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4,100 results on '"Institute of Preventive Medicine"'

1. Patient Preference in Blood Pressure Therapy

Author: Institute for Preventive Medicine and Roland E. Schmieder, Full Professor of Medicine
Published: 2020

2. EpiGraph: an open-source platform to quantify epithelial organization

Author: Ministerio de Economía y Competitividad (España), European Commission, Fundación Científica Asociación Española Contra el Cáncer, Universidad de Sevilla, Medical Research Council (UK), National Natural Science Foundation of China, The Lister Institute of Preventive Medicine (UK), Wellcome Trust, Vicente-Munuera, Pablo, Gómez-Gálvez, Pedro, Tetley, Robert J., Forja, Cristina, Tagua, Antonio, Letrán, Marta, Tozluoglu, Melda, Mao, Yanlan, Escudero, Luis M., Ministerio de Economía y Competitividad (España), European Commission, Fundación Científica Asociación Española Contra el Cáncer, Universidad de Sevilla, Medical Research Council (UK), National Natural Science Foundation of China, The Lister Institute of Preventive Medicine (UK), Wellcome Trust, Vicente-Munuera, Pablo, Gómez-Gálvez, Pedro, Tetley, Robert J., Forja, Cristina, Tagua, Antonio, Letrán, Marta, Tozluoglu, Melda, Mao, Yanlan, and Escudero, Luis M.
Abstract: Here we present EpiGraph, an image analysis tool that quantifies epithelial organization. Our method combines computational geometry and graph theory to measure the degree of order of any packed tissue. EpiGraph goes beyond the traditional polygon distribution analysis, capturing other organizational traits that improve the characterization of epithelia. EpiGraph can objectively compare the rearrangements of epithelial cells during development and homeostasis to quantify how the global ensemble is affected. Importantly, it has been implemented in the open-access platform Fiji. This makes EpiGraph very user friendly, with no programming skills required.
Published: 2020

3. TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function

Author: Medical Research Council (UK), Cancer Research UK, Consejo Superior de Investigaciones Científicas (España), European Commission, Wellcome Trust, The Lister Institute of Preventive Medicine (UK), Netherlands Organisation for Health Research and Development, Heath Research Board (Ireland), National Institutes of Health (US), Ellison Medical Foundation, Biogen, Gómez-Herreros, Fernando, Romero-Granados, Rocío, Cortés-Ledesma, Felipe, Caldecott, Keith W., Medical Research Council (UK), Cancer Research UK, Consejo Superior de Investigaciones Científicas (España), European Commission, Wellcome Trust, The Lister Institute of Preventive Medicine (UK), Netherlands Organisation for Health Research and Development, Heath Research Board (Ireland), National Institutes of Health (US), Ellison Medical Foundation, Biogen, Gómez-Herreros, Fernando, Romero-Granados, Rocío, Cortés-Ledesma, Felipe, and Caldecott, Keith W.
Abstract: Topoisomerase II (TOP2) removes torsional stress from DNA and facilitates gene transcription by introducing transient DNA double-strand breaks (DSBs). Such DSBs are normally rejoined by TOP2 but on occasion can become abortive and remain unsealed. Here we identify homozygous mutations in the TDP2 gene encoding tyrosyl DNA phosphodiesterase-2, an enzyme that repairs 'abortive' TOP2-induced DSBs, in individuals with intellectual disability, seizures and ataxia. We show that cells from affected individuals are hypersensitive to TOP2-induced DSBs and that loss of TDP2 inhibits TOP2-dependent gene transcription in cultured human cells and in mouse post-mitotic neurons following abortive TOP2 activity. Notably, TDP2 is also required for normal levels of many gene transcripts in developing mouse brain, including numerous gene transcripts associated with neurological function and/or disease, and for normal interneuron density in mouse cerebellum. Collectively, these data implicate chromosome breakage by TOP2 as an endogenous threat to gene transcription and to normal neuronal development and maintenance
Published: 2014

4. Identification of Isoflavonoid Metabolites in Humans

Author: Helsingin yliopisto, matemaattis-luonnontieteellinen tiedekunta, kemian laitos, University of Helsinki, Faculty of Science, Department of Chemistry, Laboratory of Organic Chemistry, Helsingfors universitet, matematisk-naturvetenskapliga fakulteten, kemiska institutionen, Folkhälsan Research Center, Institute for Preventive Medicine, Nutrition, and Cancer, University of Helsinki, Faculty of Medicine, Division of Clinical Chemistry, Heinonen, Satu-Maarit, Helsingin yliopisto, matemaattis-luonnontieteellinen tiedekunta, kemian laitos, University of Helsinki, Faculty of Science, Department of Chemistry, Laboratory of Organic Chemistry, Helsingfors universitet, matematisk-naturvetenskapliga fakulteten, kemiska institutionen, Folkhälsan Research Center, Institute for Preventive Medicine, Nutrition, and Cancer, University of Helsinki, Faculty of Medicine, Division of Clinical Chemistry, and Heinonen, Satu-Maarit
Abstract: Epidemiological studies have associated high soy intake with a lowered risk for certain hormone-dependent diseases, such as breast and prostate cancers, osteoporosis, and cardiovascular disease. Soy is a rich source of isoflavones, diphenolic plant compounds that have been shown to possess several biological activities. Soy is not part of the traditional Western diet, but many dietary supplements are commercially available in order to provide the proposed beneficial health effects of isoflavones without changing the original diet. These supplements are usually manufactured from extracts of soy or red clover, which is another important source of isoflavones. However, until recently, detailed studies of the metabolism of these compounds in humans have been lacking. The aim of this study was to identify urinary metabolites of isoflavones originating from soy or red clover using gas chromatography - mass spectrometry (GC-MS). To examine metabolism, soy and red clover supplementation studies with human volunteers were carried out. In addition, the metabolism of isoflavones was investigated in vitro by identification of metabolites formed during a 24-h fermentation of pure isoflavones with a human fecal inoculum. Qualitative methods for identification and analysis of isoflavone metabolites in urine and fecal fermentation samples by GC-MS were developed. Moreover, a detailed investigation of fragmentation of isoflavonoids in electron ionization mass spectrometry (EIMS) was carried out by means of synthetic reference compounds and deuterated trimethylsilyl derivatives. After isoflavone supplementation, 18 new metabolites of isoflavones were identified in human urine samples. The most abundant urinary metabolites of soy isoflavones daidzein, genistein, and glycitein were found to be the reduced metabolites, i.e. analogous isoflavanones, a-methyldeoxybenzoins, and isoflavans. Metabolites having additional hydroxyl and/or methoxy substituents, or their reduced analogs, were al, Runsaasti soijaa käyttävissä väestöissä ateroskleroosi, hormoneista riippuvaiset syövät ja osteoporoosi ovat olleet länsimaihin verrattuna harvinaisia. Soija ja soijasta valmistetut ruoat sisältävät paljon isoflavoneja, biologisesti aktiivisia difenolisia yhdisteitä. Toinen merkittävä isoflavonilähde on puna-apila. Soija ei kuulu länsimaiseen ruokavalioon, ja nykyään markkinoilla onkin runsaasti isoflavoneja sisältäviä erityisvalmisteita, jotka on valmistettu soijasta tai puna-apilasta. Näitä erityisvalmisteita markkinoidaan mm. vaihdevuosioireiden hoitoon, vahvistamaan luustoa ja hidastamaan sen haurastumista, sekä tasapainottamaan kehon hormonitoimintaa. Isoflavonien, etenkin puna-apilan isoflavonien metaboliaa ei kuitenkaan ole tarkoin tutkittu ihmisessä. Väitöskirjatyössä tunnistettiin soijaa tai puna-apilavalmistetta saaneilla vapaaehtoisilla tutkimushenkilöillä virtsaan erittyviä isoflavonien metaboliitteja käyttäen kaasukromatografia-massaspektrometria (GC-MS). Isoflavonien metaboliaa tutkittiin myös in vitro käsittelemällä tutkittavia yhdisteitä anaerobisesti ihmisen ulostemikrobien kanssa ja tunnistamalla käsittelyssä muodostuvia metaboliitteja. Virtsa- ja ulostenäytteiden analysointia varten kehitettiin kvalitatiiviset GC-MS menetelmät, ja lisäksi isoflavonien ja niiden metaboliittien tunnistamista varten selvitettiin tarkoin yhdisteiden massaspektrien tulkintaa tutkimalla yhdisteiden fragmentoitumista elektroni-ionisaatiomassaspektrometriassa (EIMS). Yhteensä 18 uutta isoflavonoidimetaboliittia tunnistettiin isoflavonisuplementaation jälkeen kerätyistä virtsanäytteistä. Valtaosa tunnistetuista soijaisoflavonien metaboliiteista oli soijan isoflavonien daidzeinin, genisteinin ja glyciteinin pelkistyneitä metaboliitteja. Näiden lisäksi näytteistä tunnistettiin myös hydroksyloituneita ja/tai metyloituneita metaboliitteja. Puna-apilaisoflavonien formononetiinin ja biochanin A:n metaboliitit olivat pääasiassa demetylaation seurauksena muodostuneet daidzein ja g
Published: 2006

5. Septins Recognize and Entrap Dividing Bacterial Cells for Delivery to Lysosomes

Author: Sina Krokowski, Dimitrios Angelis, Rut Carballido-López, Dieter Galea, Arnaud Chastanet, Elias T. Spiliotis, Gerald Larrouy-Maumus, Ricardo Henriques, Damián Lobato-Márquez, Serge Mostowy, Pedro M. Pereira, Imperial College London, Department of Immunology and Infection, London School of Hygiene and Tropical Medicine (LSHTM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris Saclay (COmUE), University College of London [London] (UCL), Department of Biology, Drexel University, Company of Biologists, European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant H2020-MSCA-IF-2016-752022, UK Biotechnology and Biological Sciences Research Council BB/M022374/1 BB/P027431/1 BB/R000697/1, UK Medical Research Council MR/K015826/1, Wellcome Trust 203276/Z/16/Z, National Institutes of Health/National Institute of General Medical Sciences GM097664, French National Research Agency ANR-12-ISV3-0004-01, Wellcome Trust Senior Research Fellowship 206444/Z/17/Z, Wellcome Trust Research Career Development Fellowship WT097411MA Lister Institute of Preventive Medicine, European Project: 311231,EC:FP7:ERC,ERC-2012-StG_20111109,BACEMO(2013), Wellcome Trust, Lister Institute of Preventive Medicine, and Medical Research Council (MRC)
Subjects: 0301 basic medicine, RING, Cellular immunity, Cell division, [SDV]Life Sciences [q-bio], Septin, FtsZ, Shigella flexneri, 0302 clinical medicine, GBPS, 1108 Medical Microbiology, Cytoskeleton, DIVISION, biology, cytoskeleton, Cell biology, mitochondria, Membrane curvature, Pseudomonas aeruginosa, INACTIVATION, biological phenomena, cell phenomena, and immunity, Life Sciences & Biomedicine, Cell Division, 0605 Microbiology, Staphylococcus aureus, GENES, Cardiolipins, Immunology, macromolecular substances, Microbiology, 03 medical and health sciences, MOTILITY, Virology, Autophagy, septins, Humans, Cell Proliferation, Science & Technology, Cell growth, fungi, DEGRADATION, 030104 developmental biology, membrane curvature, biology.protein, Commentary, Parasitology, Shigella, MEMBRANE, Lysosomes, cardiolipin, 030217 neurology & neurosurgery, Septin cytoskeleton, HeLa Cells
Abstract: International audience; The cytoskeleton occupies a central role in cellular immunity by promoting bacterial sensing and antibacterial functions. Septins are cytoskeletal proteins implicated in various cellular processes, including cell division. Septins also assemble into cage-like structures that entrap cytosolic Shigella, yet how septins recognize bacteria is poorly understood. Here, we discover that septins are recruited to regions of micron-scale membrane curvature upon invasion and division by a variety of bacterial species. Cardiolipin, a curvature-specific phospholipid, promotes septin recruitment to highly curved membranes of Shigella, and bacterial mutants lacking cardiolipin exhibit less septin cage entrapment. Chemically inhibiting cell separation to prolong membrane curvature or reducing Shigella cell growth respectively increases and decreases septin cage formation. Once formed, septin cages inhibit Shigella cell division upon recruitment of autophagic and lysosomal machinery. Thus, recognition of dividing bacterial cells by the septin cytoskeleton is a powerful mechanism to restrict the proliferation of intracellular bacterial pathogens.
Published: 2018
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6. SUMOylation of human septins is critical for septin filament bundling and cytokinesis

Author: Arnaud Echard, Serge Mostowy, Clothilde Cauvin, Pascale Cossart, Serena Boscaini, Martin Siguier, David Ribet, vicente, marie-therese, ERA-NET Infect-ERA - Subversive pro- and anti-inflammation trade-offs promote infection by Listeria monocytogenes - - PROANTILIS2013 - ANR-13-IFEC-0004 - IFEC - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Bacterial, cellular and epigenetic factors that control enteropathogenicity - BacCellEpi - - H20202015-10-01 - 2018-09-30 - 670823 - VALID, Interactions Bactéries-Cellules (UIBC), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Trafic membranaire et Division cellulaire - Membrane Traffic and Cell Division, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Imperial College London, Work in P. Cossart’s laboratory received financial support from Institut Pasteur, Institut National de la Santé et de la Recherche Médicale, Institut National de la Recherche Agronomique, the French National Research Agency (ANR, grant ERANET Infect-ERA PROANTILIS ANR-13-IFEC-0004-02), the French government’s Investissement d’Avenir program, Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (grant ANR-10-LABX-62-IBEID), the European Research Council (grant H2020-ERC-2014-ADG 670823-BacCellEpi), the Fondation le Roch les Mousquetaires, and the International Balzan Prize Foundation. Work from A. Echard’s laboratory received financial support from Institut Pasteur, Centre National de la Recherche Scientifique, Institut National du Cancer (grant 2014-1-PLBIO-04), and ANR (grant AbsyStem 15-CE13-0001-02 and grant CYTOSIGN 16-CE13-004-02). D. Ribet is a Research Associate from INSERM. S. Mostowy is supported by a Wellcome Trust Research Career Development Fellowship (grant WT097411MA) and the Lister Institute of Preventive Medicine. P. Cossart is a Senior International Research Scholar of the Howard Hughes Medical Institute., We thank Edith Gouin and Véronique Villiers for their help in antibody production and Frauke Melchior for reagents., ANR-13-IFEC-0004,PROANTILIS,Subversive pro- and anti-inflammation trade-offs promote infection by Listeria monocytogenes(2013), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 670823,H2020,ERC-2014-ADG,BacCellEpi(2015), Wellcome Trust, Lister Institute of Preventive Medicine, Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), Trafic membranaire et Division cellulaire, and ANR-10-LABX-0062/10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
Subjects: 0301 basic medicine, epithelial-cells, mammalian septin, Cell division, SUMO protein, Cell Cycle Proteins, Septin, MESH: Cell Compartmentation, 0302 clinical medicine, Genes, Reporter, budding yeast, Cytoskeleton, MESH: Phylogeny, Phylogeny, Research Articles, Microscopy, Video, MESH: Sumoylation, 11 Medical And Health Sciences, homolog, 3. Good health, Cell biology, biological phenomena, cell phenomena, and immunity, ring, Fluorescence Recovery After Photobleaching, Protein sumoylation, SEPT2, MESH: Septins, MESH: Cytokinesis, sumo, Green Fluorescent Proteins, macromolecular substances, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Article, bud neck, 03 medical and health sciences, MESH: Cell Cycle Proteins, MESH: Green Fluorescent Proteins, component, MESH: Cytoskeleton, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cytokinesis, MESH: Osteoblasts, Osteoblasts, MESH: Humans, cycle, fungi, MESH: Genes, Reporter, Sumoylation, Fluorescence recovery after photobleaching, Cell Biology, 06 Biological Sciences, Cell Compartmentation, MESH: Microscopy, Video, kinesin-like protein, 030104 developmental biology, MESH: Protein Processing, Post-Translational, MESH: HeLa Cells, Protein Processing, Post-Translational, Septins, 030217 neurology & neurosurgery, MESH: Fluorescence Recovery After Photobleaching, HeLa Cells, Developmental Biology
Abstract: Yeast septins were among the first proteins reported to be SUMOylated, but the impact of this modification on septin function is unclear. Ribet et al. show that septins are SUMOylated in humans and that SUMOylation is critical for septin bundle formation and septin function in cell division., Septins are cytoskeletal proteins that assemble into nonpolar filaments. They are critical in diverse cellular functions, acting as scaffolds for protein recruitment and as diffusion barriers for subcellular compartmentalization. Human septins are encoded by 13 different genes and are classified into four groups based on sequence homology (SEPT2, SEPT3, SEPT6, and SEPT7 groups). In yeast, septins were among the first proteins reported to be modified by SUMOylation, a ubiquitin-like posttranslational modification. However, whether human septins could be modified by small ubiquitin-like modifiers (SUMOs) and what roles this modification may have in septin function remains unknown. In this study, we first show that septins from all four human septin groups can be covalently modified by SUMOs. We show in particular that endogenous SEPT7 is constitutively SUMOylated during the cell cycle. We then map SUMOylation sites to the C-terminal domain of septins belonging to the SEPT6 and SEPT7 groups and to the N-terminal domain of septins from the SEPT3 group. We finally demonstrate that expression of non-SUMOylatable septin variants from the SEPT6 and SEPT7 groups leads to aberrant septin bundle formation and defects in cytokinesis after furrow ingression. Altogether, our results demonstrate a pivotal role for SUMOylation in septin filament bundling and cell division.
Published: 2017
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7. Preventive Medicine Study of Childhood Atopic Diseases

Author: National Science Council, Taiwan and YungLing Lee / Institute of Preventive Medicine
Published: 2009

8. Contribution of energy restriction and macronutrient composition to changes in adipose tissue gene expression during dietary weight-loss programs in obese women

Author: Claus Holst, Nathalie Vega, Moira A. Taylor, J. Alfredo Martínez, Eva Klimcakova, Thorkild I. A. Sørensen, Dominique Langin, Sébastien Déjean, Jean M. Oppert, Peter Arner, Hubert Vidal, Nathalie Viguerie, Karine Clément, Frédéric Capel, Wim H. M. Saris, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Recherche sur les obésités, CHU Toulouse [Toulouse]-Laboratoire, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Service d'anatomie et cytologie pathologiques [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Franco-Czech Laboratory for Clinical Research on Obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine Lyon-Sud, FACULTE DE LYON, Centre de Recherche en Nutrition Humaine, Hospices Civils de Lyon (HCL), Régulations métaboliques, nutrition et diabètes - UM55 (RMND UM55), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-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)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Institut de Mathématiques de Toulouse UMR5219 (IMT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Department of Midicine Karolinska Institute, Karolinska University Hospital Huddinge, Department of Sports Medicine of Charles University, Faculty of Medicine Charles University, Department of Physiology and nutrition University of Navarra, Universidad de Navarra [Pamplona] (UNAV), Department of Human Biology Nutrition and Toxicology Research Institute, Maastricht University [Maastricht], The Netherlands Institute of Preventive Medicine, Institute of Preventive Medicine, School of Biomedical Sciences Queen's Medical Center, University of Nottingham Medical School, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Toulouse, Charles University [Prague]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Department of Nutrition and Endocrinology AP / HP, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut de médecine moléculaire de Rangueil ( I2MR ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), IFR 31 Louis Bugnard ( IFR 31 ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Charles University [Prague]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hospices Civils de Lyon ( HCL ), Régulations métaboliques, nutrition et diabètes - UM55 ( RMND UM55 ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-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 ) -Hospices Civils de Lyon ( HCL ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ), Institut de Mathématiques de Toulouse UMR5219 ( IMT ), Université Toulouse 1 Capitole ( UT1 ) -Université Toulouse - Jean Jaurès ( UT2J ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-PRES Université de Toulouse-Institut National des Sciences Appliquées - Toulouse ( INSA Toulouse ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Centre National de la Recherche Scientifique ( CNRS ), Universidad de Navarra [Pamplona] ( UNAV ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP), Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Endocrinologie, maladies métaboliques et nutrition [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Transcription, Genetic, Endocrinology, Diabetes and Metabolism, MESH: Energy Intake, Biochemistry, Body Mass Index, 0302 clinical medicine, Endocrinology, Gene expression, MESH: Genetic Variation, MESH : Adaptor Proteins, Signal Transducing, Oligonucleotide Array Sequence Analysis, 0303 health sciences, Addipose tissue, Reducing, MESH: Mitochondrial Proteins, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, MESH : Oligonucleotide Array Sequence Analysis, Adipose Tissue, Body Composition, MESH: Adipose Tissue, medicine.medical_specialty, Diet, Reducing, MESH : Body Composition, MESH : Adipose Tissue, MESH: Body Mass Index, MESH : Receptors, Glucocorticoid, 03 medical and health sciences, MESH: Weight Loss, Genetic, Humans, MESH : Fatty Acid-Binding Proteins, MESH : Mitochondrial Proteins, MESH: Adaptor Proteins, Signal Transducing, MESH: Humans, MESH : Humans, Signal Transducing, Genetic Variation, MESH: Adult, Autophagy-Related Protein 8 Family, MESH: Body Composition, medicine.disease, Obesity, MESH : Energy Metabolism, MESH : Body Mass Index, Energy intake, Body mass index, MESH: Female, Candidate gene, MESH: Receptors, Glucocorticoid, Clinical Biochemistry, Adipose tissue, Blood lipids, Glucocorticoid, Weight loss, Sirtuin 3, Receptors, MESH : RNA, Sirtuins, MESH: Obesity, MESH : Female, Nutrición y dietética [Ciencias de la Salud], MESH : Diet, Reducing, 2. Zero hunger, MESH : Sirtuins, MESH: Diet, Reducing, Microfilament Proteins, MESH: Energy Metabolism, Adaptor Proteins, MESH : Adult, MESH: Sirtuins, MESH : Obesity, Female, medicine.symptom, Transcription, Adult, MESH : Microfilament Proteins, 030209 endocrinology & metabolism, Context (language use), Biology, Fatty Acid-Binding Proteins, MESH: Fatty Acid-Binding Proteins, Mitochondrial Proteins, MESH: Microfilament Proteins, Receptors, Glucocorticoid, MESH : Genetic Variation, MESH: RNA, Internal medicine, Weight Loss, medicine, 030304 developmental biology, Adaptor Proteins, Signal Transducing, MESH: Transcription, Genetic, Biochemistry (medical), MESH : Transcription, Genetic, MESH : Energy Intake, Diet, MESH: Oligonucleotide Array Sequence Analysis, RNA, MESH : Weight Loss, Energy Intake, Energy Metabolism
Abstract: Context: Hypoenergetic diets are used to reduce body fat mass and metabolic risk factors in obese subjects. The molecular changes in adipose tissue associated with weight loss and specifically related to the dietary composition are poorly understood. Objective: We investigated adipose tissue gene expression from human obese women according to energy deficit and, the fat and carbohydrate content of the diet. Design & setting: Obese subjects recruited among 8 European clinical centers followed 10 weeks of either a low fat (high carbohydrate) or a moderate fat (low carbohydrate) hypoenergetic diet. Subjects: Two sets of 47 women in each dietary arm were selected among 648 subjects matched for anthropometric and biological parameters. Main Outcome Measure: We measured adipose tissue gene expression changes in one set using a candidate gene approach. The other set was used to survey 24469 transcripts using DNA microarrays. Results were analyzed using dedicated statistical methods. Diet-sensitive regulations were confirmed on the other set of subjects. Results: The two diets induced similar weight loss and similar changes for most of the biological variables except for components of the blood lipid profile. A thousand genes were regulated by energy restriction. We validated an effect of the fat-to-carbohydrate ratio for five genes (FABP4, NR3C1, SIRT3, FNTA and GABARAPL2) with increased expression during the moderate fat diet. Conclusions: Energy restriction had a more pronounced impact on variations in human adipose tissue gene expression than macronutrient composition. The macronutrient-sensitive regulation of a subset of genes may influence adipose tissue function and metabolic response. AD - INSERM, U858, Laboratoire de Recherches sur les Obesites, Institut de Medecine Moleculaire de Rangueil, Toulouse; Universite Paul Sabatier, Institut Louis Bugnard IFR31, Toulouse; Centre Hospitalier Universitaire de Toulouse, France; Franco-Czech Laboratory for Clinical Research on Obesity, Prague, Czech Republic; INSERM, UMR -870; INRA U-1235; Faculte de Medecine Lyon-Sud universite de Lyon 1; Centre de Recherche en Nutrition Humaine, Hospices civils de Lyon; Lyon, France; Institut de Mathematiques de Toulouse UMR 5219, Universite Paul-Sabatier, Toulouse, France; Department of Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Sports Medicine, Centre of Preventive Medicine, Third Faculty of Medicine, Charles University, Prague, Czech Republic; Franco-Czech Laboratory for Clinical Research on Obesity, Prague, Czech Republic; Department of Physiology and Nutrition, University of Navarra, Pamplona, Spain; Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands; Institute of Preventive Medicine, Centre for Health and Society, Copenhagen University Hospital, Copenhagen, Denmark; School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham Medical School, Nottingham, United Kingdom; INSERM, Nutriomique U872 (Team 7), 75004 Paris, France; Universites Pierre et Marie Curie-Paris6, UMR-S 872, Cordelier Research Center & Paris Descartes, 75006 Paris; and Assistance Publique/Hopitaux de Paris (AP-HP), Pitie Salpetriere Hospital, Nutrition and Endocrinology department, 75013 Paris, France.
Published: 2008

9. The role of aircraft noise annoyance and noise sensitivity in the association between aircraft noise levels and hypertension risk: results of a pooled analysis from seven European countries

Author: BAUDIN, Clémence, Lefevre, Marie, Babisch, Wolfgang, CADUM, Ennio, CHAMPELOVIER, Patricia, Dimakopoulou, Konstantina, HOUTHUIJS, Danny, Lambert, Jacques, Laumon, Bernard, Pershagen, Göran, STANSFELD, Stephen, Velonaki, Venetia, HANSELL, Anna, EVRARD, Anne Sophie, 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-Université Gustave Eiffel, retraité, Environmental Health Unit, Dynamiques des changements de mobilité (AME-DCM ), Université de Lyon-Université Gustave Eiffel, Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National Institute for Public Health and the Environment, parent, Département Transport, Santé, Sécurité (TS2), Centre for Psychiatry, Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine, Nurses School, National and Kapodistrian University of Athens, Centre for Environmental Health and Sustainability, University of Leicester, and University of Leicester
Subjects: [SPI.ACOU]Engineering Sciences [physics]/Acoustics [physics.class-ph], BRUIT, hypertension, TENSION, aircraft noise exposure, noise sensitivity, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, AEROPORT, SENSIBILITE, aircraft noise annoyance, human activities
Abstract: Introduction Many studies, including the HYENA and the DEBATS studies, showed a significant association between aircraft noise exposure and the risk of hypertension. Few studies have considered aircraft noise annoyance and noise sensitivity as factors of interest, especially in relation to hypertension risk, or as mediating or modifying factors. The present study aims 1) to investigate the risk of hypertension in relation to aircraft noise annoyance or noise sensitivity; and 2) to examine the role of modifier or mediator of these two factors in the association between aircraft noise levels and the risk of hypertension. Methods This study included 6,105 residents of ten European airports from the HYENA and DEBATS studies. Information on aircraft noise annoyance, noise sensitivity, and demographic, socioeconomic and lifestyle factors was collected during an interview performed at home. Participants were classified as hypertensive if they had either blood pressure levels above the WHO cut-off points or physician-diagnosed hypertension in conjunction with the use of antihypertensive medication. Outdoor aircraft noise exposure was estimated for each participant's home address. Poisson regression models with adjustment for potential confounders were used. Interactions between noise exposure and country were tested to consider possible differences between countries. Results An increase in aircraft noise levels at night was weekly but significantly associated with an increased risk of hypertension (RR=1.03, 95% CI 1.01-1.06 for a 10-dB(A) increase in Lnight). A significant association was found between aircraft noise annoyance and hypertension risk (RR=1.06, 95%CI 1.00-1.13 for highly annoyed people compared to those who were not highly annoyed). The risk of hypertension was slightly higher for people highly sensitive to noise compared to people with low sensitivity in the UK (RR=1.29, 95%CI 1.05-1.59) and in France (RR=1.11, 95%CI 0.68-1.82), but not in the other countries. The association between aircraft noise levels and the risk of hypertension was higher among highly sensitive participants (RR=1.00, 95%CI 0.96-1.04; RR=1.03, 95%CI 0.90-1.11; RR=1.12, 95%CI 1.01-1.24, with a 10-dB(A) increase in Lnight for low, medium, and high sensitive people respectively) or, to a lesser extent, among highly annoyed participants (RR=1.06, 95%CI 0.95-1.18 for a 10-dB(A) increase in Lnight among highly annoyed participants, and RR=1.02, 95%CI 0.99-1.06 among those not highly annoyed). Conclusions The present study confirms findings in the small number of available studies to date suggesting adverse health effects associated with aircraft noise annoyance and noise sensitivity. The findings also indicate possible modifier effects of aircraft noise annoyance and noise sensitivity in the relationship between aircraft noise levels and the risk of hypertension. However, further investigations are needed to better understand this role using specific methodology and tools related to mediation analysis and causal inference.
Published: 2020

10. Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling

Author: Nicolas Manel, Siham Boulisfane-El Khalifi, Mary Brennan, Darragh Duffy, Nadia Nathan, Serge Amselem, Kathryn J. McKenzie, Maria José Martin-Niclos, Jonny Hertzog, Carolina Uggenti, Marie Legendre, Stéphanie Chhun, Caroline Thumerelle, Luis Seabra, Marie-Louise Frémond, Vincent Bondet, Bénédicte Neven, Joseph A. Marsh, Marie Wislez, Catherine McDougall, Marine Depp, Jan Rehwinkel, Gillian I. Rice, Aurore Coulomb L'Hermine, Yanick J. Crow, Lucienne Chatenoud, Melvin Le Bihan, Thierry Jo Molina, Karen J. Mackenzie, Alice Lepelley, Edwin Carter, Jonathan Marey, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Radcliffe Department of Medicine [Oxford], University of Oxford [Oxford], Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Royal Hospital for Sick Children [Edinburgh], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service de pathologie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Service de pneumologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Royal Infirmary of Edinburgh, Département de Pathologie [CHU Necker], Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-CHU Necker - Enfants Malades [AP-HP], Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), M.-L. Frémond received a grant from the Institut National de la Santé et de la Recherche Médicale (000427993) and acknowledges La Fondation Square. Y.J. Crow acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs), and a state subsidy managed by the Agence Nationale de la Recherche under the 'Investments for the Future' program (ANR-10-IAHU-01). Y.J. Crow and D. Duffy acknowledge the Agence Nationale de la Recherche (grant CE17001002). J.A. Marsh is supported by a Medical Research Council Career Development Award (MR/M02122X/1) and is a Lister Institute of Preventive Medicine Research Prize Fellow. N. Manel was supported by LABEX DCBIOL (ANR-10-IDEX-0001-02 PSL* and ANR-11-LABX-0043), ANR-17-CE15-0025-01, ANR-18-CE92-0022-01, Fondation BMS, Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ECTZ71745), Sidaction (VIH2016126002), and Ile-de-France Emergence. M. Le Bihan received a doctoral fellowship from Ile-de-France ARDoc. The project was supported by MSDAVENIR (Devo-Decode Project)., We thank Immunoqure AG for provision of antibodies for the Simoa assay., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-17-CE15-0025,STINGCHECK,Mécanismes des points de contrôle du senseur de l'immunité innée STING(2017), ANR-18-CE92-0022,cGAS-Vac,Analyses fonctionnelles de la voie cGAS/STING au cours d'infections bactériennes et infections virales et implications pour le développement de vaccins innovants(2018), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Oxford, Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), UF de Génétique moléculaire [CHU Trousseau], Service de Pneumologie pédiatrique [CHU Trousseau], Vougny, Marie-Christine, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Mécanismes des points de contrôle du senseur de l'immunité innée STING - - STINGCHECK2017 - ANR-17-CE15-0025 - AAPG2017 - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Analyses fonctionnelles de la voie cGAS/STING au cours d'infections bactériennes et infections virales et implications pour le développement de vaccins innovants - - cGAS-Vac2018 - ANR-18-CE92-0022 - AAPG2018 - VALID, and Definition and characterization of type I interferonopathies - T1-IFN - - EC:FP7:ERC2013-03-01 - 2018-02-28 - 309449 - VALID
Subjects: 0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Protein subunit, Immunology, Mutant, Biology, medicine.disease_cause, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Interferon, medicine, Immunology and Allergy, Gene silencing, Mutation, HEK 293 cells, Golgi apparatus, eye diseases, 3. Good health, Cell biology, Sting, 030104 developmental biology, 030220 oncology & carcinogenesis, symbols, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.drug
Abstract: International audience; Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER-Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome.
Published: 2020

11. Policy Makers', NGO, and Healthcare Workers' Accounts of Migrants' and Refugees' Healthcare Access Across Europe—Human Rights and Citizenship Based Claims

Author: Bradby, Hannah, Lebano, Adele, Hamed, Sarah, Gil-Salmerón, Alejandro, Durá-Ferrandis, Estrella, Sherlaw, William, Christova, Iva, Karnaki, Pania, Zota, Dina, Riza, Elena, Uppsala University, University of Valencia, Centre de Recherches sur l'Action Politique en Europe (ARENES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut d'Études Politiques [IEP] - Rennes-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Centre National de la Recherche Scientifique (CNRS), École des Hautes Études en Santé Publique [EHESP] (EHESP), Département des sciences humaines et sociales (SHS), National Center of Infectious and Parasitic Diseases [Sofia, Bulgarie] (NCIPD), Institute of Preventive Medicine, Environmental and Occupational Health, University of Athens Medical School [Athens], Consumers, Health, Agriculture and Food Executive Agency, and Université de Rennes (UR)-Institut d'Études Politiques [IEP] - Rennes-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Europe, Refugees, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Healthcare access, Migrants, [SHS.SCIPO]Humanities and Social Sciences/Political science
Abstract: International audience; Freely available healthcare, universally accessible to the population of citizens, is a key ideal for European welfare systems. As labor migration of the twentieth century gave way to the globalized streams of the twenty-first century, new challenges to fulfilling these ideals have emerged. The principle of freedom of movement, together with large-scale forced migration have led to large scale movements of people, making new demands on European healthcare systems which had previously been largely focused on meeting sedentary local populations' needs. Drawing on interviews with service providers working for NGOs and public healthcare systems and with policy makers across 10 European countries, this paper considers how forced migrants' healthcare needs are addressed by national health systems, with factors hindering access at organizational and individual level in particular focus. The ways in which refugees' and migrants' healthcare access is prevented are considered in terms of claims based on citizenship and on the human right to health and healthcare. Where claims based on citizenship are denied and there is no means of asserting the human right to health, migrants are caught in a new form of inequality.
Published: 2020

12. Migrants' and refugees' health status and healthcare in Europe: A scoping literature review

Author: Adele Lebano, Estrella Durá-Ferrandis, Sarah Hamed, Fabienne Azzedine, Hannah Bradby, Alejandro Gil-Salmerón, Dina Zota, Elena Riza, Athena Linos, Jorge Garcés-Ferrer, Pania Karnaki, University of Edinburgh, Uppsala University, Universitat de València (UV), Centre de Recherches sur l'Action Politique en Europe (ARENES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut d'Études Politiques [IEP] - Rennes-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Centre National de la Recherche Scientifique (CNRS), École des Hautes Études en Santé Publique [EHESP] (EHESP), National and Kapodistrian University of Athens (NKUA), Prolepsis - Institute of Preventive Medicine, Environmental and Occupational Health, Consumers, Health, Agriculture and Food Executive Agency, Chafea, and Université de Rennes (UR)-Institut d'Études Politiques [IEP] - Rennes-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Healthcare use, Economic growth, Health Status, Services, 050109 social psychology, Health Services Accessibility, 0302 clinical medicine, Order (exchange), Epidemiology, Health care, Discrimination, 030212 general & internal medicine, 10. No inequality, Migration, media_common, Transients and Migrants, Refugees, Social care, 030503 health policy & services, lcsh:Public aspects of medicine, 05 social sciences, Healthcare, virus diseases, Public Health, Global Health, Social Medicine and Epidemiology, 3. Good health, Europe, Policy, population characteristics, 0305 other medical science, geographic locations, Research Article, Hälso- och sjukvårdsorganisation, hälsopolitik och hälsoekonomi, medicine.medical_specialty, Inequality, media_common.quotation_subject, Refugee, Asylum seekers, 050105 experimental psychology, 03 medical and health sciences, Equality, medicine, Humans, 0501 psychology and cognitive sciences, business.industry, Public health, Vulnerable migrants, Public Health, Environmental and Occupational Health, lcsh:RA1-1270, Health Care Service and Management, Health Policy and Services and Health Economy, [SHS.SCIPO]Humanities and Social Sciences/Political science, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Biostatistics, business
Abstract: Background There is increasing attention paid to the arrival of migrants from outwith the EU region to the European countries. Healthcare that is universally and equably accessible needs to be provided for these migrants throughout the range of national contexts and in response to complex and evolving individual needs. It is important to look at the evidence available on provision and access to healthcare for migrants to identify barriers to accessing healthcare and better plan necessary changes. Methods This review scoped 77 papers from nine European countries (Austria, Cyprus, France, Germany, Greece, Italy, Malta, Spain, and Sweden) in English and in country-specific languages in order to provide an overview of migrants’ access to healthcare. The review aims at identifying what is known about access to healthcare as well as healthcare use of migrants and refugees in the EU member states. The evidence included documents from 2011 onwards. Results The literature reviewed confirms that despite the aspiration to ensure equality of access to healthcare, there is evidence of persistent inequalities between migrants and non-migrants in access to healthcare services. The evidence shows unmet healthcare needs, especially when it comes to mental and dental health as well as the existence of legal barriers in accessing healthcare. Language and communication barriers, overuse of emergency services and underuse of primary healthcare services as well as discrimination are described. Conclusions The European situation concerning migrants’ and refugees’ health status and access to healthcare is heterogeneous and it is difficult to compare and draw any firm conclusions due to the scant evidence. Different diseases are prioritised by different countries, although these priorities do not always correspond to the expressed needs or priorities of the migrants. Mental healthcare, preventive care (immunization) and long-term care in the presence of a growing migrant older population are identified as priorities that deserve greater attention. There is a need to improve the existing data on migrants’ health status, needs and access to healthcare to be able to tailor care to the needs of migrants. To conduct research that highlights migrants’ own views on their health and barriers to access to healthcare is key.
Published: 2020

13. EpiGraph: an open-source platform to quantify epithelial organization

Author: Melda Tozluoglu, Cristina Forja, Pedro Gómez-Gálvez, Marta Letrán, Luis M. Escudero, Pablo Vicente-Munuera, Yanlan Mao, Robert J. Tetley, Antonio Tagua, Universidad de Sevilla. Departamento de Biología Celular, Ministerio de Economia, Industria y Competitividad (MINECO). España, ramón, Ministerio de Economía y Competitividad (España), European Commission, Fundación Científica Asociación Española Contra el Cáncer, Universidad de Sevilla, Medical Research Council (UK), National Natural Science Foundation of China, The Lister Institute of Preventive Medicine (UK), and Wellcome Trust
Subjects: Multicellular organism, Epigraph, Open source, Degree of order, Computational biology, Biology, Bioinformatics, Bioimage Informatics, Applications Notes, Organism, Software
Abstract: Here we present EpiGraph, an image analysis tool that quantifies epithelial organization. Our method combines computational geometry and graph theory to measure the degree of order of any packed tissue. EpiGraph goes beyond the traditional polygon distribution analysis, capturing other organizational traits that improve the characterization of epithelia. EpiGraph can objectively compare the rearrangements of epithelial cells during development and homeostasis to quantify how the global ensemble is affected. Importantly, it has been implemented in the open-access platform Fiji. This makes EpiGraph very user friendly, with no programming skills required., L.M.E. and P.G.-G. were supported by the Ramón y Cajal program (PI13/01347); L.M.E, P.V.-M. and P.G.-G. work was funded by the Ministry of Economy, Industry and Competitiveness grant BFU2016-74975-P co-funded by FEDER funds. P.V.-M. was supported by a contract co-funded by the Asociación Fundación Española contra el Cáncer and the Seville University. A.T. and C.F. were supported by a contract from Sistema Nacional de Garantía Juvenil and Programa Operativo de Empleo Juvenil 2014-2020. R.J.T. was funded by a Medical Research Council Skills Development Fellowship (MR/N014529/1). Y.M. was funded by a Medical Research Council Fellowship (MR/L009056/1), a UCL Excellence Fellowship, a NSFC International Young Scientist Fellowship (31650110472) and a Lister Institute Research Prize Fellowship. This work was also supported by MRC funding to the MRC LMCB University Unit at UCL (award code MC_U12266B). M.T. was funded by a Sir Henry Wellcome Fellowship (Grant No: 103095).
Published: 2020

14. Shigella sonnei O-Antigen Inhibits Internalization, Vacuole Escape, and Inflammasome Activation

Author: Abigail Clements, Jayne Watson, Vincenzo Torraca, Julia Sanchez-Garrido, Avinash R. Shenoy, Philippa J. Goddard, Serge Mostowy, Medical Research Council (MRC), Lister Institute of Preventive Medicine, and Commission of the European Communities
Subjects: O-Antigen, Vacuole, medicine.disease_cause, NLRP3 INFLAMMASOME, PYROPTOSIS, Type three secretion system, fluids and secretions, Type III Secretion Systems, host-pathogen interactions, Shigella, Shigella sonnei, 0303 health sciences, Pyroptosis, O Antigens, EPITHELIAL-CELLS, Inflammasome, Endocytosis, QR1-502, 3. Good health, macrophages, SECRETION, Life Sciences & Biomedicine, 0605 Microbiology, medicine.drug, Research Article, GENES, Biology, Models, Biological, Microbiology, HUMAN MACROPHAGES, Host-Microbe Biology, 03 medical and health sciences, Shigella flexneri, Virology, medicine, Humans, Secretion, inflammasomes, Dysentery, Bacillary, 030304 developmental biology, CASPASE-1 ACTIVATION, Science & Technology, 030306 microbiology, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, bacterial infections and mycoses, digestive system diseases, GASDERMIN D, STABLE EXPRESSION, Vacuoles, VIRULENCE, bacteria
Abstract: Diarrheal disease remains the second leading cause of death in children under five. Shigella remains a significant cause of diarrheal disease with two species, S. flexneri and S. sonnei, causing the majority of infections. S. flexneri are well known to cause cell death in macrophages, which contributes to the inflammatory nature of Shigella diarrhea. Here, we demonstrate that S. sonnei causes less cell death than S. flexneri due to a reduced number of bacteria present in the cell cytosol. We identify the O-Ag polysaccharide which, uniquely among Shigella spp., is present in two forms on the bacterial cell surface as the bacterial factor responsible. Our data indicate that S. sonnei differs from S. flexneri in key aspects of infection and that more attention should be given to characterization of S. sonnei infection., Two Shigella species, Shigella flexneri and Shigella sonnei, cause approximately 90% of bacterial dysentery worldwide. While S. flexneri is the dominant species in low-income countries, S. sonnei causes the majority of infections in middle- and high-income countries. S. flexneri is a prototypic cytosolic bacterium; once intracellular, it rapidly escapes the phagocytic vacuole and causes pyroptosis of macrophages, which is important for pathogenesis and bacterial spread. In contrast, little is known about the invasion, vacuole escape, and induction of pyroptosis during S. sonnei infection of macrophages. We demonstrate here that S. sonnei causes substantially less pyroptosis in human primary monocyte-derived macrophages and THP1 cells. This is due to reduced bacterial uptake and lower relative vacuole escape, which results in fewer cytosolic S. sonnei and hence reduced activation of caspase-1 inflammasomes. Mechanistically, the O-antigen (O-Ag), which in S. sonnei is contained in both the lipopolysaccharide and the capsule, was responsible for reduced uptake and the type 3 secretion system (T3SS) was required for vacuole escape. Our findings suggest that S. sonnei has adapted to an extracellular lifestyle by incorporating multiple layers of O-Ag onto its surface compared to other Shigella species.
Published: 2019

15. Shigella MreB promotes polar IcsA positioning for actin tail formation

Author: Krokowski, S, Atwal, S, Lobato-Márquez, D, Chastanet, A, Carballido-López, R, Salje, J, Mostowy, S, Imperial College London, London School of Hygiene and Tropical Medicine (LSHTM), University of Oxford [Oxford], Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University [Bangkok], Public Health Research Institute [Newark] (PHRI), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Company of Biologists, Royal Society Dorothy Hodgkin Research Fellowship [DH140154], European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant [H2020-MSCA-IF-2016-752022], European Research Council [ERC-StG-311231], Agence Nationale de la Recherche (French National Research Agency) [ANR-12-ISV3-0004-01], Wellcome Trust [206444/Z/17/Z, WT097411MA], and Lister Institute of Preventive Medicine
Subjects: [SDV]Life Sciences [q-bio], IcsA, Short Report, Septin, Shigella, MreB, Actin
Abstract: Pathogenic Shigella bacteria are a paradigm to address key issues of cell and infection biology. Polar localisation of the Shigella autotransporter protein IcsA is essential for actin tail formation, which is necessary for the bacterium to travel from cell-to-cell; yet how proteins are targeted to the bacterial cell pole is poorly understood. The bacterial actin homologue MreB has been extensively studied in broth culture using model organisms including Escherichia coli, Bacillus subtilis and Caulobacter crescentus, but has never been visualised in rod-shaped pathogenic bacteria during infection of host cells. Here, using single-cell analysis of intracellular Shigella, we discover that MreB accumulates at the cell pole of bacteria forming actin tails, where it colocalises with IcsA. Pharmacological inhibition of host cell actin polymerisation and genetic deletion of IcsA is used to show, respectively, that localisation of MreB to the cell poles precedes actin tail formation and polar localisation of IcsA. Finally, by exploiting the MreB inhibitors A22 and MP265, we demonstrate that MreB polymerisation can support actin tail formation. We conclude that Shigella MreB promotes polar IcsA positioning for actin tail formation, and suggest that understanding the bacterial cytoskeleton during host–pathogen interactions can inspire development of new therapeutic regimes for infection control. This article has an associated First Person interview with the first author of the paper., Summary: The pathogen Shigella forms actin tails to move through the cytosol of infected cells. We show that the bacterial actin homologue MreB can help to position the autotransporter protein IcsA for such actin tail formation.
Published: 2019

16. The use of Shigella flexneri to study bacterial cell biology during infection of host cells

Author: Krokowski, Sina Katharina, Mostowy, Serge, Wigneshweraraj, Ramesh, Wellcome Trust (London, England), Lister Institute of Preventive Medicine, and Company of Biologists
Subjects: macromolecular substances
Abstract: Shigella flexneri is a facultative intracellular bacterium and a paradigm to address key issues in cell biology and cell-autonomous immunity. Cell-autonomous immunity is a system of host defence that senses invading pathogens and mobilises anti-pathogen mechanisms, including autophagy. Recently, it has become clear that the cytoskeleton is directly linked to cell-autonomous immunity. During my PhD, I used S. flexneri to investigate bacterial factors that mediate interactions with the cytoskeleton and cell-autonomous immunity. Bacteria have counterparts to the host cytoskeleton components actin (e.g. MreB), microtubules (e.g. FtsZ), intermediate filaments (e.g. CreS) and septins (MinCD). However, rearrangements of the bacterial cytoskeleton have never been followed in pathogenic bacteria during infection of host cells. In Chapter 1, I generate new tools to follow the Shigella MreB, FtsZ and MinC cytoskeleton during infection of host cells using fluorescence microscopy. S. flexneri can exploit the host actin cytoskeleton to form ‘actin tails’ for its own motility. Actin-based motility enables bacterial cell-to-cell spread and evasion of the immune system. Polar localisation of the autotransporter IcsA is required for efficient actin tail formation, yet how IcsA is targeted to the bacterial cell pole was not fully known. In Chapter 2, I use Shigella MreB-msfGFPsw to reveal that MreB targets IcsA to the bacterial cell pole to promote actin tail formation and autophagy escape. To entrap Shigella for autophagy, the host septin cytoskeleton forms cage-like structures around actin polymerising bacteria. How septins recognise bacteria is poorly understood. In Chapter 3, I report that septins sense micron-scale curvature, cardiolipin and cell growth of dividing bacterial cells to inhibit Shigella cell division via autophagy and lysosome fusion. Therefore, the host septin cytoskeleton offers great potential to boost the recognition and restriction of dividing bacterial cells. Overall, the findings in this thesis have discovered that by controlling bacterial cell polarity, morphology and division, the bacterial cytoskeleton shapes host-pathogen interactions. Moreover, they highlight that investigation of the bacterial cytoskeleton during infection can inspire the development of new therapeutic regimes for infection control. Open Access
Published: 2018

17. Salmonella-Driven Polarization of Granuloma Macrophages Antagonizes TNF-Mediated Pathogen Restriction during Persistent Infection

Author: Sophie Helaine, Jose G. Vilches-Moure, Meagan Hamblin, Denise M. Monack, Teresa L. M. Thurston, Amanda R. Jacobson, Kyler A. Lugo, Susan M. Brewer, Trung H.M. Pham, Liliana M. Massis, Jared Honeycutt, Medical Research Council (MRC), Lister Institute of Preventive Medicine, and Biotechnology and Biological Sciences Research Council (BBSRC)
Subjects: EXPRESSION, macrophage polarization, Immunology, TNF, Macrophage polarization, CD11c, IMMUNITY, Biology, TUBERCULOSIS, Microbiology, 03 medical and health sciences, 0302 clinical medicine, Salmonella, 1108 Medical Microbiology, hemic and lymphatic diseases, Virology, medicine, alternatively activated, NITRIC-OXIDE SYNTHASE, granuloma, TUMOR-NECROSIS-FACTOR, 030304 developmental biology, persistent infection, 0303 health sciences, Science & Technology, Effector, Intracellular parasite, FACTOR-ALPHA, medicine.disease, SPI-2, Chronic infection, SteE, Integrin alpha M, NEUTRALIZATION, Granuloma, biology.protein, GROWTH, Parasitology, Tumor necrosis factor alpha, REGULATOR, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, SarA, 0605 Microbiology
Abstract: Many intracellular bacteria can establish chronic infection and persist in tissues within granulomas composed of macrophages. Granuloma macrophages exhibit heterogeneous polarization states, or phenotypes, that may be functionally distinct. Here, we elucidate a host-pathogen interaction that controls granuloma macrophage polarization and long-term pathogen persistence during Salmonella Typhimurium ( STm) infection. We show that STm persists within splenic granulomas that are densely populated by CD11b +CD11c +Ly6C + macrophages. STm preferentially persists in granuloma macrophages reprogrammed to an M2 state, in part through the activity of the effector SteE, which contributes to the establishment of persistent infection. We demonstrate that tumor necrosis factor (TNF) signaling limits M2 granuloma macrophage polarization, thereby restricting STm persistence. TNF neutralization shifts granuloma macrophages toward an M2 state and increases bacterial persistence, and these effects are partially dependent on SteE activity. Thus, manipulating granuloma macrophage polarization represents a strategy for intracellular bacteria to overcome host restriction during persistent infection.
Published: 2020

18. Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase to Direct Macrophage Polarization

Author: Elliott Jennings, Enkai Jin, Daphne A.C. Stapels, Sophie Helaine, Ioanna Panagi, Teresa L. M. Thurston, Hazel Mak, Nur.Z. Subari, Susan M. Brewer, Cullum D. Stones, Samantha Y.Q. Ong, Regina A. Günster, Denise M. Monack, Trung H.M. Pham, Jingkun Zeng, Medical Research Council (MRC), Lister Institute of Preventive Medicine, and Biotechnology and Biological Sciences Research Council (BBSRC)
Subjects: Salmonella typhimurium, M2, GSK3, STAT3, Serine, Glycogen Synthase Kinase 3, Mice, 0302 clinical medicine, Salmonella, 1108 Medical Microbiology, SPI2, host-pathogen interactions, 0303 health sciences, Virulence, Kinase, Effector, Protein-Tyrosine Kinases, M2 Macrophage, 3. Good health, Cell biology, SteE, Phosphorylation, dual-specificity kinases, Tyrosine kinase, 0605 Microbiology, STAT3 Transcription Factor, macrophage polarization, Immunology, Macrophage polarization, macromolecular substances, Protein Serine-Threonine Kinases, Biology, Microbiology, Article, 03 medical and health sciences, Bacterial Proteins, Virology, Animals, Humans, 030304 developmental biology, Serine/threonine-specific protein kinase, Host Microbial Interactions, Macrophages, Macrophage Activation, Mice, Inbred C57BL, HEK293 Cells, Parasitology, Interleukin-4, 030217 neurology & neurosurgery, HeLa Cells
Abstract: Summary Many Gram-negative bacterial pathogens antagonize anti-bacterial immunity through translocated effector proteins that inhibit pro-inflammatory signaling. In addition, the intracellular pathogen Salmonella enterica serovar Typhimurium initiates an anti-inflammatory transcriptional response in macrophages through its effector protein SteE. However, the target(s) and molecular mechanism of SteE remain unknown. Here, we demonstrate that SteE converts both the amino acid and substrate specificity of the host pleiotropic serine/threonine kinase GSK3. SteE itself is a substrate of GSK3, and phosphorylation of SteE is required for its activity. Remarkably, phosphorylated SteE then forces GSK3 to phosphorylate the non-canonical substrate signal transducer and activator of transcription 3 (STAT3) on tyrosine-705. This results in STAT3 activation, which along with GSK3 is required for SteE-mediated upregulation of the anti-inflammatory M2 macrophage marker interleukin-4Rα (IL-4Rα). Overall, the conversion of GSK3 to a tyrosine-directed kinase represents a tightly regulated event that enables a bacterial virulence protein to reprogram innate immune signaling and establish an anti-inflammatory environment., Graphical Abstract, Highlights • Salmonella effector SteE drives M2 macrophage polarization via GSK3 and STAT3 • SteE alters the substrate and amino acid specificity of the host kinase GSK3 • SteE enables GSK3, a S/T kinase, to phosphorylate STAT3 on Y705 • SteE requires GSK3-mediated phosphorylation to function, Numerous bacterial effectors modulate host immune responses via diverse biochemical activities. Panagi et al. report that the Salmonella effector SteE enables the pleiotropic host serine/threonine kinase GSK3 to phosphorylate a tyrosine residue on the non-canonical substrate STAT3. By triggering this substrate switch in GSK3, SteE creates an anti-inflammatory, infection-permissive environment.
Published: 2020

19. Shigella-Induced Emergency Granulopoiesis Protects Zebrafish Larvae from Secondary Infection

Author: Willis, Alexandra R., Torraca, Vincenzo, Gomes, Margarida C., Shelley, Jennifer, Mazon-Moya, Maria, Filloux, Alain, Lo Celso, Cristina, Mostowy, Serge, Wellcome Trust, Medical Research Council (MRC), Lister Institute of Preventive Medicine, Commission of the European Communities, and Sansonetti, Philippe J
Subjects: emergency granulopoiesis, animal structures, neutrophils, stem cells, fungi, Observation, Shigella, zebrafish, Microbiology, QR1-502, 0605 Microbiology
Abstract: Emergency granulopoiesis is a hematopoietic program of stem cell-driven neutrophil production used to counteract immune cell exhaustion following infection. Shigella flexneri is a Gram-negative enteroinvasive pathogen controlled by neutrophils. In this study, we use a Shigella-zebrafish (Danio rerio) infection model to investigate emergency granulopoiesis in vivo. We show that stem cell-driven neutrophil production occurs in response to Shigella infection and requires macrophage-independent signaling by granulocyte colony-stimulating factor (Gcsf). To test whether emergency granulopoiesis can function beyond homoeostasis to enhance innate immunity, we developed a reinfection assay using zebrafish larvae that have not yet developed an adaptive immune system. Strikingly, larvae primed with a sublethal dose of Shigella are protected against a secondary lethal dose of Shigella in a type III secretion system (T3SS)-dependent manner. Collectively, these results highlight a new role for emergency granulopoiesis in boosting host defense and demonstrate that zebrafish larvae can be a valuable in vivo model to investigate innate immune memory., IMPORTANCE Shigella is an important human pathogen of the gut. Emergency granulopoiesis is the enhanced production of neutrophils by hematopoietic stem and progenitor cells (HSPCs) upon infection and is widely considered a homoeostatic mechanism for replacing exhausted leukocytes. In this study, we developed a Shigella-zebrafish infection model to investigate stem cell-driven emergency granulopoiesis. We discovered that zebrafish initiate granulopoiesis in response to Shigella infection, via macrophage-independent signaling of granulocyte colony-stimulating factor (Gcsf). Strikingly, larvae primed with a sublethal dose of Shigella are protected against a secondary lethal dose of Shigella in a type III secretion system (T3SS)-dependent manner. Taken together, we show that zebrafish infection can be used to capture Shigella-mediated stem cell-driven granulopoiesis and provide a new model system to study stem cell biology in vivo. Our results also highlight the potential of manipulating stem cell-driven granulopoiesis to boost innate immunity and combat infectious disease.
Published: 2018

20. Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

Author: Yiallouros, Panayiotis K., Escobedo-de la Peña, Jorge, Zhou, Bin, Bentham, James, Di Cesare, Mariachiara, Bixby, Honor, Danaei, Goodarz, Hajifathalian, Kaveh, Taddei, Cristina, Carrillo-Larco, Rodrigo M., Djalalinia, Shirin, Khatibzadeh, Shahab, Lugero, Charles, Peykari, Niloofar, Zhang, Wan Zhu, Bennett, James, Bilano, Ver, Stevens, Gretchen A., Cowan, Melanie J., Riley, Leanne M., Chen, Zhengming, Hambleton, Ian R., Jackson, Rod T., Kengne, Andre Pascal, Khang, Young-Ho, Laxmaiah, Avula, Liu, Jing, Malekzadeh, Reza, Neuhauser, Hannelore K., Sorić, Maroje, Starc, Gregor, Sundström, Johan, Woodward, Mark, Ezzati, Majid, Abarca-Gómez, Leandra, Abdeen, Ziad A., Abu-Rmeileh, Niveen M., Acosta-Cazares, Benjamin, Adams, Robert J., Aekplakorn, Wichai, Afsana, Kaosar, Aguilar-Salinas, Carlos A., Agyemang, Charles, Ahmad, Noor Ani, Ahmadvand, Alireza, Ahrens, Wolfgang, Ajlouni, Kamel, Akhtaeva, Nazgul, Al-Raddadi, Rajaa, Ali, Mohamed M., Ali, Osman, Alkerwi, Ala'a, Aly, Eman, Amarapurkar, Deepak N., Amouyel, Philippe, Amuzu, Antoinette, Andersen, Lars Bo, Anderssen, Sigmund A., Ängquist, Lars H., Anjana, Ranjit Mohan, Ansong, Daniel, Aounallah-Skhiri, Hajer, Araújo, Joana, Ariansen, Inger, Aris, Tahir, Arlappa, Nimmathota, Arveiler, Dominique, Aryal, Krishna K., Aspelund, Thor, Assah, Felix K., Assunção, Maria Cecília F., Avdicová, Mária, Azevedo, Ana, Azizi, Fereidoun, Babu, Bontha V., Bahijri, Suhad, Balakrishna, Nagalla, Bamoshmoosh, Mohamed, Banach, Maciej, Bandosz, Piotr, Banegas, José R., Barbagallo, Carlo M., Barceló, Alberto, Barkat, Amina, Barros, Aluisio J. D., Barros, Mauro V., Bata, Iqbal, Batieha, Anwar M., Batyrbek, Assembekov, Baur, Louise A., Beaglehole, Robert, Romdhane, Habiba Ben, Benet, Mikhail, Benson, Lowell S., Bernabe-Ortiz, Antonio, Bernotiene, Gailute, Bettiol, Heloisa, Bhagyalaxmi, Aroor, Bharadwaj, Sumit, Bhargava, Santosh K., Bi, Yufang, Bikbov, Mukharram, Bista, Bihungum, Bjerregaard, Peter, Bjertness, Espen, Bjertness, Marius B., Björkelund, Cecilia, Blokstra, Anneke, Bo, Simona, Bobak, Martin, Boeing, Heiner, Boggia, Jose G., Boissonnet, Carlos P., Bongard, Vanina, Borchini, Rossana, Bovet, Pascal, Braeckman, Lutgart, Brajkovich, Imperia, Branca, Francesco, Breckenkamp, Juergen, Brenner, Hermann, Brewster, Lizzy M., Bruno, Graziella, Bueno-de-Mesquita, H. B(as), Bugge, Anna, Burns, Con, Bursztyn, Michael, de León, Antonio Cabrera, Cacciottolo, Joseph, Cai, Hui, Cameron, Christine, Can, Günay, Cândido, Ana Paula C., Capuano, Vincenzo, Cardoso, Viviane C., Carlsson, Axel C., Carvalho, Maria J., Casanueva, Felipe F., Casas, Juan-Pablo, Caserta, Carmelo A., Chamukuttan, Snehalatha, Chan, Angelique W., Chan, Queenie, Chaturvedi, Himanshu K., Chaturvedi, Nishi, Chen, Chien-Jen, Chen, Fangfang, Chen, Huashuai, Chen, Shuohua, Cheng, Ching-Yu, Dekkaki, Imane Cherkaoui, Chetrit, Angela, Chiolero, Arnaud, Chiou, Shu-Ti, Chirita-Emandi, Adela, Chirlaque, María-Dolores, Cho, Belong, Cho, Yumi, Christofaro, Diego G., Chudek, Jerzy, Cifkova, Renata, Cinteza, Eliza, Claessens, Frank, Clays, Els, Concin, Hans, Cooper, Cyrus, Cooper, Rachel, Coppinger, Tara C., Costanzo, Simona, Cottel, Dominique, Cowell, Chris, Craig, Cora L., Crujeiras, Ana B., Cruz, Juan J., D'Arrigo, Graziella, d'Orsi, Eleonora, Dallongeville, Jean, Damasceno, Albertino, Dankner, Rachel, Dantoft, Thomas M., Dauchet, Luc, Davletov, Kairat, De Backer, Guy, De Bacquer, Dirk, de Gaetano, Giovanni, De Henauw, Stefaan, de Oliveira, Paula Duarte, De Smedt, Delphine, Deepa, Mohan, Dehghan, Abbas, Delisle, Hélène, Deschamps, Valérie, Dhana, Klodian, Di Castelnuovo, Augusto F., Dias-da-Costa, Juvenal Soares, Diaz, Alejandro, Dickerson, Ty T., Do, Ha T. P., Donfrancesco, Chiara, Donoso, Silvana P., Döring, Angela, Dorobantu, Maria, Doua, Kouamelan, Drygas, Wojciech, Dulskiene, Virginija, Džakula, Aleksandar, Dzerve, Vilnis, Dziankowska-Zaborszczyk, Elzbieta, Eggertsen, Robert, Ekelund, Ulf, El Ati, Jalila, Elliott, Paul, Elosua, Roberto, Erasmus, Rajiv T., Erem, Cihangir, Eriksen, Louise, Eriksson, Johan G., Evans, Alun, Faeh, David, Fall, Caroline H., Farzadfar, Farshad, Felix-Redondo, Francisco J., Ferguson, Trevor S., Fernandes, Romulo A., Fernández-Bergés, Daniel, Ferrante, Daniel, Ferrari, Marika, Ferreccio, Catterina, Ferrieres, Jean, Finn, Joseph D., Fischer, Krista, Föger, Bernhard, Foo, Leng Huat, Forslund, Ann-Sofie, Forsner, Maria, Fouad, Heba M., Francis, Damian K., do Carmo Franco, Maria, Franco, Oscar H., Frontera, Guillermo, Fuchs, Flavio D., Fuchs, Sandra C., Fujita, Yuki, Furusawa, Takuro, Gaciong, Zbigniew, Galvano, Fabio, Garcia-de-la-Hera, Manoli, Gareta, Dickman, Garnett, Sarah P., Gaspoz, Jean-Michel, Gasull, Magda, Gates, Louise, Geleijnse, Johanna M., Ghasemian, Anoosheh, Ghimire, Anup, Giampaoli, Simona, Gianfagna, Francesco, Gill, Tiffany K., Giovannelli, Jonathan, Goldsmith, Rebecca A., Gonçalves, Helen, Gonzalez-Gross, Marcela, González-Rivas, Juan P., Gorbea, Mariano Bonet, Gottrand, Frederic, Graff-Iversen, Sidsel, Grafnetter, Dušan, Grajda, Aneta, Grammatikopoulou, Maria G., Gregor, Ronald D., Grodzicki, Tomasz, Grøntved, Anders, Grosso, Giuseppe, Gruden, Gabriella, Grujic, Vera, Gu, Dongfeng, Guan, Ong Peng, Gudmundsson, Elias F., Gudnason, Vilmundur, Guerrero, Ramiro, Guessous, Idris, Guimaraes, Andre L., Gulliford, Martin C., Gunnlaugsdottir, Johanna, Gunter, Marc, Gupta, Prakash C., Gupta, Rajeev, Gureje, Oye, Gurzkowska, Beata, Gutierrez, Laura, Gutzwiller, Felix, Hadaegh, Farzad, Halkjær, Jytte, Hardy, Rebecca, Hari Kumar, Rachakulla, Hata, Jun, Hayes, Alison J., He, Jiang, He, Yuna, Elisabeth, Marleen, Henriques, Ana, Cadena, Leticia Hernandez, Herrala, Sauli, Heshmat, Ramin, Hihtaniemi, Ilpo Tapani, Ho, Sai Yin, Ho, Suzanne C., Hobbs, Michael, Hofman, Albert, Dinc, Gonul Horasan, Horimoto, Andrea R. V. R., Hormiga, Claudia M., Horta, Bernardo L., Houti, Leila, Howitt, Christina, Htay, Thein Thein, Htet, Aung Soe, Than Htike, Maung Maung, Hu, Yonghua, Huerta, José María, Huisman, Martijn, Husseini, Abdullatif S., Huybrechts, Inge, Hwalla, Nahla, Iacoviello, Licia, Iannone, Anna G., Ibrahim, Mohsen M., Wong, Norazizah Ibrahim, Ikeda, Nayu, Ikram, M. Arfan, Irazola, Vilma E., Islam, Muhammad, al-Safi Ismail, Aziz, Ivkovic, Vanja, Iwasaki, Masanori, Jacobs, Jeremy M., Jaddou, Hashem, Jafar, Tazeen, Jamrozik, Konrad, Janszky, Imre, Jasienska, Grazyna, Jelaković, Ana, Jelaković, Bojan, Jennings, Garry, Jeong, Seung-lyeal, Jiang, Chao Qiang, Joffres, Michel, Johansson, Mattias, Jokelainen, Jari J., Jonas, Jost B., Jørgensen, Torben, Joshi, Pradeep, Jóźwiak, Jacek, Juolevi, Anne, Jurak, Gregor, Jureša, Vesna, Kaaks, Rudolf, Kafatos, Anthony, Kajantie, Eero O., Kalter-Leibovici, Ofra, Kamaruddin, Nor Azmi, Karki, Khem B., Kasaeian, Amir, Katz, Joanne, Kauhanen, Jussi, Kaur, Prabhdeep, Kavousi, Maryam, Kazakbaeva, Gyulli, Keil, Ulrich, Boker, Lital Keinan, Keinänen-Kiukaanniemi, Sirkka, Kelishadi, Roya, Kemper, Han C. G., Kengne, Andre P., Kerimkulova, Alina, Kersting, Mathilde, Key, Timothy, Khader, Yousef Saleh, Khalili, Davood, Khateeb, Mohammad, Khaw, Kay-Tee, Kiechl-Kohlendorfer, Ursula, Kiechl, Stefan, Killewo, Japhet, Kim, Jeongseon, Kim, Yeon-Yong, Klumbiene, Jurate, Knoflach, Michael, Kolle, Elin, Kolsteren, Patrick, Korrovits, Paul, Koskinen, Seppo, Kouda, Katsuyasu, Kowlessur, Sudhir, Koziel, Slawomir, Kriemler, Susi, Kristensen, Peter Lund, Krokstad, Steinar, Kromhout, Daan, Kruger, Herculina S., Kubinova, Ruzena, Kuciene, Renata, Kuh, Diana, Kujala, Urho M., Kulaga, Zbigniew, Krishna Kumar, R., Kurjata, Pawel, Kusuma, Yadlapalli S., Kuulasmaa, Kari, Kyobutungi, Catherine, Laatikainen, Tiina, Lachat, Carl, Lam, Tai Hing, Landrove, Orlando, Lanska, Vera, Lappas, Georg, Larijani, Bagher, Laugsand, Lars E., Le Nguyen Bao, Khanh, Le, Tuyen D., Leclercq, Catherine, Lee, Jeannette, Lee, Jeonghee, Lehtimäki, Terho, León-Muñoz, Luz M., Levitt, Naomi S., Li, Yanping, Lilly, Christa L., Lim, Wei-Yen, Lima-Costa, M. Fernanda, Lin, Hsien-Ho, Lin, Xu, Lind, Lars, Linneberg, Allan, Lissner, Lauren, Litwin, Mieczyslaw, Lorbeer, Roberto, Lotufo, Paulo A., Lozano, José Eugenio, Luksiene, Dalia, Lundqvist, Annamari, Lunet, Nuno, Lytsy, Per, Ma, Guansheng, Ma, Jun, Machado-Coelho, George L. L., Machi, Suka, Maggi, Stefania, Magliano, Dianna J., Magriplis, Emmanuella, Majer, Marjeta, Makdisse, Marcia, Malhotra, Rahul, Mallikharjuna Rao, Kodavanti, Malyutina, Sofia, Manios, Yannis, Mann, Jim I., Manzato, Enzo, Margozzini, Paula, Marques-Vidal, Pedro, Marques, Larissa Pruner, Marrugat, Jaume, Martorell, Reynaldo, Mathiesen, Ellisiv B., Matijasevich, Alicia, Matsha, Tandi E., Mbanya, Jean Claude N., Mc Donald Posso, Anselmo J., McFarlane, Shelly R., McGarvey, Stephen T., McLachlan, Stela, McLean, Rachael M., McLean, Scott B., McNulty, Breige A., Mediene-Benchekor, Sounnia, Medzioniene, Jurate, Meirhaeghe, Aline, Meisinger, Christa, Menezes, Ana Maria B., Menon, Geetha R., Meshram, Indrapal I., Metspalu, Andres, Meyer, Haakon E., Mi, Jie, Mikkel, Kairit, Miller, Jody C., Minderico, Cláudia S., Francisco, Juan, Miranda, J. 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McLachlan, Stela, McLean, Rachael M, McLean, Scott B, McNulty, Breige A, Mediene-Benchekor, Sounnia, Medzioniene, Jurate, Meirhaeghe, Aline, Meisinger, Christa, Menezes, Ana Maria B, Menon, Geetha R, Meshram, Indrapal I, Metspalu, Andre, Meyer, Haakon E, Mi, Jie, Mikkel, Kairit, Miller, Jody C, Minderico, Cláudia S, Francisco, Juan, Miranda, J Jaime, Mirrakhimov, Erkin, Mišigoj-Durakovic, Marjeta, Modesti, Pietro A, Mohamed, Mostafa K, Mohammad, Kazem, Mohammadifard, Noushin, Mohan, Viswanathan, Mohanna, Salim, Mohd Yusoff, Muhammad Fadhli, Møllehave, Line T, Møller, Niels C, Molnár, Déne, Momenan, Amirabba, Mondo, Charles K, Monyeki, Kotsedi Daniel K, Moon, Jin Soo, Moreira, Leila B, Morejon, Alain, Moreno, Luis A, Morgan, Karen, Moschonis, George, Mossakowska, Malgorzata, Mostafa, Aya, Mota, Jorge, Esmaeel Motlagh, Mohammad, Motta, Jorge, Msyamboza, Kelias P, Mu, Thet Thet, Muiesan, Maria L, Müller-Nurasyid, Martina, Murphy, Neil, Mursu, Jaakko, Musil, Vera, Nabipour, Iraj, Nagel, Gabriele, Naidu, Balkish M, Nakamura, Harunobu, Námešná, Jana, Nang, Ei Ei K, Nangia, Vinay B, Narake, Sameer, Nauck, Matthia, Navarrete-Muñoz, Eva Maria, Ndiaye, Ndeye Coumba, Neal, William A, Nenko, Ilona, Neovius, Martin, Nervi, Flavio, Nguyen, Chung T, Nguyen, Nguyen D, Nguyen, Quang Ngoc, Nguyen, Quang V, Nieto-Martínez, Ramfis E, Niiranen, Teemu J, Ning, Guang, Ninomiya, Toshiharu, Nishtar, Sania, Noale, Marianna, Noboa, Oscar A, Noorbala, Ahmad Ali, Norat, Teresa, Noto, Davide, Al Nsour, Mohannad, O'Reilly, Dermot, Oda, Eiji, Oehlers, Glenn, Oh, Kyungwon, Ohara, Kumiko, Olinto, Maria Teresa A, Oliveira, Isabel O, Omar, Mohd Azahadi, Onat, Altan, Ong, Sok King, Ono, Lariane M, Ordunez, Pedro, Ornelas, Rui, Osmond, Clive, Ostojic, Sergej M, Ostovar, Afshin, Otero, Johanna A, Overvad, Kim, Owusu-Dabo, Elli, Paccaud, Fred Michel, Padez, Cristina, Pahomova, Elena, Pajak, Andrzej, Palli, Domenico, Palmieri, Luigi, Pan, Wen-Harn, Panda-Jonas, Songhomitra, Panza, Francesco, Papandreou, Dimitrio, Park, Soon-Woo, Parnell, Winsome R, Parsaeian, Mahboubeh, Patel, Nikhil D, Pecin, Ivan, Pednekar, Mangesh S, Peer, Nasheeta, Peeters, Petra H, Peixoto, Sergio Viana, Peltonen, Markku, Pereira, Alexandre C, Peters, Annette, Petersmann, Astrid, Petkeviciene, Janina, Pham, Son Thai, Pigeot, Iri, Pikhart, Hynek, Pilav, Aida, Pilotto, Lorenza, Pitakaka, Freda, Piwonska, Aleksandra, Plans-Rubió, Pedro, Polašek, Ozren, Porta, Miquel, Portegies, Marileen L P, Pourshams, Akram, Poustchi, Hossein, Pradeepa, Rajendra, Prashant, Mathur, Price, Jacqueline F, Puder, Jardena J, Puiu, Maria, Punab, Margu, Qasrawi, Radwan F, Qorbani, Mostafa, Bao, Tran Quoc, Radic, Ivana, Radisauskas, Ricarda, Rahman, Mahfuzar, Raitakari, Olli, Raj, Manu, Ramachandra Rao, Sudha, Ramachandran, Ambady, Ramos, Elisabete, Rampal, Lekhraj, Rampal, Sanjay, Rangel Reina, Daniel A, Redon, Josep, Reganit, Paul Ferdinand M, Ribeiro, Robespierre, Riboli, Elio, Rigo, Fernando, Rinke de Wit, Tobias F, Ritti-Dias, Raphael M, Robinson, Sian M, Robitaille, Cynthia, Rodríguez-Artalejo, Fernando, del Cristo Rodriguez-Perez, María, Rodríguez-Villamizar, Laura A, Rojas-Martinez, Rosalba, Romaguera, Dora, Ronkainen, Kimmo, Rosengren, Annika, Roy, Joel G R, Rubinstein, Adolfo, Sandra Ruiz-Betancourt, Blanca, Rutkowski, Marcin, Sabanayagam, Charumathi, Sachdev, Harshpal S, Saidi, Olfa, Sakarya, Sibel, Salanave, Benoit, Salazar Martinez, Eduardo, Salmerón, Diego, Salomaa, Veikko, Salonen, Jukka T, Salvetti, Massimo, Sánchez-Abanto, Jose, Sans, Susana, Santos, Diana A, Santos, Ina S, Nunes dos Santos, Renata, Santos, Rute, Saramies, Jouko L, Sardinha, Luis B, Sarganas, Giselle, Sarrafzadegan, Nizal, Saum, Kai-Uwe, Savva, Savva, Scazufca, Marcia, Schargrodsky, Herman, Schipf, Sabine, Schmidt, Carsten O, Schöttker, Ben, Schultsz, Constance, Schutte, Aletta E, Sein, Aye Aye, Sen, Abhijit, Senbanjo, Idowu O, Sepanlou, Sadaf G, Sharma, Sanjib K, Shaw, Jonathan E, Shibuya, Kenji, Shin, Dong Wook, Shin, Youchan, Si-Ramlee, Khairil, Siantar, Rosalynn, Sibai, Abla M, Santos Silva, Diego Augusto, Simon, Mary, Simons, Judith, Simons, Leon A, Sjöström, Michael, Skovbjerg, Sine, Slowikowska-Hilczer, Jolanta, Slusarczyk, Przemyslaw, Smeeth, Liam, Smith, Margaret C, Snijder, Marieke B, So, Hung-Kwan, Sobngwi, Eugène, Söderberg, Stefan, Solfrizzi, Vincenzo, Sonestedt, Emily, Song, Yi, Sørensen, Thorkild I A, Soric, Maroje, Jérome, Charles Sossa, Soumare, Aicha, Staessen, Jan A, Stathopoulou, Maria G, Stavreski, Bill, Steene-Johannessen, Jostein, Stehle, Peter, Stein, Aryeh D, Stergiou, George S, Stessman, Jochanan, Stieber, Jutta, Stöckl, Dori, Stocks, Tanja, Stokwiszewski, Jakub, Stronks, Karien, Strufaldi, Maria Wany, Sun, Chien-An, Sung, Yn-Tz, Suriyawongpaisal, Paibul, Sy, Rody G, Shyong Tai, E, Tammesoo, Mari-Lii, Tamosiunas, Abdona, Tan, Eng Joo, Tang, Xun, Tanser, Frank, Tao, Yong, Tarawneh, Mohammed Rasoul, Tarqui-Mamani, Carolina B, Tautu, Oana-Florentina, Taylor, Anne, Theobald, Holger, Theodoridis, Xenophon, Thijs, Lutgarde, Thuesen, Betina H, Tjonneland, Anne, Tolonen, Hanna K, Tolstrup, Janne S, Topbas, Murat, Topór-Madry, Roman, Tormo, María José, Torrent, Matie, Traissac, Pierre, Trichopoulos, Dimitrio, Trichopoulou, Antonia, Trinh, Oanh T H, Trivedi, Atul, Tshepo, Lechaba, Tulloch-Reid, Marshall K, Tullu, Fikru, Tuomainen, Tomi-Pekka, Tuomilehto, Jaakko, Turley, Maria L, Tynelius, Per, Tzourio, Christophe, Ueda, Peter, Ugel, Eunice E, Ulmer, Hanno, Uusitalo, Hannu M T, Valdivia, Gonzalo, Valvi, Damaskini, van der Schouw, Yvonne T, Van Herck, Koen, Van Minh, Hoang, van Rossem, Lenie, Van Schoor, Natasja M, van Valkengoed, Irene G M, Vanderschueren, Dirk, Vanuzzo, Diego, Vatten, Lar, Vega, Toma, Velasquez-Melendez, Gustavo, Veronesi, Giovanni, Monique Verschuren, W M, Verstraeten, Roosmarijn, Victora, Cesar G, Viet, Lucie, Viikari-Juntura, Eira, Vineis, Paolo, Vioque, Jesu, Virtanen, Jyrki K, Visvikis-Siest, Sophie, Viswanathan, Bharathi, Vlasoff, Tiina, Vollenweider, Peter, Voutilainen, Sari, Wade, Alisha N, Wagner, Aline, Walton, Janette, Wan Bebakar, Wan Mohamad, Wan Mohamud, Wan Nazaimoon, Wanderley, Rildo S, Wang, Ming-Dong, Wang, Qian, Wang, Ya Xing, Wang, Ying-Wei, Wannamethee, S Goya, Wareham, Nichola, Wedderkopp, Niel, Weerasekera, Deepa, Whincup, Peter H, Widhalm, Kurt, Widyahening, Indah S, Wiecek, Andrzej, Wijga, Alet H, Wilks, Rainford J, Willeit, Johann, Willeit, Peter, Williams, Emmanuel A, Wilsgaard, Tom, Wojtyniak, Bogdan, Wong-McClure, Roy A, Wong, Justin Y Y, Wong, Tien Yin, Woo, Jean, Giwercman Wu, Aleksander, Wu, Frederick C, Wu, Shouling, Xu, Haiquan, Yan, Weili, Yang, Xiaoguang, Ye, Xingwang, Yiallouros, Panayiotis K, Yoshihara, Akihiro, Younger-Coleman, Novie O, Yusoff, Ahmad Faudzi, Zainuddin, Ahmad Ali, Zambon, Sabina, Zampelas, Antoni, Zdrojewski, Tomasz, Zeng, Yi, Zhao, Dong, Zhao, Wenhua, Zheng, Wei, Zheng, Yingfeng, Zhu, Dan, Zhussupov, Baurzhan, Zimmermann, Esther, Cisneros, Julio Zuñiga, The State Key Laboratory of Cell Biology [Shanghai, China] (CAS Center for Excellence in Molecular Cell Science), Shanghai Institute of Biochemistry and Cell Biology [Shanghai, China]-University of Chinese Academy of Sciences [Shanghai, China], Imperial College London, University of Kentucky, Middlesex University, Cleveland Clinic, Universidad Peruana Cayetano Heredia (UPCH), Brandeis University, Mulago Hospital [Kampala, Ouganda], Department of Epidemiology and Public Health, Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), World Health Organisation (WHO), Al-Quds University, Discipline of Medicine, University of South Australia [Adelaide], Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Leibniz Institute for Prevention Research and Epidemiology - BIPS, Leibniz Association, Centre for Industrial Management, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Institute of Preventive Medicine, Copenhagen University Hospitals, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Dept. Atherosclerose, University of Iceland [Reykjavik], Institute for Biotechnology and Bioengineering (IBB), Technical University of Lisbon, Medical University of Łódź (MUL), Department of Preventive Medicine and Public Health, Universidad Autónoma de Madrid (UAM), Faculté de Médecine de Tunis, Université de Tunis El Manar (UTM), Sunder Lal Jain Hospital, Ufa Eye Research Institute [Bashkortostan], National Institute of Public Health, Department of Epidemiology, Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association-Leibniz Association, CHU Toulouse [Toulouse], Institute of Social and Preventive Medicine, Lausanne university hospital, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Medical Sciences [Turin, Italy] (DMS), Università degli studi di Torino = University of Turin (UNITO), ASU - School for Engineering of Matter, Transport and Energy, Arizona State University [Tempe] (ASU), Universidade do Porto = University of Porto, University of Oxford [Oxford], Cancer & Radiation Epidemiology Unit, Gertner Institute, Chaim Sheba Medical Center, Consorcio de Investigación Biomédica en Red especializado en Epidemiología y Salud Pública (CIBERESP), Los Centros de Investigación Biomédica en Red (CIBER), 2nd Department of Internal Medicine, Molecular Medicine, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-IRC KULAK, Department of Public Health, State University of Ghent, MRC Lifecourse Epidemiology Unit [Southampton, UK], University of Southampton, Réseau International des Instituts Pasteur (RIIP), Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Sahlgrenska University Hospital [Gothenburg], Institute of Metabolic Science, MRC, Institut National de Nutrition et de Technologie Alimentaire (INNTA), University of Huddersfield, IMIM-Hospital del Mar, Generalitat de Catalunya, Medstar Research Institute, Queen's University [Belfast] (QUB), Medical Research Council, Applied Sciences, National Research Institute on Food and Nutrition, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Innsbruck Medical University [Austria] (IMU), Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Laboratoire d'Etude des Mammifères Marins (LEMM), Océanopolis [Brest], Faculté de Médecine Henri Warembourg - Université de Lille, Institute of Sport Science and Clinical Biomechanics, University of Southern Denmark (SDU), Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Centro Investig Quim Aplicada, Coahuila, Mexico, Centro Investigacion en Quimica Aplicada, Coahuila, Mexico, University of Geneva [Switzerland], Department of Civil Engineering [Hamirpur], National Institute of Technology [Hamirpur], Health Services Research Unit, Danish Cancer Society, Institute of Cancer Epidemiology, London School of Hygiene and Tropical Medicine (LSHTM), University College of London [London] (UCL), The Georges Institute for International Health, The University of Sydney, School of Information Technology, Deakin University Waurn Ponds, Faculté de Médecine, Université Djilali Liabès [Sidi-Bel-Abbès], Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), CIBER de Epidemiología y Salud Pública (CIBERESP), VU University Medical Center [Amsterdam], Universiteit Gent = Ghent University [Belgium] (UGENT), Faculty of Agricultural and Food Science, American University of Beirut [Beyrouth] (AUB), Åbo Akademi University [Turku], Department of Public Health Sciences, Karolinska Institutet [Stockholm], Great Lakes Institute for Environmental Research, University of Windsor [Ca], Universität Heidelberg [Heidelberg], Research Center for Prevention and Health, University of Ljubljana, Division of Cancer Epidemiology, University of Crete School of medicine, School of Public Health and Clinical Nutrition, University of Eastern Finland, Institute of Epidemiology and Social Medicine, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Research Institute of Child Nutrition Dortmund, Rheinische Friedrich-Wilhelms-Universität Bonn, Cancer Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Department of Oncology, University of Tampere Medical School, University of Tampere, Wageningen University and Research [Wageningen] (WUR), Centre for Environmental Health, National Institue of Public Health, School of Public Health, The University of Hong Kong (HKU), Tehran University of Medical Sciences, Istituto Nazionale di Ricerca per gli Alimenti e la Nutrizione (INRAN), INRAN, National University of Singapore (NUS), Faculty of Medicine and Life Sciences [Tampere], University of Tampere [Finland], Centre Européen de Réalité Virtuelle (CERV), École Nationale d'Ingénieurs de Brest (ENIB), Uppsala Universitet [Uppsala], Department of Public Health and Community Medicine, University of Gothenburg (GU), Institute of Earthquake Science, CEA, Beijing, CEA, Beijing, University of Porto Medical School, Laboratoire de Chimie Physique D'Orsay (LCPO), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Aging Program, National research council, Padua, Italy, Baker IDI Heart and Diabetes Institute, Institute of Internal Medicine, Russian Academy of Medical Sciences, Department of Nutrition and Dietetics, Harokopio University, Emory University [Atlanta, GA], Départment of Biotechnology, Faculty of Science, University of Oran Es-Senia [Oran] | Université d'Oran Es-Senia [Oran], Institut National de la Santé et de la Recherche Médicale (INSERM), University of Tartu, Department of Community, Université Ain Shams-Faculty of Medicine-Environmental and Occupational Medicine, Pécsi Tudemányegyetem, Department of Community, Environmental and Occupational Medicine, Université Ain Shams, Research Centre in Physical Activity, Health and Leisure, Nutrition and Metabolism Section, International Agency for Research on Cancer, Bushehr University of Medical Sciences, Institute of Epidemiology and Medical Biometry [Ulm, Allemagne], Universität Ulm - Ulm University [Ulm, Allemagne], Università degli studi di Palermo - University of Palermo, MRc Environmental Epidemiology Unit, Department of Cardiology and Department of Clinical Epidemiology, Aarhus University Hospital, Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Department of Epidemiology and Population Studies, Jagiellonian University, Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute – ISPO, Social Robotics Laboratory, University of Freiburg, Freiburg im Breisgau, Department of Ophthalmology, Universitätsklinikum Mannheim, Medizinische Fakultät Mannheim der Universität Heidelberg, University of Bari Aldo Moro (UNIBA), Department of Cardiology, Eastbourne General Hospital, Julius Center for Health Sciences and Primary Care, University Medical Center [Utrecht], Laboratoire d'Innovation pour les Technologies des Energies Nouvelles et les nanomatériaux (LITEN), Institut National de L'Energie Solaire (INES), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), King‘s College London, Public Health Sciences, University of Edinburgh, Movement Disorders and Tourette Centre, Genetica medicala, Victor Babeş University of Medicine and Pharmacy (UMFT), Andrology Unit, United Laboratories of Tartu University Clinics, Tampere University Hospital, Department of Hygiene and Epidemiology, Dept of Epidemiology and Public Health, Department of Epidemiology and Biostatistics, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Department of Emergency and Cardiovascular Medicine, Sahlgrenska Academy, Institut de Veille Sanitaire (INVS), Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain, parent, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], University of São Paulo (USP), Institut de Recherche pour le Développement (IRD [France-Sud]), Institute for plasma research, Institute for Plasma Research, Department of Biosciences and Nutrition, Department of Reproductive Endocrinology, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC - Academic medical center, Central Hospital and Faculty of medicine and biomedical sciences university, University of Yaoundé [Cameroun], Department of Clinical Sciences, Lund University [Lund]-Lund University Diabetes Centre, School of Computing [Leeds], University of Leeds, Copenhagen University Hospital, Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Maastricht University [Maastricht], Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Applied Food Science, Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, University of Amsterdam, Dept. of Social Medecine, Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University Hospital, Africa Centre for Health and Population Studies, University of KwaZulu-Natal [Durban, Afrique du Sud] (UKZN)-Medical Research Council of South Africa, Center for Family and Community Medicine, Department of Neurobiology, Care Sciences and Society, Department of Cardiovascular Sciences [Leuven], Cancer Epidemiology Institute, Department of Epidemiology and Health Promotion (MONICA Data Centre), National Public Health Institute, Nutrition et Alimentation des Populations aux Suds (NutriPass), Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Havard School of Public Health, Dept of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School [Athens], University of Kuopio, Tampere University, University Medical Centre Utrecht, Department of Social Medicine, Amsterdam, Center for Metabolic Bone Diseases, Catholic University of Leuven, Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Universidad Miguel Hernández [Elche] (UMH), Institute of Public Health and Clinical Nutrition [Kuopio, Finland], Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Division of Community Health Sciences, St George's University of London, Medizinische Universität Wien = Medical University of Vienna, Medical University of Silesia (SUM), National Institute for Public Health and the Environment [Bilthoven] (RIVM), University of Innsbruck, National Institute of Hygiene Warsaw, Johns Hopkins University School of Medicine [Baltimore], Food Science and Technology, Beijing Forestry University, College of Automation Engineering, Nanjing University of Aeronautics and Astronautics (CAE-NUAA), NUAA, Chinese Center for Disease Control and Prevention, Department of Applied Mathematics, School of Science, Northwestern Polytechnical University, Xi’an, Shaanxi 710072, Siemens Corporate Research, Siemens AG [Munich], Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), This work was supported by the Wellcome Trust [101506/Z/13/Z]., NCD Risk Factor Collaboration (NCD-RisC). We thank WHO country and regional offices and the World Heart Federation for support in data identification and access., Universidad Autonoma de Madrid (UAM), University of Turin, Universidade do Porto, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Lille 2 - Faculté de Médecine, Westfälische Wilhelms-Universität Münster (WWU), Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of KwaZulu-Natal (UKZN)-Medical Research Council of South Africa, Institut de Recherche pour le Développement (IRD)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Lund University Diabetes Centre-Lund University [Lund], Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Medical University of Silesia, Katowice, Apollo - University of Cambridge Repository, University of Kentucky (UK), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Lausanne University Hospital, University of Oxford, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Université de Genève = University of Geneva (UNIGE), Deakin University [Waurn Ponds], Universiteit Gent = Ghent University (UGENT), Universität Heidelberg [Heidelberg] = Heidelberg University, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Universidade de São Paulo = University of São Paulo (USP), Lund University [Lund], Laboratoire Chrono-environnement (UMR 6249) (LCE), Leopold Franzens Universität Innsbruck - University of Innsbruck, National Institute of Public Health - National Institute of Hygiene [Poland], Yiallouros, Panayiotis K. [0000-0002-8339-9285], Giampaoli, Simona [0000-0002-6679-1488], Moschonis, George [0000-0003-3009-6675], Papandreou, Dimitrios [0000-0002-4923-484X], Stathopoulou, Maria G. [0000-0003-4376-2083], Stergiou, George S. [0000-0002-6132-0038], Trichopoulou, Antonia [0000-0002-7204-6396], Valvi, Damaskini [0000-0003-4633-229X], Chen, Z, Woodward, M, Key, T, and Smith, M
Subjects: systolic blood pressure, Settore MED/09 - Medicina Interna, blood pressure measurement, HEALTH EXAMINATION SURVEYS, Blood Pressure, Hypertension, Population Health, Global Health, Non-communicable Disease, Epidemiology, [SDV]Life Sciences [q-bio], global health, South Asia, purl.org/pe-repo/ocde/ford#3.03.09 [https], kohonnut verenpaine, Medicine and Health Sciences, middle income country, measurement method, skin and connective tissue diseases, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Kardiologi: 771, Public, Environmental & Occupational Health, adult, Population health, public health, blood pressure regulation, Public Health, Global Health, Social Medicine and Epidemiology, Non-communicable disease, kansainvälinen vertailu, health survey, aged, female, priority journal, Blood pressure, mean arterial pressure, GLOBAL TRENDS, SODIUM-INTAKE, Life Sciences & Biomedicine, survey design, hypertension, prevalence, Global health, UNITED-STATES, URBAN COMMUNITIES, Article, SECULAR TRENDS, Middle East, Central Asia, male, disease prevalence, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, kansanterveys, blood, SYSTEMATIC ANALYSIS, human, verenpainetauti, non-communicable disease, Science & Technology, Pacific Ocean, high income country, diastolic blood pressure, Pacific Rim, Blood Pressure - Epidemiology - Population, North Africa, major clinical study, HYPERTENSION PREVALENCE, verenpaine, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, ARTERIAL-HYPERTENSION, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, POTASSIUM INTAKE, sense organs, trend analysis, trend study, population research, population health, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, low income country
Abstract: Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probit-transformed) prevalence of raised blood pressure and age-group-and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the high-income Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups., This work was supported by the Wellcome Trust [101506/Z/13/Z].
Published: 2018

21. Bacterial Autophagy: How to Take a Complement

Author: Vanessa Sancho-Shimizu, Serge Mostowy, Wellcome Trust, and Lister Institute of Preventive Medicine
Subjects: 0301 basic medicine, 030106 microbiology, Cell, Immunology, Biology, Microbiology, 03 medical and health sciences, Intestinal mucosa, Immunity, 1108 Medical Microbiology, Virology, medicine, Autophagy, Humans, Intestinal Mucosa, Opsonin, Immunity, Cellular, Science & Technology, Bacteria, Complement System Proteins, Blood proteins, Cell biology, Complement (complexity), Cytosol, 030104 developmental biology, medicine.anatomical_structure, Parasitology, Life Sciences & Biomedicine, 0605 Microbiology
Abstract: Complement, a complex system of serum proteins, contributes to host defense through multiple mechanisms. In this issue of Cell Host & Microbe, Sorbara et al. (2018) discovered that cytosolic pathogens opsonized by complement are restricted by autophagy. This unexpected role for complement is important for cell-autonomous immunity in the intestinal mucosa.
Published: 2018

22. Macrophage-Microbe Interactions: Lessons from the Zebrafish Model

Author: Nagisa Yoshida, Eva-Maria Frickel, Serge Mostowy, Wellcome Trust, and Lister Institute of Preventive Medicine
Subjects: 0301 basic medicine, lcsh:Immunologic diseases. Allergy, animal structures, Mini Review, Phagocytosis, Immunology, Cell, Danio, Inflammation, macrophage, REAL-TIME VISUALIZATION, 03 medical and health sciences, HOST-DEFENSE, 0302 clinical medicine, In vivo, medicine, host-pathogen interactions, Immunology and Allergy, Macrophage, INFECTIOUS-DISEASES, 14. Life underwater, LISTERIA-MONOCYTOGENES, Zebrafish, SHIGELLA-FLEXNERI, STAPHYLOCOCCUS-AUREUS, Science & Technology, biology, GRANULOMA-FORMATION, NOD-LIKE RECEPTORS, fungi, biology.organism_classification, zebrafish, ASPERGILLUS-FUMIGATUS, infection, Cell biology, 030104 developmental biology, medicine.anatomical_structure, inflammation, MYCOBACTERIAL INFECTION, medicine.symptom, lcsh:RC581-607, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Whole Organism, host–pathogen interactions
Abstract: Macrophages provide front line defense against infections. The study of macrophage–microbe interplay is thus crucial for understanding pathogenesis and infection control. Zebrafish (Danio rerio) larvae provide a unique platform to study macrophage–microbe interactions in vivo, from the level of the single cell to the whole organism. Studies using zebrafish allow non-invasive, real-time visualization of macrophage recruitment and phagocytosis. Furthermore, the chemical and genetic tractability of zebrafish has been central to decipher the complex role of macrophages during infection. Here, we discuss the latest developments using zebrafish models of bacterial and fungal infection. We also review novel aspects of macrophage biology revealed by zebrafish, which can potentiate development of new therapeutic strategies for humans.
Published: 2017

23. Septins restrict inflammation and protect zebrafish larvae from Shigella infection

Author: Avinash R. Shenoy, Serge Mostowy, Vincenzo Torraca, Emma Colucci-Guyon, Laurent Boucontet, Alexandra R. Willis, Maria J. Mazon-Moya, Imperial College London, Macrophages et Développement de l’Immunité, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), ARW is supported by a Medical Research Council PhD studentship. VT is supported by a Marie Skłodowska-Curie Fellowship (H2020-MSCA-IF-2015 – 700088). Work in the Mostowy laboratory is supported by a Wellcome Trust Research Career Development Fellowship (WT097411MA) and the Lister Institute of Preventive Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Inflammation, MESH: Neutrophils, Pathology and Laboratory Medicine, Biochemistry, NLRP3 INFLAMMASOME, Shigella flexneri, MITOCHONDRIA, Animal Cells, 1108 Medical Microbiology, MESH: Animals, Biology (General), Intestinal Mucosa, Immune Response, Bacterial Gastroenteritis, Fishes, Bacterial Pathogens, 3. Good health, Medical Microbiology, Osteichthyes, Shigellosis, AUTOPHAGY, Cellular Types, QH301-705.5, Immune Cells, Immunology, Gastroenterology and Hepatology, Microbiology, 03 medical and health sciences, Signs and Symptoms, HOST-DEFENSE, Genetics, Humans, Microbial Pathogens, Molecular Biology, Dysentery, Bacillary, Blood Cells, Science & Technology, MESH: Humans, Bacteria, MESH: Host-Pathogen Interactions, fungi, Organisms, Biology and Life Sciences, Proteins, Tropical Diseases, Immunity, Innate, 030104 developmental biology, INTERLEUKIN-1-RECEPTOR ANTAGONIST, Parasitology, Immunologic diseases. Allergy, MESH: Disease Models, Animal, MESH: Larva, Septins, Developmental Biology, Bacterial Diseases, 0301 basic medicine, Life Cycles, MESH: Shigella flexneri, Neutrophils, [SDV]Life Sciences [q-bio], Septin, ACTIVATION, White Blood Cells, Larvae, Medicine and Health Sciences, MACROPHAGES, Zebrafish, Pathogen, biology, Animal Models, Intestinal epithelium, Gastroenteritis, Infectious Diseases, Experimental Organism Systems, 1107 Immunology, Larva, Vertebrates, Host-Pathogen Interactions, MESH: Intestinal Mucosa, MESH: Immunity, Innate, Pathogens, medicine.symptom, Life Sciences & Biomedicine, Research Article, Neglected Tropical Diseases, 0605 Microbiology, MESH: Septins, MESH: Dysentery, Bacillary, INHIBITION, Inflammation, Research and Analysis Methods, Model Organisms, Immune system, Diagnostic Medicine, Virology, medicine, Animals, MESH: Zebrafish, Innate immune system, Cell Biology, RC581-607, biology.organism_classification, Disease Models, Animal, CELL-DEATH, AUTOINFLAMMATORY DISEASE, Shigella
Abstract: Shigella flexneri, a Gram-negative enteroinvasive pathogen, causes inflammatory destruction of the human intestinal epithelium. Infection by S. flexneri has been well-studied in vitro and is a paradigm for bacterial interactions with the host immune system. Recent work has revealed that components of the cytoskeleton have important functions in innate immunity and inflammation control. Septins, highly conserved cytoskeletal proteins, have emerged as key players in innate immunity to bacterial infection, yet septin function in vivo is poorly understood. Here, we use S. flexneri infection of zebrafish (Danio rerio) larvae to study in vivo the role of septins in inflammation and infection control. We found that depletion of Sept15 or Sept7b, zebrafish orthologs of human SEPT7, significantly increased host susceptibility to bacterial infection. Live-cell imaging of Sept15-depleted larvae revealed increasing bacterial burdens and a failure of neutrophils to control infection. Strikingly, Sept15-depleted larvae present significantly increased activity of Caspase-1 and more cell death upon S. flexneri infection. Dampening of the inflammatory response with anakinra, an antagonist of interleukin-1 receptor (IL-1R), counteracts Sept15 deficiency in vivo by protecting zebrafish from hyper-inflammation and S. flexneri infection. These findings highlight a new role for septins in host defence against bacterial infection, and suggest that septin dysfunction may be an underlying factor in cases of hyper-inflammation., Author summary Shigella are human-adapted Escherichia coli and cause bacillary dysentery via inflammatory destruction of the gut epithelium. In this study, we use a zebrafish (Danio rerio) model of Shigella infection to discover new roles for the cytoskeleton in inflammation and infection control. Septins, a poorly understood component of the cytoskeleton, are important in numerous biological processes including cell division and host-pathogen interactions. Here, we show that zebrafish septins can restrict inflammation and Shigella infection in vivo. In the absence of septins, larvae infected with Shigella exhibit increased mortality and bacterial burdens associated with increased Caspase-1 activity and neutrophil death. Pharmacological suppression of Il-1β signaling rescues septin-deficiency in vivo by reducing neutrophil death and preventing larval mortality. These findings reveal a new link between septins and inflammation, and highlight the cytoskeleton as a structural determinant of host defence.
Published: 2017

24. Mitochondria promote septin assembly into cages that entrap Shigella for autophagy

Author: Sina Krokowski, Damián Lobato-Márquez, Serge Mostowy, Wellcome Trust, Medical Research Council (MRC), and Lister Institute of Preventive Medicine
Subjects: 0301 basic medicine, autophagy, Biochemistry & Molecular Biology, Cell Cycle Proteins, macromolecular substances, Mitochondrion, Septin, Mitochondrial Dynamics, Models, Biological, Cell Line, Mitochondrial Proteins, 03 medical and health sciences, DNM1L, Shigella flexneri, Humans, septin, Molecular Biology, Dynamin, biology, fungi, Autophagy, 0601 Biochemistry And Cell Biology, cytoskeleton, Cell Biology, biology.organism_classification, Autophagic Punctum, Cell biology, mitochondria, Cytoskeletal Proteins, 030104 developmental biology, Mitochondrial fission, Shigella, biological phenomena, cell phenomena, and immunity, Septins, Cytokinesis, Protein Binding
Abstract: Septins, cytoskeletal proteins with well-characterised roles in cytokinesis, form cage-like structures around cytosolic Shigella flexneri and promote their targeting to autophagosomes. However, the processes underlying septin cage assembly, and whether they influence S. flexneri proliferation, remain to be established. Using single-cell analysis, we show that the septin cages inhibit S. flexneri proliferation. To study mechanisms of septin cage assembly, we used proteomics and found mitochondrial proteins associate with septins in S. flexneri-infected cells. Strikingly, mitochondria associated with S. flexneri promote septin assembly into cages that entrap bacteria for autophagy. We demonstrate that the cytosolic GTPase dynamin-related protein 1 (Drp1) interacts with septins to enhance mitochondrial fission. To avoid autophagy, actin-polymerising Shigella fragment mitochondria to escape from septin caging. Our results demonstrate a role for mitochondria in anti-Shigella autophagy and uncover a fundamental link between septin assembly and mitochondria.
Published: 2017

25. The association and a potential pathway between gender-based violence and induced abortion in Thai Nguyen province, Vietnam

Author: Sarah C. Keithly, Lan Tran Mai, Hoa Quynh Pham, Phuong T. Nguyen, Loan Thi Thu Luong, Son V. Nguyen, Nam Nguyen, Manh Quang Nguyen, and Institute for Preventive Medicine and Public Health, Hanoi Medical University, Vietnam
Subjects: Adult, Domestic Violence, medicine.medical_specialty, Adolescent, Thai Nguyen, Population, Poison control, Abortion, Social issues, Young Adult, Pregnancy, Gender-based violence, medicine, Humans, Psychiatry, education, reproductive and urinary physiology, Reproductive health, education.field_of_study, Marital Status, business.industry, Health Policy, lcsh:Public aspects of medicine, Sex Offenses, Public Health, Environmental and Occupational Health, Pregnancy, Unplanned, Abortion, Induced, lcsh:RA1-1270, Public Health in Vietnam: Here's the Data, Where's the Action?, Middle Aged, abortion, contraceptive use, unintended pregnancy, Vietnam, Cross-Sectional Studies, Logistic Models, Sexual abuse, Family planning, Female, Community Health, Public Health, business, Unintended pregnancy, Demography
Abstract: Background: Gender-based violence (GBV) has profound adverse consequences on women’s physical, mental, and reproductive health. Although Vietnam has high rates of induced abortion and GBV, literature examining this relationship is lacking.Objective: This study examines the association of GBV with induced abortion among married or partnered women of reproductive age in Thai Nguyen province, Vietnam. In addition, we explore contraceptive use and unintended pregnancy as mediators in the pathway between GBV and induced abortion. Design and methods: Data were drawn from a cross-sectional survey of 1,281 women aged 18-49 years in four districts of Thai Nguyen province. Bivariate and multivariate logistic regression analyses were applied to examine the associations between lifetime history of GBV, contraceptive use, unintended pregnancy, induced abortion, and repeat abortion, controlling for other covariates.Results: One-third of respondents had undergone induced abortion in their lifetime (33.4%), and 11.5% reported having repeat abortions. The prevalence of any type of GBV was 29.1% (17.0% physical violence, 10.4% sexual violence, and 20.1% emotional violence). History of GBV was associated with induced abortion (OR=1.61, 95% CI: 1.20-2.16) and repeat abortion (OR=2.22, 95% CI: 1.48-3.32). Physical violence was significantly associated with induced abortion, and all three types of violence were associated with repeat abortion. Abused women were more likely than non-abused women to report using contraceptives and having an unintended pregnancy, and these factors were in turn associated with increased risk of induced abortion.Conclusions: GBV is pervasive in Thai Nguyen province and is linked to increased risks of induced abortion and repeat abortion. The findings suggest that a pathway underlying this relationship is increased risk of unintended pregnancy due in part to ineffective use of contraceptives. These findings emphasize the importance of screening and identification of GBV and incorporating women’s empowerment in reproductive health and family planning programs.Keywords: Gender-based violence; abortion; contraceptive use; unintended pregnancy; Thai Nguyen; Vietnam(Published: 29 November 2012)Citation: Glob Health Action 2012, 5: 19006 - http://dx.doi.org/10.3402/gha.v5i0.19006This paper is part of Supplement 2, 2013 entitled Public health in Vietnam: here's the data, where's the action? - more papers from this supplement (incl the complete file) can be found here.
Published: 2012

26. Septins and bacterial infection

Author: Torraca, Vincenzo, Mostowy, Serge, Wellcome Trust, Lister Institute of Preventive Medicine, and Commission of the European Communities
Subjects: 0301 basic medicine, autophagy, Listeria, Mini Review, Phagocytosis, macromolecular substances, Mitochondrion, Biology, medicine.disease_cause, Septin, Microbiology, Cell and Developmental Biology, 03 medical and health sciences, Listeria monocytogenes, medicine, septins, Cytoskeleton, lcsh:QH301-705.5, Actin, Autophagy, fungi, cytoskeleton, Cell Biology, Cell biology, mitochondria, 030104 developmental biology, lcsh:Biology (General), cell-autonomous immunity, Shigella, biological phenomena, cell phenomena, and immunity, actin, Developmental Biology
Abstract: Septins, a unique cytoskeletal component associated with cellular membranes, are increasingly recognized as having important roles in host defense against bacterial infection. A role for septins during invasion of Listeria monocytogenes into host cells was first proposed in 2002. Since then, work has shown that septins assemble in response to a wide variety of invasive bacterial pathogens, and septin assemblies can have different roles during the bacterial infection process. Here we review the interplay between septins and bacterial pathogens, highlighting septin s as a structural determinant of host defense. We also discuss how investigation of septin assembly in response to bacterial infection can yield insight into basic cellular processes including phagocytosis, autophagy, and mitochondrial dynamics.
Published: 2016

27. Injections of predatory bacteria work alongside host immune cells to treat Shigella Infection in zebrafish larvae

Author: Willis, Alexandra R, Moore, Christopher, Mazon-Moya, Maria, Krokowski, Sina, Lambert, Carey, Till, Robert, Mostowy, Serge, Sockett, R Elizabeth, Wellcome Trust, and Lister Institute of Preventive Medicine
Subjects: Biochemistry & Molecular Biology, animal structures, Shigella flexneri, Bdellovibrio, 17 Psychology And Cognitive Sciences, Report, Drug Resistance, Multiple, Bacterial, antibiotic, Antibiosis, Animals, innate immunity, Dysentery, Bacillary, Immunity, Cellular, Science & Technology, Bacteria, Agricultural and Biological Sciences(all), Biochemistry, Genetics and Molecular Biology(all), fungi, Cell Biology, 11 Medical And Health Sciences, BDELLOVIBRIO-BACTERIOVORUS, 06 Biological Sciences, zebrafish, Immunity, Innate, Anti-Bacterial Agents, MODEL, antibacterial, Larva, Shigella, predation, Gram-Negative Bacterial Infections, Life Sciences & Biomedicine, Developmental Biology
Abstract: Summary Bdellovibrio bacteriovorus are predatory bacteria that invade and kill a range of Gram-negative bacterial pathogens in natural environments and in vitro [1, 2]. In this study, we investigated Bdellovibrio as an injected, antibacterial treatment in vivo, using zebrafish (Danio rerio) larvae infected with an antibiotic-resistant strain of the human pathogen Shigella flexneri. When injected alone, Bdellovibrio can persist for more than 24 hr in vivo yet exert no pathogenic effects on zebrafish larvae. Bdellovibrio injection of zebrafish containing a lethal dose of Shigella promotes pathogen killing, leading to increased zebrafish survival. Live-cell imaging of infected zebrafish reveals that Shigella undergo rounding induced by the invasive predation from Bdellovibrio in vivo. Furthermore, Shigella-dependent replication of Bdellovibrio was captured inside the zebrafish larvae, indicating active predation in vivo. Bdellovibrio can be engulfed and ultimately eliminated by host neutrophils and macrophages, yet have a sufficient dwell time to prey on pathogens. Experiments in immune-compromised zebrafish reveal that maximal therapeutic benefits of Bdellovibrio result from the synergy of both bacterial predation and host immunity, but that in vivo predation contributes significantly to the survival outcome. Our results demonstrate that successful antibacterial therapy can be achieved via the host immune system working together with bacterial predation by Bdellovibrio. Such cooperation may be important to consider in the fight against antibiotic-resistant infections in vivo., Highlights • Injected predatory Bdellovibrio bacteria persist non-pathogenically in zebrafish • Bdellovibrio injection promotes Shigella killing and increases zebrafish survival • Bdellovibrio are eventually cleared by the zebrafish immune system • Antibacterial therapy is achieved via the host immune system working with Bdellovibrio, In an era of global antibiotic resistance, Willis et al. characterize the “living-antibiotic” action of predatory Bdellovibrio bacteria in zebrafish larvae versus the human pathogen Shigella flexneri. Results are proof of principle that predators assist the immune system to promote animal survival upon infection by Gram-negative pathogens.
Published: 2016

28. Plasma phospholipid long-chain n-3 polyunsaturated fatty acids and body weight change

Author: Giovanna Tagliabue, Ingegerd Johansson, José María Huerta, Domenico Palli, Anne Tjønneland, Petra H.M. Peeters, Aurelio Barricarte, Anne M. May, Göran Hallmans, Francesca L. Crowe, Madlen Schütze, Daphne L. van der A, Françoise Clavel-Chapelon, Birgit Teucher, George Makrygiannis, Thorkild I. A. Sørensen, Jonas Manjer, Isabelle Romieu, Laudina Rodríguez, H. B. Bueno-de-Mesquita, Veronique Chajes, Kim Overvad, Guy Fagherazzi, Nadia Slimani, Karen Margrete Due, Nicholas J. Wareham, Dimosthenis Zylis, Heiner Boeing, Pilar Amiano, Kay-Tee Khaw, Claus Dethlefsen, Amalia Mattiello, Marianne Uhre Jakobsen, Rudolf Kaaks, Jytte Halkjær, Marie-Christine Boutron-Ruault, Elisabet Wirfält, Esther Molina-Montes, Noémie Travier, Elio Riboli, Antonia Trichopoulou, [Jakobsen,MU] Department of Clinical Epidemiology. [Jakobsen,MU, Dethlefsen,C, Due,KM, Overvad,K] Department of Cardiology, Center for Cardiovascular Research, Aalborg Hospital, Aarhus University Hospital, Aalborg. [Jakobsen,MU, Overvad,K] Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark. [Slimani,N, Chajès,V, Romieu,I] Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France. [May,AM, Peeter,PHM] Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht. [May,AM, van der A,DL, Bueno-de-Mesquita,HB] National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. [Sørensen,TIA] Institute of Preventive Medicine, Copenhagen University Hospital. [Halkjær,J, Tjønneland,A] The Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen, Denmark. [Clavel-Chapelon,F, Boutron-Ruault,M, Fagherazzi,G] Inserm, Centre for Research in Epidemiology and Population Health, Institut Gustave Roussy. Paris South University, Villejuif, France. [Teucher,B, Kaaks,R] German Cancer Research Center, Department of Cancer Epidemiology, Heidelberg. [Boeing,H, Schütze,M, Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany. [Trichopoulou,A, Zylis,D] WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School. [Trichopoulou,A, Zylis,D, Makrygiannis,G] Hellenic Health Foundation, Athens, Greece. [Palli,D] Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute, ISPO, Florence. [Mattiello,A] Department of Clinical and Experimental Medicine, Federico II University, Naples. [Tagliabue,G] Cancer Registry and Environmental Epidemiology Division, National Cancer Institute, Milan, Italy. [Bueno-de-Mesquita,HB] Department of Gastroenterology and Hepatology, University Medical Centre Utrecht (UMCU), Utrecht, The Netherlands. [Rodríguez,L] Public Health and Participation Directorate, Health and Health Care Services Council, Asturias. [Travier,N] Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology, IDIBELL, Barcelona. [Molina-Montes,E] Andalusian School of Public Health, Granada. [Molina-Montes,E, Huerta,JM, Barricarte,A, Amiano,P] CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona. [Huerta,JM] Department of Epidemiology, Murcia Regional Health Council, Murcia. [Barricarte,A] Public Health Institute of Navarra, Pamplona. [Amiano,P] Public Health Division of Gipuzkoa, Basque Government, Spain. [Manjer,J] Department of Surgery, Skåne University Hospital Malmö, Lund University. [Wirfält,E] Department of Clinical Sciences in Malmö/Nutrition Epidemiology, Lund University, Malmö. [Johansson,I] Department of Odontology, Umeå University. [Hallmans,G] Department of Public Health and Clinical Medicine, Umeå University, Nutritional Research, Umeå, Sweden. [Khaw,K] Clinical Gerontology Unit, Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge. [Wareham, NJ] MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge. [Crowe,F] Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford. [Riboli,E, Peeters, PHM] Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK., This work is part of the project Physical Activity, Nutrition, Alcohol, Cessation of Smoking, Eating out of Home and Obesity (PANACEA), which is supported by the European Union in the framework of the Public Health Programmme (Contract 2005328). The work was further supported by the European Commission: Public Health and Consumer Protection Directorate 1993–2004, Research Directorate-General 2005, Ligue contre le Cancer, Société 3M, Mutuelle Générale de l’Education Nationale, Institut National de la Santé de la Recherche Médicale (INSERM) (France), German Cancer Aid, German Cancer Research Center, Federal Ministry of Education and Research (Germany), Danish Cancer Society (Denmark), ISCIII (RETICC RD06/0020) of the Spanish Ministry of Health, the participating regional governments and institutions (Spain), Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, The Wellcome Trust (UK), Greek Ministry of Health, Greek Ministry of Education, Hellenic Ministry of Health, Stavros Niarchos Foundation, and the Hellenic Health Foundation (Greece), Italian Association for Research on Cancer, National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports, Dutch Ministry of Health, Dutch Prevention Funds, LK Research Funds, Dutch Zorg Onderzoek Nederland (ZON), World Cancer Research Fund (WCRF) (The Netherlands), and and Swedish Cancer Society, Swedish Scientific Council, Regional Government of Skane and Västerbotten (Sweden). This work is also part of the project Hepatic and Adipose Tissue and Functions in the Metabolic Syndrome (HEPADIP, www.hepadip.org), which is supported by the European Commission as an Integrated Project under the 6th Framework Programme (Contract LSHM-CT-2005-018734) and part of the research program of the Danish Obesity Research Centre (DanORC, www.danorc.dk), which is supported by the Danish Council for Strategic Research (Contract 2101-06-0005).
Subjects: Male, Health (social science), 030309 nutrition & dietetics, Obesidad, Ácidos grasos omega-3, Named Groups::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], chemistry.chemical_compound, 0302 clinical medicine, Estudios prospectivos, Fosfolípidos, Modelos lineales, Prospective Studies, Masculino, Prospective cohort study, Phospholipids, chemistry.chemical_classification, 0303 health sciences, education.field_of_study, Weight change, Femenino, Middle Aged, n-3 fatty acids, Humanos, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Female, Original Article, lipids (amino acids, peptides, and proteins), Cohort study, Polyunsaturated fatty acid, medicine.medical_specialty, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Prospective Studies [Medical Subject Headings], Population, Phospholipid, Check Tags::Male [Medical Subject Headings], 030209 endocrinology & metabolism, 03 medical and health sciences, Chemicals and Drugs::Lipids::Fats::Dietary Fats::Dietary Fats, Unsaturated::Fatty Acids, Omega-3 [Medical Subject Headings], Physiology (medical), Internal medicine, Fatty Acids, Omega-3, Omega-3 fatty acids, medicine, Humans, Obesity, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Models, Statistical::Linear Models [Medical Subject Headings], Chemicals and Drugs::Lipids::Phospholipids [Medical Subject Headings], education, Mediana edad, business.industry, Body Weight, Peso corporal, Body weight, Confidence interval, Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity [Medical Subject Headings], Endocrinology, Check Tags::Female [Medical Subject Headings], chemistry, Linear Models, Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Body Weight [Medical Subject Headings], sense organs, business
Abstract: Journal Article; Research Support, Non-U.S. Gov't; OBJECTIVE We investigated the association between the proportion of long-chain n-3 polyunsaturated fatty acids (PUFA) in plasma phospholipids from blood samples drawn at enrollment and subsequent change in body weight. Sex, age, and BMI were considered as potential effect modifiers. METHOD A total of 1,998 women and men participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) were followed for a median of 4.9 years. The associations between the proportion of plasma phospholipid long-chain n-3 PUFA and change in weight were investigated using mixed-effect linear regression. RESULTS The proportion of long-chain n-3 PUFA was not associated with change in weight. Among all participants, the 1-year weight change was -0.7 g per 1% point higher long-chain n-3 PUFA level (95% confidence interval: -20.7 to 19.3). The results when stratified by sex, age, or BMI groups were not systematically different. CONCLUSION The results of this study suggest that the proportion of long-chain n-3 PUFA in plasma phospholipids is not associated with subsequent change in body weight within the range of exposure in the general population. Yes
Published: 2016

29. Analyses of single nucleotide polymorphisms in selected nutrient-sensitive genes in weight-regain prevention: the DIOGENES study

Author: Lesli H. Larsen, Marie Kunešová, Arne Astrup, Dominique Langin, Marleen A. van Baak, J. Alfredo Martínez, Susan A. Jebb, Wim H. M. Saris, Karani Santhanakrishnan Vimaleswaran, Andreas Pfeiffer, Claus Holst, Teodora Handjieva-Darlenska, Nathalie Viguerie, Angeliki Papadaki, Jorg Hager, Lars Ängquist, Thomas Larsen, Thorkild I. A. Sørensen, Ruth J. F. Loos, Department of Human Nutrition, Faculty of Life Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Institute of Preventive Medicine, Copenhagen University Hospitals, MRC Epidemiology Unit, Addenbrooke's Hospital-Institute of Metabolic Science, Institut de Génomique d'Evry (IG), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Franco-czech Laboratory for clinical research on obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Metabolic Science, MRC, Department of Nutrition, Dietetics and Metabolic Diseases, National Transport Hospital, MRC Human Nutrition Research, Elsie Widdowson Laboratory, Institute of Endocrinology, Obesity Management Center, Department of Physiology and Nutrition, Universidad de Navarra [Pamplona] (UNAV), Department of Social Medicine, University of Crete [Heraklion] (UOC), Department of Endocrinology, Diabetes & Nutrition, German Institute of Human Nutrition-Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism-Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht]-Maastricht University [Maastricht], University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Simon, Marie Francoise, Humane Biologie, and RS: NUTRIM - R1 - Metabolic Syndrome
Subjects: Male, 030309 nutrition & dietetics, BEHAVIOR INTERACTIONS, MESH: Dietary Proteins, PROTEIN, Medicine (miscellaneous), MESH: Food Habits, Weight Gain, Body Mass Index, MESH: Genotype, 0302 clinical medicine, Weight loss, MESH: Obesity, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, 0303 health sciences, Nutrition and Dietetics, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH: DNA, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Glycemic index, OBESITY, MESH: Waist Circumference, MESH: Weight Gain, DIETS, Female, Dietary Proteins, Waist Circumference, medicine.symptom, Adult, medicine.medical_specialty, Waist, Genotype, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, LOSS MAINTENANCE, Biology, Polymorphism, Single Nucleotide, MESH: Genetic Loci, MESH: Body Mass Index, 03 medical and health sciences, MESH: Weight Loss, Internal medicine, Weight Loss, medicine, Humans, Caloric Restriction, Glycemic, MESH: Caloric Restriction, MESH: Humans, MESH: Adult, DNA, Feeding Behavior, medicine.disease, Obesity, MESH: Male, Endocrinology, Genetic Loci, MESH: Glycemic Index, GLYCEMIC INDEX, Body mass index, Weight gain, MESH: Female
Abstract: International audience; BACKGROUND: Differences in the interindividual response to dietary intervention could be modified by genetic variation in nutrient-sensitive genes. OBJECTIVE: This study examined single nucleotide polymorphisms (SNPs) in presumed nutrient-sensitive candidate genes for obesity and obesity-related diseases for main and dietary interaction effects on weight, waist circumference, and fat mass regain over 6 mo. DESIGN: In total, 742 participants who had lost ≥ 8% of their initial body weight were randomly assigned to follow 1 of 5 different ad libitum diets with different glycemic indexes and contents of dietary protein. The SNP main and SNP-diet interaction effects were analyzed by using linear regression models, corrected for multiple testing by using Bonferroni correction and evaluated by using quantile-quantile (Q-Q) plots. RESULTS: After correction for multiple testing, none of the SNPs were significantly associated with weight, waist circumference, or fat mass regain. Q-Q plots showed that ALOX5AP rs4769873 showed a higher observed than predicted P value for the association with less waist circumference regain over 6 mo (-3.1 cm/allele; 95% CI: -4.6, -1.6; P/Bonferroni-corrected P = 0.000039/0.076), independently of diet. Additional associations were identified by using Q-Q plots for SNPs in ALOX5AP, TNF, and KCNJ11 for main effects; in LPL and TUB for glycemic index interaction effects on waist circumference regain; in GHRL, CCK, MLXIPL, and LEPR on weight; in PPARC1A, PCK2, ALOX5AP, PYY, and ADRB3 on waist circumference; and in PPARD, FABP1, PLAUR, and LPIN1 on fat mass regain for dietary protein interaction. CONCLUSION: The observed effects of SNP-diet interactions on weight, waist, and fat mass regain suggest that genetic variation in nutrient-sensitive genes can modify the response to diet. This trial was registered at clinicaltrials.gov as NCT00390637.
Published: 2016

30. Circulating ACE is a predictor of weight loss maintenance not only in overweight and obese women, but also in men

Author: Wang, P., Holst, C., Wodzig, W. K. W. H., Andersen, M. R., Astrup, A., Van Baak, M. A., Larsen, T. M., Jebb, S. A., Kafatos, A., Pfeiffer, A. F. H., Martinez, J. A., Handjieva-Darlenska, T., Kunesova, M., Viguerie, N., Langin, D., Saris, W. H. M., Mariman, E. C. M., Diogenes, Consortium, Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism-Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht]-Maastricht University [Maastricht], Institute of Preventive Medicine / Institut for Sygdomsforebyggelse, Copenhagen University Hospital-Frederiksberg Hospital Hovedvejen, Department of Clinical Chemistry, Maastricht University Medical Centre (MUMC), Department of Clinical Biochemistry, Copenhagen University Hospital, Department of Human Nutrition, Faculty of Life Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Elsie Widdowson Laboratory, MRC Human Nutrition Research, Department of Social Medicine, Preventive Medicine and Nutrition Clinic, University of Crete [Heraklion] (UOC), Department of Clinical Nutrition, German Institute of Human Nutrition, Department of Endocrinology, Diabetes and Nutrition, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Physiology and Nutrition, Universidad de Navarra [Pamplona] (UNAV), Department of Nutrition, Dietetics and Metabolic Diseases, National Multiprofile Transport Hospital, Obesity Management Centre, Institute of Endocrinology, Obesity Research Laboratory, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Department of Human Biology Nutrition and Toxicology Research (Diogenes), Maastricht University [Maastricht]-Institute Maastricht (NUTRIM), Humane Biologie, MUMC+: DA CDL Algemeen (9), RS: NUTRIM - R4 - Gene-environment interaction, RS: NUTRIM - R1 - Metabolic Syndrome, Simon, Marie Francoise, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Cross-sectional study, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), MESH: Energy Intake, 030204 cardiovascular system & hematology, Overweight, Weight Gain, 0302 clinical medicine, Weight loss, MESH: Obesity, 2. Zero hunger, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Diet, Reducing, 0303 health sciences, Nutrition and Dietetics, MESH: Middle Aged, MESH: Sex Distribution, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Predictive Value of Tests, 3. Good health, MESH: Weight Gain, Female, medicine.symptom, Adult, medicine.medical_specialty, Diet, Reducing, Peptidyl-Dipeptidase A, 03 medical and health sciences, MESH: Weight Loss, MESH: Cross-Sectional Studies, Predictive Value of Tests, Internal medicine, Weight Loss, medicine, Humans, Obesity, Sex Distribution, 030304 developmental biology, MESH: Humans, business.industry, MESH: Biological Markers, MESH: Adult, Odds ratio, Anthropometry, Confidence interval, MESH: Male, MESH: Peptidyl-Dipeptidase A, Endocrinology, Cross-Sectional Studies, business, Energy Intake, Weight gain, Body mass index, MESH: Female, Biomarkers
Abstract: BACKGROUND:Circulating angiotensin-converting enzyme (ACE) was identified as a predictor of weight loss maintenance in overweight/obese women of the Diogenes project.OBJECTIVE:To investigate whether ACE acted also as a predictor in men of the Diogenes study and to compare it with that in women.DESIGN:Subjects, who lost >/=8% of body weight induced by low-caloric diet in an 8-week weight loss period, were assigned to weight loss maintenance with dietary intervention for 6 months.SUBJECTS:125 overweight/obese healthy men from eight European countries who completed whole intervention.MEASUREMENTS:Concentrations and activity of serum ACE at baseline and after the 8-week weight loss, in addition to anthropometric and physiological parameters.RESULTS:Serum ACE concentration decreased by 11.3+/-10.6% during the weight loss period in men. A greater reduction is associated with less body weight regain during the maintenance period (r=0.227, P=0.012). ACE change was able to predict a weight regain
Published: 2012

31. Overdiagnosis associated with breast cancer screening: A simulation study to compare lead-time adjustment methods

Author: Arnaud Seigneurin, Marc Colonna, José Labarère, Stephen W. Duffy, Biologie Computationnelle et Mathématique (TIMC-IMAG-BCM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Unité de qualitique et d'évaluation médicale - pole Santé Publique, CHU Grenoble, Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, and Registre du Cancer de l'Isère
Subjects: Adult, Cancer Research, medicine.medical_specialty, Simulation study, Overdiagnosis, Epidemiology, [SDV]Life Sciences [q-bio], Population, Medical Overuse, Breast cancer screening, Breast cancer, medicine, Humans, Mammography, education, Early Detection of Cancer, Mass screening, Aged, Gynecology, education.field_of_study, medicine.diagnostic_test, business.industry, Incidence (epidemiology), Incidence, Cancer, Middle Aged, medicine.disease, 3. Good health, Oncology, Female, Breast neoplasms, business, Lead time, Demography
Abstract: Objective Estimating overdiagnosis associated with breast cancer screening may use annual incidence rates of cancer. We simulated populations invited to screening programmes to assess two lead-time adjustment methods. Methods Overdiagnosis estimates were computed using the compensatory drop method, which considered the decrease in incidence of cancers among older age groups no longer offered screening, and the method based on the decrease in incidence of late-stage cancers. Results The true value of overdiagnosis was 0% in all the data sets simulated. The compensatory drop method yielded an overdiagnosis estimate of −0.1% (95% credibility interval −0.5% to 0.5%) when participation rates among the population and risk of cancers were constant. However, if participation rates increased with calendar year as well as risk of cancer with birth cohorts, the overdiagnosis estimated was 11.0% (10.5–11.6%). Using the method based on the incidence of early- and late-stage cancers, overdiagnosis estimates were 8.9% (8.5–9.3%) and 17.6% (17.4–17.9%) when participation rates and risks of cancer were constant or increased with time, respectively. Conclusion Adjustment for lead time based on the compensatory drop method is accurate only when participation rates and risks of cancer remain constant, whereas the adjustment method based on the incidence of early- and late-stage cancers results in overestimating overdiagnosis regardless of stability of participation rates and breast cancer risk.
Published: 2015

32. Population estimates of survival in women with screen-detected and symptomatic breast cancer taking account of lead time and length bias

Author: Olive Kearins, P Allgood, Nancy Tappenden, Matthew G. Wallis, Nehmat Houssami, Emma O'Sullivan, Gill Lawrence, Fay H. Cafferty, Iris D. Nagtegaal, Jane Warwick, Stephen W. Duffy, West Midlands Cancer Intelligence Unit, Public Health Building, University of Alabama at Birmingham [ Birmingham] (UAB), Breast Screening Unit, University Hospitals Coventry and Warwickshire, Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Department of Pathology 824, Radboud University Medical Center [Nijmegen], Screening & Test Evaluation Program, School of Public Health A27, The University of Sydney, and The Planning Office, Academic services
Subjects: Risk, Oncology, Cancer Research, medicine.medical_specialty, Population, Breast Neoplasms, Kaplan-Meier Estimate, Aetiology, screening and detection [ONCOL 5], Time, Cohort Studies, Population screening, Breast cancer, Bias, Translational research [ONCOL 3], Internal medicine, medicine, Humans, Mass Screening, Mammography, Overdiagnosis, education, Aged, education.field_of_study, Hereditary cancer and cancer-related syndromes [ONCOL 1], medicine.diagnostic_test, business.industry, Self-selection bias, Cancer, Middle Aged, medicine.disease, Survival Analysis, Surgery, Cancer registry, Lead time bias, Research Design, Female, Breast disease, Length bias, business, Lead-time bias
Abstract: Contains fulltext : 79506.pdf (Publisher’s version ) (Closed access) BACKGROUND: Evidence of the impact of breast screening is limited by biases inherent in non-randomised studies and often by lack of complete population data. We address this by estimating the effect of screen detection on cause-specific fatality in breast cancer, corrected for all potential biases, using population cancer registry data. METHODS: Subjects (N = 26,766) comprised all breast cancers notified to the West Midlands Cancer Intelligence Unit and diagnosed in women aged 50-74, from 1988 to 2004. These included 10,100 screen-detected and 15,862 symptomatic breast cancers (6,009 women with interval cancers and 9,853 who had not attended screening). Our endpoint was survival to death from breast cancer. We estimated the relative risk (RR) of 10-year cause-specific fatality (screen-detected compared to symptomatic cancers) correcting for lead time bias and performing sensitivity analyses for length bias. To exclude self-selection bias, survival analyses were also performed with interval cancers as the comparator symptomatic women. FINDINGS: Uncorrected RR associated with screen-detection was 0.34 (95% CI 0.31-0.37). Correcting for lead time, RR was 0.49 (95% CI 0.45-0.53); length bias analyses gave a range of RR corrected for both phenomena of 0.49-0.59, with a median of 0.51. Self-selection bias-corrected estimates yielded a median RR of 0.68. INTERPRETATION: After adjusting for various potential biases, women with screen-detected breast cancer have a substantial survival advantage over those with symptomatic breast cancer.
Published: 2008

33. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author: Winkler, Thomas W, Justice, Anne E, Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F, Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O, Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H, Rüeger, Sina, Teumer, Alexander, Ehret, Georg B, Ferreira, Teresa, Heard-Costa, Nancy L, Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D, Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M, Jansen, Rick, Westra, Harm-Jan, White, Charles C, Absher, Devin, Ahluwalia, Tarunveer S, Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L, de Craen, Anton JM, Bis, Joshua C, Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston WK, Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E, Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B, Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E, Jackson, Anne U, Jacobs, Kevin B, Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E, Lahti, Jari, Mateo Leach, Irene, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela AF, Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L, Montasser, May E, Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M, Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W, Renström, Frida, Rizzi, Federica, Rose, Lynda M, Ryan, Kathy A, Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J, Sung, Yun Ju, Tachmazidou, Ioanna, Tanaka, Toshiko, Thorleifsson, Gudmar, Trompet, Stella, Pervjakova, Natalia, Tyrer, Jonathan P, Vandenput, Liesbeth, van der Laan, Sander W, van der Velde, Nathalie, van Setten, Jessica, van Vliet-Ostaptchouk, Jana V, Verweij, Niek, Vlachopoulou, Efthymia, Waite, Lindsay L, Wang, Sophie R, Wang, Zhaoming, Wild, Sarah H, Willenborg, Christina, Wilson, James F, Wong, Andrew, Yang, Jian, Yengo, Loïc, Yerges-Armstrong, Laura M, Yu, Lei, Zhang, Weihua, Zhao, Jing Hua, Andersson, Ehm A, Bakker, Stephan JL, Baldassarre, Damiano, Banasik, Karina, Barcella, Matteo, Barlassina, Cristina, Bellis, Claire, Benaglio, Paola, Blangero, John, Blüher, Matthias, Bonnet, Fabrice, Bonnycastle, Lori L, Boyd, Heather A, Bruinenberg, Marcel, Buchman, Aron S, Campbell, Harry, Chen, Yii-Der Ida, Chines, Peter S, Claudi-Boehm, Simone, Cole, John, Collins, Francis S, de Geus, Eco JC, de Groot, Lisette CPGM, Dimitriou, Maria, Duan, Jubao, Enroth, Stefan, Eury, Elodie, Farmaki, Aliki-Eleni, Forouhi, Nita G, Friedrich, Nele, Gejman, Pablo V, Gigante, Bruna, Glorioso, Nicola, Go, Alan S, Gottesman, Omri, Gräßler, Jürgen, Grallert, Harald, Grarup, Niels, Gu, Yu-Mei, Broer, Linda, Ham, Annelies C, Hansen, Torben, Harris, Tamara B, Hartman, Catharina A, Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew T, Heath, Andrew C, Henders, Anjali K, Hernandez, Dena, Hillege, Hans, Holmen, Oddgeir, Hovingh, Kees G, Hui, Jennie, Husemoen, Lise L, Hutri-Kähönen, Nina, Hysi, Pirro G, Illig, Thomas, De Jager, Philip L, Jalilzadeh, Shapour, Jørgensen, Torben, Jukema, J Wouter, Juonala, Markus, Kanoni, Stavroula, Karaleftheri, Maria, Khaw, Kay Tee, Kinnunen, Leena, Kittner, Steven J, Koenig, Wolfgang, Kolcic, Ivana, Kovacs, Peter, Krarup, Nikolaj T, Kratzer, Wolfgang, Krüger, Janine, Kuh, Diana, Kumari, Meena, Kyriakou, Theodosios, Langenberg, Claudia, Lannfelt, Lars, Lanzani, Chiara, Lotay, Vaneet, Launer, Lenore J, Leander, Karin, Lindström, Jaana, Linneberg, Allan, Liu, Yan-Ping, Lobbens, Stéphane, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Magnusson, Patrik K, McArdle, Wendy L, Menni, Cristina, Merger, Sigrun, Milani, Lili, Montgomery, Grant W, Morris, Andrew P, Narisu, Narisu, Nelis, Mari, Ong, Ken K, Palotie, Aarno, Pérusse, Louis, Pichler, Irene, Pilia, Maria G, Pouta, Anneli, Rheinberger, Myriam, Ribel-Madsen, Rasmus, Richards, Marcus, Rice, Kenneth M, Rice, Treva K, Rivolta, Carlo, Salomaa, Veikko, Sanders, Alan R, Sarzynski, Mark A, Scholtens, Salome, Scott, Robert A, Scott, William R, Sebert, Sylvain, Sengupta, Sebanti, Sennblad, Bengt, Seufferlein, Thomas, Silveira, Angela, Slagboom, P Eline, Smit, Jan H, Sparsø, Thomas H, Stirrups, Kathleen, Stolk, Ronald P, Stringham, Heather M, Swertz, Morris A, Swift, Amy J, Syvänen, Ann-Christine, Tan, Sian-Tsung, Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Tsafantakis, Emmanouil, van der Most, Peter J, Völker, Uwe, Vohl, Marie-Claude, Vonk, Judith M, Waldenberger, Melanie, Walker, Ryan W, Wennauer, Roman, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Wright, Alan F, Zillikens, M Carola, van Dijk, Suzanne C, van Schoor, Natasja M, Asselbergs, Folkert W, de Bakker, Paul IW, Beckmann, Jacques S, Beilby, John, Bennett, David A, Bergman, Richard N, Bergmann, Sven, Böger, Carsten A, Boehm, Bernhard O, Boerwinkle, Eric, Boomsma, Dorret I, Bornstein, Stefan R, Bottinger, Erwin P, Bouchard, Claude, Chambers, John C, Chanock, Stephen J, Chasman, Daniel I, Cucca, Francesco, Cusi, Daniele, Dedoussis, George, Erdmann, Jeanette, Eriksson, Johan G, Evans, Denis A, de Faire, Ulf, Farrall, Martin, Ferrucci, Luigi, Ford, Ian, Franke, Lude, Franks, Paul W, Froguel, Philippe, Gansevoort, Ron T, Gieger, Christian, Grönberg, Henrik, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Per, Hamsten, Anders, van der Harst, Pim, Hayward, Caroline, Heliövaara, Markku, Hengstenberg, Christian, Hicks, Andrew A, Hingorani, Aroon, Hofman, Albert, Hu, Frank, Huikuri, Heikki V, Hveem, Kristian, James, Alan L, Jordan, Joanne M, Jula, Antti, Kähönen, Mika, Kajantie, Eero, Kathiresan, Sekar, Kiemeney, Lambertus ALM, Kivimaki, Mika, Knekt, Paul B, Koistinen, Heikki A, Kooner, Jaspal S, Koskinen, Seppo, Kuusisto, Johanna, Maerz, Winfried, Martin, Nicholas G, Laakso, Markku, Lakka, Timo A, Lehtimäki, Terho, Lettre, Guillaume, Levinson, Douglas F, Lind, Lars, Lokki, Marja-Liisa, Mäntyselkä, Pekka, Melbye, Mads, Metspalu, Andres, Mitchell, Braxton D, Moll, Frans L, Murray, Jeffrey C, Musk, Arthur W, Nieminen, Markku S, Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J, Oostra, Ben A, Palmer, Lyle J, Pankow, James S, Pasterkamp, Gerard, Pedersen, Nancy L, Pedersen, Oluf, Penninx, Brenda W, Perola, Markus, Peters, Annette, Polašek, Ozren, Pramstaller, Peter P, Psaty, Bruce M, Qi, Lu, Quertermous, Thomas, Raitakari, Olli T, Rankinen, Tuomo, Rauramaa, Rainer, Ridker, Paul M, Rioux, John D, Rivadeneira, Fernando, Rotter, Jerome I, Rudan, Igor, den Ruijter, Hester M, Saltevo, Juha, Sattar, Naveed, Schunkert, Heribert, Schwarz, Peter EH, Shuldiner, Alan R, Sinisalo, Juha, Snieder, Harold, Sørensen, Thorkild IA, Spector, Tim D, Staessen, Jan A, Stefania, Bandinelli, Thorsteinsdottir, Unnur, Stumvoll, Michael, Tardif, Jean-Claude, Tremoli, Elena, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, Verbeek, André LM, Vermeulen, Sita H, Viikari, Jorma S, Vitart, Veronique, Völzke, Henry, Vollenweider, Peter, Waeber, Gérard, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J, Watkins, Hugh, Zeggini, Eleftheria, arcOGEN Consortium, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Chakravarti, Aravinda, Clegg, Deborah J, Cupples, L Adrienne, Gordon-Larsen, Penny, Jaquish, Cashell E, Rao, DC, Abecasis, Goncalo R, Assimes, Themistocles L, Barroso, Inês, Berndt, Sonja I, Boehnke, Michael, Deloukas, Panos, Fox, Caroline S, Groop, Leif C, Hunter, David J, Ingelsson, Erik, Kaplan, Robert C, McCarthy, Mark I, Mohlke, Karen L, O'Connell, Jeffrey R, Schlessinger, David, Strachan, David P, Stefansson, Kari, van Duijn, Cornelia M, Hirschhorn, Joel N, Lindgren, Cecilia M, Heid, Iris M, North, Kari E, Borecki, Ingrid B, Kutalik, Zoltán, Loos, Ruth JF, Division of Statistical Genomics, Washington University School of Medicine, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Estonian Genome and Medicine, University of Tartu, Institute of Molecular and Cell Biology, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Metabolic Science, MRC, Brown University, Center for Biological Sequence Analysis [Lyngby], Technical University of Denmark [Lyngby] (DTU), King‘s College London, Groningen Bioinformatics Centre, GBB, University of Groningen [Groningen], University of Queensland [Brisbane], National Institut of Food Science and Technology, University of Agriculture, Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of neurology, Leiden University Medical Center (LUMC), University of Washington [Seattle], Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Genetic Epidemiology Unit, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Deptartment of Medical Biochemistry and Microbiology, Uppsala University, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Limnology, Ecology, Department of Ecology and Evolutionary Biology, University of California, Core Genotyping Facility, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Division of Cancer Epidemiology and Genetics, Institute of Health Sciences and Biocenter Oulu, University of Oulu, Department of Chemical Engineering Taiwan (DCET - NTHU), National Tsing Hua University [Hsinchu] (NTHU), University of Oxford [Oxford], Department of Epidemiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Human Genetics, The Wellcome Trust Sanger Institute [Cambridge], Departments of Epidemiology and Nutrition, Harvard School of Public Health, Department of Clinical Sciences, Lund University [Lund]-Lund University Diabetes Centre, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, Department of Medical Sciences, Department of Educational Psychology and Counseling, National Taiwan Normal University (NTNU), Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE Genetics, deCODE genetics [Reykjavik], Interuniversity Cardiology Institute Netherlands, Molecular Genetics Section, University of Groningen [Groningen]-University Medical Centre Groningen, Kidney Center, University Medical Center Groningen [Groningen] (UMCG), The University of Texas Health Science Center at Houston (UTHealth), Texas Biomedical Research Institute [San Antonio, TX], Medical Department III, Universität Leipzig [Leipzig], Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], GNS Science, Blackett Laboratory, Imperial College London, Medstar Research Institute, University of Rochester [USA], MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Dept Biochem & Mol Biol, Pennsylvania State University (Penn State), Penn State System-Penn State System, Genomic Research Laboratory, Service of Infectious Disease, Hôpitaux Universitaires de Genève (HUG), Epidemiology, University Medical Centre Groningen, Unit for Molecular Epidemiology, German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Research Centre for Prevention and Health (RCPH), Department of Public Health [Copenhagen], 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)-Capital Region of Denmark, University of Copenhagen = Københavns Universitet (KU), Faculty of Medicine, Institute of Public Health, Aalborg University [Denmark] (AAU), Department of Nutrition-Dietetics, Harokopio University of Athens, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, MRC National Survey of Health and Development, MRC Unit for Lifelong Health and Ageing, Department of Epidemiology and Public Health, University College of London [London] (UCL), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Research Center for Prevention and Health, Glostrup Hospital, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Cambridge Institute of Public Health, University of Cambridge [UK] (CAM), Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare [Helsinki], Queensland Institute of Medical Research, Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Head of Medical Sequencing, Department of Biostatistics, University of Washington, Department of Chronic Disease Prevention, Molecular Epidemiology, Department of Genetics, Université Laval [Québec] (ULaval), Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Department of Internal Medicine, Université de Lausanne (UNIL), Carl Gustav Carus University Hospital, Loughborough University, Genomics and Bioinformatics Platform, Fondazione Filarete, Department of Medicine, Surgery, and Dentistry, University of Milano, Medizinische Klinik II, Universität zu Lübeck [Lübeck], Department of Genomic Medicine, University of Manchester [Manchester], The Wellcome Trust Centre for Human Genetics [Oxford], National Institutes of Health [Bethesda] (NIH), Department of Nephrology, University Medical Center, University of Groningen, Helmholtz-Zentrum München (HZM), Icelandic Heart Association, Kopavogur, Iceland., Faculty of Medicine, University of Iceland [Reykjavik], Genetics and Pathology, Department of child and adolescent psychiatry, Universität Duisburg-Essen [Essen], Department of Internal Medicine II, Division of Respirology, University of Regensburg, Regensburg, Germany, Universität Regensburg (UR), Franz-Volhard-Centrum für Klinische Forschung, ECRC, Department of Clinical Physiology, University of Tampere [Finland]-Tampere University Hospital, Finnish Institute of Occupational Health of Helsinki, Department of Clinical Chemistry, Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Department of Oncology, University of Tampere Medical School, University of Tampere, Department of Physiology, University of Eastern Finland-Institute of Biomedicine, Department of Medicine, Montreal, Developmental Brain and Behaviour Unit, University of Southampton, Division of Gastroenterology and Hepatology, Department of Immunology, Mayo Clinic, Centre for Bone and Arthritis Research, Institute of Medicine-University of Gothenburg (GU), Interdisciplinary Center for Psychiatric Epidemiology, Experimental Cardiology Laboratory, University Medical Center [Utrecht], Peter MacCallum Cancer Center, Faculty of Health Sciences, Aarhus University [Aarhus], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Department of Health Services, University of Washington, Group Health Research Institute, Group Health Cooperative, Department of Epidemiology, University of Washington, Department of Medicine, University of Washington, Cardiovascular Health Research Unit, University of Washington, The Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku University Hospital (TYKS), Erasmus Medical Centre, Cedars-Sinai Medical Center, Department of Pathological Biochemistry, Royal Infirmary, Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, Department of Pediatrics, Augusta University - Medical College of Georgia, University System of Georgia (USG)-University System of Georgia (USG), Institute of Preventive Medicine, Copenhagen University Hospital-Bispebjerg and Frederiksberg Hospitals, Maastricht University [Maastricht], Department of Public Health, South Ostrobothnia Central Hospital, Department of Clinical and Preventive Medicine, Danube-University Krems, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Department of Epidemiology & Biostatistics, Radboud University Medical Center [Nijmegen], Institute for Community Medicine, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), MRC epidemiology Unit, Framingham Heart Study, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), Metabolic Disease Group, University of Cambridge Metabolic Research Laboratories, Department of Genetics and Biotechnology, Wellcome Trust, Divisions of Genetics and Endocrinology and Program in Genomics, Boston Children's Hospital, Metabolism Initiative and Program in Medical and Population Genetics, Endocrinology and Metabolism, The Churchill Hospital-Oxford Centre for Diabetes, Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Department of Medical Genetics, Epidemiology Unit, Addenbrooke's Hospital-Medical Research Council (MRC), P30 AG010161/AG/NIA NIH HHS/United States, Psychiatry, Epidemiology and Data Science, NCA - Neurobiology of mental health, EMGO - Lifestyle, overweight and diabetes, APH - Amsterdam Public Health, AMS - Amsterdam Movement Sciences, Geriatrics, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Other departments, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, RS: CARIM - R3 - Vascular biology, MUMC+: DA BV AIOS Radiologie (9), Epidemiologie, Orthopedie, Institute for Molecular Medicine Finland, Helsinki Collegium for Advanced Studies, Behavioural Sciences, University of Helsinki, Transplantation Laboratory, Medicum, Research Programs Unit, Research Programme of Molecular Medicine, Aarno Palotie / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Children's Hospital, Lastentautien yksikkö, Marja-Liisa Lokki / Principal Investigator, Kardiologian yksikkö, Leif Groop Research Group, Quantitative Genetics, Developmental Psychology Research Group, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, Ehret, Georg Benedikt, Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Universiteit Leiden-Universiteit Leiden, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), University of California (UC), University of Oxford, Lund University [Lund], Universität Leipzig, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Helmholtz Zentrum München = German Research Center for Environmental Health, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Capital Region of Denmark, University of Copenhagen = Københavns Universitet (UCPH), Université de Lausanne = University of Lausanne (UNIL), Universität zu Lübeck = University of Lübeck [Lübeck], Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of Gothenburg (GU)-Institute of Medicine, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Luan, Jian'an [0000-0003-3137-6337], Tyrer, Jonathan [0000-0003-3724-4757], Forouhi, Nita [0000-0002-5041-248X], Khaw, Kay-Tee [0000-0002-8802-2903], Langenberg, Claudia [0000-0002-5017-7344], Luben, Robert [0000-0002-5088-6343], Ong, Kenneth [0000-0003-4689-7530], Johnson, Kathleen [0000-0002-6823-3252], Wareham, Nicholas [0000-0003-1422-2993], Barroso, Ines [0000-0001-5800-4520], Apollo - University of Cambridge Repository, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Biochemistry, Surgery, Internal Medicine, Public Health, Medical Oncology, Pathology, Erasmus MC other, Child and Adolescent Psychiatry / Psychology, and Clinical Genetics
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Male, Cancer Research, endocrine system diseases, Biological pathways, QH426-470, Genome, Body Mass Index, Body Size, Genetics (clinical), ddc:616, Genetics & Heredity, Sex Characteristics, Loci, MAGIC Consortium, Mass index, Age Factors, Chromosome Mapping, Middle Aged, Genealogy, Self-reported height, Peripheral-blood, Scale (social sciences), ICBP Consortium, Female, Life Sciences & Biomedicine, Medical Genetics, Research Article, arcOGEN Consortium, musculoskeletal diseases, Adult, European Continental Ancestry Group, Natural menopause, Aged, Body Size/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Biology, Body size, DIAGRAM Consortium, Age and sex, White People, Fat distribution, GLGC Consortium, 03 medical and health sciences, Life-course, Genetics, Weight-gain, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Medicinsk genetik, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0604 Genetics, Science & Technology, nutritional and metabolic diseases, Correction, 030104 developmental biology, GWAS meta-analysis, Global-BPGen Consortium, Common SNPS, CHARGE Consortium, 3111 Biomedicine, Developmental Biology
Abstract: Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR, Author Summary Adult body size and body shape differ substantially between men and women and change over time. More than 100 genetic variants that influence body mass index (measure of body size) or waist-to-hip ratio (measure of body shape) have been identified. While there is evidence that some genetic loci affect body shape differently in men than in women, little is known about whether genetic effects differ in older compared to younger adults, and whether such changes differ between men and women. Therefore, we conducted a systematic genome-wide search, including 114 studies (>320,000 individuals), to specifically identify genetic loci with age- and or sex-dependent effects on body size and shape. We identified 15 loci of which the effect on BMI was different in older compared to younger adults, whereas we found no evidence for loci with different effects in men compared to women. The opposite was seen for body shape as we identified 44 loci of which the effect on waist-to-hip ratio differed between men and women, but no difference between younger and older adults were observed. Our observations may provide new insights into the biology that underlies weight change with age or the sexual dimorphism of body shape.
Published: 2014

34. TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function

Author: Sean Ennis, Elijah Chaila, Stuart L. Rulten, Rocío Romero-Granados, Felipe Cortés-Ledesma, Bert B.A. de Vries, Norman Delanty, Judith Conroy, Janneke H M Schuurs-Hoeijmakers, Fernando Gómez-Herreros, Gianpiero L. Cavalleri, Timothy J. Counihan, Marie T. Greally, Sherif F. El-Khamisy, Mark McCormack, Arjan P.M. de Brouwer, Keith W. Caldecott, Medical Research Council (UK), Cancer Research UK, Consejo Superior de Investigaciones Científicas (España), European Commission, Wellcome Trust, The Lister Institute of Preventive Medicine (UK), Netherlands Organisation for Health Research and Development, Heath Research Board (Ireland), National Institutes of Health (US), Ellison Medical Foundation, and Biogen
Subjects: Transcription, Genetic, axonal neuropathy, Fluorescent Antibody Technique, Endogeny, Mice, chemistry.chemical_compound, spinocerebellar ataxia, Transcription (biology), DNA Breaks, Double-Stranded, Exome, genes, Poly-ADP-Ribose Binding Proteins, Neurons, biology, Homozygote, Brain, Nuclear Proteins, receptor-associated factors, 3. Good health, DNA-Binding Proteins, medicine.anatomical_structure, medicine.symptom, Chromosome breakage, phosphodiesterase, ttrap, ii-beta, Chromatin Immunoprecipitation, Ataxia, Interneuron, Molecular Sequence Data, Other Research Donders Center for Medical Neuroscience [Radboudumc 0], mediated DNA-damage, Real-Time Polymerase Chain Reaction, Antigens, Neoplasm, Seizures, Intellectual Disability, Genetics, medicine, Animals, Humans, Abnormalities, Multiple, Gene, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Base Sequence, Phosphoric Diester Hydrolases, Topoisomerase, Sequence Analysis, DNA, Microarray Analysis, Molecular biology, DNA Topoisomerases, Type II, chemistry, repair, biology.protein, cells, DNA, Transcription Factors
Abstract: Gómez-Herreros, Fernando et al., Topoisomerase II (TOP2) removes torsional stress from DNA and facilitates gene transcription by introducing transient DNA double-strand breaks (DSBs). Such DSBs are normally rejoined by TOP2 but on occasion can become abortive and remain unsealed. Here we identify homozygous mutations in the TDP2 gene encoding tyrosyl DNA phosphodiesterase-2, an enzyme that repairs 'abortive' TOP2-induced DSBs, in individuals with intellectual disability, seizures and ataxia. We show that cells from affected individuals are hypersensitive to TOP2-induced DSBs and that loss of TDP2 inhibits TOP2-dependent gene transcription in cultured human cells and in mouse post-mitotic neurons following abortive TOP2 activity. Notably, TDP2 is also required for normal levels of many gene transcripts in developing mouse brain, including numerous gene transcripts associated with neurological function and/or disease, and for normal interneuron density in mouse cerebellum. Collectively, these data implicate chromosome breakage by TOP2 as an endogenous threat to gene transcription and to normal neuronal development and maintenance, This work was funded in the Caldecott laboratory by the Medical Research Council (MRC; MR/J006750/1 and G0901606/1) and Cancer Research UK (C6563/A16771), in the Cortes-Ledesma laboratory by the Spanish government (SAF2010-21017, RYC-2009-03928 and JAE-Doc 2010-011) and European Union (PERG07-2010-268466), in the El-Khamisy laboratory by the Wellcome Trust (fellowship 085284 and grant 091043) and the Lister Institute of Preventative Medicine (fellowship), and in part by the Netherlands Organization for Health Research and Development (ZonMW; VIDI grant 917-86-319 to B.B.A.d.V.), the GENCODYS project (EU-7th-2010-241995 to B.B.A.d.V. and A.P.M.d.B.), a Brainwave–Irish Epilepsy Association/Medical Research Charities Group of Ireland/Health Research Board award (2009/001) and a Health Research Board of Ireland Translational Research Scholars award. Control samples were funded by National Institute for Mental Health (NIMH) awards (RC2MH089915, K01MH098126, R01MH099216 and R01MH097971), the Epi4K Gene Discovery in Epilepsy study (National Institute for Neurological Disorders and Stroke (NINDS) U01NS077303), the Epilepsy Genome/Phenome Project (EPGP; NINDS U01NS053998), the Center for HIV/AIDS Vaccine Immunology (CHAVI) study (National Institute of Allergy and Infectious Diseases (NIAID) UO1AIO67854), the Ellison Medical Foundation New Scholar award (AG-NS-0441-08), SAIC-Frederick, Inc. (M11-074) and Biogen Idec, Inc.
Published: 2014

35. SRF selectively controls tip cell invasive behavior in angiogenesis

Author: Ian Rosewell, Markus Fruttiger, Raquel Blanco, Irene M. Aspalter, Elena Mylonas, Holger Gerhardt, Nicolas Diguet, Virgine Penard-Lacronique, Zhenlin Li, Jacqueline Gao-Li, Anne Vaahtokari, Natalia Kazakova, Jocelyne Blanc, Mathias Mericskay, Ara Parlakian, Claudio A. Franco, Génétique et Physiopathologie des Tissus Musculaires (GPTM), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Agence Nationale de la Recherche [ANR-08-GENOPAT-038], Fondation ARC pour la recherche sur le cancer [A09/3/5065], Cancer Research UK, Lister Institute of Preventive Medicine, Leducq Transatlantic Network Grant (Artemis), EMBO, Marie Curie Actions Fellowship of the FP7 People Program, Austrian Academy of Sciences, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Serum Response Factor, Mouse, Angiogenesis, [SDV]Life Sciences [q-bio], Myosin, 02 engineering and technology, Myosins, Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Serum response factor, Human Umbilical Vein Endothelial Cells, Animals, Humans, Pseudopodia, RNA, Small Interfering, Molecular Biology, Transcription factor, Actin, 030304 developmental biology, Sprouting angiogenesis, Filopodia, 0303 health sciences, Neovascularization, Pathologic, Gene Expression Profiling, Gene Expression Regulation, Developmental, Retinal Vessels, Cell Biology, Hematopoietic Stem Cells, 021001 nanoscience & nanotechnology, Embryonic stem cell, Actins, Cell biology, Endothelial stem cell, Vascular endothelial growth factor A, 030220 oncology & carcinogenesis, embryonic structures, cardiovascular system, Blood Vessels, SRF, MYL9, 0210 nano-technology, Gene Deletion, Neoplasm Transplantation, Developmental Biology
Abstract: International audience; Efficient angiogenic sprouting is essential for embryonic, postnatal and tumor development. Serum response factor (SRF) is known to be important for embryonic vascular development. Here, we studied the effect of inducible endothelial-specific deletion of Srf in postnatal and adult mice. We find that endothelial SRF activity is vital for postnatal growth and survival, and is equally required for developmental and pathological angiogenesis, including during tumor growth. Our results demonstrate that SRF is selectively required for endothelial filopodia formation and cell contractility during sprouting angiogenesis, but seems dispensable for vascular remodeling. At the molecular level, we observe that vascular endothelial growth factor A induces nuclear accumulation of myocardin-related transcription factors (MRTFs) and regulates MRTF/SRF-dependent target genes including Myl9, which is important for endothelial cell migration in vitro. We conclude that SRF has a unique function in regulating migratory tip cell behavior during sprouting angiogenesis. We hypothesize that targeting the SRF pathway could provide an opportunity to selectively target tip cell filopodia-driven angiogenesis to restrict tumor growth.
Published: 2013

36. Change in proportional protein intake in a 10-week energy-restricted low- or high-fat diet, in relation to changes in body size and metabolic factors

Author: J. Alfredo Martínez, Jan Polak, Claus Holst, Tanja Stocks, Thorkild I. A. Sørensen, Wim H. M. Saris, Arne Astrup, Peter Arner, Stephan Rössner, Ian A. Macdonald, Jean-Michel Oppert, Lars Ängquist, Dominique Langin, Moira A. Taylor, Institute of Preventive Medicine, Copenhagen University Hospital-Bispebjerg and Frederiksberg Hospitals, Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, School of Biomedical Sciences, University of Nottingham, UK (UON), Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Centre de Recherche en Nutrition Humaine d'Ile-de-France (CRNH-IDF), Université Paris 13 (UP13)-CETAF-Institut National Agronomique Paris-Grignon (INA P-G)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut de Veille Sanitaire (INVS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Physiology and Nutrition, Universidad de Navarra [Pamplona] (UNAV), The Obesity Unit, Department of Medicine, Department of Sports Medicine, Centre of Preventive Medicine, Third Faculty of Medicine, Charles University, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Human Biology, Nutrition and Toxicology, Maastricht University [Maastricht]-Research Institute Maastricht, Department of Nutrition, Exercise and Sports [Copenhagen], Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Université Paris 13 (UP13)-CETAF-Institut National Agronomique Paris-Grignon (INA P-G)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut de Veille Sanitaire (INVS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, Simon, Marie Francoise, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Health (social science), 030204 cardiovascular system & hematology, chemistry.chemical_compound, 0302 clinical medicine, Weight loss, 030212 general & internal medicine, Diet, Fat-Restricted, lcsh:RC620-627, Dietary fats, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, Nutrition and Dietetics, Dietary intake, Blood glucoses, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Protein intake, Lipids, Näringslära, lcsh:Nutritional diseases. Deficiency diseases, Cholesterol, Endokrinologi och diabetes, Original Article, Female, medicine.symptom, lcsh:Nutrition. Foods and food supply, Adult, medicine.medical_specialty, Dietary proteins, Diet, Reducing, lcsh:TX341-641, Body size, Endocrinology and Diabetes, Diet, High-Fat, 03 medical and health sciences, Physiology (medical), Internal medicine, Weight Loss, medicine, Humans, Blood glucose, Obesity, Triglycerides, Caloric Restriction, Triglyceride, business.industry, High fat diet, Feeding Behavior, medicine.disease, Endocrinology, chemistry, Energy Intake, business
Abstract: Objective: To investigate in a secondary analysis of a randomised trial the effects of a low-/high-fat diet and reported change from baseline in energy% from protein (prot%), in relation to changes in body size and metabolic factors. Methods: Obese adults (n = 771) were randomised to a 600 kcal energy-deficient low-fat (20-25 fat%) or high-fat (40-45 fat%) diet over 10 weeks. Dietary intake data at baseline and during the intervention were available in 585 completers. We used linear regression to calculate the combined effects of randomised group and groups of prot% change (2) on outcomes. Results: The low-fat group with >2 prot% increase lost 1.1 kg more weight (p = 0.03) and reduced cholesterol by 0.25 mmol/l more (p = 0.003) than the high-fat group with >2 prot% decrease. These differences were 2.5-fold and 1.8-fold greater than the differences between the low-fat and high-fat groups while not considering prot% change. The high-fat group reduced plasma triglycerides more than the low-fat group, but not compared to those in the low-fat group with >2 units prot% increase (p fat-protein interaction = 0.01). Conclusions: Under energy restriction, participants on a low-fat diet who had increased the percentage energy intake from protein showed the greatest reduction in weight and cholesterol, and a triglyceride reduction equally large to that of participants on a high-fat diet.
Published: 2013

37. Determinants of human adipose tissue gene expression: impact of diet, sex, metabolic status, and cis genetic regulation

Author: Balbine Roussel, Hubert Vidal, Karine Clément, Dominique Langin, Arne Astrup, Nathalie Viguerie, Jason S. Iacovoni, Claus Holst, Marion Combes, Nathalie Villa-Vialaneix, Jörg Hager, Carine Valle, J. Alfredo Martínez, Emilie Montastier, Jean-José Maoret, Wim H. M. Saris, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Statistique, Analyse et Modélisation Multidisciplinaire (SAmos-Marin Mersenne) (SAMM), Université Paris 1 Panthéon-Sorbonne (UP1), Department of Physiology and Nutrition, Universidad de Navarra [Pamplona] (UNAV), Institute of Preventive Medicine, Copenhagen University Hospitals, Department of Human Nutrition, Faculty of Life Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-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)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de nutrition [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), Institut de Génomique d'Evry (IG), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Franco-czech Laboratory for clinical research on obesity, Institut National de la Santé et de la Recherche Médicale (INSERM)-Charles University [Prague] (CU), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], European Communities [DiOGenes FP6-513946, MoIPAGE LSHG-CT-2004-512066, ADAPT HEALTH-F2-2008-2011 00], Fondation pour la Recherche Medicale ANR LIPOB and OBELIP, Region Midi-Pyrenees, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], 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)-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), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Vialaneix, Nathalie, Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de médecine moléculaire de Rangueil ( I2MR ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Statistique, Analyse et Modélisation Multidisciplinaire (SAmos-Marin Mersenne) ( SAMM ), Université Panthéon-Sorbonne ( UP1 ), Universidad de Navarra [Pamplona] ( UNAV ), Faculty of Life Sciences-University of Copenhagen ( KU ), Cardiovasculaire, métabolisme, diabétologie et nutrition ( CarMeN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hospices Civils de Lyon ( HCL ) -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 ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Institut National de la Recherche Agronomique ( INRA ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Genomics Institute, Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Charles University [Prague]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Panthéon-Sorbonne (UP1), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Charles University [Prague]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Cancer Research, Adipose tissue, Gene Expression, [SDV.GEN] Life Sciences [q-bio]/Genetics, Body Mass Index, 0302 clinical medicine, Weight loss, Gene expression, Molecular Cell Biology, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics (clinical), 2. Zero hunger, Regulation of gene expression, Gene expression regulation, Metabolic Syndrome, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, Genomics, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Santé publique et épidémiologie, obésité, Adipose Tissue, Medicine, Female, medicine.symptom, Research Article, medicine.medical_specialty, lcsh:QH426-470, Calorie restriction, Médecine humaine et pathologie, 030209 endocrinology & metabolism, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 03 medical and health sciences, Sex Factors, Internal medicine, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Weight Loss, medicine, Genetics, Genome-Wide Association Studies, Humans, Obesity, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Nutrition, Caloric Restriction, Regulatory Networks, [SDV.GEN]Life Sciences [q-bio]/Genetics, Lipogenesis, Computational Biology, Human Genetics, medicine.disease, lcsh:Genetics, Endocrinology, Gene Expression Regulation, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Human health and pathology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Metabolic syndrome, Genome Expression Analysis, Energy Intake, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Body mass index, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Weight control diets favorably affect parameters of the metabolic syndrome and delay the onset of diabetic complications. The adaptations occurring in adipose tissue (AT) are likely to have a profound impact on the whole body response as AT is a key target of dietary intervention. Identification of environmental and individual factors controlling AT adaptation is therefore essential. Here, expression of 271 transcripts, selected for regulation according to obesity and weight changes, was determined in 515 individuals before, after 8-week low-calorie diet-induced weight loss, and after 26-week ad libitum weight maintenance diets. For 175 genes, opposite regulation was observed during calorie restriction and weight maintenance phases, independently of variations in body weight. Metabolism and immunity genes showed inverse profiles. During the dietary intervention, network-based analyses revealed strong interconnection between expression of genes involved in de novo lipogenesis and components of the metabolic syndrome. Sex had a marked influence on AT expression of 88 transcripts, which persisted during the entire dietary intervention and after control for fat mass. In women, the influence of body mass index on expression of a subset of genes persisted during the dietary intervention. Twenty-two genes revealed a metabolic syndrome signature common to men and women. Genetic control of AT gene expression by cis signals was observed for 46 genes. Dietary intervention, sex, and cis genetic variants independently controlled AT gene expression. These analyses help understanding the relative importance of environmental and individual factors that control the expression of human AT genes and therefore may foster strategies aimed at improving AT function in metabolic diseases., Author Summary In obesity, an excess of adipose tissue is associated with dyslipidemia and diabetic complications. Gene expression is under the control of various genetic and environmental factors. As a central organ for the control of metabolic disturbances in conditions of both weight gain and loss, a comprehensive understanding of the control of adipose tissue gene expression is of paramount interest. We analyzed adipose tissue gene expression in obese individuals from the DiOGenes protocol, one of the largest dietary interventions worldwide. We found evidence for composite control of adipose tissue gene expression by nutrition, metabolic syndrome, body mass index, sex, and genotype with two main novel features. First, we observed a preeminent effect of sex on adipose tissue gene expression, which was independent of nutritional status, fat mass, and sex chromosomes. Second, the control of gene expression by cis genetic factors was unaffected by sex and nutritional status. Altogether, the effects of the investigated factors were most often independent of each other. Comprehension of the relative importance of environmental and individual factors that control the expression of human adipose tissue genes may help deciphering strategies aimed at controlling adipose tissue function during metabolic disorders.
Published: 2012

38. Dietary Factors Impact on the Association between CTSS Variants and Obesity Related Traits

Author: Henri Hooton, Jörg Hager, Domenico Palli, Karani Santhanakrishnan Vimaleswaran, Dominique Langin, Heiner Boeing, Marianne Uhre Jakobsen, Anne Tjønneland, Claus Holst, Edith J. M. Feskens, Karine Clément, NJ Wareham, Rikke Dalgaard Hansen, Nina Roswall, Kim Overvad, Lars Ängquist, Nabila Bouatia-Naji, Wim H. M. Saris, Karina Meidtner, Giovanna Masala, Francis Rousseau, Ruth J. F. Loos, Daphne L. van der A, Thorkild I. A. Sørensen, Simon, Marie Francoise, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute of Preventive Medicine, Copenhagen University Hospitals, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), INTEGRAGEN, IntegraGen, Cancer Epidemiology Institute, Danish Cancer Society, National Institute for Public Health and the Environment [Bilthoven] (RIVM), Department of Cardiology, Aarhus University Hospital, Department of Clinical Epidemiology, Department of Epidemiology, German Institute of Human Nutrition, Molecular and Nutritional Epidemiology Unit (ISPO), Cancer Research and Prevention Institute, Epidemiology Unit, Addenbrooke's Hospital-Medical Research Council (MRC), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Human Biology (NUTRIM), Nutrition and Toxicology Research Institute of Maastricht, Division of Human Nutrition, Wageningen University and Research [Wageningen] (WUR), Centre for Paediatric Epidemiology and Biostatistics and MRC Centre of Epidemiology for Child Health, UCL Institute of Child Health, Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], 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)-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), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie clinique, CHU Toulouse [Toulouse], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de nutrition [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), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), National Institute for Public Health and the Environment [Bilthoven] ( RIVM ), Aalborg Hospital-Aarhus University Hospital, Molecular and Nutritional Epidemiology Unit ( ISPO ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Human Biology ( NUTRIM ), Wageningen University and Research Centre [Wageningen] ( WUR ), Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), The Novo Nordisk Foundation Center for Basic Metabolic Research, Universiy of Copenhagen, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Humane Biologie, and RS: NUTRIM - R1 - Metabolic Syndrome
Subjects: Male, Nutrition and Disease, Epidemiology, lcsh:Medicine, adipose-tissue, Biochemistry, Body Mass Index, Cohort Studies, 0302 clinical medicine, Weight loss, Voeding en Ziekte, cathepsin-k gene, Body Fat Distribution, lcsh:Science, 2. Zero hunger, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, Multidisciplinary, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, low-fat diets, Lipids, Glycemic index, Genetic Epidemiology, Medicine, Female, women, Dietary Proteins, medicine.symptom, weight-loss, Research Article, medicine.medical_specialty, Waist, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Molecular Genetics, 03 medical and health sciences, Internal medicine, medicine, Genetics, cancer, Humans, Obesity, Genetic Association Studies, VLAG, 030304 developmental biology, Glycemic, Nutrition, Population Biology, lcsh:R, Body Weight, Computational Biology, Human Genetics, populations, medicine.disease, Lipid Metabolism, Cathepsins, Diet, Endocrinology, flip-flop, Glycemic Index, Genetics of Disease, Genetic Polymorphism, glycemic index, lcsh:Q, Basal Metabolism, protein, Weight gain, Body mass index, Population Genetics
Abstract: BACKGROUND/AIMS: Cathepsin S, a protein coded by the CTSS gene, is implicated in adipose tissue biology-this protein enhances adipose tissue development. Our hypothesis is that common variants in CTSS play a role in body weight regulation and in the development of obesity and that these effects are influenced by dietary factors-increased by high protein, glycemic index and energy diets. METHODS: Four tag SNPs (rs7511673, rs11576175, rs10888390 and rs1136774) were selected to capture all common variation in the CTSS region. Association between these four SNPs and several adiposity measurements (BMI, waist circumference, waist for given BMI and being a weight gainer-experiencing the greatest degree of unexplained annual weight gain during follow-up or not) given, where applicable, both as baseline values and gain during the study period (6-8 years) were tested in 11,091 European individuals (linear or logistic regression models). We also examined the interaction between the CTSS variants and dietary factors-energy density, protein content (in grams or in % of total energy intake) and glycemic index-on these four adiposity phenotypes. RESULTS: We found several associations between CTSS polymorphisms and anthropometric traits including baseline BMI (rs11576175 (SNP N degrees 2), p = 0.02, beta = -0.2446), and waist change over time (rs7511673 (SNP N degrees 1), p = 0.01, beta = -0.0433 and rs10888390 (SNP N degrees 3), p = 0.04, beta = -0.0342). In interaction with the percentage of proteins contained in the diet, rs11576175 (SNP N degrees 2) was also associated with the risk of being a weight gainer (p(interaction) = 0.01, OR = 1.0526)-the risk of being a weight gainer increased with the percentage of proteins contained in the diet. CONCLUSION: CTSS variants seem to be nominally associated to obesity related traits and this association may be modified by dietary protein intake.
Published: 2012

39. On the Futility of Screening for Genes That Make You Fat

Author: Terho Lehtimäki, Emily Sonestedt, Göran Hallmans, Andy R Ness, Simin Liu, Tuija Tammelin, John J. Nolan, Massimo Mangino, Nicholas J. Timpson, George Dedoussis, Aline Meirhaeghe, Lu Qi, Pål R. Njølstad, Ruth J. F. Loos, Mustafa Atalay, Mao Fu, Natalia V. Rivera, Marju Orho-Melander, Thorkild I. A. Sørensen, Philippe Froguel, André G. Uitterlinden, Torben Hansen, Debbie A Lawlor, M. Carola Zillikens, Tapani Rönnemaa, Vilmundur Gudnason, Esther Zimmermann, Claes Ohlsson, Cornelia M. van Duijn, Paul M. Ridker, Marjo-Riitta Järvelin, Samia Mora, María Teresa Martínez Larrad, Alena Stančáková, Thomas Illig, Zoltán Kutalik, Sven Bergmann, Jonatan R. Ruiz, Luigi Palla, Kathleen A. Jablonski, Günther Silbernagel, Ulla Sovio, Soren Snitker, Karina Meidtner, Bo Isomaa, Stephen J. Sharp, Jana V. van Vliet-Ostaptchouk, Louis Pérusse, Mika Kähönen, Daniel I. Chasman, Najaf Amin, Johanna Kuusisto, Toshiko Tanaka, Ingrid B. Borecki, John-Olov Jansson, Christine Cavalcanti-Proença, N. Charlotte Onland-Moret, Kay-Tee Khaw, Camilla H. Sandholt, Ulf Ekelund, Luigi Ferrucci, Mark Walker, Yiqing Song, Jose C. Florez, Oluf Pedersen, Leif Groop, Ying Wu, Soren Brage, Tuomas O. Kilpeläinen, Anders Grøntved, Frida Renström, Meena Kumari, Stéphane Cauchi, Michael Boehnke, Tamara B. Harris, Christine S. Autenrieth, Jeffery Metter, Beverley Balkau, Dmitry Shungin, Karen L. Mohlke, Markku Laakso, Matti Uusitupa, Nicholas J. Wareham, Andreas Fritsche, Jaakko Tuomilehto, Albert Hofman, Shah Ebrahim, Mary F. Feitosa, Melissa E. Garcia, Stefan Johansson, Tim D. Spector, Paul W. Franks, E. Shyong Tai, Frank B. Hu, Jonathan T. Tan, Maarit Hakanen, Heiner Boeing, Manuel Serrano Ríos, Olli T. Raitakari, Michael Marmot, Meian He, Jennifer L. Bragg-Gresham, Claude Bouchard, Tariq Ahmad, Ellen W. Demerath, Keri L. Monda, Robert A. Scott, Marika Kaakinen, Chris Power, Stefania Bandinelli, Christina Holzapfel, Timo A. Lakka, Heather M. Stringham, Stavroula Kanoni, Elina Hyppönen, Pamela L. Lutsey, Internal Medicine, Medical Microbiology & Infectious Diseases, Epidemiology, Urology, Institute of Metabolic Science, MRC, Departments of Epidemiology and Nutrition, Harvard School of Public Health, Department of Clinical Sciences, Lund University Diabetes Centre-Lund University [Lund], Division of Epidemiology and Community Health, University of Minnesota [Twin Cities] (UMN), University of Minnesota System-University of Minnesota System, Division of Cardiology, Duke University Medical Center, Brigham and Women's Hospital [Boston], Institute of Health Sciences and Biocenter Oulu, University of Oulu, Hagedorn Research Institute, Else Kroener Fresenius Centre - Zentralinstitut für Ernährungs und Lebensmittelfors (ZIEL), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Department of Population Health Sciences, University of Wisconsin-Madison, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Centre for Paediatric Epidemiology and Biostatistics, University College of London [London] (UCL), MRC Centre for Epidemiology of Child Health, UCL Institute of Child Health, Institut de biologie de Lille - UMS 3702 (IBL), Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), Department of Medical Genetics, Université de Lausanne (UNIL), Department of Epidemiology and Public Health, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, Department of Epidemiology, Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association-Leibniz Association, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), National University of Singapore (NUS)-Yong Loo Lin School of Medicine, King‘s College London, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, Division of Preventive Medicine, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Department of Internal Medicine, Erasmus University Medical Center [Rotterdam] (Erasmus MC), The Biostatistics Center, The George Washington University (GW), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Mental Health Sciences Unit, Department of Clinical Medicine, University of Bergen (UiB), Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Genetics, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Molecular Genetics Section, University of Groningen [Groningen]-University Medical Centre Groningen, Complex Genetics Section, University Medical Center [Utrecht], Julius Center for Health Sciences and Primary Care, Institute of Preventive Medicine, Copenhagen University Hospital, Department of Biomedical Sciences [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Genetic Epidemiology Unit, Medstar Research Institute, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease, and Clinical Chemistry, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Department of Nutrition-Dietetics, Harokopio University of Athens, Division of Statistical Genomics, Washington University School of Medicine, University of Maryland School of Medicine, University of Maryland System, Unit for Preventive Nutrition, Karolinska Institutet [Stockholm], Department of Physical Education and Sport, University of Granada [Granada], Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Hospital Clínico San Carlos, Department of Physiology, University of Eastern Finland-Institute of Biomedicine, The Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Institute of Sport Science and Clinical Biomechanics, University of Southern Denmark (SDU), Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU)-Sahlgrenska Academy at University of Gothenburg [Göteborg], Department of Clinical Physiology, University of Tampere [Finland]-Tampere University Hospital, Steno Diabetes Centre, Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health Sciences, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Department of Odontology, Department of Medical Statistics, London School of Hygiene and Tropical Medicine (LSHTM), LIKES Research Center for Sport and Health Sciences, Finnish Institute of Occupational Health, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Human Genomics Laboratory, Pennington Biomedical Research Center, Louisiana State University (LSU)-Louisiana State University (LSU), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Division of Endocrinology, Diabetes and Nutrition, University of Maryland System-University of Maryland System, Institute of Cell and Molecular Biosciences, Newcastle University [Newcastle], Centre for Bone and Arthritis Research, Institute of Medicine-University of Gothenburg (GU), Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze, Centre for Medical Systems Biology, Faculty of Epidemiology and Population Health [London], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland [Reykjavik], Department of Public Health, South Ostrobothnia Central Hospital, Department of Clinical and Preventive Medicine, Danube-University Krems, Department of Clinical Chemistry, Turku University Hospital (TYKS), Folkhälsan Research Centre, Department of Pediatrics, Haukeland University Hospital, University of Bergen (UiB)-University of Bergen (UiB), Center for Human Genetic Research and Diabetes Research Center, Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Program for Medical and Population Genetics, Broad Institute [Cambridge], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT)-Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Center for Metabolic Disease Prevention, University of California [Los Angeles] (UCLA), University of California-University of California-David Geffen School of Medicine [Los Angeles], University of California-University of California, School of Oral and Dental Sciences, University of Bristol [Bristol], National University of Singapore (NUS), Department of Genomics of Common Disease, Imperial College London, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Department of Epidemiology and Biostatistics, Department of Life Course and Services, National Institute for Health and Welfare [Helsinki], Autard, Delphine, Lund University [Lund], Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne = University of Lausanne (UNIL), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Universidad de Granada = University of Granada (UGR), University of Gothenburg (GU)-Institute of Medicine, University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], University of California (UC)-University of California (UC), Medical Research Council (MRC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Brage, Soren [0000-0002-1265-7355], Sharp, Stephen [0000-0003-2375-1440], Sovio, Ulla [0000-0002-0799-1105], Khaw, Kay-Tee [0000-0002-8802-2903], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Hjelt Institute (-2014), Harvard University-Massachusetts Institute of Technology (MIT)-Harvard University-Massachusetts Institute of Technology (MIT), Kilpeläinen, Tuomas O, Qi, Lu, Brage, Soren, Sharp, Stephen J, Hypponen, Elina, and Loos, Ruth JF
Subjects: Male, Heredity, endocrine system diseases, Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical genetics: 714 [VDP], Epidemiology, Social and Behavioral Sciences, no keywords, MESH: Genotype, 0302 clinical medicine, MESH: Child, GENETIC-VARIANTS, MESH: Proteins, 10. No inequality, Child, 0303 health sciences, Anthropometry, MESH: Polymorphism, Single Nucleotide, General Medicine, 11 Medical And Health Sciences, Genomics, MESH: Motor Activity, Adipose Tissue, Perspective, Medicine, Public Health, WAIST CIRCUMFERENCE, MESH: Adipose Tissue, medicine.medical_specialty, Genotype, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Endocrinology and Diabetes, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genomic Medicine, Genetics, Humans, Genetic Testing, Gene Prediction, Biology, Adipose Tissue/metabolism, Adolescent, Adult, Aged, Female, Genetic Predisposition to Disease, Motor Activity, Obesity/genetics, Obesity/metabolism, Polymorphism, Single Nucleotide, Proteins/genetics, Risk Factors, MESH: Adolescent, Science & Technology, MESH: Humans, Computational Biology, nutritional and metabolic diseases, Proteins, MESH: Adult, Odds ratio, medicine.disease, Obesity, RS9939609 POLYMORPHISM, Endocrinology, Anthropology, Physiological Processes, Body mass index, MESH: Female, Population Genetics, obesity, Genetic Screens, Anatomy and Physiology, FTO gene, IDENTICAL-TWINS, MESH: Risk Factors, MESH: Obesity, adolescents, 030212 general & internal medicine, MESH: Aged, MESH: Genetic Predisposition to Disease, 3142 Public health care science, environmental and occupational health, ENVIRONMENT INTERACTION, Genetic Epidemiology, childhood obesity, Life Sciences & Biomedicine, Research Article, Clinical Research Design, UNITED-STATES, WEIGHT-LOSS, Childhood obesity, body weight, Medicine, General & Internal, Genome Analysis Tools, Internal medicine, General & Internal Medicine, medicine, Allele, Sports and Exercise Medicine, Genetic Association Studies, 030304 developmental biology, Nutrition, Clinical Genetics, Population Biology, business.industry, Human Genetics, MESH: Male, COMMON VARIANT, meta-analysis, Minor allele frequency, BODY-MASS INDEX, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Genetics of Disease, Genetic Polymorphism, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Meta-Analyses, business, Energy Metabolism, genetic predisposition, DIABETES PREVENTION
Abstract: Ruth Loos and colleagues report findings from a meta-analysis of multiple studies examining the extent to which physical activity attenuates effects of a specific gene variant, FTO, on obesity in adults and children. They report a fairly substantial attenuation by physical activity on the effects of this genetic variant on the risk of obesity in adults., Background The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). Methods and Findings All studies identified to have data on the FTO rs9939609 variant (or any proxy [r 2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A−) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20–1.26), but PA attenuated this effect (p interaction = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19–1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24–1.36). No such interaction was found in children and adolescents. Conclusions The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity. Please see later in the article for the Editors' Summary, Editors’ Summary Background Two in three Americans are overweight, of whom half are obese, and the trend towards increasing obesity is now seen across developed and developing countries. There has long been interest in understanding the impact of genes and environment when it comes to apportioning responsibility for obesity. Carrying a change in the FTO gene is common (found in three-quarters of Europeans and North Americans) and is associated with a 20%–30% increased risk of obesity. Some overweight or obese individuals may feel that the dice are loaded and there is little point in fighting the fat; it has been reported that those made aware of their genetic susceptibility to obesity may still choose a poor diet. A similar fatalism may occur when overweight and obese people consider physical activity. But disentangling the influence of physical activity on those genetically susceptible to obesity from other factors that might impact weight is not straightforward, as it requires large sample sizes, could be subject to publication bias, and may rely on less than ideal self-reporting methods. Why Was This Study Done? The public health ramifications of understanding the interaction between genetic susceptibility to obesity and physical activity are considerable. Tackling the rising prevalence of obesity will inevitably include interventions principally aimed at changing dietary intake and/or increasing physical activity, but the evidence for these with regards to those genetically susceptible has been lacking to date. The authors of this paper set out to explore the interaction between the commonest genetic susceptibility trait and physical activity using a rigorous meta-analysis of a large number of studies. What Did the Researchers Do and Find? The authors were concerned that a meta-analysis of published studies would be limited both by the data available to them and by possible bias. Instead of this more widely used approach, they took the literature search as their starting point, identified other studies through their collaborators’ network, and then undertook a meta-analysis of all available studies using a new and standardized analysis plan. This entailed an extremely large number of authors mining their data afresh to extract the relevant data points to enable such a meta-analysis. Physical activity was identified in the original studies in many different ways, including by self-report or by using an external measure of activity or heart rate. In order to perform the meta-analysis, participants were labeled as physically active or inactive in each study. For studies that had used a continuous scale, the authors decided that the bottom 20% of the participants were inactive (10% for children and adolescents). Using data from over 218,000 adults, the authors found that carrying a copy of the susceptibility gene increased the odds of obesity by 1.23-fold. But the size of this influence was 27% less in the genetically susceptible adults who were physically active (1.22-fold) compared to those who were physically inactive (1.30-fold). In a smaller study of about 19,000 children, no such effect of physical activity was seen. What Do these Findings Mean? This study demonstrates that people who carry the susceptibility gene for obesity can benefit from physical activity. This should inform health care professionals and the wider public that the view of genetically determined obesity not being amenable to exercise is incorrect and should be challenged. Dissemination, implementation, and ensuring uptake of effective physical activity programs remains a challenge and deserves further consideration. That the researchers treated “physically active” as a yes/no category, and how they categorized individuals, could be criticized, but this was done for pragmatic reasons, as a variety of means of assessing physical activity were used across the studies. It is unlikely that the findings would have changed if the authors had used a different method of defining physically active. Most of the studies included in the meta-analysis looked at one time point only; information about the influence of physical activity on weight changes over time in genetically susceptible individuals is only beginning to emerge. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001116. This study is further discussed in a PLoS Medicine Perspective by Lennert Veerman The US Centers for Disease Control and Prevention provides obesity-related statistics, details of prevention programs, and an overview on public health strategy in the United States A more worldwide view is given by the World Health Organization The UK National Health Service website gives information on physical activity guidelines for different age groups, while similar information can also be found from US sources
Published: 2011

40. Sexual behaviour and HPV infection in British women, by postal questionnaires and telephone interviews

Author: Akua Asare, Alexandra Sargent, Isabel dos Santos Silva, Andrew Turner, Mina Desai, Henry C Kitchener, A. Bailey, Maribel Almonte, Clare Gilham, Julian Peto, Cancer Research UK Centre for Epidemiology, Mathematics & Statistics. Wolfson Institute of Preventive Medicine, Queen Mary University of London (QMUL), Non-Communicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine (LSHTM), Department of Paediatric Oncology, Royal Marsden NHS Foundation Trust, Manchester Clinical Virology, Central Manchester University NHS Foundation Trust, Manchester Cytology Centre, Central Manchester NHS Foundation Trust, School of Cancer & Imaging Sciences, and University of Manchester [Manchester]
Subjects: Adult, medicine.medical_specialty, Sexual Behavior, Hpv prevalence, law.invention, Interviews as Topic, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Risk Factors, law, Surveys and Questionnaires, Virology, Prevalence, Humans, Medicine, 030212 general & internal medicine, Papillomaviridae, Cervical cancer, Gynecology, Cervical screening, business.industry, Data Collection, Papillomavirus Infections, HPV infection, Odds ratio, Middle Aged, medicine.disease, United Kingdom, 3. Good health, Sexual intercourse, Sexual Partners, Infectious Diseases, Sexual behavior, 030220 oncology & carcinogenesis, DNA, Viral, Female, business, Demography
Abstract: Sexually transmitted human papillomaviruses (HPVs), most frequently HPV 16, are the primary cause of cervical carcinogenesis. The aim of this study was to evaluate the relationship between sexual behavior and prevalence and acquisition of HPV infection among British women attending regular cervical screening who responded to postal questionnaires and/or telephone interviews. A total of 1,880 women who had been tested for HPV in the ARTISTIC (A Randomized Trial In Screening To Improve Cytology) trial were randomized to three methods of data collection: group 1 (questionnaire including sexual history, no interview), group 2 (questionnaire excluding sexual history, short interview including sexual history), and group 3 (questionnaire and long interview including sexual history in both). Questions on sexual history included age at first sexual intercourse, sexually transmitted diseases, lifetime (total and regular) sexual partners, and number of partners in the last 5 years (total and new). Demographics, reproductive, cervical screening, and smoking history were also collected in questionnaires. The overall participation rate was 35%. There was good agreement (87.4-95.5%) on sexual behavior answers in questionnaires and interviews in women in group 3 and no significant differences between data obtained by questionnaire or interview. Odds ratios (OR) for both HPV prevalence and acquisition increased consistently with increasing numbers of lifetime sexual partners, regular partners, and new partners in the last 5 years (recent partners). No significant association was found for other characteristics investigated. The effect of recent sexual partners on HPV acquisition (OR for 2+ recent partners: 4.4, 95% CI: 1.7-11.2) was stronger than that of earlier (> 5 years ago) partners (OR for 2+ earlier partners: 2.2, 95% CI: 0.7-6.7) suggesting that most incident HPV infections are newly acquired rather than recurrent.
Published: 2011

41. Long working hours and symptoms of anxiety and depression: a 5-year follow-up of the Whitehall II study

Author: Jane E. Ferrie, Marianna Virtanen, Martin J. Shipley, Kirsi Ahola, Stephen Stansfeld, Jussi Vahtera, Michael Marmot, Mika Kivimäki, Archana Singh-Manoux, Finnish Institute of Occupational Health, Department of Epidemiology and Public Health, University College of London [London] (UCL), Centre de Gérontologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ste Périne, Santé publique et épidémiologie des déterminants professionnels et sociaux de la santé, Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre for Psychiatry, Queen Mary's School of Medicine and Dentistry-Wolfson Institute of Preventive Medicine, Department of Public Health, University of Turku, Turku University Hospital (TYKS), The Whitehall II study has been supported by grants from the Medical Research Council, British Heart Foundation, Health and Safety Executive, Department of Health, National Heart Lung and Blood Institute (HL36310), US, NIH: National Institute on Aging (AG13196), US, NIH, Agency for Health Care Policy Research (HS06516), and the John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health. MK and JV are supported by the Academy of Finland (Projects no. 124271, 124322 and 129264) and Finnish Work Environment Foundation, MK is also supported by the BUPA Foundation and the EU New OSH ERA research programme, AS-M is supported by a 'EURYI‟ award from the European Science Foundation and MGM is supported by a MRC Research Professorship. J.E.F. is supported by the Medical Research Council (Grant number G8802774)and M.J.S. is supported by the British Heart Foundation., Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Schmaus, Annie
Subjects: Adult, Male, medicine.medical_specialty, Time Factors, Article, Work hours, 03 medical and health sciences, 0302 clinical medicine, Sex Factors, Internal medicine, Work Schedule Tolerance, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Risk factor, Prospective cohort study, Psychiatry, Applied Psychology, Depression (differential diagnoses), Proportional Hazards Models, overtime work, Psychiatric Status Rating Scales, Proportional hazards model, Hazard ratio, Absolute risk reduction, Middle Aged, prospective, anxiety, 030210 environmental & occupational health, Psychiatry and Mental health, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, depression, Anxiety, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, medicine.symptom, Psychology, Cohort study, Follow-Up Studies
Abstract: BackgroundAlthough long working hours are common in working populations, little is known about the effect of long working hours on mental health.MethodWe examined the association between long working hours and the onset of depressive and anxiety symptoms in middle-aged employees. Participants were 2960 full-time employees aged 44 to 66 years (2248 men, 712 women) from the prospective Whitehall II cohort study of British civil servants. Working hours, anxiety and depressive symptoms, and covariates were measured at baseline (1997–1999) followed by two subsequent measurements of depressive and anxiety symptoms (2001 and 2002–2004).ResultsIn a prospective analysis of participants with no depressive (n=2549) or anxiety symptoms (n=2618) at baseline, Cox proportional hazard analysis adjusted for baseline covariates showed a 1.66-fold [95% confidence interval (CI) 1.06–2.61] risk of depressive symptoms and a 1.74-fold (95% CI 1.15–2.61) risk of anxiety symptoms among employees working more than 55 h/week compared with employees working 35–40 h/week. Sex-stratified analysis showed an excess risk of depression and anxiety associated with long working hours among women [hazard ratios (HRs) 2.67 (95% CI 1.07–6.68) and 2.84 (95% CI 1.27–6.34) respectively] but not men [1.30 (0.77–2.19) and 1.43 (0.89–2.30)].ConclusionsWorking long hours is a risk factor for the development of depressive and anxiety symptoms in women.
Published: 2011

42. A distinct adipose tissue gene expression response to caloric restriction predicts 6-mo weight maintenance in obese subjects

Author: Claus Holst, M. Ramzi Temanni, Marleen A. van Baak, Véronique Pelloux, Celia G. Walker, Dominique Langin, Teodora Handjieva-Darlenska, Dimitris K. Babalis, Arne Astrup, Jean-Daniel Zucker, Karine Clément, J. Alfredo Martínez, David M. Mutch, Wim H. M. Saris, Adriana Márquez-Quiñones, Tune H. Pers, Nathalie Viguerie, Simon, Marie Francoise, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Human Health and Nutritional Sciences, University of Guelph, Center for Biological Sequence Analysis [Lyngby], Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Institute of Preventive Medicine, Copenhagen University Hospital, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Fédératif de Recherche Bio-médicale Institution (IFR150), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), the Department of Physiology and Nutrition, Universidad de Navarra [Pamplona] (UNAV), Department of Internal Medicine, University Hospital of Heraklion, Nutrition Research Centre (NUTRIM), Maastricht University [Maastricht], National Multiprofile Transport Hospital, Human Nutrition Research, Medical Research Council, Department of Human Nutrition, Faculty of Life Science [Copenhagen], University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Technical University of Denmark [Lyngby] ( DTU ), Service Nutrition, Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut Français pour la Nutrition - IFN-Centre de Recherche en Nutrition Humaine - CRNH-Ile de France-CHU Pitié-Salpêtrière [APHP], Institut Fédératif de Recherche Bio-médicale, Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-IFR 150, Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Universidad de Navarra [Pamplona] ( UNAV ), Nutrition Research Centre ( NUTRIM ), Faculty of Life Sciences-University of Copenhagen ( KU ), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Technical University of Denmark [Lyngby] (DTU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-IFR150, and University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)
Subjects: Weight loss, Calorie, medicine.medical_treatment, MESH : Insulin, [SDV]Life Sciences [q-bio], Gene Expression, Medicine (miscellaneous), Adipose tissue, PROTEIN, REGAIN, MESH : Analysis of Variance, Weight Gain, 0302 clinical medicine, Insulin Secretion, Insulin, MESH: Obesity, MESH : Female, 0303 health sciences, Glucose tolerance test, Nutrition and Dietetics, MESH: Middle Aged, medicine.diagnostic_test, MESH : Gene Expression Regulation, MESH : Weight Gain, Middle Aged, MESH : Adult, MESH: Gene Expression Regulation, [SDV] Life Sciences [q-bio], BODY-WEIGHT, Gene xxpression, MESH : Subcutaneous Fat, MESH: Young Adult, MESH: Weight Gain, DIETS, Female, MESH : Obesity, medicine.symptom, SENSITIVITY, INTERVENTIONS, Adult, medicine.medical_specialty, MESH : Caloric Restriction, MESH: Gene Expression, MESH: Glucose Tolerance Test, Caloric restriction, Subcutaneous Fat, MESH : Young Adult, 030209 endocrinology & metabolism, MESH: Insulin, Biology, INSULIN-SECRETION, MESH : Glucose Tolerance Test, Young Adult, 03 medical and health sciences, MESH: Weight Loss, MESH: Subcutaneous Fat, Internal medicine, Diabetes mellitus, MESH: Analysis of Variance, Weight Loss, medicine, EXTRACELLULAR-MATRIX, Humans, MESH : Middle Aged, Obesity, Weight gain, Caloric Restriction, 030304 developmental biology, Analysis of Variance, MESH: Caloric Restriction, MESH: Humans, MESH : Humans, MESH: Adult, Glucose Tolerance Test, medicine.disease, MESH : Gene Expression, ENERGY-INTAKE, Endocrinology, Gene Expression Regulation, MESH : Weight Loss, GAIN, MESH: Female
Abstract: Background: Weight loss has been shown to reduce risk factors associated with cardiovascular disease and diabetes; however, successful maintenance of weight loss continues to pose a challenge. Objective: The present study was designed to assess whether changes in subcutaneous adipose tissue (scAT) gene expression during a low-calorie diet (LCD) could be used to differentiate and predict subjects who experience successful short-term weight maintenance from subjects who experience weight regain. Design: Forty white women followed a dietary protocol consisting of an 8-wk LCD phase followed by a 6-mo weight-maintenance phase. Participants were classified as weight maintainers (WMs; 0‐10% weight regain) and weight regainers (WRs; 50‐100% weight regain) by considering changes in body weight during the 2 phases. Anthropometric measurements, bioclinical variables, and scAT gene expression were studied in all individuals before and after the LCD. Energy intake was estimated by using 3-d dietary records. Results: No differences in body weight and fasting insulin were observed between WMs and WRs at baseline or after the LCD period. The LCD resulted in significant decreases in body weight and in several plasma variables in both groups. WMs experienced a significant reduction in insulin secretion in response to an oralglucose-tolerance test after the LCD; in contrast, no changes in insulin secretion were observed in WRs after the LCD. An ANOVA of scAT gene expression showed that genes regulating fatty acid metabolism, citric acid cycle, oxidative phosphorylation, and apoptosis were regulated differently by the LCD in WM and WR subjects. Conclusion: This study suggests that LCD-induced changes in insulin secretion and scAT gene expression may have the potential to predict successful short-term weight maintenance. This trial was registered at clinicaltrials.gov as NCT00390637. Am J Clin Nutr 2011;94:1399‐409.
Published: 2011

43. Obesity-related polymorphisms and their associations with the ability to regulate fat oxidation in obese Europeans: the NUGENOB study

Author: Philippe Froguel, Jean-Michel Oppert, Ellen E. Blaak, Oluf Pedersen, Wim H. M. Saris, Thorkild I. A. Sørensen, Jan Polak, Claus Holst, Ian A. Macdonald, Peter Arner, Dominique Langin, Eva Corpeleijn, Liselotte Petersen, J. Alfredo Martínez, Arne Astrup, Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, Department of Human Biology, Maastricht University [Maastricht], National Centre for Register-based Research, Institute of Preventive Medicine, Copenhagen University Hospital, Department of Human Nutrition, Royal Veterinary and Agricultural University = Kongelige Veterinær- og Landbohøjskole (KVL ), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham, Medical School, University of Nottingham, UK (UON), Department of Physiology and Nutrition, Universidad de Navarra [Pamplona] (UNAV), Service de nutrition, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital de l'Hôtel-Dieu, Department of Sports Medicine, Charles University [Prague] (CU)-Third Faculty of Medicine, Steno Diabetes Center and Hagedorn Research Institute, Department of Biomedical Sciences [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Faculty of Health Science, Institut de biologie de Lille - UMS 3702 (IBL), Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Simon, Marie Francoise, and Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: CD36 Antigens, Male, Amino Acid Transport Systems, INTERLEUKIN-6, Endocrinology, Diabetes and Metabolism, CD36, Saturated fat, Medicine (miscellaneous), ACID UPTAKE, Antigens, CD36, Linkage Disequilibrium, GLUCOSE, Fats, 0302 clinical medicine, Endocrinology, Gene Frequency, Weight loss, 0303 health sciences, INSULIN-RESISTANCE, Nutrition and Dietetics, biology, Chemistry, Fasting, Middle Aged, Postprandial Period, Phenotype, Postprandial, BALANCE, Female, medicine.symptom, Sterol Regulatory Element Binding Protein 1, Oxidation-Reduction, Adult, medicine.medical_specialty, Genotype, European Continental Ancestry Group, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, WEIGHT-LOSS, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, White People, DIET, Young Adult, 03 medical and health sciences, Insulin resistance, Internal medicine, medicine, Humans, Obesity, 030304 developmental biology, Interleukin-6, Genetic Variation, Proteins, Lipid Metabolism, medicine.disease, GENOTYPES, GENE, BODY-MASS INDEX, Amino Acid Transport Systems, Neutral, biology.protein, Energy Metabolism, Body mass index
Abstract: International audience; Both obesity and insulin resistance have been related to low fat oxidation rates, which may be genetically determined. The association between variation in fat oxidation rates among obese subjects and genotype was studied for 42 common single-nucleotide polymorphisms (SNPs) in 26 candidate genes for fat oxidation, insulin resistance, and obesity, including FTO. Energy expenditure (EE) and fat oxidation were measured with indirect calorimetry during fasting and 3 h after a high fat load containing 95 energy% of fat (60% saturated fat, energy content 50% of estimated resting EE) in 722 obese subjects (541 women, 181 men) from 8 European centers. After adjustment for center and gender, -178 A>C CD36 (rs2232169) (P = 0.02), -22510 C>G SLC6A14 (women, rs2011162) (P = 0.03), and T690S C>G PCSK1 (rs6235) (P = 0.02) were related to a reduced fat oxidation, whereas 17 C>G SREBF1 (17 C>G) (P = 0.01) was related to increased fat oxidation in the fasting state. The ability to increase fat oxidation after a high fat load was increased in subjects with -174 G>C IL6 (rs1800795) (P = 0.01). Effect sizes range from 1.1 to 3.1% differences in fat oxidation (expressed as % of EE). FTO rs9939609 was not related to fat oxidation. At the same time, the results are not adjusted for multiple testing, thus none of the associations can be considered statistically significant. The results should therefore only be considered as leads to new hypotheses about effects of specific genetic polymorphisms on fasting and postprandial fat oxidation.
Published: 2010

44. TCF7L2 rs7903146-macronutrient interaction in obese individuals' responses to a 10-wk randomized hypoenergetic diet

Author: Katrine Grau, J. Alfredo Martínez, Eva Klimcakova, Ian A. Macdonald, Jean-Michel Oppert, Dominique Langin, Oluf Pedersen, Claus Holst, Ellen E. Blaak, Stéphane Cauchi, Arne Astrup, Thorkild I. A. Sørensen, Peter Arner, Wim H. M. Saris, Stephan Rössner, Philippe Froguel, Institute of Preventive Medicine, Copenhagen University Hospital-Centre for HealthSociet, Genomic Medicine, Imperial College London-Hammersmith Hospital, Center for Pharmacogenomics, Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Department of Drug Design and Pharmacology [Copenhagen] (ILF), University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Institut de biologie de Lille - UMS 3702 (IBL), Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), Department of Human Nutrition, Faculty of Life Science [Copenhagen], Department of PhysiologyNutrition, Universidad de Navarra [Pamplona] (UNAV), Department of Human Biology NutritionToxicology, Maastricht University [Maastricht]-Research Institute Maastricht, Service de nutrition, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital de l'Hôtel-Dieu, Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Obesity Unit Department of Medicine Karolinska University Hospital Huddinge, Karolinska Institutet [Stockholm]-Karolinska University Hospital Huddinge, School of Biomedical Science, University of Nottingham Medical School-Queen's Medical Centre, Department of Sports Medicine, Charles University [Prague] (CU)-Third Faculty of Medicine-Centre of Preventive Medicine, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Steno Diabetes Center, Hagedorn Research Institute, Department of Biomedical Sciences [Copenhagen], Faculty of Health Science, Department of Drug Design and Pharmacology [Copenhagen] (ILF), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: Blood Glucose, Male, MESH: Dietary Carbohydrates, MESH: Chi-Square Distribution, endocrine system diseases, Medicine (miscellaneous), Type 2 diabetes, SUSCEPTIBILITY, Polymerase Chain Reaction, GLUCOSE, MESH: Genotype, 0302 clinical medicine, Weight loss, Insulin, MESH: Obesity, 2. Zero hunger, RISK, MESH: Diet, Reducing, 0303 health sciences, INSULIN-RESISTANCE, Nutrition and Dietetics, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH: DNA, HOMEOSTASIS MODEL ASSESSMENT, Middle Aged, MESH: Basal Metabolism, MESH: Dietary Fats, HIGH-FAT, Female, medicine.symptom, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein, Adult, medicine.medical_specialty, Diet, Reducing, Genotype, TYPE-2 DIABETIC-PATIENTS, 030209 endocrinology & metabolism, MESH: Insulin, Biology, GENE POLYMORPHISMS, Polymorphism, Single Nucleotide, 03 medical and health sciences, Insulin resistance, BETA-CELL FUNCTION, Internal medicine, Diabetes mellitus, medicine, Dietary Carbohydrates, Humans, Resting energy expenditure, Obesity, 030304 developmental biology, Chi-Square Distribution, MESH: Humans, nutritional and metabolic diseases, MESH: Adult, MESH: Polymerase Chain Reaction, DNA, medicine.disease, Dietary Fats, MESH: Male, ENERGY-INTAKE, Endocrinology, Basal metabolic rate, MESH: Blood Glucose, Basal Metabolism, TCF7L2, MESH: Female, MESH: TCF Transcription Factors
Abstract: International audience; BACKGROUND: Transcription factor 7-like 2 (TCF7L2) rs7903146 associates with type 2 diabetes and may operate via impaired glucagon-like peptide 1 secretion, which is stimulated more by fat than by carbohydrate ingestion. OBJECTIVE: The objective was to examine the interaction between TCF7L2 rs7903146 and dietary fat and carbohydrate [high-fat, low-carbohydrate: 40-45% of energy as fat (HF); compared with low-fat, high-carbohydrate: 20-25% of energy as fat (LF)] in obese individuals' responses to a 10-wk hypoenergetic diet (-600 kcal/d). DESIGN: European, obese participants (n = 771) were randomly assigned to receive an HF or an LF diet. Body weight, fat mass (FM), fat-free mass (FFM), waist circumference (WC), resting energy expenditure (REE), fasting fat oxidation in percentage of REE (FatOx), homeostasis model assessed insulin release (HOMA-beta), and HOMA-insulin resistance (HOMA-IR) were determined at baseline and after the intervention; 739 individuals were genotyped for rs7903146. RESULTS: Average weight loss was 6.9 kg with the LF and 6.6 kg with the HF (difference between diets, NS) diet. Among individuals who were homozygous for the T-risk allele, those in the HF diet group experienced smaller weight losses (Deltaweight) (2.6 kg; P = 0.009; n = 622), smaller DeltaFFM (1.6 kg; P = 0.027; n = 609), smaller DeltaWC (3.3 cm; P = 0.010; n = 608), and a smaller DeltaHOMA-IR (1.3 units; P = 0.004; n = 615) than did the LF diet group. For C allele carriers, there were no differences between the HF and LF diet groups. For the HF diet group, each additional T allele was associated with a reduced loss of FM (0.67 kg; P = 0.019; n = 609). TCF7L2 rs7903146 was not associated with DeltaREE, DeltaFatOx, DeltaHOMA-beta, or dropout. CONCLUSION: Our results suggest that obese individuals who are homozygous for the TCF7L2 rs7903146 T-risk allele are more sensitive to LF than to HF weight-loss diets.
Published: 2010

45. Adipose tissue transcriptome reflects variations between subjects with continued weight loss and subjects regaining weight 6 mo after caloric restriction independent of energy intake

Author: Adriana Márquez-Quiñones, Dominique Langin, Karine Clément, Wim H. M. Saris, Teodora Handjieva-Darlenska, Marion Combes, Ping Wang, Andreas Pfeiffer, Dimitris K. Babalis, David M. Mutch, Thomas Meinert Larsen, Susan A. Jebb, Claus Holst, Edwin C. M. Mariman, Hubert Vidal, Arne Astrup, Nathalie Viguerie, Pavla Kalouskova, Balbine Roussel, Cyrille Debard, J. Alfredo Martínez, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Santé Publique et Informatique Médicale (SPIM), Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Human Health and Nutritional Sciences, University of Guelph, Régulations métaboliques, nutrition et diabètes - UM55 (RMND UM55), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-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)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Department of Human Biology, Maastricht University [Maastricht], Institute of Preventive Medicine, Copenhagen University Hospitals, Department of Physiology and Nutrition, Universidad de Navarra [Pamplona] (UNAV), Department of Pharmacology and Toxicology, Medical Faculty, Medical University, Obesity Management Centre, Institute of Endocrinology, Human Nutrition Research, Elsie Widdowson Laboratory, Department of Internal Medicine, University Hospital of Heraklion, Department of Clinical Nutrition, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Human Nutrition, Faculty of Life Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Centre de Recherche en Nutrition Humaine d'Ile-de-France (CRNH-IDF), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], European Community [FP6-513946], Institut National de la Sante et de la Recherche Medicale, Region Midi-Pyrenees, Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil ( I2MR ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Santé Publique et Informatique Médicale ( SPIM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Régulations métaboliques, nutrition et diabètes - UM55 ( RMND UM55 ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-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 ) -Hospices Civils de Lyon ( HCL ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ), Universidad de Navarra [Pamplona] ( UNAV ), Charité Universitäts Medizin Berlin, University of Copenhagen ( KU ), Centre de Recherche en Nutrition Humaine d'Ile-de-France ( CRNH-IDF ), Université Paris 13 ( UP13 ) -Institut National de la Recherche Agronomique ( INRA ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Institut National Agronomique Paris-Grignon ( INA P-G ) -CETAF-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Université Paris 13 (UP13)-CETAF-Institut National Agronomique Paris-Grignon (INA P-G)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut de Veille Sanitaire (INVS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humane Biologie, RS: NUTRIM - R4 - Gene-environment interaction, and RS: NUTRIM - R1 - Metabolic Syndrome
Subjects: MESH: Treatment Failure, Blood Pressure, MESH: Energy Intake, Transcriptome, 0302 clinical medicine, HIGH-PROTEIN, Models, MESH: Models, Genetic, GENE-EXPRESSION, Oligonucleotide Array Sequence Analysis, MESH: Treatment Outcome, 0303 health sciences, MACRONUTRIENT, Reducing, MESH : Reverse Transcriptase Polymerase Chain Reaction, MESH: Blood Pressure, MESH: Follow-Up Studies, LOW-FAT, Gene expression profiling, 3. Good health, MESH : Oligonucleotide Array Sequence Analysis, Adipose Tissue, MESH: Adipose Tissue, medicine.medical_specialty, Diet, Reducing, LOSS MAINTENANCE, MESH : Adipose Tissue, 03 medical and health sciences, MESH: Gene Expression Profiling, MESH: Weight Loss, MESH : Treatment Failure, Genetic, Humans, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Humans, MESH : Gene Expression Profiling, MESH : Humans, MESH : Follow-Up Studies, MESH: Adult, Anthropometry, medicine.disease, Obesity, Endocrinology, MICROARRAY DATA, Energy intake, MESH: Female, Calorie, Time Factors, Medicine (miscellaneous), Adipose tissue, MESH : Models, Genetic, HUMAN OBESITY, Weight loss, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH : RNA, MESH: Obesity, MESH : Female, Treatment Failure, MESH : Diet, Reducing, 2. Zero hunger, MESH: Diet, Reducing, Nutrition and Dietetics, Reverse Transcriptase Polymerase Chain Reaction, MESH : Adult, ADIPOCYTES, Glycemic index, Treatment Outcome, MESH : Obesity, Female, medicine.symptom, Dieting, MESH : Time Factors, Adult, 030209 endocrinology & metabolism, MESH : Treatment Outcome, Biology, DiOGenes, MESH: RNA, Internal medicine, Weight Loss, medicine, MESH : Blood Pressure, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, LOSS DIETS, Models, Genetic, Gene Expression Profiling, MESH: Time Factors, MESH : Energy Intake, Diet, MESH: Oligonucleotide Array Sequence Analysis, GLYCEMIC INDEX, RNA, MESH : Weight Loss, Energy Intake, Follow-Up Studies
Abstract: Background: The mechanisms underlying body weight evolution after diet-induced weight loss are poorly understood. Objective: We aimed to identify and characterize differences in the subcutaneous adipose tissue (SAT) transcriptome of subjects with different weight changes after energy restriction-induced weight loss during 6 mo on 4 different diets. Design: After an 8-wk low-calorie diet (800 kcal/d), we randomly assigned weight-reduced obese subjects from 8 European countries to receive 4 diets that differed in protein and glycemic index content. In addition to anthropometric and plasma markers, SAT biopsies were taken at the beginning [clinical investigation day (CID) 2] and end (CID3) of the weight follow-up period. Microarray analysis was used to define SAT gene expression profiles at CID2 and CID3 in 22 women with continued weight loss (successful group) and in 22 women with weight regain (unsuccessful group) across the 4 dietary arms. Results: Differences in SAT gene expression patterns between successful and unsuccessful groups were mainly due to weight variations rather than to differences in dietary macronutrient content. An analysis of covariance with total energy intake as a covariate identified 1338 differentially expressed genes. Cellular growth and proliferation, cell death, cellular function, and maintenance were the main biological processes represented in SAT from subjects who regained weight. Mitochondrial oxidative phosphorylation was the major pattern associated with continued weight loss. Conclusions: The ability to control body weight loss independent of energy intake or diet composition is reflected in the SAT transcriptome. Although cell proliferation may be detrimental, a greater mitochondrial energy gene expression is suggested as being beneficial for weight control. This trial was registered at clinicaltrials.gov as NCT00390637. © 2010 American Society for Nutrition.
Published: 2010

46. Macrophages and adipocytes in human obesity: adipose tissue gene expression and insulin sensitivity during calorie restriction and weight stabilization

Author: Capel, Frédéric, Klimcáková, Eva, Viguerie, Nathalie, Roussel, Balbine, Vítková, Michaela, Kováciková, Michaela, Polák, Jan, Kovácová, Zuzana, Galitzky, Jean, Maoret, Jean-José, Hanácek, Jirí, Pers, Tune H, Bouloumié, Anne, Stich, Vladimir, Langin, Dominique, Franco-Czech Laboratory for Clinical Research on Obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Sports Medicine, Third Faculty of Medicine Charles University, Institute for Mother and Child Care, Center for Biological Sequence Analysis [Lyngby], Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Institute of Preventive Medicine, Copenhagen University Hospital, Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Technical University of Denmark [Lyngby] (DTU), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], and CHU Toulouse [Toulouse]
Subjects: Diet, Reducing, Biopsy, MESH: Insulin, MESH: Energy Intake, MESH: Glucose Clamp Technique, MESH: Biopsy, MESH: Gene Expression Profiling, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: C-Reactive Protein, Adipocytes, MESH: Obesity, Humans, Insulin, MESH: Genetic Variation, Obesity, RNA, Messenger, MESH: Adipocytes, MESH: RNA, Messenger, MESH: Diet, Reducing, MESH: Humans, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Macrophages, Body Weight, MESH: Macrophages, Genetic Variation, MESH: Body Weight, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, C-Reactive Protein, Glucose Clamp Technique, Original Article, Energy Intake, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Obesity Studies
Abstract: International audience; OBJECTIVE: We investigated the regulation of adipose tissue gene expression during different phases of a dietary weight loss program and its relation with insulin sensitivity. RESEARCH DESIGN AND METHODS: Twenty-two obese women followed a dietary intervention program composed of an energy restriction phase with a 4-week very-low-calorie diet and a weight stabilization period composed of a 2-month low-calorie diet followed by 3-4 months of a weight maintenance diet. At each time point, a euglycemic-hyperinsulinemic clamp and subcutaneous adipose tissue biopsies were performed. Adipose tissue gene expression profiling was performed using a DNA microarray in a subgroup of eight women. RT-quantitative PCR was used for determination of mRNA levels of 31 adipose tissue macrophage markers (n = 22). RESULTS: Body weight, fat mass, and C-reactive protein level decreased and glucose disposal rate increased during the dietary intervention program. Transcriptome profiling revealed two main patterns of variations. The first involved 464 mostly adipocyte genes involved in metabolism that were downregulated during energy restriction, upregulated during weight stabilization, and unchanged during the dietary intervention. The second comprised 511 mainly macrophage genes involved in inflammatory pathways that were not changed or upregulated during energy restriction and downregulated during weight stabilization and dietary intervention. Accordingly, macrophage markers were upregulated during energy restriction and downregulated during weight stabilization and dietary intervention. The increase in glucose disposal rates in each dietary phase was associated with variation in expression of sets of 80-110 genes that differed among energy restriction, weight stabilization, and dietary intervention. CONCLUSIONS: Adipose tissue macrophages and adipocytes show distinct patterns of gene regulation and association with insulin sensitivity during the various phases of a dietary weight loss program.
Published: 2009

47. Macronutrient-specific effect of FTO rs9939609 in response to a 10-week randomized hypo-energetic diet among obese Europeans

Author: Katrine Grau, Arne Astrup, O. Pedersen, José Alfredo Martínez, Claus Holst, Torben Hansen, J.-M. Oppert, T I A Sørensen, Ian A. Macdonald, Stephan Rössner, Dominique Langin, Peter Arner, W. H. M. Saris, Joseph F. Polak, Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, Institute of Preventive Medicine, Copenhagen University Hospital, Center for Pharmacogenomics, Department of Drug Design and Pharmacology [Copenhagen] (ILF), 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), Steno Diabetes Center, Steno Diabetes Center of Copenhagen, Department of Human Nutrition, Faculty of Life Science [Copenhagen], Department of Human Biology (NUTRIM), Maastricht University [Maastricht]-Nutrition and Toxicology Research Institute Maastricht, Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Obesity Unit, karolinska institute-Karolinska University Hospital [Stockholm], School of Biomedical Science, Nottingham Medical School-Queen's Medical Centre, Department of Sport Medicine, Third Faculty of Medicine Charles University, Service de nutrition, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital de l'Hôtel-Dieu, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Physiology and Nutrition, Universidad de Navarra [Pamplona] (UNAV), Hagedorn Research Institute, Hagedom Research Institute, Department of Biomedical Sciences [Copenhagen], Faculty of Health Science, Simon, Marie Francoise, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, medicine.medical_specialty, Waist, Diet, Reducing, Genotype, Endocrinology, Diabetes and Metabolism, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Medicine (miscellaneous), Body Mass Index, Young Adult, Insulin resistance, Weight loss, Internal medicine, Dietary Carbohydrates, Humans, Medicine, Genetic Predisposition to Disease, Resting energy expenditure, Obesity, Diet, Fat-Restricted, Caloric Restriction, Nutrition and Dietetics, business.industry, Proteins, nutritional and metabolic diseases, Middle Aged, medicine.disease, Dietary Fats, Europe, Endocrinology, Basal metabolic rate, Female, medicine.symptom, Energy Intake, Energy Metabolism, business, Body mass index
Abstract: International audience; Background:The A risk allele of rs9939609 of the fat mass- and obesity-associated gene (FTO) increases body fat mass.Objective:To examine whether FTO rs9939609 affects obese individuals' response to a high-fat, low-carbohydrate (CHO) (HF) or low-fat, high-CHO (LF), hypo-energetic diet and whether the effect of the FTO variant depends on dietary fat and CHO content.Design:In a 10-week, European, multi-centre dietary intervention study 771 obese women and men were randomized to either LF (20-25% of energy (%E) from fat, 60-65%E from CHO) or HF (40-45%E from fat, 40-45%E from CHO), hypo-energetic diet (measured resting metabolic rate multiplied by 1.3-600 kcal day(-1)). Body weight, fat mass (FM), fat-free mass (FFM), waist circumference (WC), resting energy expenditure (REE), fasting fat oxidation as % of REE (FatOx), insulin release (HOMA-beta) and a surrogate measure of insulin resistance (HOMA-IR) were measured at baseline and after the intervention. In all, 764 individuals were genotyped for FTO rs9939609.Results:For A-allele carriers the drop-out rate was higher on HF than LF diet (in AT, P=0.002; in AT/AA combined, P=0.003). Among those individuals completing the intervention, we found no effect of FTO rs9939609 genotype on Deltaweight, DeltaFM, DeltaFFM, DeltaWC or DeltaFatOx. However, participants with TT had a smaller reduction in REE on LF than on HF diet (75 kcal/24 h; interaction: P=0.0055). These individuals also showed the greatest reduction in HOMA-beta and HOMA-IR (interaction: P=0.0083 and P=0.047).Conclusion:The FTO rs9939609 may interact with the macronutrient composition in weight loss diets in various ways; carriers of the A allele on LF diet appear to have a lower risk for drop out, and TT individuals have a smaller decrease in REE and greater decrease in HOMA-beta and HOMA-IR on LF than on HF diet.International Journal of Obesity advance online publication, 18 August 2009; doi:10.1038/ijo.2009.159.
Published: 2009

48. Effects of TCF7L2 polymorphisms on obesity in European populations

Author: Michel Marre, Fritz F. Horber, Katrine Grau, David Meyre, Alex Duval, Christian Dina, Christine Proença, Hélène Choquet, Guillaume Charpentier, Thorkild I. A. Sørensen, Stéphane Cauchi, Philippe Froguel, Ruth Gutierrez-Aguilar, Beverley Balkau, Dominique Langin, Frédéric Capel, Natascha Potoczna, Simon, Marie Francoise, Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Preventive Medicine, Copenhagen University Hospital, Instabilité des microsatellites et cancers [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Déterminants génétiques du diabète de type 2 et de ses complications vasculaires ((U 695)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Obesity Centre, Klinik Lindberg, Obesity Center Klink Lindberg, Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital de Corbeil, Genomic Medicine, Imperial College London-Hammersmith Hospital, Medical Research Council G0600331, Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Instabilité des microsatellites et cancers [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], and Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, endocrine system diseases, Polymorphism, Single Nucleotide/*genetics, Endocrinology, Diabetes and Metabolism, TCF Transcription Factors/*genetics/metabolism, Medicine (miscellaneous), Adipose tissue, Type 2 diabetes, Body Mass Index, 0302 clinical medicine, Endocrinology, Risk Factors, MESH: Risk Factors, Medicine, MESH: Obesity, MESH: Aged, 0303 health sciences, education.field_of_study, Nutrition and Dietetics, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, MESH: European Continental Ancestry Group, Middle Aged, MESH: Case-Control Studies, Pedigree, Diabetes Mellitus, Type 2/ethnology/etiology, Female, France, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein, MESH: Diabetes Mellitus, Type 2, Adult, medicine.medical_specialty, endocrine system, MESH: Pedigree, Population, Subcutaneous Fat, Genetic Predisposition to Disease/ethnology/genetics, 030209 endocrinology & metabolism, Polymorphism, Single Nucleotide, White People, MESH: Body Mass Index, 03 medical and health sciences, MESH: Subcutaneous Fat, Internal medicine, Humans, Genetic Predisposition to Disease, Obesity, Allele, education, Alleles, 030304 developmental biology, Aged, MESH: Humans, business.industry, MESH: Alleles, Case-control study, nutritional and metabolic diseases, Obesity/complications/ethnology/*genetics, MESH: Adult, Odds ratio, medicine.disease, MESH: Male, European Continental Ancestry Group/ethnology/genetics, MESH: France, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Diabetes Mellitus, Type 2, Case-Control Studies, business, TCF7L2, MESH: Female, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, MESH: TCF Transcription Factors, Subcutaneous Fat/metabolism
Abstract: 1930-7381 (Print) Journal Article Research Support, Non-U.S. Gov't; International audience; The transcription factor 7-like 2 (TCF7L2) rs7903146 T allele was previously associated with type 2 diabetes (T2D) and decreased BMI whereas haplotypes carrying the rs7903146 C and rs10885406 A alleles (HapA) were associated with increased BMI. The functional relevance of TCF7L2 polymorphisms and their effects on T2D and obesity remained to be further investigated.In white European populations, we found that the rs7903146 T allele was more associated with T2D in 3,547 non-obese individuals (odds ratio (OR) = 1.88 (1.69-2.10)) than in 1,110 class III obese subjects (OR = 1.24 (1.03-1.50)). No direct effect of the rs7903146 C allele and HapA was found on any form of obesity in 3,507 normal glucose tolerant (NGT) individuals, 1,106 pedigrees with familial obesity and 5,512 individuals from the French general population. However, in T2D subjects, the rs7903146 C allele was less prevalent in the 1,111 non-obese individuals (55.2%) compared to 659 class III obese subjects (67.5% OR = 1.69 (1.46-1.95)). Functional studies showed that the rs7903146 T allele is less prone to be bound by protein factors than the C allele in 3T3-L1, HepG2 and beta-TC3 cell lines and that TCF7L2 expression decreases in subcutaneous adipose tissue from NGT obese T/T carriers under calorie restriction.In conclusion, TCF7L2 is not a risk factor for obesity in European populations, but its effect on T2D risk is modulated by obesity. Furthermore, our data suggest that the rs7903146 T allele may be possibly functional and associated with a nominal decrease in TCF7L2 expression in adipose tissue of individuals under calorie restriction.
Published: 2008

49. Cereal alkylresorcinols as dietary biomarkers-absorption and occurrence in biological membranes

Author: Linko-Parvinen, Anna-Maria, University of Helsinki, Faculty of Medicine, Institute of Clinical Medicine, Clinical Chemistry, Institute for Preventive Medicine, Nutrition and Cancer, Folkhälsan Research Center, Helsingin yliopisto, lääketieteellinen tiedekunta, kliininen laitos, Helsingfors universitet, medicinska fakulteten, institutionen för klinisk medicin, Mäkelä, Sari, Adlercreutz, Herman, and Peñalvo, José
Subjects: lääketiede
Abstract: Several studies link the consumption of whole-grain products to a lowered risk of chronic diseases, such as certain types of cancer, type II diabetes, and cardiovascular diseases. However, the final conclusions of the exact protective mechanisms remain unclear, partly due to a lack of a suitable biomarker for the whole-grain cereals intake. Alkylresorcinols (AR) are phenolic lipids abundant in the outer parts of wheat and rye grains usually with homologues of C15:0- C25:0 alkyl chains, and are suggested to function as whole-grain biomarkers. Mammalian lignan enterolactone has also previously been studied as a potential whole-grain biomarker. In the present work a quantified gas chromatography-mass spectrometry method for the analysis of AR in plasma, erythrocytes, and lipoproteins was developed. The method was used to determine human and pig plasma AR concentrations after the intake of whole-grain wheat and rye products compared to low-fibre wheat bread diets to assess the usability of AR as biomarkers of whole-grain intake. AR plasma concentrations were compared to serum ENL concentrations. AR absorption and elimination kinetics were investigated in a pig model. AR occurrence in human erythrocyte membranes and plasma lipoproteins were determined, and the distribution of AR in blood was evaluated. Plasma AR seem to be absorbed via the lymphatic system from the small intestine, like many other lipophilic compounds. Their apparent elimination half-life is relatively short and is similar to that of tocopherols, which have a similar chemical structure. Plasma AR concentrations increased significantly after a one- to eight-week intake of whole-grain wheat and further on with whole-grain rye bread. The concentrations were also higher after habitual Finnish diet compared to diet with low-fibre bread. Inter-individual variation after a one-week intake of the same amount of bread was high, but the mean plasma AR concentrations increased with increasing AR intake. AR are incorporated into erythrocyte membranes and plasma lipoproteins, and VLDL and HDL were the main AR carriers in human plasma. Based on these studies, plasma AR could function as specific biomarkers of dietary whole-grain products. AR are exclusively found in whole-grains and are more suitable as specific biomarkers of whole-grain intake than previously investigated mammalian lignan enterolactone, that is formed from several plants other than cereals in the diet. Plasma AR C17:0/C21:0 -ratio could distinguish whether whole-grain products in the diet are mainly wheat or rye. AR could be used in epidemiological studies to determine whole-grain intake and to better assess the role of whole-grains in disease prevention. Kokojyväviljojen käytön on todettu vähentävän riskiä sairastua useisiin kroonisiin sairauksiin, kuten tiettyihin syöpäsairauksiin, tyypin II diabetekseen ja sydän- ja verisuonisairauksiin. Lopulliset päätelmät suojaavista mekanismeista puuttuvat. Osaltaan tähän on vaikuttanut sopivan kokojyvätuotteiden käytön mittarin puute. Alkyyliresorsinolit (AR) ovat rasvaliukoisia yhdisteitä, joita esiintyy vehnän ja rukiin viljan kuorikerroksissa C17:0-C25:0 -pituisten hiiliketjujen kanssa. Niiden on ehdotettu toimivan kokojyväviljojen saannin mittarina. Enterolaktonin toimimista tällaisena mittarina on myös tutkittu. Tässä työssä kehitimme kaasukromatografia-massaspektometrisen menetelmän, jolla mittasimme AR:n pitoisuuksia plasmassa, punasoluissa ja lipoproteiineissa. Vertasimme pitoisuuksia ihmisen plasmassa kokojyvävehnäleivän ja -ruisleivän syönnin jälkeen sekä matalakuituisen vehnäleivän syönnin jälkeen. Tutkimme AR:n toimimista kokojyvätuotteiden saannin mittareina ja vertasimme niitä enterolaktoniin. AR:n kinetiikkaa tutkittiin porsailla tehdyssä kokeessa. Tutkimme myös AR:n esiintymistä ihmisen punasoluissa ja lipoproteiineissa. Plasman AR imeytyvät imujärjestelmän kautta ohutsuolesta, kuten monet muutkin rasvaliukoiset yhdisteet. Niiden puoliintumisaika on verraten lyhyt ja verrattavissa rakenteeltaan samankaltaiseen tokoferoliin. AR:n plasmapitoisuudet nousivat merkittävästi kokojyvävehnäleivän syönnin jälkeen ja vielä enemmän kokojyväruisleivän syönnin jälkeen. Pitoisuudet olivat korkeat myös keskimääräisen suomalaisen ruokavalion jälkeen verrattuna matalakuituisen vehnäleivän syöntiin. Ihmisten väliset pitoisuudet erosivat melko paljon yhden ja kahdeksan viikon kokojyväleivän syönnin jälkeen, mutta nousivat suhteessa AR:n saantiin ruokavaliosta. AR:a esiintyy punasolujen solukalvoissa ja lipoproteiineissa. Lipoproteiinit HDL ja VLDL ovat AR:n pääasialliset kuljettajat ihmisen plasmassa. Tutkimuksemme pohjalta voimme päätellä, että AR:t, joita ihmisen ravinnossa esiintyy vain kokojyvävehnässä ja -rukiissa, voivat toimia erityisesti kokojyvätuotteiden mittarina verrattuna esimerkiksi enterolaktoniin. Enterolaktonia muodostuu paljon kokojyvätuotteista mutta myös muista kasvituotteista. Plasman AR C17:0/C21:0 -suhde voi erottaa, onko kokojyvätuote ravinnossa pääasiassa peräisin vehnästä vai rukiista. AR:a voidaan käyttää epidemiologisissa tutkimuksissa kokojyvätuotteiden saannin mittarina ja siten pystytään paremmin määrittämään alkyyliresorsinolien mahdollisia sairauksilta suojaavia mekanismeja.
Published: 2006

50. Identification of Isoflavonoid Metabolites in Humans

Author: Heinonen, Satu-Maarit, University of Helsinki, Faculty of Science, Department of Chemistry, Laboratory of Organic Chemistry, Folkhälsan Research Center, Institute for Preventive Medicine, Nutrition, and Cancer, University of Helsinki, Faculty of Medicine, Division of Clinical Chemistry, Helsingin yliopisto, matemaattis-luonnontieteellinen tiedekunta, kemian laitos, Helsingfors universitet, matematisk-naturvetenskapliga fakulteten, kemiska institutionen, Metzler, Manfred, Adlercreutz, Herman, and Wähälä, Kristiina
Subjects: orgaaninen kemia
Abstract: Epidemiological studies have associated high soy intake with a lowered risk for certain hormone-dependent diseases, such as breast and prostate cancers, osteoporosis, and cardiovascular disease. Soy is a rich source of isoflavones, diphenolic plant compounds that have been shown to possess several biological activities. Soy is not part of the traditional Western diet, but many dietary supplements are commercially available in order to provide the proposed beneficial health effects of isoflavones without changing the original diet. These supplements are usually manufactured from extracts of soy or red clover, which is another important source of isoflavones. However, until recently, detailed studies of the metabolism of these compounds in humans have been lacking. The aim of this study was to identify urinary metabolites of isoflavones originating from soy or red clover using gas chromatography - mass spectrometry (GC-MS). To examine metabolism, soy and red clover supplementation studies with human volunteers were carried out. In addition, the metabolism of isoflavones was investigated in vitro by identification of metabolites formed during a 24-h fermentation of pure isoflavones with a human fecal inoculum. Qualitative methods for identification and analysis of isoflavone metabolites in urine and fecal fermentation samples by GC-MS were developed. Moreover, a detailed investigation of fragmentation of isoflavonoids in electron ionization mass spectrometry (EIMS) was carried out by means of synthetic reference compounds and deuterated trimethylsilyl derivatives. After isoflavone supplementation, 18 new metabolites of isoflavones were identified in human urine samples. The most abundant urinary metabolites of soy isoflavones daidzein, genistein, and glycitein were found to be the reduced metabolites, i.e. analogous isoflavanones, a-methyldeoxybenzoins, and isoflavans. Metabolites having additional hydroxyl and/or methoxy substituents, or their reduced analogs, were also identified. The main metabolites of red clover isoflavones formononetin and biochanin A were identified as daidzein and genistein. In addition, reduced and hydroxylated metabolites of formononetin and biochanin A were identified; however, they occurred at much lower levels in urine samples than daidzein or genistein or their reduced metabolites. The results of this study show that the metabolism of isoflavones is diverse. More studies are needed to determine whether the new isoflavonoid metabolites identified here have biological activities that contribute to the proposed beneficial effects of isoflavones on human health. Another task is to develop validated quantitative methods to determine the actual levels of isoflavones and their metabolites in biological matrices in order to assess the role of isoflavones in prevention of chronic diseases. Runsaasti soijaa käyttävissä väestöissä ateroskleroosi, hormoneista riippuvaiset syövät ja osteoporoosi ovat olleet länsimaihin verrattuna harvinaisia. Soija ja soijasta valmistetut ruoat sisältävät paljon isoflavoneja, biologisesti aktiivisia difenolisia yhdisteitä. Toinen merkittävä isoflavonilähde on puna-apila. Soija ei kuulu länsimaiseen ruokavalioon, ja nykyään markkinoilla onkin runsaasti isoflavoneja sisältäviä erityisvalmisteita, jotka on valmistettu soijasta tai puna-apilasta. Näitä erityisvalmisteita markkinoidaan mm. vaihdevuosioireiden hoitoon, vahvistamaan luustoa ja hidastamaan sen haurastumista, sekä tasapainottamaan kehon hormonitoimintaa. Isoflavonien, etenkin puna-apilan isoflavonien metaboliaa ei kuitenkaan ole tarkoin tutkittu ihmisessä. Väitöskirjatyössä tunnistettiin soijaa tai puna-apilavalmistetta saaneilla vapaaehtoisilla tutkimushenkilöillä virtsaan erittyviä isoflavonien metaboliitteja käyttäen kaasukromatografia-massaspektrometria (GC-MS). Isoflavonien metaboliaa tutkittiin myös in vitro käsittelemällä tutkittavia yhdisteitä anaerobisesti ihmisen ulostemikrobien kanssa ja tunnistamalla käsittelyssä muodostuvia metaboliitteja. Virtsa- ja ulostenäytteiden analysointia varten kehitettiin kvalitatiiviset GC-MS menetelmät, ja lisäksi isoflavonien ja niiden metaboliittien tunnistamista varten selvitettiin tarkoin yhdisteiden massaspektrien tulkintaa tutkimalla yhdisteiden fragmentoitumista elektroni-ionisaatiomassaspektrometriassa (EIMS). Yhteensä 18 uutta isoflavonoidimetaboliittia tunnistettiin isoflavonisuplementaation jälkeen kerätyistä virtsanäytteistä. Valtaosa tunnistetuista soijaisoflavonien metaboliiteista oli soijan isoflavonien daidzeinin, genisteinin ja glyciteinin pelkistyneitä metaboliitteja. Näiden lisäksi näytteistä tunnistettiin myös hydroksyloituneita ja/tai metyloituneita metaboliitteja. Puna-apilaisoflavonien formononetiinin ja biochanin A:n metaboliitit olivat pääasiassa demetylaation seurauksena muodostuneet daidzein ja genistein, sekä näiden pelkistyneet metabolitit. Myös formononetiinin ja biokaniini A:n pelkistyneitä ja hydroksyloituneita metaboliitteja löydettiin näytteistä, tosin huomattavasti vähemmässä määrin kuin daidzeinia ja genisteiniä tai niiden pelkistyneitä metaboliitteja. Tutkimuksen tulokset osoittavat, että isoflavonien metabolia on monimuotoista ja paljon rakenteeltaan erilaisia isoflavonimetaboliittejä erittyy virtsaan. Tutkimalla väitöskirjatyössä tunnistettujen metaboliittien biologisia aktiivisuuksia ja niiden pitoisuuksia biologisissa näytteissä, tuloksia voidaan hyödyntää selvitettäessä isoflavonien vaikutusmekanismeja sekä niiden merkitystä terveyttä edistävinä tekijöinä.
Published: 2006

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