneyo Mimori, René E. M. Toes, Ryo Yamada, Elizabeth W. Karlson, Katherine P. Liao, Jian Yang, Javier Martin, Katsunori Ikari, John Bowes, Philippe Dieudé, Yuta Kochi, Luis Rodriguez-Rodriguez, Namrata Gupta, Atsushi Takahashi, Yukinori Okada, Eli A. Stahl, Huji Xu, Gosia Trynka, Di Wu, Chikashi Terao, A. Manoharan, Dorothee Diogo, Tushar Bhangale, Koichiro Ohmura, Akari Suzuki, Philip L. De Jager, Ding Feng Su, Takahisa Kawaguchi, Jing Cui, Dimitrios A. Pappas, E.C. Keystone, Henk-Jan Guchelaar, Marieke J H Coenen, Lisbeth Ärlestig, Pilar Galan, Paul P. Tak, Leonid Padyukov, Lars Klareskog, Harm-Jan Westra, Solbritt Rantapää-Dahlqvist, Hye Soon Lee, Towfique Raj, Peter K. Gregersen, Atsuo Taniguchi, Xuezhong Zhou, Barbara E. Stranger, Lindsey A. Criswell, Joshua C. Denny, Michiaki Kubo, Steve Eyre, So Young Bang, Piet L. C. M. van Riel, Katherine A. Siminovitch, Mark Lathrop, Shinji Yoshida, Tõnu Esko, Lingying Ye, Mart A F J van de Laar, Peter M. Visscher, Hisashi Yamanaka, Soumya Raychaudhuri, Gang Xie, Michael H. Guo, Miguel A. Gonzalez-Gay, Alexandra Zhernakova, Anne Barton, Fumihiko Matsuda, Yoichiro Kamatani, Xavier Mariette, Robert J. Carroll, Ward Ortmann, Matthew A. Brown, Robert R. Graham, Tom W J Huizinga, Larry W. Moreland, Jun Liu, Niek de Vries, Lei Jiang, Jane Worthington, Andres Metspalu, Sang Cheol Bae, Kazuhiko Yamamoto, Hyon K. Choi, Keiko Myouzen, Joel M. Kremer, Timothy W. Behrens, Jeff Greenberg, Corinne Miceli-Richard, Jian Yin, Shigeki Momohara, Faculty of Behavioural, Management and Social Sciences, Harvard University [Cambridge], Broad Institute of Harvard and MIT, Partenaires INRAE, Monash University, Brigham and Women's Hospital, Kyoto University [Kyoto], Tokyo Women's Medical University (TWMU), Riken, RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Genetic Engineering Technology, Vanderbilt University [Nashville], New York University School of Medicine, NYU System (NYU), Albany Medical Center, Columbia University [New York], Second Military Medical University, University of Queensland [Brisbane], Mount Sinai Hospital [Toronto, Canada] (MSH), University of Toronto, University of Groningen, All Children’s Hospital, University of Tartu, Beijing Jiaotong University (BJTU), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Radboud university [Nijmegen], Twente University, Medish Spectrum Twente, Leiden University, Leiden Univ, Med Ctr, Dept Rheumatol, NL-2300 RC Leiden, Netherlands, Université Paris Diderot - Paris 7 (UPD7), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Sud - Paris 11 (UP11), University of Alabama at Birmingham (UAB), University of Cambridge [UK] (CAM), Glaxo Smith Kline, University of Amsterdam [Amsterdam] (UvA), Hanyang University, Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Hospital Universitario Marqués de Valdecilla [Santander], San Carlos Clinical Hospital, Umeå University, Boston University [Boston] (BU), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), McGill University = Université McGill [Montréal, Canada], National Institutes of Health (NIH) R01-AR057108 R01-AR056768 U01-GM092691 R01-AR059648, Burroughs Wellcome Fund, Japan Society of the Promotion of Science, Australian National Health and Medical Research Council 1036541, Netherlands Organization for Scientific Research, Dutch Reumafonds 11-1-101, Rosalind Franklin Fellowship, University of Groningen, Korea Healthcare technology R&D project, Ministry for Health and Welfare A121983, RETICS program RIER, Instituto de Salud Carlos III, Health Ministry RD12/0009, Medical Biobank of Northern Sweden, NIH (NIAMS) R01-AR056768 R01-AR056291 R01-AR065944 P60 AR047785 R21 AR056042, European Research Council, NIH R01AR063759-01A1 K08-KAR055688A, National Health and Medical Research Foundation Senior Principal Research Fellowship, Queensland State Government Premier's Fellowship, China Ministry of Science and Technology 2011CB946100, National Natural Science Foundation of China 30972339 81020108029 81273283, Science and Technology Commission of Shanghai Municipality 08XD1400400 11410701600 10JC1418400, Canada Research Chair, Sherman Family Chair in Genomics Medicine, Canadian Institutes for Health Research 79321, Ontario Research Fund 05-075, Health and Labour Sciences Research Grants, Ministry of Education, Culture, Sports, Science and Technology of the Japanese government, BE THE CURE (BTCure) project, Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), Clinical Immunology and Rheumatology, AII - Amsterdam institute for Infection and Immunity, ProdInra, Migration, Kyoto University, Radboud University [Nijmegen], and University of Twente

Subjects
Male, Candidate gene, IR-88943, In silico, [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Disease, Biology, Quantitative trait locus, SUSCEPTIBILITY, VARIANTS, Bioinformatics, Polymorphism, Single Nucleotide, METIS-300765, Article, White People, DISEASE, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], Arthritis, Rheumatoid, Mice, Asian People, RESOURCE, Drug Discovery, Animals, Humans, Genetic Predisposition to Disease, Molecular Targeted Therapy, GENOME-WIDE ASSOCIATION, RECEPTOR INHIBITION, Alleles, Genetics, Mice, Knockout, RISK, Multidisciplinary, IDENTIFICATION, Drug discovery, Drug Repositioning, Computational Biology, Human genetics, 3. Good health, [SDV] Life Sciences [q-bio], Drug repositioning, Case-Control Studies, Hematologic Neoplasms, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Female, TRAITS, Genome-Wide Association Study
Abstract

International audience; A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Published
2014
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23. Photodynamic therapy for malignant brain tumors in children and young adolescents.

Author

Chiba K, Aihara Y, Oda Y, Fukui A, Tsuzuk S, Saito T, Nitta M, Muragaki Y, and Kawamata T

Abstract

Photodynamic therapy (PDT) targets tumor cell remnants after resection. Here, we evaluated the feasibility of PDT for malignant brain tumors in children and young adolescents. This was a single-center, non-randomized, phase I/II clinical study. The primary endpoints were the safety of treatment with talaporfin sodium (TS) (phase I) and overall survival (OS) after PDT (phase II). The secondary endpoint was progression-free survival (PFS) after PDT. The TS dose was determined by dose escalation from 10 to 20 to 40 mg/m 2 for every three cases starting from the initial enrolled case. Eight patients with a mean age of 170.2 months (129-214 months) at the time of PDT received nine procedures with a mean follow-up duration of 16.8 months (1-42 months) after PDT. Histopathological diagnoses included supratentorial anaplastic ependymoma (n = 2), anaplastic astrocytoma (n = 1), diffuse midline glioma with H3K27M mutation (n = 1), glioblastoma (n = 3), and pediatric high-grade glioma (n = 1). The outcome was survival in five patients and death in three patients. Recurrence occurred in six of the eight patients; the remaining two were recurrence-free after PDT. Therefore, OS and PFS were calculated as 21 and 6 months, respectively. Seizures and fevers, which were likely surgery-related symptoms, were commonly observed. Photosensitive skin rashes or liver dysfunction, which are common adverse effects in adults, were not observed. Our results showed that TS can be used safely in children at doses comparable to those used in adults, as there was no major complication associated with TS administration. However, we cannot make a definitive conclusion about the efficacy of PDT because of the small number of participants. Accumulating cases was difficult because of the rarity of pediatric brain tumors and the difficulty in making a preoperative differential diagnosis, considering the wide range of histopathological findings. Moreover, the psychological stress associated with light-shielding management in pediatric patients was more severe than initially expected. In conclusion, TS at doses comparable to those used in adults may be safe for use in children and young adolescents between the ages of 6 and 20 years. However, further studies are needed to clarify its efficacy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chiba, Aihara, Oda, Fukui, Tsuduki, Saito, Nitta, Muragaki and Kawamata.)

Published
2022
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24. The best outcomes for going through pregnancy with diabetes-Clinical features of four recipients of the Lilly Insulin 50-Year Award.

Author

Omori Y, Yanagisawa K, and Sato A

Abstract

The Lilly Insulin 50-Year Award of Japan has been held since 2003. This Award is presented to people with diabetes based on their efforts in injecting insulin for 50 years. Among the 23 recipients of this Award in 2018, four were recognized because of their excellent efforts in receiving continuous treatment for diabetes mellitus before, during and throughout their life after pregnancy. This report focuses on the clinical features of these recipients with successful delivery of newborns at Tokyo Women's Medical University approximately 40-50 years ago. Three of the recipients [type 2 diabetes, n  = 2 (cases 1 and 3); type 1 diabetes, n  = 1 (case 4)] were treated before, during and after pregnancy, whereas one patient with type 2 diabetes (case 2) was only treated during pregnancy. Even though three recipients had a past history of stillbirth due to insufficient control of diabetes, all four recipients were directed to try to maintain normoglycemia before and during pregnancy, which resulted in the delivery of newborns without major events. The current ages of the recipients are 82, 78, 78 and 63 years old, respectively. No diabetic complications were observed in case 1. However, simple retinopathy occurred after ophthalmological treatment in case 3, and case 2 has received hemodialysis. Nevertheless, all of the patients have spent active lives with the confidence of successful delivery, even though none of the patient's HbA1c levels fell below 7% after delivery. The authors as their doctors are proud of the continuous efforts made by these four recipients to receive diabetes treatment before, during and after pregnancy. We therefore advocate "the best outcome for going through pregnancy with diabetes" to all diabetic patients who hope to become pregnant based on a planned pregnancy with the normalization of blood glucose., Competing Interests: Conflict of interestNone of the authors have any conflicts interest associated with this study., (© The Japan Diabetes Society 2019.)

Published
2019
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25. Estimation of parasympathetic nerve function during sleep in patients with obstructive sleep apnea by instantaneous time-frequency analysis.

Author

Yamaguchi K, Ohki N, Kobayashi M, Satoya N, Inoue Y, Onizawa S, Maeda Y, Sekiguchi H, Suzuki M, Tsuji T, Aoshiba K, and Nagai A

Subjects
Aged, Female, Heart Rate physiology, Humans, Male, Middle Aged, Respiratory Rate physiology, Signal Processing, Computer-Assisted, Sleep Stages physiology, Autonomic Nervous System Diseases physiopathology, Continuous Positive Airway Pressure, Parasympathetic Nervous System physiology, Polysomnography methods, Sleep Apnea, Obstructive physiopathology, Sleep Apnea, Obstructive therapy
Abstract

Background and Objectives: The pathophysiologic aspects of parasympathetic nerve (PN) function during sleep in patients with obstructive sleep apnea (OSA) studied by classical power spectrum analysis on heart rate variability (HRV) are highly controversial. The controversy is attributed to methodologic concerns, such as poor time resolution involved in power spectrum analysis. We aimed to establish the appropriate method for the investigation of PN function in OSA patients with apneas and hypopneas using instantaneous time-frequency analysis with complex demodulation (CD) and sufficient time resolution., Methods: A total of 30 patients with PSG-confirmed mild to severe OSA were recruited for the analysis of frequency spectra contained in R-R intervals (RRI) of overnight electrocardiograph (ECG) tracings. High-frequency (HF) domains ranging between 0.15 and 0.40 Hz were selected for analysis. Among these domains, the HF domain with the maximum instantaneous amplitude was defined as the main HF peak and was used as the surrogate marker of PN discharge. Based on density spectrum array (DSA) map for main HF peak constructed with a time scale of 1s and a frequency resolution of 0.002 Hz (HF-DSA map), the shift in central frequency (CF) of main HF peak over time was continuously monitored. When the main HF peak with the same CF lasted for more than 20 s or 5 min on HF-DSA map, the PN function was considered to be stable or very stable. The measurements were then repeated after continuous positive airway pressure (CPAP) treatment., Results: The extent of PN-evoked modulation of RRI was enhanced in nonrapid eye movement (NREM) sleep, though the stability was reduced in both NREM and rapid eye movement (REM) sleep. These peculiar behaviors of PN function were reversed by CPAP treatment., Conclusion: We found that instantaneous time-frequency analysis allowed estimation of transitional changes in PN function during sleep in OSA patients., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Published
2014
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26. Hyperzincemia with systemic inflammation: a heritable disorder of calprotectin metabolism with rheumatic manifestations?

Author

Saito Y, Saito K, Hirano Y, Ikeya K, Suzuki H, Shishikura K, Manno S, Takakuwa Y, Nakagawa K, Iwasa A, Fujikawa S, Moriya M, Mizoguchi N, Golden BE, and Osawa M

Subjects
Adolescent, Adult, Age of Onset, Arthritis, Juvenile complications, Creatine Kinase blood, Female, Hepatomegaly, Humans, Leukocyte L1 Antigen Complex, Leukopenia complications, Male, Metabolism, Inborn Errors complications, Muscular Dystrophies complications, Splenomegaly, Arthritis, Juvenile genetics, Calcium-Binding Proteins metabolism, Membrane Glycoproteins metabolism, Metabolism, Inborn Errors genetics, Neural Cell Adhesion Molecules metabolism, Zinc blood
Abstract

A boy had infantile-onset systemic inflammation, growth failure, hepatosplenomegaly, anemia, leukocytopenia, progressive muscular dystrophy, and hypercalprotectinemia, resulting in marked hyperzincemia. His mother had a history of chronic arthritis since childhood and also showed hypercalprotectinemia/hyperzincemia. We postulate an inherent defect in calprotectin metabolism.

Published
2002
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