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1. General practitioners' role in cancer care: a French-Norwegian study

Author: Janine Bachimont, Tommy Thorsen, Martine Bungener, Knut Holtedahl, Alain Letourmy, Lise Demagny, Centre de recherche Médecine, Science, Santé et Société (CERMES), Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-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), Institute of Community Medicine, University of Tromsø (UiT), CERMES - Centre de recherche Médecine, Science, Santé Société (CERMES - UMR 8169 / U750), CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société (CERMES3 - UMR 8211 / U988 / UM 7), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-École des hautes études en sciences sociales (EHESS), and BMC, Ed.
Subjects: medicine.medical_specialty, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Allmennmedisin: 751, Psa screening, education, Alternative medicine, Short Report, lcsh:Medicine, Norwegian, General Biochemistry, Genetics and Molecular Biology, [SHS]Humanities and Social Sciences, 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Terminal care, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030212 general & internal medicine, lcsh:Science (General), lcsh:QH301-705.5, Medicine(all), [SHS.SOCIO]Humanities and Social Sciences/Sociology, business.industry, Biochemistry, Genetics and Molecular Biology(all), lcsh:R, Cancer, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Family practice: 751, General Medicine, 16. Peace & justice, medicine.disease, language.human_language, 3. Good health, lcsh:Biology (General), 13. Climate action, 030220 oncology & carcinogenesis, Clinical diagnosis, Family medicine, language, Medical training, business, lcsh:Q1-390
Abstract: Background In cancer care, a GP's work is rarely defined clearly. Our aim was to assess GPs' work with cancer patients in France and in Norway, where the roles of the GP and the organization of the system are rather different. Findings A questionnaire with 40 closed-ended questions about GP involvement in diagnosis, treatment, follow-up and terminal care was constructed and mailed to samples of GPs. The patients had seen the doctor at least once over the past year. In France 1679 and in Norway 386 individual patient questionnaires were completed. GPs have a major role in the diagnosis of cancer, and this role varies according to cancer type. The GPs participated actively in different phases of follow-up after cancer treatment. Low response rates do not allow direct comparison between countries, but higher PSA screening rates in France seem to increase the percentage of patients diagnosed after screening rather than after a clinical suspicion. Interaction between GPs and specialists during cancer treatment and follow-up was important in both countries. Conclusion Both in France and in Norway GPs participate actively in cancer care. Early clinical diagnosis is a challenge. More research is needed about how GPs can improve their early diagnostic work. Organisational issues may influence cancer responsibilities for the GP, and national health systems should be challenged to look at possible new roles for GPs in cancer care. Medical training, both pre- and post-graduate, should prepare doctors for collaboration between primary and secondary care, particularly important in cancer care.
Published: 2019

2. MicroRNA-125a is over-expressed in insulin target tissues in a spontaneous rat model of Type 2 Diabetes

Author: Helen Lockstone, Dominique Gauguier, Jennifer M. Taylor, Christina Fernandez, Cecilia M. Lindgren, Amy Barrett, Jiannis Ragoussis, Mark I. McCarthy, Blanca M. Herrera, Pamela J. Kaisaki, Quin F. Wills, Carme Camps, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Endocrinology and Metabolism, The Churchill Hospital-Oxford Centre for Diabetes, Department of Statistics [Oxford], 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), Funding for this study was provided by Diabetes UK (grant code BDA: RD06/0003287) the Throne-Holst Foundation and Nuffield Department of Medicine. DG holds a Wellcome Senior Fellowship in Basic Biomedical Science (057733). C.M.L. is a Wellcome Trust Research Career Development Fellow (086596)., University of Oxford, Wellcome Trust Centre for Human Genetics, Department of Statistics, 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 ), and BMC, Ed.
Subjects: lcsh:Internal medicine, lcsh:QH426-470, medicine.medical_treatment, Adipose tissue, Biology, 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microRNA, Gene expression, Genetics, medicine, Glucose homeostasis, Genetics(clinical), lcsh:RC31-1245, Gene, Genetics (clinical), 030304 developmental biology, 2. Zero hunger, Regulation of gene expression, 0303 health sciences, Insulin, Molecular biology, lcsh:Genetics, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], DNA microarray, Research Article
Abstract: Background MicroRNAs (miRNAs) are non-coding RNA molecules involved in post-transcriptional control of gene expression of a wide number of genes, including those involved in glucose homeostasis. Type 2 diabetes (T2D) is characterized by hyperglycaemia and defects in insulin secretion and action at target tissues. We sought to establish differences in global miRNA expression in two insulin-target tissues from inbred rats of spontaneously diabetic and normoglycaemic strains. Methods We used a miRNA microarray platform to measure global miRNA expression in two insulin-target tissues: liver and adipose tissue from inbred rats of spontaneously diabetic (Goto-Kakizaki [GK]) and normoglycaemic (Brown-Norway [BN]) strains which are extensively used in genetic studies of T2D. MiRNA data were integrated with gene expression data from the same rats to investigate how differentially expressed miRNAs affect the expression of predicted target gene transcripts. Results The expression of 170 miRNAs was measured in liver and adipose tissue of GK and BN rats. Based on a p-value for differential expression between GK and BN, the most significant change in expression was observed for miR-125a in liver (FC = 5.61, P = 0.001, P adjusted = 0.10); this overexpression was validated using quantitative RT-PCR (FC = 13.15, P = 0.0005). MiR-125a also showed over-expression in the GK vs. BN analysis within adipose tissue (FC = 1.97, P = 0.078, P adjusted = 0.99), as did the previously reported miR-29a (FC = 1.51, P = 0.05, P adjusted = 0.99). In-silico tools assessing the biological role of predicted miR-125a target genes suggest an over-representation of genes involved in the MAPK signaling pathway. Gene expression analysis identified 1308 genes with significantly different expression between GK and BN rats (P adjusted < 0.05): 233 in liver and 1075 in adipose tissue. Pathways related to glucose and lipid metabolism were significantly over-represented among these genes. Enrichment analysis suggested that differentially expressed genes in GK compared to BN included more predicted miR-125a target genes than would be expected by chance in adipose tissue (FDR = 0.006 for up-regulated genes; FDR = 0.036 for down-regulated genes) but not in liver (FDR = 0.074 for up-regulated genes; FDR = 0.248 for down-regulated genes). Conclusion MiR-125a is over-expressed in liver in hyperglycaemic GK rats relative to normoglycaemic BN rats, and our array data also suggest miR-125a is over-expressed in adipose tissue. We demonstrate the use of in-silico tools to provide the basis for further investigation of the potential role of miR-125a in T2D. In particular, the enrichment of predicted miR-125a target genes among differentially expressed genes has identified likely target genes and indicates that integrating global miRNA and mRNA expression data may give further insights into miRNA-mediated regulation of gene expression.
Published: 2016

3. Extensive characterization of NF-κB binding uncovers non-canonical motifs and advances the interpretation of genetic functional traits

Author: Imtiaz Nisar Lone, David Saliba, Trevor Siggers, Martha L. Bulyk, Irina A. Udalova, Jiannis Ragoussis, Ana Teixeira, Peter Humburg, Stefan Dimitrov, Daniel Wong, Spyros Oikonomopoulos, Dimitar Angelov, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Kennedy Institute of Rheumatology, Imperial College London, Division of Genetics, Brigham and Women's Hospital [Boston], Harvard-MIT Division of Health Sciences and Technology (HST), Harvard Medical School [Boston] (HMS), Department of Pathology, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U823, équipe 4 (Chromatine et Epigénétique), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), The research leading to these results has received funding from the European Community's Seventh Framework Programme FP7/2007-2013: Model-In (222008) awarded to JR, IAU, DA and SD, the FP7 ITN Network INTEGER (214902) awarded to JR. In addition, the MRC project grant G0700818 awarded to IAU and JR. JR was also supported by the Wellcome Trust through grant 075491/Z/04., European Project: 222008,EC:FP7:HEALTH,FP7-HEALTH-2007-B,MODEL-IN(2008), University of Oxford, École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), BMC, Ed., Genomic determinants of inflammation: from physical measurements to system perturbation and mathematical modeling - MODEL-IN - - EC:FP7:HEALTH2008-12-01 - 2012-05-31 - 222008 - VALID, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Harvard University--MIT Division of Health Sciences and Technology, and Bulyk, Martha L.
Subjects: Quantitative Trait Loci, SPECIFICITIES, Protein Array Analysis, Single-nucleotide polymorphism, [SDV.GEN] Life Sciences [q-bio]/Genetics, Plasma protein binding, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Polymorphism, Single Nucleotide, Deep sequencing, IN-VITRO SELECTION, SACCHAROMYCES-CEREVISIAE, 03 medical and health sciences, 0302 clinical medicine, Transcription (biology), [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Consensus Sequence, Humans, Nucleotide Motifs, Transcription factor, Alleles, 030304 developmental biology, Genetics, 0303 health sciences, TRANSCRIPTION-FACTOR-BINDING, SITES, [SDV.GEN]Life Sciences [q-bio]/Genetics, Binding Sites, Base Sequence, Research, TNF PROMOTER REGION, NF-kappa B, RECOGNITION, Chromatin, DNA binding site, DNA-PROTEIN INTERACTIONS, 030220 oncology & carcinogenesis, DISEASES, P50/P65 HETERODIMER, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], DNA microarray, Genome-Wide Association Study
Abstract: Background Genetic studies have provided ample evidence of the influence of non-coding DNA polymorphisms on trait variance, particularly those occurring within transcription factor binding sites. Protein binding microarrays and other platforms that can map these sites with great precision have enhanced our understanding of how a single nucleotide polymorphism can alter binding potential within an in vitro setting, allowing for greater predictive capability of its effect on a transcription factor binding site. Results We have used protein binding microarrays and electrophoretic mobility shift assay-sequencing (EMSA-Seq), a deep sequencing based method we developed to analyze nine distinct human NF-κB dimers. This family of transcription factors is one of the most extensively studied, but our understanding of its DNA binding preferences has been limited to the originally described consensus motif, GGRRNNYYCC. We highlight differences between NF-κB family members and also put under the spotlight non-canonical motifs that have so far received little attention. We utilize our data to interpret the binding of transcription factors between individuals across 1,405 genomic regions laden with single nucleotide polymorphisms. We also associated binding correlations made using our data with risk alleles of disease and demonstrate its utility as a tool for functional studies of single nucleotide polymorphisms in regulatory regions. Conclusions NF-κB dimers bind specifically to non-canonical motifs and these can be found within genomic regions in which a canonical motif is not evident. Binding affinity data generated with these different motifs can be used in conjunction with data from chromatin immunoprecipitation-sequencing (ChIP-Seq) to enable allele-specific analyses of expression and transcription factor-DNA interactions on a genome-wide scale., Wellcome Trust (London, England) (grant 075491/Z/04), European Commission (Seventh Framework Programme FP7/2007-2013: Model-In (222008)), European Commission (Seventh Framework Programme FP7 ITN Network INTEGER (214902)), Medical Research Council (Canada) (MRC project grant G0700818)
Published: 2016

4. A short-term in vivo model for giant cell tumor of bone

Author: Christian August, Nicholas A. Athanasou, Martin Hagedorn, Konstantin Agelopoulos, Karoly Szuhai, Georg Gosheger, Pancras C.W. Hogendoorn, Horst Buerger, Maurice Balke, Anna Neumann, BMC, Ed., Department of Trauma and Orthopedic Surgery, University of Witten-Herdecke, Department of Orthopedic Surgery, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Gerhard-Domagk-Institute of Pathology, Department of Pathology, Leiden University Medical Center (LUMC), Molecular Cell Biology Department, Department of Medicine, Hematology and Oncology, Institute of Pathology, Klinikum Hanau GmbH, University of Oxford-Nuffield Orthopaedic Centre, Institute of pathology, Mécanismes moléculaires de l'angiogénèse, Université de Lille, Sciences et Technologies-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sciences et Technologies - Bordeaux 1 (UB), and This work was supported by EuroBoNet, a sixth framework Network of Excellence for studying pathology and genetics of bone tumors.
Subjects: Male, Pathology, Cancer Research, H&E stain, Osteoclasts, Chick Embryo, Metastasis, MESH: Osteoclasts, MESH: Animals, MESH: In Situ Hybridization, Fluorescence, In Situ Hybridization, Fluorescence, MESH: Aged, Giant Cell Tumor of Bone, MESH: Middle Aged, MESH: Chick Embryo, Middle Aged, MESH: Bone Neoplasms, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Oncology, MESH: Young Adult, Female, Giant-cell tumor of bone, Research Article, Adult, medicine.medical_specialty, MESH: Xenograft Model Antitumor Assays, chorioallantoic membrane long-bone follow-up angiogenesis metastasis system microcirculation curettage therapy fish, Adolescent, MESH: Giant Cell Tumor of Bone, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bone Neoplasms, Biology, lcsh:RC254-282, MESH: Interphase, Young Adult, [SDV.CAN] Life Sciences [q-bio]/Cancer, In vivo, medicine, Genetics, Animals, Humans, Giant Cell Tumors, Interphase, Aged, MESH: Adolescent, MESH: Humans, Tumour pathology, Histology, MESH: Adult, medicine.disease, Xenograft Model Antitumor Assays, MESH: Male, Staining, Disease Models, Animal, Giant cell, MESH: Disease Models, Animal, MESH: Female
Abstract: Background Because of the lack of suitable in vivo models of giant cell tumor of bone (GCT), little is known about its underlying fundamental pro-tumoral events, such as tumor growth, invasion, angiogenesis and metastasis. There is no existing cell line that contains all the cell and tissue tumor components of GCT and thus in vitro testing of anti-tumor agents on GCT is not possible. In this study we have characterized a new method of growing a GCT tumor on a chick chorio-allantoic membrane (CAM) for this purpose. Methods Fresh tumor tissue was obtained from 10 patients and homogenized. The suspension was grafted onto the CAM at day 10 of development. The growth process was monitored by daily observation and photo documentation using in vivo biomicroscopy. After 6 days, samples were fixed and further analyzed using standard histology (hematoxylin and eosin stains), Ki67 staining and fluorescence in situ hybridization (FISH). Results The suspension of all 10 patients formed solid tumors when grafted on the CAM. In vivo microscopy and standard histology revealed a rich vascularization of the tumors. The tumors were composed of the typical components of GCT, including (CD51+/CD68+) multinucleated giant cells whichwere generally less numerous and contained fewer nuclei than in the original tumors. Ki67 staining revealed a very low proliferation rate. The FISH demonstrated that the tumors were composed of human cells interspersed with chick-derived capillaries. Conclusions A reliable protocol for grafting of human GCT onto the chick chorio-allantoic membrane is established. This is the first in vivo model for giant cell tumors of bone which opens new perspectives to study this disease and to test new therapeutical agents.
Published: 2016

5. Measuring physical activity-related environmental factors: Reliability and predictive validity of the European environmental questionnaire ALPHA

Author: Julien Gloanec, Charlie Foster, Ilse De Bourdeaudhuij, Christopher Gidlow, Harry Rutter, Sylvia Titze, Maïté Verloigne, Jean-Michel Oppert, Michael Sjöström, Heleen Spittaels, Pekka Oja, Department of Movement and Sports Sciences, Universiteit Gent = Ghent University [Belgium] (UGENT), Centre for Sport and Exercise Research, Staffordshire University, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Institute of Sports Science, Karl-Franzens-Universität [Graz, Autriche], Department of Public Health, University of Oxford [Oxford], National Obesity Observatory, Urho Kaleva Kekkonen Institute for Health Promotion Research, Department of Biosciences, Karolinska Institutet [Stockholm], This study is being carried out with financial support from the Commission of the European Communities, specifically the Public Health Programme 2003- 2008 of the Directorate General Health and Consumer Protection Luxembourg, 800259 'Instruments for Assessing Levels of Physical Activity and related Health Determinants' (ALPHA)., Ghent University [Belgium] (UGENT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], University of Graz, BMC, Ed., Universiteit Gent = Ghent University (UGENT), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-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)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Karl-Franzens-Universität Graz, University of Oxford, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA)
Subjects: Predictive validity, medicine.medical_specialty, Intraclass correlation, Physical activity, Medicine (miscellaneous), Physical Therapy, Sports Therapy and Rehabilitation, DETERMINANTS, 03 medical and health sciences, 0302 clinical medicine, Medicine and Health Sciences, Food and Nutrition, Medicine, 030212 general & internal medicine, lcsh:RC620-627, Reliability (statistics), ASSOCIATIONS, 030505 public health, Nutrition and Dietetics, BUILT-ENVIRONMENT, business.industry, lcsh:Public aspects of medicine, Research, lcsh:RA1-1270, ADULTS, SCIENCE, European population, Alpha (navigation), Test (assessment), B900, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, lcsh:Nutritional diseases. Deficiency diseases, Alimentation et Nutrition, Physical therapy, Completion time, 0305 other medical science, business, WALKING, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Background A questionnaire to assess physical activity related environmental factors in the European population (a 49-item and an 11-item version) was created as part of the framework of the EU-funded project "Instruments for Assessing Levels of PHysical Activity and fitness (ALPHA)". This paper reports on the development and assessment of the questionnaire's test-retest stability, predictive validity, and applicability to European adults. Methods The first pilot test was conducted in Belgium, France and the UK. In total 190 adults completed both forms of the ALPHA questionnaire twice with a one-week interval. Physical activity was concurrently measured (i) by administration of the long version of the International Physical Activity Questionnaire (IPAQ) by interview and (ii) by accelerometry (Actigraph™ device). After adaptations, the second field test took place in Belgium, the UK and Austria; 166 adults completed the adapted questionnaire at two time points, with minimum one-week interval. In both field studies intraclass correlation coefficients (ICC) and proportion of agreement were computed to assess the stability of the two test scores. Predictive validity was examined in the first field test by correlating the results of the questionnaires with physical activity data from accelerometry and long IPAQ-last 7 days. Results The reliability scores of the ALPHA questionnaire were moderate-to good in the first field testing (ICC range 0.66 - 0.86) and good in the second field testing (ICC range 0.71 - 0.87). The proportion of agreement for the ALPHA short increased significantly from the first (range 50 - 83%) to the second field testing (range 85 - 95%). Environmental scales from both versions of the ALPHA questionnaire were significantly associated with self-reported minutes of transport-related walking, and objectively measured low intensity physical activity levels, particularly in women. Both versions were easily administered with an average completion time of six minutes for the 49-item version and less than two minutes for the short version. Conclusion The ALPHA questionnaire is an instrument to measure environmental perceptions in relation to physical activity. It appears to have good reliability and predictive validity. The questionnaire is now available to other researchers to investigate its usefulness and applicability across Europe.
Published: 2016

6. Allergic Rhinitis and Its Impact on Asthma in Asia Pacific and the ARIA Update 2008

Author: Jean Bousquet, Ruby Pawankar, Nikolai Khaltaev, Chaweewan Bunnag, Department of Pediatrics, Nippon Medical School, Rhinology & Allergy Division, Mahidol University [Bangkok]-Faculty of Medicine Siriraj Hospital, Service des Maladies Respiratoires, Hôpital Arnaud de Villeneuve-Institut National de la Santé et de la Recherche Médicale (INSERM), and BMC, Ed.
Subjects: lcsh:Immunologic diseases. Allergy, Pulmonary and Respiratory Medicine, Allergy, Pediatrics, medicine.medical_specialty, Evidence-based practice, Immunology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Asia Paciﬁc, 03 medical and health sciences, ARIA update, 0302 clinical medicine, Quality of life (healthcare), evidence-based, Environmental health, Epidemiology, Health care, medicine, Immunology and Allergy, 030223 otorhinolaryngology, Socioeconomic status, 030304 developmental biology, Asthma, 0303 health sciences, allergic rhinitis, business.industry, Guideline, asthma, medicine.disease, 3. Good health, 030228 respiratory system, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, lcsh:RC581-607, business
Abstract: The prevalence of allergic diseases such as allergic rhinitis (AR) and asthma are markedly increasing to epidemic proportions worldwide as societies adopt Western lifestyles. An estimated 300 million persons worldwide have asthma, about 50% of whom live in developing countries, and about 400 million people suffer from AR. AR has a marked impact on quality of life, socially, at school, and in the workplace and is a huge socioeconomic burden. Thus, there was clearly a need for a global evidence-based guideline not only for managing AR but also highlighting the interactions between the upper and lower airways including diagnosis, epidemiology, common risk factors, management, and prevention. The Allergic Rhinitis and its Impact on Asthma (ARIA) document was first published in 2001 as a state-of-the-art document for the specialist, the general practitioner, and other health care professionals. Subsequent research and increasing knowledge have resulted in the ARIA 2008 update. The present review summarizes the ARIA update with particular emphasis on the current status of AR and asthma in Asia Pacific. Keywords: allergic rhinitis, asthma, ARIA update, evidence-based, Asia Pacific
Published: 2012

7. Key Role of Water-Insoluble Allergens of Pollen Cytoplasmic Granules in Biased Allergic Response in a Rat Model

Author: Oussama Abou Chakra, Jean-Pierre Sutra, Hélène Sénéchal, Pascal Poncet, Ghislaine Lacroix, BMC, Ed., Laboratoire Environnement et Chimie Analytique (LECA), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Département Infection et Epidémiologie - Department of Infection and Epidemiology, Institut Pasteur [Paris] (IP), Institut National de l'Environnement Industriel et des Risques (INERIS), French Ministry of Environment and Sustainable Development (BCRD-DRC-05-AP-2005)., and Institut Pasteur [Paris]
Subjects: lcsh:Immunologic diseases. Allergy, Pulmonary and Respiratory Medicine, Allergy, water-insoluble allergens, Immunology, grass pollen, medicine.disease_cause, Immunoglobulin E, Microbiology, Alveolar cells, 03 medical and health sciences, 0302 clinical medicine, Pollen, otorhinolaryngologic diseases, medicine, Immunology and Allergy, Original Research, 030304 developmental biology, water-soluble allergens, 0303 health sciences, medicine.diagnostic_test, biology, Cell growth, food and beverages, Aeroallergen, respiratory system, medicine.disease, medicine.anatomical_structure, Bronchoalveolar lavage, allergenicity, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Allergic response, biology.protein, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, IgE, pollen cytoplasmic granules, lcsh:RC581-607, 030215 immunology
Abstract: Background Grass pollen grain, an important aeroallergen, can disperse in the environment pollen cytoplasmic granules (PCGs) able to release water-soluble allergens when they are washed out by rainfall. The allergenicity of these washed PCGs is, however, preserved.Objective The purpose of the study was to assess the allergenic potential of washed and unwashed PCGs, from Phleum pratense pollen grains, in the Brown Norway rat, and to study the IgE reactivity of sera of sensitized rats to water-soluble and water-insoluble extracts of PCGs and pollen grains.Methods Rats were sensitized and challenged intratracheally with washed or unwashed PCGs or pollen grains. Using water-soluble and -insoluble extracts of pollen grains and/or PCGs, IgE ELISA and immunoblotting were performed with rat sera. Proliferation of bronchial lymph node cells was monitored by [3H]-thymidine incorporation in a lymph node assay. Alveolar cells, proteins, and TH1 and TH2 cytokines were quantified in bronchoalveolar lavage fluid.Results Rats sensitized with unwashed PCGs showed a predominant humoral response with high serum IgE and reactivity to water-soluble and -insoluble proteins together with low lymph node cell proliferation. Conversely, in rats sensitized to washed PCGs, cellular responses were higher with significant increases in eosinophils, lymphocytes, and TH2 cytokines observed in bronchoalveolar lavage fluid.Conclusion Allergic and inflammatory responses were induced by both grass pollen grains and their isolated washed and unwashed PCGs. However, on the basis of humoral and cellular responses, differential patterns were observed. Water-insoluble allergens seem to play a role in the centrally mediated inflammatory response, whereas water-soluble allergens may be involved in the peripheral humoral response. Keywords: allergenicity, grass pollen, IgE, pollen cytoplasmic granules, water-insoluble allergens, water-soluble allergens
Published: 2011

8. TIP47 is Required for the Production of Infectious HIV-1 Particles from Primary Macrophages

Author: Katy Janvier, Anne Hosmalin, Guillaume Hoeffel, Clarisse Berlioz-Torrent, Sandra López-Vergès, Hélène Bauby, Fabrizio Mammano, Delphine Delcroix-Genête, BMC, Ed., Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Virus et Immunité, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherche Antivirale, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 Pasteur [Paris] - Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UM3 (UMR 8104 / U1016)), and Université Paris Diderot - Paris 7 (UPD7) - Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: viruses, Viral pathogenesis, Human immunodeficiency virus (HIV), Vesicular Transport Proteins, Pregnancy Proteins, Matrix (biology), medicine.disease_cause, gag Gene Products, Human Immunodeficiency Virus, Biochemistry, MESH: HIV-1, Protein structure, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Structural Biology, MESH: RNA, Small Interfering, RNA, Small Interfering, ComputingMilieux_MISCELLANEOUS, Infectivity, MESH: Pregnancy Proteins, 0303 health sciences, Mutation, 030302 biochemistry & molecular biology, Intracellular Signaling Peptides and Proteins, env Gene Products, Human Immunodeficiency Virus, virus diseases, MESH: gag Gene Products, Human Immunodeficiency Virus, 3. Good health, Cell biology, DNA-Binding Proteins, Infectious Diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, lcsh:Immunologic diseases. Allergy, MESH: Virus Assembly, MESH: Mutation, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunoprecipitation, Morphogenesis, Biology, Perilipin-3, 03 medical and health sciences, Virology, MESH: Intracellular Signaling Peptides and Proteins, Genetics, medicine, Compartment (development), Humans, Gene silencing, Molecular Biology, 030304 developmental biology, MESH: Humans, 030306 microbiology, MESH: Immunoprecipitation, Macrophages, Virus Assembly, MESH: Macrophages, Colocalization, Cell Biology, MESH: Hela Cells, Poster Presentation, biology.protein, HIV-1, MESH: env Gene Products, Human Immunodeficiency Virus, lcsh:RC581-607, MESH: DNA-Binding Proteins, HeLa Cells
Abstract: Macrophages are, along with T CD4+lymphocytes, the major targets of HIV-1 infection and play a key role in viral pathogenesis as a significant reservoir. Identification of the cellular cofactors involved in the production of infectious HIV-1 from macrophages is thus crucial. Nevertheless molecular mechanisms allowing the production of infectious particles from macrophages are not entirely deciphered. In this study, we investigated the role of the cellular cofactor TIP47 in HIV-1 morphogenesis in primary macrophages. Our data show that TIP47 is essential for HIV-1 infectivity and propagation. Mutations in HIV-1 Gag or Envelope (Env) proteins, which abolish interaction with TIP47, impair HIV-1 propagation and infectivity preventing colocalization of Gag and Env, and thereby inhibiting Env incorporation into virions. Whereas disruption of Gag-TIP47 interaction increases slightly Gag particles production, impaired Env-TIP47 binding reduces Gag particles release and, strikingly, induces their retention in the viral assembly compartments. Thus, as in T lymphocytes, TIP47 is critical for the efficient release of infectious HIV-1 particles from the assembly compartment of primary macrophages, making TIP47 a new potential therapeutic target for limiting HIV-1 infectivity and spreading. This work is funded by ANRS, SIDACTION, ANR-07-JCJC-0102 programs and is part of the activities of the HIV-ACE research network (HEALTH-F3-2008-201095) supported by a grant of the European Commission, within the Priority 1 ''Health'' work programme of the 7th Framework Programme of the EU.
Published: 2010

9. HIV resistance to raltegravir

Author: François Clavel, Génétique et Ecologie des Virus, Génétique des Virus et Pathogénèse des Maladies Virales, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and BMC, Ed.
Subjects: Drug, media_common.quotation_subject, lcsh:Medicine, HIV Infections, [SDV.GEN] Life Sciences [q-bio]/Genetics, Drug resistance, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Review, Genome, Viral, Biology, Genome, Raltegravir Potassium, 03 medical and health sciences, Drug Resistance, Viral, medicine, Humans, HIV Integrase Inhibitors, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cross-resistance, 030304 developmental biology, Dominance (genetics), media_common, Genetics, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, 030306 microbiology, lcsh:R, HIV, General Medicine, Raltegravir, Virology, Pyrrolidinones, 3. Good health, Integrase, biology.protein, medicine.drug
Abstract: International audience; Similar to all antiretroviral drugs, failure of raltegravirbased treatment regimens to fully supress HIV replication almost invariably results in emergence of HIV resistance to this new drug. HIV resistance to raltegravir is the consequence of mutations located close to the integrase active site, which can be divided into three main evolutionary pathways: the N155H, the Q148R/H/K and the Y143R/C pathways. Each of these primary mutations can be accompanied by a variety of secondary mutations that both increase resistance and compensate for the variable loss of viral replicative capacity that is often associated with primary resistance mutations. One unique property of HIV resistance to raltegravir is that each of these different resistance pathways are mutually exclusive and appear to evolve separately on distinct viral genomes. Resistance is frequently initiated by viruses carrying mutations of the N155H pathway, followed by emergence and further dominance of viral genomes carrying mutations of the Q148R/H/K or of the Y143R/C pathways, which express higher levels of resistance. Even if some natural integrase polymorphisms can be part of this evolution process, these polymorphisms do not affect HIV susceptibility in the absence of primary mutations. Therefore, all HIV-1 subtypes and groups, together with HIV-2, are naturally susceptible to raltegravir. Finally, because interaction of integrase strand transfer inhibitors with the HIV integrase active site is comparable from one compound to another, raltegravir-resistant viruses express significant cross resistance to most other compounds of this new class of antiretroviral drugs.
Published: 2009

10. IRX-2, a novel immunotherapeutic, protects human T cells from tumor-induced cell death

Author: Theresa L. Whiteside, Marta Szajnik, H Brandwein, Miroslaw J. Szczepanski, J W Hadden, J Han, K Signorelli, K Quadrini, Malgorzata Czystowska, BMC, Ed., Centre de recherche Croissance et signalisation (UMR_S 845), 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 de recherche Croissance et signalisation ( UMR_S 845 ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: Time Factors, MESH : Cytokines, T-Lymphocytes, medicine.medical_treatment, MESH : Dose-Response Relationship, Drug, Apoptosis, CD8-Positive T-Lymphocytes, Fas ligand, MESH: Dose-Response Relationship, Drug, MESH: Janus Kinase 3, Jurkat Cells, Phosphatidylinositol 3-Kinases, MESH: Jurkat Cells, STAT5 Transcription Factor, Cytotoxic T cell, MESH : Jurkat Cells, bcl-2-Associated X Protein, MESH: Cytokines, tofacitinib, Bcl-2-Like Protein 11, MESH : STAT5 Transcription Factor, MESH : CD8-Positive T-Lymphocytes, MESH: CD8-Positive T-Lymphocytes, MESH : Antineoplastic Agents, MESH : Proto-Oncogene Proteins c-akt, Cytokine, MESH : Proto-Oncogene Proteins, Cytokines, MESH: Membrane Proteins, JAK3, MESH : Apoptosis Regulatory Proteins, MESH : Time Factors, MESH : Janus Kinase 3, Programmed cell death, MESH: Cell Line, Tumor, kidney transplantation, Antineoplastic Agents, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Article, Cell Line, Tumor, Proto-Oncogene Proteins, medicine, Humans, MESH: bcl-2-Associated X Protein, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Protein kinase B, PI3K/AKT/mTOR pathway, MESH : T-Lymphocytes, MESH: Humans, Dose-Response Relationship, Drug, MESH : bcl-2-Associated X Protein, MESH : Cell Line, Tumor, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH: Proto-Oncogene Proteins c-akt, MESH: Apoptosis Regulatory Proteins, MESH: Apoptosis, MESH: STAT5 Transcription Factor, MESH : Humans, MESH: Time Factors, MESH : Phosphatidylinositol 3-Kinases, Janus Kinase 3, Membrane Proteins, Cell Biology, Molecular biology, MESH: Proto-Oncogene Proteins, MESH: T-Lymphocytes, MESH : Membrane Proteins, MESH: Phosphatidylinositol 3-Kinases, MESH: Antineoplastic Agents, Apoptosis Regulatory Proteins, Proto-Oncogene Proteins c-akt, MESH : Apoptosis, CD8
Abstract: International audience; IRX-2 is a cytokine-based biologic agent that has the potential to enhance antitumor immune responses. We investigated whether IRX-2 can protect T cells from tumor-induced apoptosis. Tumor-derived microvesicles (MV) expressing FasL were purified from supernatants of tumor cells and incubated with activated CD8(+) T cells. MV induced significant CD8(+) T-cell apoptosis, as evidenced by Annexin binding (64.4+/-6.4%), caspase activation (58.1+/-7.6%), a loss of mitochondrial membrane potential (82.9+/-3.9%) and DNA fragmentation. T-cell pretreatment with IRX-2 prevented apoptosis. IRX-2-mediated cytoprotection was dose and time dependent and was comparable to effects of IL-2, IL-7 or IL-15. IRX-2 prevented MV-induced downregulation of JAK3 and TCRzeta chain and induced STAT5 activation in T cells. IRX-2 prevented MV-induced Bax and Bim upregulation (P
Published: 2009

11. Pediatric Hemophagocytic Syndromes: A Diagnostic and Therapeutic Challenge

Author: Geneviève de Saint Basile, Christine McCusker, Nada Jabado, BMC, Ed., Department of Paediatrics, McGill University = Université McGill [Montréal, Canada]-Montreal Children's Hospital, McGill University Health Center [Montreal] (MUHC)-McGill University Health Center [Montreal] (MUHC), Division of Allergy and Immunology, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), McGill University-Montreal Children's Hospital, McGill University Health Center [Montreal, Canada] ( MUHC ) -McGill University Health Center [Montreal, Canada] ( MUHC ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: Pulmonary and Respiratory Medicine, lcsh:Immunologic diseases. Allergy, Pediatrics, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, business.industry, Hemophagocytic syndromes, Immunology, Review, General Medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Medicine, Effective treatment, Immunology and Allergy, [SDV.IMM]Life Sciences [q-bio]/Immunology, Identification (biology), business, lcsh:RC581-607
Abstract: Pediatric hemophagocytic syndrome (HS) is a severe and often fatal clinical disorder. This syndrome is frequently unrecognized, and thus, affected children may receive suboptimal management, leading to an increase in mortality. The purpose of this review is to provide a clinical guide to (1) the recognition of HS based on clinical, biologic, and pathologic features; (2) the identification of the primary cause of HS in a given affected child; and (3) the initiation of effective treatment in a timely manner.
Published: 2005

12. Comparative genomics highlights the unique biology of Methanomassiliicoccales, a Thermoplasmatales-related seventh order of methanogenic archaea that encodes pyrrolysine

Author: Nicolas Parisot, Simonetta Gribaldo, Guillaume Borrel, Pierre Peyret, Kasie Raymann, Eric Peyretaillade, Nadia Gaci, William Tottey, Jean-François Brugère, Hugh M. B. Harris, Olivier Bardot, Paul W. O'Toole, Conception, Ingénierie et Développement de l'Aliment et du Médicament (CIDAM), Université d'Auvergne - Clermont-Ferrand I (UdA), School of Microbiology and Alimentary Pharmabiotic Centre, University College Cork (UCC), Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Biologie Moléculaire du Gène chez les Extrêmophiles (BMGE), Institut Pasteur [Paris] (IP), Cellule Pasteur UPMC, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP), This work was supported by three PhD. Scholarship supports, one from the 'Direction Générale de l'Armement' (DGA) to N.P., one from the French 'Ministère de l'Enseignement Supérieur et de la Recherche' to N.G. and one of the European Union (UE) and the Auvergne Council to W.T. (FEDER). P.W.O.T. was supported by Science Foundation Ireland through a Principal Investigator award, by a CSET award to the Alimentary Pharmabiotic Centre, and by an FHRI award to the ELDERMET project by the Dept. Agriculture, Fisheries and Marine of the Government of Ireland. SG is supported by the Investissement d'Avenir grant 'Ancestrome' (ANR-10- BINF-01-01). KR is a scholar from the Pasteur - Paris University (PPU) International PhD program and receives a stipend from the Paul W. Zuccaire Foundation. JFB thanks the 'centre hospitalier Paul Ardier' in Issoire, especially Dr Mansoor, Dr Denozi and their staff for their valuable help, and Agnès Mihajlovski for her help in initiating this project., ANR-10-BINF-0001,ANCESTROME,Approche de phylogénie intégrative pour la reconstruction de génomes ancestraux(2010), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Université d'Auvergne - Clermont-Ferrand I (UdA), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Institut Pasteur [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), BMC, Ed., and Bio-informatique - Approche de phylogénie intégrative pour la reconstruction de génomes ancestraux - - ANCESTROME2010 - ANR-10-BINF-0001 - BINF - VALID
Subjects: Provides acquired-resistance, RNA, Archaeal, Genome streamlining, Methanosarcina-mazei, Genome, Glycine betaine, Genome, Archaeal, Clustered Regularly Interspaced Short Palindromic Repeats, Phylogeny, Genomic organization, Genetics, 0303 health sciences, biology, Transfer-rna, Short palindromic repeats, Evolutionary genomics, Methanomassiliicoccus, Pyrrolysine Pyl, Codon usage bias, CRISPR, Codon, Terminator, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Biotechnology, Research Article, Archaeal Proteins, Molecular Sequence Data, Thermoplasmata, H2-dependent methylotrophic methanogenesis, Replication Origin, Thermoplasmales, High-throughput, Energy conservation, Human gut, 03 medical and health sciences, Phylogenetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Methanomethylophilus, 030304 developmental biology, Comparative genomics, 030306 microbiology, Lysine, Origin of replication (ORI) binding (ORB) motif, biology.organism_classification, Archaea, Methanomassiliicoccales, Biosynthetic Pathways, Thermoplasmatales, RNA, Ribosomal, Ech hydrogenase, Energy Metabolism
Abstract: Background A seventh order of methanogens, the Methanomassiliicoccales, has been identified in diverse anaerobic environments including the gastrointestinal tracts (GIT) of humans and other animals and may contribute significantly to methane emission and global warming. Methanomassiliicoccales are phylogenetically distant from all other orders of methanogens and belong to a large evolutionary branch composed by lineages of non-methanogenic archaea such as Thermoplasmatales, the Deep Hydrothermal Vent Euryarchaeota-2 (DHVE-2, Aciduliprofundum boonei) and the Marine Group-II (MG-II). To better understand this new order and its relationship to other archaea, we manually curated and extensively compared the genome sequences of three Methanomassiliicoccales representatives derived from human GIT microbiota, “Candidatus Methanomethylophilus alvus", “Candidatus Methanomassiliicoccus intestinalis” and Methanomassiliicoccus luminyensis. Results Comparative analyses revealed atypical features, such as the scattering of the ribosomal RNA genes in the genome and the absence of eukaryotic-like histone gene otherwise present in most of Euryarchaeota genomes. Previously identified in Thermoplasmatales genomes, these features are presently extended to several completely sequenced genomes of this large evolutionary branch, including MG-II and DHVE2. The three Methanomassiliicoccales genomes share a unique composition of genes involved in energy conservation suggesting an original combination of two main energy conservation processes previously described in other methanogens. They also display substantial differences with each other, such as their codon usage, the nature and origin of their CRISPRs systems and the genes possibly involved in particular environmental adaptations. The genome of M. luminyensis encodes several features to thrive in soil and sediment conditions suggesting its larger environmental distribution than GIT. Conversely, “Ca. M. alvus” and “Ca. M. intestinalis” do not present these features and could be more restricted and specialized on GIT. Prediction of the amber codon usage, either as a termination signal of translation or coding for pyrrolysine revealed contrasted patterns among the three genomes and suggests a different handling of the Pyl-encoding capacity. Conclusions This study represents the first insights into the genomic organization and metabolic traits of the seventh order of methanogens. It suggests contrasted evolutionary history among the three analyzed Methanomassiliicoccales representatives and provides information on conserved characteristics among the overall methanogens and among Thermoplasmata. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-679) contains supplementary material, which is available to authorized users.
Published: 2014

13. The niche reduction approach: an opportunity for optimal control of infectious diseases in low-income countries?

Author: Marc Choisy, Jean-Daniel Zucker, Bernard Cazelles, Hélène Broutin, Yann Chevaleyre, Sylvain Godreuil, Romulus Breban, Guillaume Constantin de Magny, Benjamin Roche, Frédéric Simard, Unité de modélisation mathématique et informatique des systèmes complexes [Bondy] (UMMISCO), Institut de Recherche pour le Développement (IRD)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université de Yaoundé I-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), Pathogénèse et contrôle des infections chroniques (PCCI), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Du gène à l'écosystème (MIVEGEC-GeneSys), Pathogènes, Environnement, Santé Humaine (EPATH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Laboratoire d'Informatique de Paris-Nord (LIPN), Université Paris 13 (UP13)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Centre National de la Recherche Scientifique (CNRS), Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris] (IP)-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 Pasteur [Paris] (IP)-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), Laboratoire Ecologie et évolution, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Diversity, ecology, evolution & Adaptation of arthropod vectors (MIVEGEC-DEEVA), Evolution des Systèmes Vectoriels (ESV), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université de Yaoundé I-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier )-Université de Montpellier (UM), Université Sorbonne Paris Cité (USPC)-Institut Galilée-Université Paris 13 (UP13)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), École normale supérieure - Paris (ENS Paris), Génétique et évolution des maladies infectieuses (GEMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Génétique et évolution des maladies infectieuses (GEMI), and BMC, Ed.
Subjects: ECOLOGIE DES PARASITES, medicine.medical_specialty, Debate, Developing country, HIV Infections, Biology, POLITIQUE DE SANTE, ENDEMIE, RELATION HOTE PARASITE, EPIDEMIE, METHODE DE LUTTE, Development economics, Yellow Fever, medicine, Smallpox, Western world, Humans, Temporal scales, Developing Countries, Poverty, 2. Zero hunger, Public health, Vaccination, 1. No poverty, Public Health, Environmental and Occupational Health, medicine.disease, EVOLUTION, 3. Good health, Malaria, NICHE ECOLOGIQUE, ETUDE DE CAS, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Immunology, Communicable Disease Control, Evolutionary ecology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Public Health, AGENT PATHOGENE, Measles
Abstract: International audience; BACKGROUND: During the last century, WHO led public health interventions that resulted in spectacular achievements such as the worldwide eradication of smallpox and the elimination of malaria from the Western world. However, besides major successes achieved worldwide in infectious diseases control, most elimination/control programs remain frustrating in many tropical countries where specific biological and socio-economical features prevented implementation of disease control over broad spatial and temporal scales. Emblematic examples include malaria, yellow fever, measles and HIV. There is consequently an urgent need to develop affordable and sustainable disease control strategies that can target the core of infectious diseases transmission in highly endemic areas. DISCUSSION: Meanwhile, although most pathogens appear so difficult to eradicate, it is surprising to realize that human activities are major drivers of the current high rate of extinction among upper organisms through alteration of their ecology and evolution, i.e., their "niche". During the last decades, the accumulation of ecological and evolutionary studies focused on infectious diseases has shown that the niche of a pathogen holds more dimensions than just the immune system targeted by vaccination and treatment. Indeed, it is situated at various intra- and inter- host levels involved on very different spatial and temporal scales. After developing a precise definition of the niche of a pathogen, we detail how major advances in the field of ecology and evolutionary biology of infectious diseases can enlighten the planning and implementation of infectious diseases control in tropical countries with challenging economic constraints. SUMMARY: We develop how the approach could translate into applied cases, explore its expected benefits and constraints, and we conclude on the necessity of such approach for pathogen control in low-income countries.
Published: 2014

14. Microsaccades enable efficient synchrony-based visual feature learning and detection

Author: Timothée Masquelier, Geoffrey Portelli, Pierre Kornprobst, Institut de la Vision, 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), Mathematical and Computational Neuroscience (NEUROMATHCOMP), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (JAD), Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), BMC, Ed., 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), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (LJAD)
Subjects: genetic structures, Computer science, Spike train, Retinal ganglion, 03 medical and health sciences, Cellular and Molecular Neuroscience, Synaptic weight, 0302 clinical medicine, Parvocellular cell, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030304 developmental biology, 0303 health sciences, business.industry, General Neuroscience, Eye movement, Pattern recognition, eye diseases, Receptive field, Poster Presentation, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], sense organs, Artificial intelligence, Microsaccade, business, Neuroscience, 030217 neurology & neurosurgery, Coincidence detection in neurobiology
Abstract: Fixational eye movements are common across vertebrates, yet their functional roles, if any, are debated [1]. To investigate this issue, we exposed the Virtual Retina simulator [2] to natural images, generated realistic drifts and microsaccades using the model of ref. [3], and analyzed the output spike trains of the parvocellular retinal ganglion cells (RGC). We first computed cross-correlograms between pairs of RGC that are strongly excited by the image corresponding to the mean eye position. Not surprisingly, in the absence of eye movements, that is when analyzing the tonic (sustained) response to a static image, these cross-correlograms are flat. Adding some slow drift (~20 min/s, self-avoiding random walk) creates long timescale (>1s) correlations because both cells tend to have high firing rates for central positions. Adding microsaccades (~0.5° in 25ms, that is ~20°/s) creates short timescale (tens of ms) correlations: cells that are strongly excited at a particular landing location tend to spike synchronously shortly after the landing. What do the patterns of synchronous spikes represent? To investigate this issue, we fed the RGC spike trains to neurons equipped with spike timing-dependent plasticity (STDP) and lateral inhibitory connections, as in ref. [4]. Neurons self-organized, and each one selected a set of afferents that consistently fired synchronously. We then reconstructed the corresponding visual stimuli by convolving the synaptic weight matrices with the RGC receptive fields. In most cases, we could easily recognize what was learned (e.g. a face), and the neuron was selective (e.g. only responded for microsaccades that landed on a face). Without eye movements, or with only the drift, the STDP-based learning failed, because it needs correlations at a timescale roughly matching the STDP time constants [5]. Microsaccades are thus necessary to generate a synchrony-based coding scheme. More specifically, after each microsaccade landing, cells that are strongly excited by the image corresponding to the landing location tend to fire their first spikes synchronously. Patterns of synchronous spikes can be decoded rapidly – as soon as the first spikes are received – by downstream “coincidence detector” neurons, which do not need to know the landing times. Finally, the required connectivity to do so can spontaneously emerge with STDP. As a whole, these results suggest a new role for microsaccades – to enable efficient visual feature learning and detection thanks to synchronization – that differs from other proposals such as time-to-first spike coding with respect to microsaccade landing times.
Published: 2014

15. AIDS and non-AIDS severe morbidity associated with hospitalizations among HIV-infected patients in two regions with universal access to care and antiretroviral therapy, France and Brazil, 2000–2008: hospital-based cohort studies

Author: Paula Mendes, Luz, Mathias, Bruyand, Sayonara, Ribeiro, Fabrice, Bonnet, Ronaldo Ismério, Moreira, Mojgan, Hessamfar, Dayse Perreira, Campos, Carine, Greib, Charles, Cazanave, Valdilea Gonçalves, Veloso, François, Dabis, Beatriz, Grinsztejn, Geneviève, Chêne, B, Uwamaliya-Nziyumvira, BMC, Ed., Instituto Nacional de Infectologia Evandro Chagas [Rio de Janeiro] (INI), Fundação Oswaldo Cruz (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Epidémiologie et Biostatistique [Bordeaux], Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Université Bordeaux Segalen - Bordeaux 2, CIC-EC - Bordeaux, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Coordination Régionale de la lutte contre l'infection à VIH (COREVIH Aquitaine), CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin-Hôpital du Tondu, Unité de médecine interne, maladies infectieuses et systémiques, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Service des Maladies Infectieuses et Tropicales A [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, This study was partially funded by the grant 'Cooperation Franco-Bresilienne en Recherche Medicale Accord Inserm (Institut National de la Santé et de la Recherche Medicale)/FIOCRUZ 2010'. The ANRS C03 Aquitaine Cohort is supported by grants from the French Agency for AIDS and hepatitis research (ANRS) through the HIV Cohort Program (AC7) together with the Bordeaux School of Public Health (ISPED - Bordeaux University), Inserm CIC-EC7 and U897 (Bordeaux) and the COREVIH Aquitaine (Bordeaux University Hospital). BG and PML acknowledge funding from the National Council of Technological and Scientific Development (CNPq) and the Research Funding Agency of the State of Rio de Janeiro (FAPERJ)., IPEC/FIOCRUZ Cohort and the Aquitaine ANRS C03 Study Group, and Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, medicine.medical_specialty, Pediatrics, HIV Infections, Context (language use), Cohort Studies, Medical microbiology, Acquired immunodeficiency syndrome (AIDS), Quality of life, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine, Humans, Generalized estimating equation, Acquired Immunodeficiency Syndrome, business.industry, HIV, Middle Aged, medicine.disease, Hospitals, CD4 Lymphocyte Count, Antiretroviral therapy, 3. Good health, AIDS, Hospitalization, Infectious Diseases, Tropical medicine, Cohort, Quality of Life, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, France, Morbidity, Cohort study, business, Severe morbidity, Brazil, Research Article
Abstract: International audience; BACKGROUND: In high-income settings, the spectrum of morbidity and mortality experienced by Human Immunodeficiency Virus (HIV)-infected individuals receiving combination antiretroviral therapy (cART) has switched from predominantly AIDS-related to non-AIDS-related conditions. In the context of universal access to care, we evaluated whether that shift would apply in Brazil, a middle-income country with universal access to treatment, as compared to France. METHODS: Two hospital-based cohorts of HIV-infected individuals were used for this analysis: the ANRS CO3 Aquitaine Cohort in South Western France and the Evandro Chagas Research Institute (IPEC) Cohort of the Oswaldo Cruz Foundation in Rio de Janeiro, Brazil. Severe morbid events (AIDS- and non-AIDS-related) were defined as all clinical diagnoses associated with a hospitalization of ≥48 hours. Trends in the incidence rate of events and their determinants were estimated while adjusting for within-subject correlation using generalized estimating equations models with an auto-regressive correlation structure and robust standard errors. RESULT: Between January 2000 and December 2008, 7812 adult patients were followed for a total of 41,668 person-years (PY) of follow-up. Throughout the study period, 90% of the patients were treated with cART. The annual incidence rate of AIDS and non-AIDS events, and of deaths significantly decreased over the years, from 6.2, 21.1, and 1.9 AIDS, non-AIDS events, and deaths per 100 PY in 2000 to 4.3, 14.9, and 1.5/100 PY in 2008. The annual incidence rates of non-AIDS events surpassed that of AIDS-events during the entire study period. High CD4 cell counts were associated with a lower incidence rate of AIDS and non-AIDS events as well as with lower rates of specific non-AIDS events, such as bacterial, hepatic, viral, neurological, and cardiovascular conditions. Adjusted analysis showed that severe morbidity was associated with lower CD4 counts and higher plasma HIV RNAs but not with setting (IPEC versus Aquitaine). CONCLUSIONS: As information on severe morbidities for HIV-infected patients remain scarce, data on hospitalizations are valuable to identify priorities for case management and to improve the quality of life of patients with a chronic disease requiring life-long treatment. Immune restoration is highly effective in reducing AIDS and non-AIDS severe morbid events irrespective of the setting.
Published: 2014

16. Intratumoral distribution of EGFR mutations and copy number in metastatic lung cancer, what impact on the initial molecular diagnosis?

Author: Hélène Blons, Marco Alifano, Pierre Laurent-Puig, Fabrice Devez, Diane Damotte, Fanny Lemaitre, Audrey Mansuet-Lupo, Anne Tallet, Marie-Christine Charpentier, Fouzia Zouiti, Véronique Ducruit, Service de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu, 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), Service de Biologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de chirurgie thoracique et vasculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), We thank The French National Cancer Institute (INCa) for its financial support (Plan cancer 2009-2013), BMC, Ed., Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Hôtel-Dieu, 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)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Bases moléculaires de la réponse aux xénobiotiques ( U775 (IFR95) ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Lung Neoplasms, DNA Copy Number Variations, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Genetic heterogeneity, [SDV.CAN] Life Sciences [q-bio]/Cancer, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, medicine, TaqMan, Humans, EGFR amplification, Epidermal growth factor receptor, Neoplasm Metastasis, Pathology, Molecular, Lung cancer, Genotyping, Aged, Aged, 80 and over, Medicine(all), Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Biochemistry, Genetics and Molecular Biology(all), Research, Point mutation, General Medicine, Middle Aged, medicine.disease, Primary tumor, 3. Good health, ErbB Receptors, Cancer research, biology.protein, Female, EGFR mutation, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; BACKGROUND: Activating epidermal growth factor receptor (EGFR) mutations characterize a subgroup of non-small-cell lung cancer that benefit from first line EGFR tyrosine kinase inhibitors (EGFR-TKI). However, the existence of polyclonal cell populations may hinder personalized-medicine strategies as patients' screening often depends upon a single tumor-biopsy sample. The purpose of this study is to clarify and to validate in clinical testing conditions the accuracy of EGFR genotyping using different tumor sites and various types of samples (transthoracic, surgical or endoscopic biopsies and cytology specimens). METHODS: We conducted a retrospective review of 357 consecutive patients addressed for EGFR mutation screening in accordance with the directive of the European Medicines Agency (stage IV NSCLC). Fifty-seven samples were EGFR mutated and 40 had adequate tumor specimens for analysis on multiple spatially separated sites. Ten wild type samples were also analyzed. A total of 153 and 39 tumor fragments, from mutated and non-mutated cases respectively, were generated to analyze tumor heterogeneity or primary-metastatic discordances. After histological review of all fragments, EGFR genotyping was assessed using the routine diagnostic tools: fragment analysis for insertions and deletions and allele specific TaqMan probes for point mutations. EGFR copy number (CN) was evaluated by qPCR using TaqMan probes. RESULTS: The identification of EGFR mutations was independent of localization within primary tumor, of specimen type and consistent between primary and metastases. At the opposite, for half of the samples, tumor loci showed different EGFR copy number that may affect mutation detection cut-off. CONCLUSIONS: This is the largest series reporting multiple EGFR testing in Caucasians. It validates the accuracy of EGFR mutation screening from single tumor-biopsy samples before first line EGFR-TKI. The unpredictable variability in EGFR CN and therefore in EGFR wild type/mutant allelic ratio justifies the implementation of sensitive methods to identify patients with EGFR mutated tumors.
Published: 2014

17. Chronic Bickerstaff’s encephalitis with cognitive impairment, a reality?

Author: Jean-Baptiste Chanson, Nicolas Collongues, Jerome Aupy, Guillaume Camuset, Frédéric Blanc, Mathilde Renaud, Jérôme De Seze, Unité de Neuropsychologie, CHU Strasbourg-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre Mémoire de Ressources et de Recherche (CMRR), Unité des Maladies Infectieuses, CHR Réunion (G H Sud Réunion), Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques (BMNST), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe IMIS/neurcrypto, Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Unité de Neuropsychologie, CHU Strasbourg-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre Mémoire de Ressources et de Recherche (CMRR)-CHU Strasbourg-Centre Mémoire de Ressources et de Recherche (CMRR)-Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Unité de Neuropsychologie, CHU Strasbourg-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre Mémoire de Ressources et de Recherche (CMRR)-CHU Strasbourg-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre Mémoire de Ressources et de Recherche (CMRR)-Fédération de Médecine Translationnelle de Strasbourg (FMTS), and BMC, Ed.
Subjects: Male, Pediatrics, Neurology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Aucun, Case Report, Chronic inflammatory demyelinating polyneuropathy, Neuropsychological Tests, Anti-ganglioside antibodies, immunology, Gangliosides, Campylobacter Infections, Demyelinating disease, Guillain-Barre syndrome, Brain, General Medicine, 3. Good health, Bickerstaff, Bickerstaff’s encephalitis, Encephalitis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Adult, Weakness, medicine.medical_specialty, Ataxia, complications, Clinical Neurology, etiology, psychology, Guillain-Barre Syndrome, Campylobacter jejuni, s encephalitis, Cognitive dysfunction, medicine, Humans, Dementia, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business.industry, therapy, Immunization, Passive, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Mild cognitive impairment, medicine.disease, Chronic encephalitis, Chronic Disease, Immunology, Neurology (clinical), Cognition Disorders, business, Molecular mimicry
Abstract: BACKGROUND: Bickerstaff's encephalitis (BE) is an acute post-infectious demyelinating disease with albuminocytological dissociation. A chronic form has rarely been described previously. CASE PRESENTATION: A 44-year-old man was hospitalized for drowsiness, cognitive complaint limb weakness, ataxia and sensory disturbance after diarrhea. Neuropsychological evaluation showed slowing, memory and executive function impairment, while analysis of the CSF showed albuminocytological dissociation. Immunologic tests showed positive anti-ganglioside antibodies (anti-GM1 IgM, anti-GD1a IgG and anti-GD1b IgM). Brain MRI was normal but SPECT showed bilateral temporal and frontal hypoperfusion. Outcome under immunoglobulin treatment (IVIG) was favorable with an initial improvement but was marked by worsening after a few weeks. Consequently, the patient was treated with IVIG every 2 months due to the recurrence of symptoms after 6 weeks. CONCLUSION: This case raises the question of the existence of a chronic form of BE with cognitive impairment, in the same way as chronic inflammatory demyelinating polyneuropathy is considered to be a chronic form of Guillain-Barré syndrome. journal article research support, non-u.s. gov't 2014 May 06 2014 05 06 imported
Published: 2014

18. Extracts from medicinal plants inhibit cancer cell proliferation, induce apoptosis in ovary, lung and neuronal cancer cell lines

Author: David Vaudry, Thierry Jouenne, Mohamed Nejib Marzouki, Wafa Ghali, Laboratory of Protein Engineering and Active Biomolecules, Université de Carthage - University of Carthage, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Polymères Biopolymères Surfaces (PBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Tunisian Ministry of High Education and Scientific Research, INSERM and Rouen University., BMC, Ed., Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), and Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pathology, medicine.medical_specialty, Antioxidant, DPPH, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pheochromocytoma, chemistry.chemical_compound, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Viability assay, Cytotoxicity, ComputingMilieux_MISCELLANEOUS, Caspase, biology, business.industry, medicine.disease, Psychiatry and Mental health, medicine.anatomical_structure, chemistry, Apoptosis, Poster Presentation, biology.protein, Cancer research, business, Adrenal medulla
Abstract: Materials and methods Our work aimed to evaluate the antioxidant activity, protective properties and anti-proliferative capacity of Lycium europeaum and Jatropha podagrica extracts on the proliferation and evolution of A547 (ovarian cancer cell line), OVCAR-3 (human ovary adenocarcinoma cell line), A549 (Human lung adenocarcinoma cell line) and PC12 (rat adrenal medulla Pheochromocytoma cells). The cytotoxicity of the studied extracts was also evaluated on cerebellar granule cells. Cell viability was monitored using thiazolyl blue tetrazolium bromide (MTT) reduction assay. Induction of apoptosis in treated cells was measured through caspases 3/7 activity. Cytoprotective properties of the extracts were assessed by monitoring the effect of induced-oxidative stress damages on cellular macromolecules. Free radical scavenging capacity was investigated by different methods such as DPPH and reducing power.
Published: 2014

19. Metformin targets the GTPase Rac1 to inhibit prostate cancer cell migration

Author: Kathiane Laurent, Frédéric Larbret, Bernard Malavaud, Jean-François Tanti, Muriel Golzio, Frédéric Bost, Isabelle Ader, Mireille Cormont, Béatrice Dirat, Emmanuel Lemichez, Amel Mettouchi, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Urologie, andrologie et transplantation rénale, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], BMC, Ed., Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Département d'Urologie-Andrologie et Transplantation Rénale [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Cytoskeleton organization, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bioinformatics, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, DU145, medicine, Small GTPase, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, Cell migration, medicine.disease, 3. Good health, Psychiatry and Mental health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Oral Presentation, Guanine nucleotide exchange factor, Signal transduction, business
Abstract: Results We show here that metformin reduces the occurrence of metastases in an orthotopic metastatic prostate cancer cell model established in nude mice. As predicted, metformin hampers cell motility in PC3 and DU145 prostate cancer cells and triggers a radical reorganization of the cell cytoskeleton. The small GTPase Rac1 is a master regulator of cytoskeleton organization and cell migration. We report that metformin inhibits Rac1 GTPase activity by interfering with some of its multiple upstream signaling pathways, namely P-Rex1 (a Guanine nucleotide exchange factor and activator of Rac1), cyclic AMP and CXCL12/CXCR4, resulting in decreased migration of prostate cancer cells. Importantly, overexpression of a constitutively active form of Rac1 (Rac1-Q61L or Rac1-V12), or P-Rex1 as well as the inhibition of the adenylate cyclase were able to reverse the anti-migratory effects of metformin.
Published: 2014

20. Associations between quality of life and socioeconomic factors, functional impairments and dissatisfaction with received information and home-care services among survivors living at home two years after stroke onset

Author: Kénora Chau, Michèle Baumann, Nearkasen Chau, Etienne Le Bihan, Research Unit INSIDE, Université du Luxembourg (Uni.lu)-Institute Health & Behaviour, Service de Médecine Interne et Médecine Générale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Troubles du comportement alimentaire de l'adolescent (UMR_S 669), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), The project 'Living in the Grand-Duchy of Luxembourg after a cerebrovascular disease: family repercussions and quality of life. Equality of access to home-care and social resources' was financed by the National Fund for Research, Luxembourg FNR/VIVRE 06/06/06., Institute Health & Behaviour-Université du Luxembourg (Uni.lu), Université Paris-Sud - Paris 11 (UP11)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), BMC, Ed., University of Luxembourg - UL [sponsor], Integrative Research Unit: Social and Individual Development (INSIDE) > Institute for Health and Behaviour [research center], Institute Health & Behaviour - Univergity of Luxembourg, and Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Paris-Sud - Paris 11 (UP11)
Subjects: Gerontology, Male, functional impairments, [SHS.SOCIO] Humanities and Social Sciences/Sociology, Luxembourg, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Newsqol, Santé publique, services médicaux & soins de santé [D22] [Sciences de la santé humaine], information, Quality of life, Surveys and Questionnaires, Information, Survivors, Stroke, media_common, Aged, 80 and over, [SHS.SOCIO]Humanities and Social Sciences/Sociology, Stroke Rehabilitation, dissatisfaction, Cognition, Home-care services, General Medicine, Middle Aged, Home Care Services, humanities, Feeling, Sociology & social sciences [H10] [Social & behavioral sciences, psychology], Patient Satisfaction, Female, Dissatisfaction, Research Article, services, Public health, health care sciences & services [D22] [Human health sciences], media_common.quotation_subject, MEDLINE, Clinical Neurology, Interpersonal relationship, Sociologie & sciences sociales [H10] [Sciences sociales & comportementales, psychologie], Patient satisfaction, stroke survivors, medicine, Humans, Socioeconomic status, Aged, Newcastle Stroke-Specific Quality of Life, business.industry, Post-stroke, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, quality of life, Socioeconomic Factors, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), business
Abstract: International audience; BACKGROUND: Quality of life (QoL) assessment is important when monitoring over time the recovery of stroke-survivors living at home. This study explores the associations between QoL and socioeconomic factors, functional impairments and self-reported dissatisfaction with received information and home-care services among survivors two years after stroke onset. This problem remains partially addressed though optimal information and services may improve survivors' QoL. METHODS: Stroke-survivors admitted to all hospitals in Luxembourg 18 months or more previously were identified using the only care-expenditure-reimbursement national system database. The clinical diagnosis was confirmed. Ninety four patients aged 65 years and living at home were interviewed to gather socioeconomic characteristics, functional impairments, dissatisfaction with information and home-care services, and QoL (using the Newcastle Stroke-Specific QoL, newsqol) assessing 11 domains. Data were analyzed using multiple linear regression models. RESULTS: About 50% of survivors had low education and lower income. Functional impairments were common: sensory (45%), motor (35%), memory (32%), language (31%), and vision (20%). Survivors with education (
Published: 2014

21. Vascular calcification in patients with type 2 diabetes: the involvement of matrix Gla protein

Author: Sophie, Liabeuf, Olivier, Bourron, Bourron, Olivier, Cees, Vemeer, Elke, Theuwissen, Elke, Magdeleyns, Carole Elodie, Aubert, Michel, Brazier, Romuald, Mentaverri, Agnes, Hartemann, Ziad A, Massy, Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Mécanismes physiologiques et conséquences des calcifications cardiovasculaires: rôle des remodelages cardiovasculaires et osseux, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Picardie Jules Verne (UPJV), Service de Diabétologie [CHU Pitié-Salpétrière], 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), VitaK, Maastricht University [Maastricht], Service Néphrologie/Dialyse [AP-HP Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], This study was supported by a fund from Lilly Company., Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), BMC, Ed., Service de diabétologie [CHU Pitié-Salpétrière], Promovendi NTM, RS: CARIM - R1 - Thrombosis and haemostasis, and Biochemie
Subjects: Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Renal function, Type 2 diabetes, Matrix gla protein, Cohort Studies, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Diabetes mellitus, Humans, Medicine, Peripheral calcification, Vascular Calcification, Aged, Angiology, Extracellular Matrix Proteins, biology, business.industry, Calcium-Binding Proteins, Middle Aged, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Arterial calcification, Cross-Sectional Studies, Endocrinology, Diabetes Mellitus, Type 2, biology.protein, Population study, Female, Erratum, Cardiology and Cardiovascular Medicine, business, Biomarkers, Calcification
Abstract: International audience; BACKGROUND: Matrix Gla protein (MGP) is an important inhibitor of calcification. The objective of the present study of patients with type 2 diabetes and normal or slightly altered kidney function was to evaluate levels of inactive, dephospho-uncarboxylated MGP(dp-ucMGP) and total uncarboxylated MGP(t-ucMGP) and assess their links with biological and clinical parameters (including peripheral vascular calcification). METHODS: The DIACART study is a cross-sectional cohort study of 198 patients with type 2 diabetes and normal or slightly altered kidney function. Matrix Gla protein levels were measured with an ELISA and all patients underwent multislice spiral computed tomography scans to score below-knee arterial calcification. RESULTS: In the study population as a whole, the mean dp-ucMGP and t-ucMGP levels were 627 +/- 451 pM and 4868 +/- 1613 nM, respectively. Glomerular filtration rate, age and current vitamin K antagonist use were independently associated with dp-ucMGP levels. When the study population was divided according to the median peripheral arterial calcification score, patients with the higher score displayed significantly lower t-ucMGP and significantly higher dp-ucMGP levels. Furthermore, plasma dp-ucMGP was positively associated with the peripheral arterial calcification score (independently of age, gender, previous cardiovascular disease and t-ucMGP levels). CONCLUSIONS: High dp-ucMGP levels were independently associated with below-knee arterial calcification score in patients with type 2 diabetes and normal or slightly altered kidney function. The reversibility of the elevation of dp-ucMGP levels and the latter's relationship with clinical events merit further investigation.
Published: 2014

22. Guideline-concordant administration of prothrombin complex concentrate and vitamin K is associated with decreased mortality in patients with severe bleeding under vitamin K antagonist treatment (EPAHK study)

Author: Karim, Tazarourte, Bruno, Riou, Benjamin, Tremey, Charles-Marc, Samama, Eric, Vicaut, Bernard, Vigué, Arnaud, Delahaye, Service d'Aide Médicale Urgente 77 (SAMU 77), Centre hospitalier Marc Jacquet (Melun), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'Anesthésie Réanimation [Ambroise Paré], Clinique Ambroise Paré, Service d'Anesthésie et de Soins Intensifs, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5), Service de Statistiques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service d'Anesthésie et de Soins Intensifs [Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, EPAHK study group, Service d'Aide Médicale Urgente 77 ( SAMU 77 ), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 ( UPD7 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and BMC, Ed.
Subjects: Male, Vitamin, medicine.medical_specialty, Vitamin K, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine.drug_class, Hemorrhage, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, Gastroenterology, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Prospective Studies, Mortality, Prospective cohort study, Aged, Aged, 80 and over, business.industry, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Research, 030208 emergency & critical care medicine, Odds ratio, Guideline, Middle Aged, Vitamin K antagonist, Prothrombin complex concentrate, Blood Coagulation Factors, 3. Good health, Surgery, Treatment Outcome, chemistry, Practice Guidelines as Topic, Cohort, Drug Therapy, Combination, Female, business, medicine.drug, Cohort study
Abstract: Introduction: In vitamin K antagonist (VKA)-treated patients with severe hemorrhage, guidelines recommend prompt VKA reversal with prothrombin complex concentrate (PCC) and vitamin K. The aim of this observational cohort study was to evaluate the impact of guideline concordant administration of PCC and vitamin K on seven-day mortality. Methods: Data from consecutive patients treated with PCC were prospectively collected in 44 emergency departments. Type of hemorrhage, coagulation parameters, type of treatment and seven-day mortality mortality were recorded. Guideline-concordant administration of PCC and vitamin K (GC-PCC-K) were defined by at least 20 IU/kg factor IX equivalent PCC and at least 5 mg of vitamin K performed within a predefined time frame of eight hours after admission. Multivariate analysis was used to assess the effect of appropriate reversal on seven-day mortality in all patients and in those with intracranial hemorrhage (ICH). Results: Data from 822 VKA-treated patients with severe hemorrhage were collected over 14 months. Bleeding was gastrointestinal (32%), intracranial (32%), muscular (13%), and “other” (23%). In the whole cohort, seven-day mortality was 13% and 33% in patients with ICH. GC-PCC-K was performed in 38% of all patients and 44% of ICH patients. Multivariate analysis showed a two-fold decrease in seven-day mortality in patients with GC-PCC-K (odds ratio (OR) = 2.15 (1.20 to 3.88); P = 0.011); this mortality reduction was also observed when only ICH was considered (OR = 3.23 (1.53 to 6.79); P = 0.002). Conclusions: Guideline-concordant VKA reversal with PCC and vitamin K within eight hours after admission was associated with a significant decrease in seven-day mortality.
Published: 2014

23. EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness

Author: Hayet Lebdi, Christine Petit, Malek Louha, Yahia Rous, Andrea Lelli, Asma Behlouli, Samia Abdi, Ahmed Cheknane, Mohamed Makrelouf, Crystel Bonnet, Cataldo Schietroma, Jean-Pierre Hardelin, Akila Zenati, Aicha Bouaita, Kamel Boudjelida, Laboratoire de Biochimie Génétique, CHU de Bab El Oued-Université d'Alger 1, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Génétique et Biologie, Université Saâd Dahlab Blida 1 (UB1)- Centre Hospitalo-Universitaire de Blida (CHU Blida), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service ORL, Centre Hospitalo-Universitaire de Blida (CHU Blida), Service Ophtalmologie, This work was supported by grants from the LHW-Stiftung, ERC grant 'Hair bundle' (ERC-2011-AdG 294570), Foundation BNP Paribas, 'Lifesenses' Labex, the Tassili Project and the Algerian government., Chaire Génétique et physiologie cellulaire, Université de Saâd Dahlab [Blida] (USDB )- Centre Hospitalo-Universitaire de Blida (CHU Blida), and BMC, Ed.
Subjects: Male, Hearing loss, Stereocilia (inner ear), Hearing Loss, Sensorineural, Nonsense mutation, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, EPS8, Stereocilia, 03 medical and health sciences, Mice, 0302 clinical medicine, Hair Cells, Auditory, medicine, otorhinolaryngologic diseases, Epidermal growth factor receptor pathway substrate 8, Animals, Humans, Genetics(clinical), Pharmacology (medical), Exome, Actin-binding protein, Genetics (clinical), Exome sequencing, 030304 developmental biology, Adaptor Proteins, Signal Transducing, DNA Primers, Medicine(all), Genetics, 0303 health sciences, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, Congenital deafness, Research, General Medicine, Actins, 3. Good health, Pedigree, Whole-exome sequencing, biology.protein, Female, medicine.symptom, Actin dynamics, Stereocilia bundle, 030217 neurology & neurosurgery
Abstract: International audience; BACKGROUND: Almost 90% of all cases of congenital, non-syndromic, severe to profound inherited deafness display an autosomal recessive mode of transmission (DFNB forms). To date, 47 causal DFNB genes have been identified, but many others remain to be discovered. We report the study of two siblings born to consanguineous Algerian parents and affected by isolated, profound congenital deafness. METHOD: Whole-exome sequencing was carried out on these patients after a failure to identify mutations in the DFNB genes frequently involved. RESULTS: A biallelic nonsense mutation, c.88C > T (p.Gln30*), was identified in EPS8 that encodes epidermal growth factor receptor pathway substrate 8, a 822 amino-acid protein involved in actin dynamics. This mutation predicts a truncated inactive protein or no protein at all. The mutation was also present, in the heterozygous state, in one clinically unaffected sibling and in both unaffected parents, and was absent from the other two unaffected siblings. It was not found in 120 Algerian normal hearing control individuals or in the Exome Variant Server database. EPS8 is an F-actin capping and bundling protein. Mutant mice lacking EPS8 (Eps8-/- mice), which is present in the hair bundle, the sensory antenna of the auditory sensory cells that operate the mechano-electrical transduction, are also profoundly deaf and have abnormally short hair bundle stereocilia. CONCLUSION: This new DFNB form is likely to arise from abnormal hair bundles resulting in compromised detection of physiological sound pressures.
Published: 2014

24. A comprehensive study of small non-frameshift insertions/deletions in proteins and prediction of their phenotypic effects by a machine learning method (KD4i)

Author: Hoan-Ngoc Nguyen, Julie D. Thompson, Olivier Poch, Carlos Bermejo-Das-Neves, Fédération de médecine translationnelle, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INSB-05-01, Instruct as part of the European Strategy Forum on Research Infrastructures (ESFRI), the ANR Investissement d'Avenir project BIP-BIP and institute funds from the CNRS, INSERM, and the Université de Strasbourg., and BMC, Ed.
Subjects: Kinesins, Single-nucleotide polymorphism, Biology, Machine learning, computer.software_genre, Biochemistry, Frameshift mutation, 03 medical and health sciences, Indeuctive logic programming, 0302 clinical medicine, INDEL Mutation, Structural Biology, Artificial Intelligence, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetic variation, Coding region, Humans, Insertion/deletion, Indel, Molecular Biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 030304 developmental biology, Genetics, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], business.industry, Applied Mathematics, Proteins, food and beverages, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Computer Science Applications, Phenotype, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Human genome, Artificial intelligence, DNA microarray, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, computer, Genotype-phenotype relationship, 030217 neurology & neurosurgery, Research Article
Abstract: International audience; BACKGROUND: Small insertion and deletion polymorphisms (Indels) are the second most common mutations in the human genome, after Single Nucleotide Polymorphisms (SNPs). Recent studies have shown that they have significant influence on genetic variation by altering human traits and can cause multiple human diseases. In particular, many Indels that occur in protein coding regions are known to impact the structure or function of the protein. A major challenge is to predict the effects of these Indels and to distinguish between deleterious and neutral variants. When an Indel occurs within a coding region, it can be either frameshifting (FS) or non-frameshifting (NFS). FS-Indels either modify the complete C-terminal region of the protein or result in premature termination of translation. NFS-Indels insert/delete multiples of three nucleotides leading to the insertion/deletion of one or more amino acids. RESULTS: In order to study the relationships between NFS-Indels and Mendelian diseases, we characterized NFS-Indels according to numerous structural, functional and evolutionary parameters. We then used these parameters to identify specific characteristics of disease-causing and neutral NFS-Indels. Finally, we developed a new machine learning approach, KD4i, that can be used to predict the phenotypic effects of NFS-Indels. CONCLUSIONS: We demonstrate in a large-scale evaluation that the accuracy of KD4i is comparable to existing state-of-the-art methods. However, a major advantage of our approach is that we also provide the reasons for the predictions, in the form of a set of rules. The rules are interpretable by non-expert humans and they thus represent new knowledge about the relationships between the genotype and phenotypes of NFS-Indels and the causative molecular perturbations that result in the disease.
Published: 2014

25. Fungal allergy in asthma-state of the art and research needs

Author: Laurence Delhaes, Stefano Del Giacco, Svetlana Sergejeva, Andrew J. Wardlaw, Cendrine Godet, David W. Denning, Domink Hartl, Catherine H. Pashley, The National Aspergillosis Centre, Wythenshawe Hospital-University Hospital of South Manchester, Education and Research Centre, Respiratory Biomedical Research Unit, University of Leicester-Leicester Institute for Lung Health-Glenfield Hospital, Department of Pediatrics, Infectious Diseases & Immunology, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Service des Maladies Infectieuses, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Hôpital de La Milétrie, Department of Medical Sciences 'M. Aresu', University of Cagliari, Service de Parasitologie et de Mycologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Translational Immunology Group, Tartu University, Pulmonology Centre, North Estonia Medical Centre, BMC, Ed., University of Tartu, Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)
Subjects: Pulmonary and Respiratory Medicine, Allergy, Severe asthma, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Disease, Eosinophil, 03 medical and health sciences, 0302 clinical medicine, Hypertonic saline, Position Article and Guidelines, medicine, ABPM, Immunology and Allergy, Corticosteroid, SAFS, Asthma, 0303 health sciences, Bronchiectasis, 030306 microbiology, business.industry, Chronic pulmonary aspergillosis, ABPA, medicine.disease, 3. Good health, Natural history, Aspergillus, 030228 respiratory system, [SDV.IMM]Life Sciences [q-bio]/Immunology, IgE, Allergic bronchopulmonary aspergillosis, Itraconazole, business
Abstract: International audience; : Sensitization to fungi and long term or uncontrolled fungal infection are associated with poor control of asthma, the likelihood of more severe disease and complications such as bronchiectasis and chronic pulmonary aspergillosis. Modelling suggests that >6.5 million people have severe asthma with fungal sensitizations (SAFS), up to 50% of adult asthmatics attending secondary care have fungal sensitization, and an estimated 4.8 million adults have allergic bronchopulmonary aspergillosis (ABPA). There is much uncertainty about which fungi and fungal allergens are relevant to asthma, the natural history of sensitisation to fungi, if there is an exposure response relationship for fungal allergy, and the pathogenesis and frequency of exacerbations and complications. Genetic associations have been described but only weakly linked to phenotypes. The evidence base for most management strategies in ABPA, SAFS and related conditions is weak. Yet straightforward clinical practice guidelines for management are required. The role of environmental monitoring and optimal means of controlling disease to prevent disability and complications are not yet clear. In this paper we set out the key evidence supporting the role of fungal exposure, sensitisation and infection in asthmatics, what is understood about pathogenesis and natural history and identify the numerous areas for research studies.
Published: 2014

26. Nation related participation and performance trends in ‘Ironman Hawaii’ from 1985 to 2012

Author: Philippe Dähler, Beat Knechtle, Christoph Alexander Rüst, Thomas Rosemann, Romuald Lepers, Institute of General Practice and for Health Services Research, Universität Zürich [Zürich] = University of Zurich (UZH), Cognition, Action, et Plasticité Sensorimotrice [Dijon - U1093] (CAPS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Facharzt FMH für Allgemeinmedizin, Gesundheitszentrum St. Gallen, BMC, Ed., University of Zürich [Zürich] ( UZH ), Cognition, Action, et Plasticité Sensorimotrice [Dijon - U1093] ( CAPS ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and University of Zurich
Subjects: 11035 Institute of General Practice, Veterinary medicine, medicine.medical_specialty, Sports medicine, 610 Medicine & health, Physical Therapy, Sports Therapy and Rehabilitation, Triathlon, Finisher, Running, German, 03 medical and health sciences, Race (biology), 2732 Orthopedics and Sports Medicine, 0302 clinical medicine, Medicine, Orthopedics and Sports Medicine, 030212 general & internal medicine, 3612 Physical Therapy, Sports Therapy and Rehabilitation, Nationality, Swimming, biology, Athletes, business.industry, Rehabilitation, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, Cycling, 030229 sport sciences, 16. Peace & justice, biology.organism_classification, language.human_language, 2742 Rehabilitation, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, language, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Research Article, Demography
Abstract: Background This study examined participation and performance trends in ‘Ironman Hawaii’ regarding the nationality of the finishers. Methods Associations between nationalities and race times of 39,706 finishers originating from 124 countries in the ‘Ironman Hawaii’ from 1985 to 2012 were analyzed using single and multi-level regression analysis. Results Most of the finishers originated from the United States of America (47.5%) followed by athletes from Germany (11.7%), Japan (7.9%), Australia (6.7%), Canada (5.2%), Switzerland (2.9%), France (2.3%), Great Britain (2.0%), New Zealand (1.9%), and Austria (1.5%). German women showed the fastest increase in finishers (r2 = 0.83, p 2 = 0.78, p 2 = 0.78, p 2 = 0.69, p 2 = 0.01, p > 0.05). For men, athletes from France showed the steepest increase (r2 = 0.85, p 2 = 0.68, p 2 = 0.67, p 2 = 0.60, p 2 = 0.46, p 2 = 0.26, p 2 = 0.21, p = 0.013) and Switzerland (r2 = 0.14, p = 0.0044). The number of Japanese men decreased (r2 = 0.35, p = 0.0009). The number of men from Canada (r2 = 0.02, p > 0.05) and New Zealand (r2 = 0.02, p > 0.05) remained unchanged. Regarding female performance, the largest improvements were achieved by Japanese women (17.3%). The fastest race times in 2012 were achieved by US-American women. Women from Japan, Canada, Germany, Australia, and the United States of America improved race times. For men, the largest improvements were achieved by athletes originating from Brazil (20.9%) whereas the fastest race times in 2012 were achieved by athletes from Germany. Race times for athletes originating from Brazil, Austria, Great Britain, Switzerland, Germany, Australia, Canada, Japan, New Zealand and France decreased. Race times in athletes originating from Australia and the United States of America showed no significant changes. Regarding the fastest race times ever, the fastest women originated from the United States (546 ± 7 min) followed by Great Britain (555 ± 15 min) and Switzerland (558 ± 8 min). In men, the fastest finishers originated from the United States (494 ± 7 min), Germany (496 ± 6 min) and Australia (497 ± 5 min). Conclusions The ‘Ironman Hawaii’ has been dominated by women and men from the United States of America in participation and performance.
Published: 2014

27. Cervical cancer prevention in reproductive health services: knowledge, attitudes and practices of midwives in Côte d’Ivoire, West Africa

Author: Antoine Jaquet, François Dabis, Apollinaire Horo, Annie J. Sasco, Catherine Sauvaget, Boris Tchounga, Privat Guie, Patrick A. Coffie, Didier K. Ekouevi, Innocent Adoubi, BMC, Ed., Programme PAC-CI, CHU de Treichville, Epidémiologie et Biostatistique [Bordeaux], Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Université Bordeaux Segalen - Bordeaux 2, Service des Maladies Infectieuses et Tropicales, Service de Gynécologie Obstétrique, CHU de Yopougon, IARC- Screening Group, Early Detection and Prevention Section, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO)-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Service de Cancérologie, Programme National de Lutte contre le Cancer, and National Cancer Institute (NCI), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institute of Allergy and Infectious Diseases (NIAID) (grant n° 5U01AI069919).
Subjects: Adult, Health Knowledge, Attitudes, Practice, medicine.medical_specialty, Uterine Cervical Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Midwifery, Health informatics, Midwives, Health administration, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Nursing, Surveys and Questionnaires, Confidence Intervals, Humans, Mass Screening, Medicine, 030212 general & internal medicine, Mass screening, HPV vaccine, Reproductive health, Cervical cancer, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Prevention, 4. Education, Health Policy, Nursing research, Public health, 1. No poverty, Cancer, Middle Aged, medicine.disease, 3. Good health, Cote d'Ivoire, Cross-Sectional Studies, 030220 oncology & carcinogenesis, Africa, Screening, Regression Analysis, Female, Reproductive Health Services, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract: International audience; BACKGROUND: Cervical cancer is the most common cancer among women and the leading cause of cancer deaths in women in Cote d'Ivoire. Low resource countries can now prevent this cancer by using HPV vaccine and effective and affordable screening tests. However the implementation of these prevention strategies needs well-trained human resources. Part of the solution could come from midwives by integrating cervical cancer prevention into reproductive health services. The aim of this survey was to assess knowledge, attitudes and practices of midwives towards cervical cancer prevention in Abidjan, Cote d'Ivoire, and to find out factors associated with appropriate knowledge. METHODS: A cross-sectional survey was conducted among midwives in the urban district of Abidjan, using a self-administered questionnaire. Knowledge was assessed by two scores. Factors associated with appropriate knowledge were determined using a logistic regression analysis. Attitudes and practices were described and compare using the Chi2 test. RESULTS: A total of 592 midwives were enrolled, including 24.5% of final-year students. 55.7% of midwives had appropriate knowledge on cervical cancer, and 42.4% of them had appropriate knowledge on cervical cancer prevention strategies. Conferences, courses taken at school of midwifery and special training sessions on cervical cancer (OR = 4.9, 95% CI [1.9 to 12.6], p
Published: 2014

28. Prospective study of Hepatitis E Virus infection among pregnant women in France

Author: Christophe Locher, Abdelouahab Moumen, Vincent Gobert, Oumar Timbely, Anne-Marie Roque-Afonso, Christophe Renou, Janine Savary, Hôpital de Jour, Centre Hospitalier d’Hyères, Maladies de l'Appareil Digestif, Centre Hospitalier de Meaux, Gynécologie-Obstétrique-Maternité, Service de Virologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse, Pathogénèse et traitement de l'hépatite fulminante et du cancer du foie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was funded by a grant from the French Health Department, Association Nationale des Hépato-Gastroentérologues des Hôpitaux Généraux (ANGH), and BMC, Ed.
Subjects: Adult, Poor prognosis, viruses, Short Report, Seroprevalence, medicine.disease_cause, Antibodies, Viral, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Hepatitis E virus, Seroepidemiologic Studies, Pregnancy, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Virology, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Seroconversion, Pregnancy Complications, Infectious, Prospective cohort study, 030304 developmental biology, 0303 health sciences, business.industry, Incidence (epidemiology), virus diseases, medicine.disease, digestive system diseases, 3. Good health, Hepatitis E, Infectious Diseases, HEV, Immunoglobulin G, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, France, business, Hepatitis E virus infection
Abstract: International audience; BACKGROUND: Hepatitis E Virus (HEV) infection has a poor prognosis among pregnant women from high endemic countries. HEV-prevalence and incidence among pregnant women is unknown in high-income countries such as France. This prospective study was conducted to assess HEV infection in this setting. FINDINGS: An overall HEV prevalence of 7.74% was observed among 315 pregnant women. Seroprevalence was higher in south than in north of France (29.3% vs. 3.6%, p < 0.0001), and women with detectable IgG were older. No IgG seroconversion or IgM detection were observed during pregnancy. CONCLUSIONS: Data suggest that HEV infection is a rare occurrence during pregnancy even in regions of western countries with high seroprevalence rates.
Published: 2014

29. EPIPAGE 2: a preterm birth cohort in France in 2011

Author: François Goffinet, Pierre-Yves Ancel, URC - CIC P1419, Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Cochin Hôtel-Dieu, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS), Institut National de la Recherche Agronomique (INRA) - Université Paris Diderot - Paris 7 (UPD7) - Université Paris Descartes - Paris 5 (UPD5) - Université Paris 13 - Institut National de la Santé et de la Recherche Médicale (INSERM), Maternité Port-Royal, The French Institute of Public Health Research/Institute of Public Health and its partners: the French Health Ministry, the National Institute of Health and Medical Research (INSERM), the National Institute of Cancer, and the National Solidarity Fund for Autonomy (CNSA). The French EQUIPEX program of investments in the future. The PREMUP Foundation., EPIPAGE 2 Writing Group, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Mère Enfant Necker Cochin Paris Centre (CIC 1419), CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Maternité Port-Royal [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and BMC, Ed.
Subjects: Male, Pediatrics, medicine.medical_specialty, Developmental Disabilities, Intelligence, Population, Gestational Age, Growth, Cohort Studies, Study Protocol, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Surveys and Questionnaires, Intensive care, medicine, Humans, Very Preterm Birth, Pediatrics, Perinatology, and Child Health, education, Population-based study, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Pregnancy, education.field_of_study, business.industry, Obstetrics, Infant, Newborn, Cohort, Gestational age, medicine.disease, Preterm births, 3. Good health, Pediatrics, Perinatology and Child Health, Quality of Life, Gestation, Female, France, business, Infant, Premature, Cohort study
Abstract: International audience; BACKGROUND: Children born at low gestational ages face a range of risks and number of neonates surviving very preterm birth is increasing. We present the objectives and methods of a French national cohort of very and moderately preterm children, the EPIPAGE 2 study. It aims to examine short- and long-term outcomes of very preterm children and their determinants.Methods/design: Eligible participants for this prospective population-based study include all infants live born or stillborn and all terminations of pregnancy between 22 and 31 completed weeks of gestation in all the maternity units in 25 French regions. In addition, a sample of moderate preterm births, i.e. births and late terminations at 32-34 weeks, was included in the same regions. In all, 7804 babies (stillbirths and live births) and terminations of pregnancy out of 8400 eligible births in France in 2011 that were either very (22-31 weeks) or moderately preterm (32-34 weeks) were included. Data on pregnancy, delivery, and neonatal events were extracted from the obstetric and neonatal records. The follow-up will collect information at corrected ages of one and 2 years and at 5, 8, and 12 years of age. Of the 4467 children discharged alive from the hospital and eligible for follow-up, 155 (4%) families refused further follow-up and 22 died before one-year of age. Finally, 4290 were included in the follow-up.Eight additional projects investigating specific hypotheses among subsamples of the cohort by collecting specific data in addition to the core cohort data are being conducted to investigate 1) diagnosis of histologic chorioamnionitis, 2) early biomarkers of child health, 3) attitudes of care for extremely preterm infants, 4) painful procedures in neonatal intensive care units, 5) neonatal MRI cerebral abnormalities and their relation to executive functions, 6) associations between early gut colonization and early and late onset diseases, 7) impact of neonatal nutrition on child development, and 8) mother-infant attachment. DISCUSSION: This project seeks to provide new data on the prognosis and etiology of very preterm birth and to assess related medical practices. Accordingly, it should lead to the development of new strategies of management and prevention in high-risk babies.
Published: 2014

30. HGCS: an online tool for prioritizing disease-causing gene variants by biological distance

Author: Jean-Laurent Casanova, Lluis Quintana-Murci, Avinash Abhyankar, Bertrand Boisson, Laurent Abel, Mark Mazel, Patrick Nitschke, Stéphanie Boisson-Dupuis, Yuval Itan, Shen-Ying Zhang, Benjamin Mazel, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Bio-informatic, New York Genome Center, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Unité d'Immunologie-Hématologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunology, Medicine and Translational Research, Howard Hughes Medical Institute (HHMI), This work was funded in part by the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), National Institutes of Health (NIH) Grant 8 UL1 TR000043., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), The Rockefeller University, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), 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 Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], and BMC, Ed.
Subjects: Candidate gene, Genomics, Computational biology, Web Browser, Biology, Computational and Statistical Genetics, User-Computer Interface, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Databases, Genetic, Genetics, Humans, Genetic Association Studies, Computational genomics, Computational Biology, Reproducibility of Results, Phenotype, Human genetics, 3. Good health, ComputingMethodologies_PATTERNRECOGNITION, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], ComputingMethodologies_GENERAL, DNA microarray, Functional genomics, Software, Biotechnology
Abstract: International audience; BACKGROUND: Identifying the genotypes underlying human disease phenotypes is a fundamental step in human genetics and medicine. High-throughput genomic technologies provide thousands of genetic variants per individual. The causal genes of a specific phenotype are usually expected to be functionally close to each other. According to this hypothesis, candidate genes are picked from high-throughput data on the basis of their biological proximity to core genes -- genes already known to be responsible for the phenotype. There is currently no effective gene-centric online interface for this purpose. RESULTS: We describe here the human gene connectome server (HGCS), a powerful, easy-to-use interactive online tool enabling researchers to prioritize any list of genes according to their biological proximity to core genes associated with the phenotype of interest. We also make available an updated and extended version for all human gene-specific connectomes. The HGCS is freely available to noncommercial users from: http://hgc.rockefeller.edu/. CONCLUSIONS: The HGCS should help investigators from diverse fields to identify new disease-causing candidate genes more effectively, via a user-friendly online interface.
Published: 2014

31. Reliability of the nitrogen washin-washout technique to assess end-expiratory lung volume at variable PEEP and tidal volumes

Author: Céline Pouzot, Juan Sebastian Gonzalez, Jean-Christophe Richard, Claude Guérin, Alfredo Morales Pinzón, Franck Lavenne, Maciej Orkisz, Bruno Neyran, Marcela Hernández Hoyos, BMC, Ed., Service de Réanimation Médicale, Hospices Civils de Lyon (HCL)-Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), 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)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Urgences animaux compagnie SIAMU, VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre Hospitalier d'Enseignement Vétérinaire (C.H.E.V.), Hémostase, Inflammation et sepsis (EA 4609), Université de Lyon-Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Imagerie et modélisation Vasculaires, Thoraciques et Cérébrales (MOTIVATE), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Grupo Imagine, Universidad de los Andes [Bogota] (UNIANDES), Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), AMP was supported by a Colombian doctoral grant from Colciencias and by a Rhône-Alpes Region grant CMIRA., Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Hospices Civils de Lyon ( HCL ) -Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon ( HCL ), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé ( CREATIS ), Hospices Civils de Lyon ( HCL ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ), VetAgro Sup ( VAS ) -Centre Hospitalier d'Enseignement Vétérinaire (C.H.E.V.), Hémostase, Inflammation et sepsis, Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-VetAgro Sup ( VAS ), 1 - Imagerie et modélisation Vasculaires, Thoraciques et Cérébrales ( MOTIVATE ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Hospices Civils de Lyon ( HCL ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Universidad de Los Andes, Centre d'Exploration et de Recherche Médicales par Émission de Positons ( CERMEP ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon ( HCL ) -CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Grupo IMAGINE, Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Centre d'Exploration et de Recherche Médicales par Émission de Positons (CERMEP), Université Joseph Fourier - Grenoble 1 (UJF)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Réanimation Médicale, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Université de Lyon, Lyon, France, Hôpital de la Croix-Rousse [CHU - HCL], and Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)
Subjects: medicine.medical_specialty, ARDS, Computed tomography, Acute respiratory distress, Critical Care and Intensive Care Medicine, Fraction of inspired oxygen, Internal medicine, End-expiratory lung volume, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, medicine, Lung volumes, [ SDV.IB ] Life Sciences [q-bio]/Bioengineering, ComputingMilieux_MISCELLANEOUS, Reliability (statistics), PEEP, [SPI.SIGNAL] Engineering Sciences [physics]/Signal and Image processing, [SDV.IB] Life Sciences [q-bio]/Bioengineering, medicine.diagnostic_test, business.industry, Research, Washout, Lung volume measurement, respiratory system, medicine.disease, Surgery, respiratory tract diseases, Cardiology, [SDV.IB]Life Sciences [q-bio]/Bioengineering, business, therapeutics, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, circulatory and respiratory physiology
Abstract: Background End-expiratory lung volume measurement by the nitrogen washin-washout technique (EELVWI-WO) may help titrating positive end-expiratory pressure (PEEP) during acute respiratory distress syndrome (ARDS). Validation of this technique has been previously performed using computed tomography (EELVCT), but at mild PEEP levels, and relatively low fraction of inspired oxygen (FiO2), which may have insufficiently challenged the validity of this technique. The aims of this study were (1) to evaluate the reliability of EELVWI-WO measurements at different PEEP and V T during experimental ARDS and (2) to evaluate trending ability of EELVWI-WO to detect EELV changes over time. Methods ARDS was induced in 14 piglets by saline lavage. Optimal PEEP was selected during a decremental PEEP trial, based on best compliance, best EELVWI-WO, or a PEEP-FiO2 table. Eight V T (4 to 20 mL · kg-1) were finally applied at optimal PEEP. EELVWI-WO and EELVCT were determined after ARDS onset, at variable PEEP and V T. Results EELVWI-WO underestimated EELVCT with a non-constant linear bias, as it decreased with increasing EELV. Limits of agreement for bias were ±398 mL. Bias between methods was greater at high PEEP, and further increased when high PEEP was combined with low V T. Concordance rate of EELV changes between consecutive measurements was fair (79%). Diagnostic accuracy was good for detection of absolute EELV changes above 200 mL (AUC = 0.79). Conclusions The reliability of the WI-WO technique is critically dependent on ventilatory settings, but sufficient to accurately detect EELV change greater than 200 mL.
Published: 2014

32. Neurodevelopmental and environmental hypotheses of negative symptoms of schizophrenia

Author: Frédéric Limosin, Centre de Psychiatrie et Neurosciences (CPN - U894), Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Paris Descartes - Paris 5 (UPD5), Service de psychiatrie adulte et gériatrique, Assistance publique - Hôpitaux de Paris (AP-HP) - Université Paris Descartes - Paris 5 (UPD5) - Hôpitaux Universitaires Paris Ouest - Hôpital Corentin Celton [Issy-les-Moulineaux], Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Hôpital Corentin Celton [Issy-les-Moulineaux], 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and BMC, Ed.
Subjects: Adult, Hypothalamo-Hypophyseal System, Alogia, Dopamine, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Pituitary-Adrenal System, Review, Disease, Environment, 03 medical and health sciences, Glutamatergic, 0302 clinical medicine, medicine, Humans, Tonic (music), Apathy, Child, Avolition, Maternal deprivation, Brain, medicine.disease, 3. Good health, 030227 psychiatry, Psychiatry and Mental health, Schizophrenia, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Negative symptoms, Neurodevelopmental hypothesis, medicine.symptom, Psychology, 030217 neurology & neurosurgery, Clinical psychology
Abstract: International audience; The negative symptoms of schizophrenia, avolition, alogia, apathy and impaired or nonexistent social functioning, are strongly correlated with the progressive course and long-term prognosis of the disease, undermining the patient's ability to integrate socially, interpersonal skills and quality of life. At a time when new drug strategies are being developed, a better understanding of the etiology and pathogenesis underpinning the occurrence of negative symptoms constitutes an essential prerequisite for real therapeutic advances. Approaching this vulnerability from the neurodevelopmental perspective is especially pertinent with regard to the experimental studies conducted in animals. Several models have been put forward, involving a variety of topics such as the deleterious impact of a prenatal infection or of early maternal deprivation on brain development, or else the consequences of trauma and abuse suffered during childhood. These various models are based on biological abnormalities that could guide the identification of new therapeutic targets. They notably include the hyperreactivity of the hypothalamic-pituitary-adrenal axis and dysfunction of corticostriatal glutamatergic transmission. As such, in the traumagenic model, which associates neurodevelopmental and neurodegenerative processes, the dysfunction of corticostriatal glutamatergic transmission, by reducing the tonic dopamine release, could be the cause of an increase in the phasic dopamine release linked to stress. This excessive phasic response to stress may induce cerebral damage by increasing excitotoxicity and oxidative stress.
Published: 2014

33. Resting and active motor thresholds versus stimulus–response curves to determine transcranial magnetic stimulation intensity in quadriceps femoris

Author: John Temesi, Samuel Verges, Thomas Rupp, Mathieu Gruet, Guillaume Y. Millet, Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM), Laboratoire HP2, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Laboratoire Motricité Humaine Expertise Sport Santé (LAMHESS), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université de Toulon (UTLN)-Université Côte d'Azur (UCA), Hypoxie et physiopathologies cardiovasculaire et respiratoire, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Human Performance, University of Calgary, Rhône-Alpes Region, Fonds de Dotation Recherche en Santé Respiratoire, appel d'offres 2011, Laboratoire Interuniversitaire de Biologie de la Motricité ( LIBM ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble, Laboratoire Motricité Humaine Expertise Sport Santé ( LAMHESS ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Université de Toulon ( UTLN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), BMC, Ed., Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Hypoxie : Physiopathologie Respiratoire et Cardiovasculaire (HP2), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, medicine.medical_specialty, genetic structures, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Vastus medialis, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.medical_treatment, Health Informatics, Stimulation, Electromyography, Stimulus (physiology), Stimulus intensity determination, Quadriceps Muscle, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, Humans, Methodological considerations, Fatigue, medicine.diagnostic_test, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Research, Rehabilitation, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Motor Cortex, 030229 sport sciences, Evoked Potentials, Motor, C600, Transcranial Magnetic Stimulation, Coactivation, body regions, Transcranial magnetic stimulation, medicine.anatomical_structure, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Physical therapy, medicine.symptom, Psychology, human activities, 030217 neurology & neurosurgery, Muscle Contraction, Muscle contraction, Motor cortex
Abstract: International audience; BACKGROUND: Transcranial magnetic stimulation (TMS) is a widely-used investigative technique in motor cortical evaluation. Recently, there has been a surge in TMS studies evaluating lower-limb fatigue. TMS intensity of 120-130% resting motor threshold (RMT) and 120% active motor threshold (AMT) and TMS intensity determined using stimulus-response curves during muscular contraction have been used in these studies. With the expansion of fatigue research in locomotion, the quadriceps femoris is increasingly of interest. It is important to select a stimulus intensity appropriate to evaluate the variables, including voluntary activation, being measured in this functionally important muscle group. This study assessed whether selected quadriceps TMS stimulus intensity determined by frequently employed methods is similar between methods and muscles. METHODS: Stimulus intensity in vastus lateralis, rectus femoris and vastus medialis muscles was determined by RMT, AMT (i.e. during brief voluntary contractions at 10% maximal voluntary force, MVC) and maximal motor-evoked potential (MEP) amplitude from stimulus-response curves during brief voluntary contractions at 10, 20 and 50% MVC at different stimulus intensities. RESULTS: Stimulus intensity determined from a 10% MVC stimulus-response curve and at 120 and 130% RMT was higher than stimulus intensity at 120% AMT (lowest) and from a 50% MVC stimulus-response curve (p < 0.05). Stimulus intensity from a 20% MVC stimulus-response curve was similar to 120% RMT and 50% MVC stimulus-response curve. Mean stimulus intensity for stimulus-response curves at 10, 20 and 50% MVC corresponded to approximately 135, 115 and 100% RMT and 180, 155 and 130% AMT, respectively. Selected stimulus intensity was similar between muscles for all methods (p > 0.05). CONCLUSIONS: Similar optimal stimulus intensity and maximal MEP amplitudes at 20 and 50% MVC and the minimal risk of residual fatigue at 20% MVC suggest that a 20% MVC stimulus-response curve is appropriate for determining TMS stimulus intensity in the quadriceps femoris. The higher selected stimulus intensities at 120-130% RMT have the potential to cause increased coactivation and discomfort and the lower stimulus intensity at 120% AMT may underestimate evoked responses. One muscle may also act as a surrogate in determining optimal quadriceps femoris stimulation intensity.
Published: 2014

34. [18F]DPA-714 as a biomarker for positron emission tomography imaging of rheumatoid arthritis in an animal model

Author: Géraldine Pottier, Nicholas Bernards, Raphaël Boisgard, Frédéric Dollé, Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-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), Imagerie Moléculaire in Vivo (IMIV - U1023 - ERL9218), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by CEA-I2BM intramural programs, as well as the European Union's Seventh Framework Programme [FP7/2007-2013] INMiND (Grant agreement number HEALTH-F2- 2011-278850)., 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, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and BMC, Ed.
Subjects: medicine.medical_specialty, Pathology, Fluorine Radioisotopes, Immunology, Systemic inflammation, Multimodal Imaging, Arthritis, Rheumatoid, Rheumatology, Synovitis, Internal medicine, medicine, Translocator protein, Immunology and Allergy, Animals, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, biology, medicine.diagnostic_test, business.industry, Early Inflammatory Arthritis, medicine.disease, Arthritis, Experimental, Immunohistochemistry, 3. Good health, Rats, Pyrimidines, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Positron emission tomography, Rheumatoid arthritis, Positron-Emission Tomography, biology.protein, Biomarker (medicine), Pyrazoles, medicine.symptom, Radiopharmaceuticals, business, Tomography, X-Ray Computed, Research Article
Abstract: Introduction: Rheumatoid arthritis (RA) is a chronic disease, affecting 0.5 to 1% of adults in industrialized countries,in which systemic inflammation and synovitis drive joint destruction. [18F]DPA-714 is a specific tracer of the 18 kDatranslocator protein (TSPO), which is overexpressed on activated macrophages, and proposed as a biomarker ofneuroinflammation. Today, diagnosis of patients with early inflammatory arthritis is limited by poor sensitivity andspecificity. The present study aims to investigate the potential of [18F]DPA-714 to monitor in vivo inflammatoryprocesses at a preclinical stage via positron emission tomography (PET). Methods: RA was induced in Dark Agouti rats by subcutaneous injection of inactivated Mycobacterium tuberculosis.Development of arthritis clinical signs was investigated daily and the severity of the disease evaluated. Animalswere imaged at the peak of inflammation using [18F]DPA-714 and a small-animal PET-CT tomograph. Results: The first clinical signs appeared at 10 days post-injection, with a peak of inflammation at 20 days. At thistime, PET-analyses showed a clear uptake of [18F]DPA-714 in swollen ankles, with mean values of 0.52 ± 0.18%injected dose (ID/cc) for treated (n = 11) and 0.19 ± 0.09 for non-treated (n = 6) rats. A good correlation between[18F]DPA-714’s uptake and swelling was also found. Immunohistochemistry showed an enhanced TSPO expressionin hind paws, mainly co-localized with the macrophages specific antigen CD68 expressing cells. Conclusion: These preliminary results demonstrate that the TSPO 18kDa specific radioligand [18F]DPA-714 isadapted for the study and follow-up of inflammation linked to RA in our experimental model, suggesting also astrong potential for clinical imaging of peripheral inflammation.
Published: 2014

35. Obesogenic environments: a systematic review of the association between the physical environment and adult weight status, the SPOTLIGHT project

Author: Hélène Charreire, Jeroen Lakerveld, Giel Nijpels, Ilse De Bourdeaudhuij, Harry Rutter, Sofie Compernolle, Ketevan Glonti, Johannes Brug, Joreintje D. Mackenbach, Jean-Michel Oppert, Department of General Practice and Elderly Care Medicine, The EMGO Institute for Health and Care Research-VU University Medical Center [Amsterdam], European Centre on Health of Societies in Transition, London School of Hygiene and Tropical Medicine (LSHTM), Department of Movement and Sport Sciences, Universiteit Gent = Ghent University (UGENT), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-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)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Department of Epidemiology and Biostatistics, Research related to this article was funded by the Seventh Framework Programme (CORDIS FP7) of the European Commission (FP7-HEALTH-2011)., Universiteit Gent = Ghent University [Belgium] (UGENT), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Ghent University [Belgium] (UGENT), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], Epidemiology and Data Science, General practice, EMGO - Lifestyle, overweight and diabetes, Mackenbach, Joreintje D., and BMC, Ed.
Subjects: Physical environment, Quality assessment, NEIGHBORHOOD ENVIRONMENT, GREEN SPACE, Review, Scientific literature, Level design, FOOD ENVIRONMENTS, 0302 clinical medicine, Risk Factors, 11. Sustainability, Medicine and Health Sciences, 030212 general & internal medicine, City Planning, Built environment, MULTILEVEL ANALYSIS, adulte, Multilevel model, Urban sprawl, URBAN SPRAWL, 3. Good health, obésité, CARDIOVASCULAR-DISEASE, Public Health, NEW-YORK-CITY, 0305 other medical science, Research Article, Adult, medicine.medical_specialty, STREET CONNECTIVITY, Environment, 03 medical and health sciences, Urban planning, Environmental health, medicine, Humans, Adults, Obesity, 030505 public health, business.industry, Public health, Public Health, Environmental and Occupational Health, surpoids, Overweight, BODY-MASS INDEX, BUILT ENVIRONMENT, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, North America, Environment Design, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Biostatistics, business
Abstract: International audience; BACKGROUND: Understanding which physical environmental factors affect adult obesity, and how best to influence them, is important for public health and urban planning. Previous attempts to summarise the literature have not systematically assessed the methodological quality of included studies, or accounted for environmental differences between continents or the ways in which environmental characteristics were measured. METHODS: We have conducted an updated review of the scientific literature on associations of physical environmental factors with adult weight status, stratified by continent and mode of measurement, accompanied by a detailed risk-of-bias assessment. Five databases were systematically searched for studies published between 1995 and 2013. RESULTS: Two factors, urban sprawl and land use mix, were found consistently associated with weight status, although only in North America. CONCLUSIONS: With the exception of urban sprawl and land use mix in the US the results of the current review confirm that the available research does not allow robust identification of ways in which that physical environment influences adult weight status, even after taking into account methodological quality.
Published: 2014

36. AGEs breaking and antioxidant treatment improves endothelium-dependent dilation without effect on flow-mediated remodeling of resistance arteries in old Zucker diabetic rats

Author: Anne-Laure Guihot, Bertrand Toutain, Mohamed Lamine Freidja, Laurent Loufrani, Emilie Vessieres, Céline Fassot, Daniel Henrion, Marc-Antoine Custaud, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), This work was supported in part by the Foundation for Medical Research (Fondation pour la Recherche Médicale, FRM), Paris, France. MLF was supported by a grant from Intervet Schering Plough, Angers, France., Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Biologie Neurovasculaire Intégrée (BNVI), Physiologie et pharmacologie vasculaire et rénale, IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), and BMC, Ed.
Subjects: Glycation End Products, Advanced, Male, medicine.medical_specialty, Aging, Endothelium, Endocrinology, Diabetes and Metabolism, Vasodilation, medicine.disease_cause, Antioxidants, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Glycation, Diabetes mellitus, Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Original Investigation, business.industry, Blood flow, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Rats, Rats, Zucker, medicine.anatomical_structure, Endocrinology, Treatment Outcome, Ageing, Vascular resistance, Vascular Resistance, Endothelium, Vascular, business, Cardiology and Cardiovascular Medicine, Oxidative stress, Blood Flow Velocity
Abstract: International audience; BACKGROUND: A chronic increase in blood flow in resistance arteries is associated with increased lumen diameter (outward remodeling) and improved endothelium (NO)-mediated relaxation. Flow-mediated remodeling of resistance arteries is essential for revascularization in ischemic diseases. Nevertheless, it is impaired in 12 to 24-month old rats and in young Zucker Diabetic Fatty (ZDF) rats due to advanced glycation end products (AGEs) and oxidative stress. As type 2 diabetes occurs preferentially in older subjects we investigated flow-mediated remodeling and the effect of the AGEs breaker ALT-711 associated or not to the antioxidant TEMPOL in one-year old lean (LZ) and ZDF rats. METHODS: Mesenteric resistance arteries were exposed to high (HF) or normal blood flow (NF) in vivo. They were collected after 2 weeks for in vitro analysis. RESULTS: In LZ rats, diameter expansion did not occur despite a significant increase in blood flow in HF arteries. Nevertheless, endothelium-mediated relaxation was higher in HF than in NF arteries. ALT-711, alone or in combination with TEMPOL, restored outward remodeling in HF arteries in association with AGEs reduction. TEMPOL alone had no effect. ALT-711, TEMPOL or the combination of the 2 drugs did not significantly affect endothelium-mediated relaxation in HF and NF arteries.In ZDF rats, diameter did not increase despite the increase in blood flow and endothelium-mediated relaxation was further decreased in HF arteries in association with AGEs accumulation and excessive oxidative stress. In both NF and HF arteries, endothelium-mediated relaxation was lower in ZDF than in LZ rats. ALT-711, TEMPOL or their combination did not improve remodeling (diameter equivalent in HF and NF arteries). In parallel, they did not reduce AGEs level and did not improve MMPs activity. Nevertheless, ALT-711 and TEMPOL partly improved endothelium-mediated relaxation through a reduction of oxidative stress and the association of ALT-711 and TEMPOL fully restored relaxation to the level found in LZ rats. CONCLUSIONS: ALT-711 did not improve outward remodeling in mature ZDF rats but it reduced oxidative stress and consequently improved endothelium-dependent relaxation. In mature LZ rats, ALT-711 improved outward remodeling and reduced AGEs level. Consequently, AGEs breaking is differently useful in ageing whether it is associated with diabetes or not.
Published: 2014

37. Promyelocytic leukemia zinc-finger induction signs mesenchymal stem cell commitment: identification of a key marker for stemness maintenance?

Author: Christian Jorgensen, Paul Chuchana, Danièle Noël, Karine Toupet, Claire Bony, Farida Djouad, Marie Maumus, Gautier Tejedor, Anne Blangy, Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Service d'Immuno-Rhumatologie Clinique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, This work was supported by Inserm and grants from the Medical Research Foundation (project FRM 2011 'Comité Languedoc-Roussillon-Rouergue (LRR)'), from 'La region Languedoc-Roussillon project Chercheuses/eurs d'avenir 2011', from the French National Research Agency as part of the 'Investments for the Future' program ANR-11-INBS-0005 and funding from the European Community (Key action LSH 1.2.4-3, Integrated project: 'Adult mesenchymal stem cells engineering for connective tissue disorders. From the bench to the bed side', contract 503161)., Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), BMC, Ed., Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR3, and Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)
Subjects: Kruppel-Like Transcription Factors, Medicine (miscellaneous), Core Binding Factor Alpha 1 Subunit, [SDV.GEN] Life Sciences [q-bio]/Genetics, Mice, SCID, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Mesenchymal Stem Cell Transplantation, Biochemistry, Genetics and Molecular Biology (miscellaneous), Chondrocyte, Mice, 03 medical and health sciences, 0302 clinical medicine, Osteogenesis, medicine, Animals, Humans, Promyelocytic Leukemia Zinc Finger Protein, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cells, Cultured, 030304 developmental biology, Stem cell transplantation for articular cartilage repair, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Research, Mesenchymal stem cell, Mesenchymal Stem Cells, SOX9 Transcription Factor, Osteoblast, Cell Biology, Chondrogenesis, Cell biology, Mice, Inbred C57BL, RUNX2, medicine.anatomical_structure, Mice, Inbred DBA, Adipogenesis, 030220 oncology & carcinogenesis, Immunology, Molecular Medicine, Stem cell
Abstract: International audience; INTRODUCTION: Mesenchymal stem cells (MSC) are an attractive cell source for cartilage and bone tissue engineering given their ability to differentiate into chondrocytes and osteoblasts. However, the common origin of these two specialized cell types raised the question about the identification of regulatory pathways determining the differentiation fate of MSC into chondrocyte or osteoblast. METHODS: Chondrogenesis, osteoblastogenesis and adipogenesis of human and mouse MSC were induced using specific inductive culture conditions. Expression of promyelocytic leukemia zinc-finger (PLZF) or differentiation markers in MSC was determined by RT-qPCR. PLZF-expressing MSC were implanted in a mouse osteochondral defect model and the neotissue was analyzed by routine histology and micro-computed tomography. RESULTS: We found out that PLZF is not expressed in MSC and its expression at early stages of MSC differentiation is the mark of their commitment toward the three main lineages. PLZF acts as an upstream regulator of both Sox9 and Runx2 and its overexpression in MSC enhances chondrogenesis and osteogenesis while it inhibits adipogenesis. In vivo, implantation of PLZF-expressing MSC in mice with full thickness osteochondral defects resulted in the formation of a reparative tissue resembling cartilage and bone. CONCLUSIONS: Our findings demonstrate that absence of PLZF is required for stemness maintenance and its expression is an early event at the onset of MSC commitment during the differentiation processes of the three main lineages.
Published: 2014

38. Analysis of sex differences in open-water ultra-distance swimming performances in the FINA World Cup races in 5 km, 10 km and 25 km from 2000 to 2012

Author: Beat Knechtle, Matthias Alexander Zingg, Christoph Alexander Rüst, Thomas Rosemann, Romuald Lepers, Institute of General Practice and for Health Services Research, Universität Zürich [Zürich] = University of Zurich (UZH), Cognition, Action, et Plasticité Sensorimotrice [Dijon - U1093] (CAPS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Facharzt FMH für Allgemeinmedizin, Gesundheitszentrum St. Gallen, BMC, Ed., University of Zurich, University of Zürich [Zürich] ( UZH ), Cognition, Action, et Plasticité Sensorimotrice [Dijon - U1093] ( CAPS ), and Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: 11035 Institute of General Practice, Water sport, business.industry, Performance, Rehabilitation, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, 610 Medicine & health, Physical Therapy, Sports Therapy and Rehabilitation, Endurance, 2742 Rehabilitation, Swimming speed, 2732 Orthopedics and Sports Medicine, Animal science, Open water, Athlete, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Water Sport, Woman, Man, Medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Orthopedics and Sports Medicine, 3612 Physical Therapy, Sports Therapy and Rehabilitation, business, Research Article
Abstract: International audience; BACKGROUND: The present study investigated the changes in swimming speeds and sex differences for elite male and female swimmers competing in 5 km, 10 km and 25 km open-water FINA World Cup races held between 2000 and 2012. METHODS: The changes in swimming speeds and sex differences across years were analysed using linear, non-linear, and multi-level regression analyses for the annual fastest and the annual ten fastest competitors. RESULTS: For the annual fastest, swimming speed remained stable for men and women in 5 km (5.50 ± 0.21 and 5.08 ± 0.19 km/h, respectively), in 10 km (5.38 ± 0.21 and 5.05 ± 0.26 km/h, respectively) and in 25 km (5.03 ± 0.32 and 4.58 ± 0.27 km/h, respectively). In the annual ten fastest, swimming speed remained constant in 5 km in women (5.02 ± 0.19 km/h) but decreased significantly and linearly in men from 5.42 ± 0.03 km/h to 5.39 ± 0.02 km/h. In 10 km, swimming speed increased significantly and linearly in women from 4.75 ± 0.01 km/h to 5.74 ± 0.01 km/h but remained stable in men at 5.36 ± 0.21 km/h. In 25 km, swimming speed decreased significantly and linearly in women from 4.60 ± 0.06 km/h to 4.44 ± 0.08 km/h but remained unchanged at 4.93 ± 0.34 km/h in men. For the annual fastest, the sex difference in swimming speed remained unchanged in 5 km (7.6 ± 3.0%), 10 km (6.1 ± 2.5%) and 25 km (9.0 ± 3.7%). For the annual ten fastest, the sex difference remained stable in 5 km at 7.6 ± 0.6%, decreased significantly and linearly in 10 km from 7.7 ± 0.7% to 1.2 ± 0.3% and increased significantly and linearly from 4.7 ± 1.4% to 9.6 ± 1.5% in 25 km. CONCLUSIONS: To summarize, elite female open-water ultra-distance swimmers improved in 10 km but impaired in 25 km leading to a linear decrease in sex difference in 10 km and a linear increase in sex difference in 25 km. The linear changes in sex differences suggest that women will improve in the near future in 10 km, but not in 25 km.
Published: 2014

39. Impact of chromosomal instability on colorectal cancer progression and outcome

Author: Blandine Massemin, Janick Selves, Karine Gordien, Christophe Cazaux, Valérie Dapremont, Frédéric Bibeau, Béatrice Orsetti, Charles Theillet, Rosine Guimbaud, Laurence Lasorsa, Isabelle Soubeyran, François Paraf, Caroline Bascoul-Mollevi, Michel Longy, Isabelle Hostein, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Service d'Anatomie et Cytologie Pathologiques, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), 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)-Centre National de la Recherche Scientifique (CNRS), Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-CHU Limoges, Plateforme de génétique moléculaire des cancers d'Aquitaine, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Gastro - Entérologie et Nutrition, CHU Toulouse [Toulouse]-Hôpital de Rangueil, Validation et identification de nouvelles cibles en oncologie (VINCO), UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), This study was supported by INCA (Canceropole GSO, grant ACI 'Genetic instability as a negative outcome' 2004/2007 and 2008/2009)., Institut de recherche en cancérologie de Montpellier ( IRCM ), Université Montpellier 1 ( UM1 ) -CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), UNICANCER - Institut régional du Cancer [Montpellier] ( ICM ), CRLCC Val d'Aurelle - Paul Lamarque, Centre de Recherche en Cancérologie de Toulouse ( CRCT ), Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Homéostasie Cellulaire et Pathologies ( HCP ), Université de Limoges ( UNILIM ) -CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ), Génétique tumorale - Pathologie, CHU Bordeaux [Bordeaux]-Centre Régional de Lutte Contre le Cancer Institut Bergonié (Bordeaux), Centre Hospitalier Universitaire de Toulouse - CHU Toulouse (FRANCE), Validation et identification de nouvelles cibles en oncologie ( VINCO ), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Institut Bergonié - CRLCC Bordeaux, Université de Limoges ( UNILIM ) -Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -CHU Limoges, Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale (INSERM), BMC, Ed., Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Endocrinologie, maladies métaboliques et nutrition [CHU Toulouse], and Pôle Cardiovasculaire et Métabolique [CHU Toulouse]
Subjects: Male, Genome instability, Oncology, Cancer Research, Colorectal cancer, Array CGH, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Metastasis, Chromosome Breakpoints, Surgical oncology, Chromosome instability, Medicine, Neoplasm Metastasis, Stage (cooking), Outcome, Comparative Genomic Hybridization, 16p13.3, Middle Aged, Prognosis, 19q13.3, 3. Good health, Treatment Outcome, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Breakpoint, Disease Progression, Female, Colorectal Neoplasms, Carcinoma in Situ, Research Article, Adult, Genomic instability, Adenoma, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, CIN tumors, Chromosomal Instability, Internal medicine, Genetics, Humans, Aged, business.industry, Primary tumors, Carcinoma in situ, medicine.disease, Neoplasm Recurrence, Local, business, Comparative genomic hybridization
Abstract: International audience; BACKGROUND: It remains presently unclear whether disease progression in colorectal carcinoma (CRC), from early, to invasive and metastatic forms, is associated to a gradual increase in genetic instability and to a scheme of sequentially occurring Copy Number Alterations (CNAs). METHODS: In this work we set to determine the existence of such links between CRC progression and genetic instability and searched for associations with patient outcome. To this aim we analyzed a set of 162 Chromosomal Instable (CIN) CRCs comprising 131 primary carcinomas evenly distributed through stage 1 to 4, 31 metastases and 14 adenomas by array-CGH. CNA profiles were established according to disease stage and compared. We, also, asked whether the level of genomic instability was correlated to disease outcome in stage 2 and 3 CRCs. Two metrics of chromosomal instability were used; (i) Global Genomic Index (GGI), corresponding to the fraction of the genome involved in CNA, (ii) number of breakpoints (nbBP). RESULTS: Stage 1, 2, 3 and 4 tumors did not differ significantly at the level of their CNA profiles precluding the conventional definition of a progression scheme based on increasing levels of genetic instability. Combining GGI and nbBP,we classified genomic profiles into 5 groups presenting distinct patterns of chromosomal instability and defined two risk classes of tumors, showing strong differences in outcome and hazard risk (RFS: p = 0.012, HR = 3; OS: p < 0.001, HR = 9.7). While tumors of the high risk group were characterized by frequent fractional CNAs, low risk tumors presented predominantly whole chromosomal arm CNAs. Searching for CNAs correlating with negative outcome we found that losses at 16p13.3 and 19q13.3 observed in 10% (7/72) of stage 2-3 tumors showed strong association with early relapse (p < 0.001) and death (p < 0.007, p < 0.016). Both events showed frequent co-occurrence (p < 1x10-8) and could, therefore, mark for stage 2-3 CRC susceptible to negative outcome. CONCLUSIONS: Our data show that CRC disease progression from stage 1 to stage 4 is not paralleled by increased levels of genetic instability. However, they suggest that stage 2-3 CRC with elevated genetic instability and particularly profiles with fractional CNA represent a subset of aggressive tumors.
Published: 2014

40. Assessing the role of multiple pregnancies in the association between tetralogy of Fallot and assisted reproductive techniques: a path-analysis approach

Author: François Goffinet, Lucile Houyel, Karim Tararbit, Nathalie Lelong, Damien Bonnet, Babak Khoshnood, Recherche Epidémiologique en Santé Périnatale et Santé des Femmes et des Enfants ( UMR_S 953 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris-Sud - Paris 11 ( UP11 ), Chirurgie des cardiopathies congénitales, Centre chirurgical Marie Lannelongue, Centre de Référence des cardiopathies congénitales ( M3C ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Maternité Port-Royal [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], This work was supported by grants from the Agence de Biomédecine (Saint-Denis La Plaine, France) (to B.K.). The Paris Registry of Congenital Malformations received financial support from INSERM (Paris, France) and the Institut de Veille Sanitaire (Saint-Maurice, France). The EPICARD study was supported by three grants from the Ministry of Health (PHRC 2004, 2008 and 2011). Additional funding for the EPICARD study was provided by the AREMCAR Association (Association pour la Recherche et l ' Etude des Maladies Cardiovasculaires), On behalf of the EPICARD study group, Recherche Epidémiologique en Santé Périnatale et Santé des Femmes et des Enfants (UMR_S 953), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris-Sud - Paris 11 (UP11), Centre de Référence des cardiopathies congénitales (M3C), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Université Paris-Sud - Paris 11 (UP11)-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 Chirurgical Marie Lannelongue (CCML), and BMC, Ed.
Subjects: Adult, medicine.medical_specialty, Assi sted, Reproductive Techniques, Assisted, Reproductive techniques, Epidemiology, medicine.medical_treatment, Population, [SDV.GEN] Life Sciences [q-bio]/Genetics, Intracytoplasmic sperm injection, Cohort Studies, Young Adult, Congenital, Pregnancy, Internal medicine, Medicine, Humans, Genetics(clinical), Pharmacology (medical), education, Genetics (clinical), Tetralogy of Fallot, Medicine(all), education.field_of_study, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Obstetrics, Research, Multiple pregnancies, Case-control study, General Medicine, medicine.disease, Endocrinology, Assisted, Case-Control Studies, Population study, Heart defects, Female, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Cohort study
Abstract: International audience; BACKGROUND: Assisted reproductive techniques (ART) are associated with a higher risk of tetralogy of Fallot (TOF) and multiple pregnancies may be associated with a higher risk of congenital anomalies. We assessed the extent to which the association between ART and risk of TOF may be mediated by the higher risk of multiple pregnancies associated with ART. METHODS: We conducted a case-control study using population-based data from the Paris Registry of Congenital Malformations for the period 1987-2009 and a cohort study of congenital heart defects (EPICARD). The study population included 395 cases of TOF and 4104 malformed controls with no known associations with ART. The analysis was based on a path-analysis model using a counterfactual approach, which allows decomposition of the total effect of ART into an indirect effect (that mediated by the association between ART and multiple pregnancies) and a direct effect. RESULTS: ART (all methods combined) were associated with a 2.6-fold higher odds of TOF after adjustment for maternal and paternal characteristics and year of birth (adjusted OR 2.6, 95%CI, 1.5-4.5). Most (79%) of the effect associated with ART was a direct effect (i.e., not mediated by multiple pregnancies), whereas 21% of the effect of ART was due to its association with multiple pregnancies (i.e., the indirect effect). In vitro fertilization with intracytoplasmic sperm injection was associated with a 3.5-fold higher odds of TOF (adjusted OR 3.5, 95%CI, 1.1-11.2); 11% of this effect was mediated through the association of ICSI with multiple pregnancies. CONCLUSIONS: By far, most of the higher risk of TOF associated with ART is a direct effect and only a small proportion of the effect may be mediated by multiple pregnancies.
Published: 2014

41. Idiopathic eosinophilic pneumonia in children: the French experience

Author: Jacques de Blic, Virginie Feret, François Bremont, Nadia Nathan, Jean Christophe Dubus, Thierry Leblanc, M. Albertini, Véronique Houdouin, Lisa Giovannini-Chami, Michèle Berlioz-Baudoin, Karine Morelle, Michael Fayon, Annick Clement, Alice Hadchouel, Service de Pneumologie Allergologie pédiatriques, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpitaux pédiatriques de Nice CHU-Lenval, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Service de Pneumologie Allergologie [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 Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pneumologie [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Pédiatrie - Pneumologie, Allergologie, Hôpital des Enfants, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service de pneumologie pédiatrique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-CHU Marseille, CHU Bordeaux [Bordeaux], CIC - Bordeaux, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service d'hématologie et immunologie pédiatrique, the French Respirare® Group, CHU Nice-Hôpitaux pédiatriques de Nice CHU-Lenval, Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de pneumologie, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -CHU Marseille, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), BMC, Ed., Université Nice Sophia Antipolis (1965 - 2019) (UNS), Service Pneumologie et allergologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Trousseau [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Pediatrics, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Idiopathic acute eosinophilic pneumonia, Eosinophilic lung disease, Interstitial lung disease, [SDV.GEN] Life Sciences [q-bio]/Genetics, Disease, medicine, Extracorporeal membrane oxygenation, Eosinophilic pneumonia, Humans, Genetics(clinical), Pharmacology (medical), Idiopathic chronic eosinophilic pneumonia, Pulmonary Eosinophilia, Child, Idiopathic interstitial pneumonia, Genetics (clinical), Retrospective Studies, Medicine(all), [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Research, Retrospective cohort study, General Medicine, medicine.disease, 3. Good health, Child, Preschool, Immunology, Female, France, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, business, Tomography, X-Ray Computed, Bronchoalveolar Lavage Fluid, Rare disease
Abstract: International audience; BACKGROUND: Idiopathic eosinophilic pneumonia is extremely rare in children and adults. We present herein the first series describing the specificities of idiopathic chronic (ICEP) and acute (IAEP) eosinophilic pneumonia in children. METHODS: We retrospectively analyzed all cases of ICEP and IAEP in children that were retrieved from French Reference Centers for rare pediatric lung diseases. RESULTS: Five cases of pediatric ICEP were identified. Corticosteroid or immunosuppressive therapy dramatically improved the outcome in three cases. The remaining two cases had a persistent interstitial pattern with progressive development of cystic airspace lesions. Three cases of IAEP in adolescents were reported, with one requiring four days of extracorporeal membrane oxygenation. CONCLUSION: ICEP is a rare disease with a polymorphic clinical presentation in children. We identified patients with persistent interstitial patterns progressing to cystic airspace regions, for which the boundaries with idiopathic interstitial pneumonias are difficult to establish. We therefore propose a specific pediatric definition and classification algorithm. IAEP in children remains an inflammatory reaction of the lung to an acute toxic exposure, mainly tobacco, as in adults. International studies are required to comprehensively assess the various clinical forms of the disease as well as the appropriate therapeutic regimens.
Published: 2014

42. The 23rd Annual Meeting of the European Tissue Repair Society (ETRS) in Reims, France

Author: Sabine A. Eming, Magnus S. Ågren, Johannes W. Von den Hoff, Bernard Coulomb, Jean-Jacques Lataillade, Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center [Nijmegen], Department of Clinical Medicine [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Bispebjerg Hospital, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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), Department of Dermatology, University of Cologne, Thérapie cellulaire des brûlures graves, Hôpital d'instruction des Armées Percy, Service de Santé des Armées-Service de Santé des Armées-Hôpital Militaire Percy, We are also grateful to all other sponsors of this meeting: Awel, Bose, Corning, Genbiotech, Gueule Cassées, Laboratoires Urgo, Miltenyl Biotec, PeproTech, PromoCell, and Smith & Nephew, Department of Clinical Medicine, Bispebjerg Hospital - University of Copenhagen (KU), Paris-Centre de Recherche Cardiovasculaire (PARCC - U970), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Hôpital Européen Georges Pompidou [APHP] (HEGP), Service de Santé des Armées - Service de Santé des Armées - Hôpital Militaire Percy, BMC, Ed., Bispebjerg Hospital-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: medicine.medical_specialty, Medicine (miscellaneous), Wound healing, Dermatology, Stem cells, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Meeting Report, Regenerative medicine, Biomaterials, Rheumatology, Tissue engineering, Medicine, Tissue repair, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Hepatology, business.industry, General surgery, Gastroenterology, 3. Good health, Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10], Stem cell, business, Infection, Burns
Abstract: Contains fulltext : 136940.pdf (Publisher’s version ) (Open Access) The 23rd Annual Meeting of the European Tissue Repair Society, Reims, France, October 23 to 25, 2013 focused on tissue repair and regenerative medicine covering topics such as stem cells, biomaterials, tissue engineering, and burns.
Published: 2014

43. Quality comparison of electronic versus paper death certificates in France, 2010

Author: Delphine Lefeuvre, Gérard Pavillon, Eric Jougla, Albertine Aouba, A. Fouillet, Grégoire Rey, Agathe Lamarche-Vadel, Centre d'épidémiologie sur les causes médicales de décès (CépiDc), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie, Institut de Veille Sanitaire (INVS), This work was supported by the National Institute of Health and Medical Research (Inserm), and BMC, Ed.
Subjects: Epidemiology, Research methodology, media_common.quotation_subject, Underlying cause of death, Electronic certification, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Medicine, Quality (business), 030212 general & internal medicine, Poisson regression, Causes of death, media_common, 030505 public health, business.industry, Research, Public Health, Environmental and Occupational Health, Quality, Death certificate, 3. Good health, Coding system, Death certification, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, symbols, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 0305 other medical science, business, Demography
Abstract: Background Electronic death certification was established in France in 2007. A methodology based on intrinsic characteristics of death certificates was designed to compare the quality of electronic versus paper death certificates. Methods All death certificates from the 2010 French mortality database were included. Three specific quality indicators were considered: (i) amount of information, measured by the number of causes of death coded on the death certificate; (ii) intrinsic consistency, explored by application of the International Classification of Disease (ICD) General Principle, using an international automatic coding system (Iris); (iii) imprecision, measured by proportion of death certificates where the selected underlying cause of death was imprecise. Multivariate models were considered: a truncated Poisson model for indicator (i) and binomial models for indicators (ii) and (iii). Adjustment variables were age, gender, and cause, place, and region of death. Results 533,977death certificates were analyzed. After adjustment, electronic death certificates contained 19% [17%-20%] more codes than paper death certificates for people deceased under 65 years, and 12% [11%-13%] more codes for people deceased over 65 years. Regarding deceased under and over 65 respectively, the ICD General Principle could be applied 2% [0%-4%] and 6% [5%-7%] more to electronic than to paper death certificates. The proportion of imprecise death certificates was 51% [46%-56%] lower for electronic than for paper death certificates. Conclusion The method proposed to evaluate the quality of death certificates is easily reproducible in countries using an automatic coding system. According to our criteria, electronic death certificates are better completed than paper death certificates. The transition to electronic death certificates is positive in many aspects and should be promoted.
Published: 2014

44. The effect of patient characteristics on second primary cancer risk in France

Author: Jérémie Jégu, Michel Velten, Anne-Sophie Woronoff, Olivier Ganry, Laetitia Daubisse-Marliac, Brigitte Trétarre, Véronique Bouvier, Simona Bara, Anne-Valérie Guizard, Marc Colonna, Xavier Troussard, Progression tumorale et microenvironnement. Approches translationnelles et épidémiologie, Institut Régional du Cancer-Université de Strasbourg (UNISTRA)-CHU Strasbourg-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC), FRANCIM, Réseau des registres français du cancer, Les Hôpitaux Universitaires de Strasbourg (HUS), Registre des cancers du Bas-Rhin, Registre des cancers de l’Isère [CHU de Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU)-Université Grenoble Alpes (UGA), Institut Claudius Regaud, Registre des Tumeurs de l'Hérault, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Registre général des cancers de la Somme, CHU Amiens-Picardie, Cancers et préventions, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Public du Cotentin (CHPC), Registre des hémopathies malignes de Basse-Normandie [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), This work was supported by the Institut de Recherche en Santé Publique (IReSP) as part of the French Cancer Plan 2009-2013 and was carried out within the context of a four-institute research-program partnership that involved the Institut National du Cancer (INCa), the Institut de Veille Sanitaire (InVS), the French Network of Cancer Registries (FRANCIM) and the Hospices Civils de Lyon., Université de Strasbourg (UNISTRA)-CHU Strasbourg-Les Hôpitaux Universitaires de Strasbourg (HUS)-Institut Régional du Cancer-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC), Service de Santé Publique, Francim : Réseau français des registres des cancers, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Registre des cancers de l'Isère, CHU Grenoble, Registre des cancers du Tarn, Association humanitaire (entraide, action sociale) - Albi, CRLCC Institut Claudius Regaud, Registre des tumeurs de l'Hérault, CRISAP-LR, COLRIM, EPC du CRLC-Centres privés de radiothérapie de l'Hérault-Laboratoires d'Hématologie CPAM - MSA - Caisse militaire, Registre des cancers de la Somme, Registre des cancers de la Manche, Centre Hospitalier Public du Cotentin, Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Service d'Epidémiologie et de Biostatistique, Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC), Université de Strasbourg ( UNISTRA ) -CHU Strasbourg-Les Hôpitaux Universitaires de Strasbourg (HUS)-Institut Régional du Cancer-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Registre des hémopathies malignes de Basse-Normandie, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), BMC, Ed., CH Centre Hospitalier Public du Cotentin (CHPC), and Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO)
Subjects: Adult, Male, Cancer Research, Pediatrics, medicine.medical_specialty, Multivariate statistics, animal structures, Multivariate analysis, Alcohol Drinking, MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, Second primary, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Cohort Studies, [SDV.CAN] Life Sciences [q-bio]/Cancer, Risk Factors, Surgical oncology, Neoplasms, Genetics, medicine, Humans, Registries, Aged, Risk assessment, business.industry, Incidence (epidemiology), Smoking, fungi, Cancer, Neoplasms, Second Primary, Middle Aged, medicine.disease, 3. Good health, Surgery, Oncology, Population Surveillance, Female, France, business, Follow-Up Studies, Research Article, Cohort study
Abstract: International audience; BACKGROUND: Although cancer survivors are known to be at greater risk of developing second primary cancer (SPC), SPC incidence estimates in France are thus far lacking. We used a multivariate approach to compute these estimates and analyzed the effect of patient characteristics (gender, age at diagnosis, first cancer site, year of diagnosis and follow-up) on SPC risk. METHODS: Data from ten French population-based cancer registries were used to establish a cohort of all patients diagnosed with a first cancer between 1989 and 2004 and followed up until December 31, 2007. The person-year approach was used to estimate standardized incidence ratios (SIRs) and excess absolute risks (EARs) of metachronous SPC. Multivariate Poisson regression models were then used to model SIRs and EARs separately by gender, adjusting for age, year of diagnosis, follow-up and first cancer site. RESULTS: Among the 289,967 followed-up patients with a first primary cancer, 21,226 developed a SPC. The SIR was of 1.36 (95% CI, 1.35-1.38) and the EAR was of 39.4 excess cancers per 10,000 person-years (95% CI, 37.4-41.3). Among male and female patients, multivariate analyses showed that age, year of diagnosis, follow-up and first cancer site were often independently associated with SIRs and EARs. Moreover, the EAR of SPC remained elevated during patient follow-up. CONCLUSIONS: French cancer survivors face a dramatically increased risk of SPC which is probably related to the high rate of tobacco and alcohol consumption in France. Multivariate modeling of SPC risk will facilitate the construction of a tailored prediction tool to optimize SPC prevention and early detection strategies.
Published: 2014

45. Socioeconomic environment and cancer incidence: a French population-based study in Normandy

Author: Olivier Dejardin, Véronique Bouvier, Guy Launoy, Anne-Valérie Guizard, X. Troussard, Marc Colonna, Simona Bara, Ludivine Launay, Françoise Galateau-Sallé, Joséphine Bryère, Carole Pornet, Lydia Guittet, Cancers et préventions, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération des registres de cancers de Basse-Normandie, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Registre des Tumeurs Digestives [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Registre des cancers de l’Isère [CHU de Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU)-Université Grenoble Alpes (UGA), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Registre des cancers de la Manche [CHPC - Site Louis Pasteur], Site Louis Pasteur [CHPC], CH Centre Hospitalier Public du Cotentin (CHPC)-CH Centre Hospitalier Public du Cotentin (CHPC), We thank INSERM (Institut National de la Sante et de la Recherche Medicale) and the Basse - Normandie regional government that have supported this work., BMC, Ed., UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, and UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)
Subjects: Adult, Male, Cancer Research, medicine.medical_specialty, Pediatrics, Adolescent, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Social Environment, Vulnerable Populations, Young Adult, Population attributable fraction, [SDV.CAN] Life Sciences [q-bio]/Cancer, Risk Factors, Neoplasms, Epidemiology, Genetics, medicine, Humans, Socioeconomic inequalities, Registries, Child, 10. No inequality, education, Aged, education.field_of_study, business.industry, Incidence, Incidence (epidemiology), Infant, Newborn, Infant, Social environment, Cancer, Middle Aged, medicine.disease, 3. Good health, Social deprivation, Socioeconomic Factors, Oncology, Child, Preschool, Population Surveillance, Attributable risk, Population study, Female, France, business, Cancer incidence, Research Article, Demography
Abstract: International audience; BACKGROUND: The struggle against social inequalities is a priority for many international organizations. The objective of the study was to quantify the cancer burden related to social deprivation by identifying the cancer sites linked to socioeconomic status and measuring the proportion of cases associated with social deprivation. METHODS: The study population comprised 68 967 cases of cancer diagnosed between 1997 and 2009 in Normandy and collected by the local registries. The social environment was assessed at an aggregated level using the European Deprivation Index (EDI). The association between incidence and socioeconomic status was assessed by a Bayesian Poisson model and the excess of cases was calculated with the Population Attributable Fraction (PAF). RESULTS: For lung, lips-mouth-pharynx and unknown primary sites, a higher incidence in deprived was observed for both sexes. The same trend was observed in males for bladder, liver, esophagus, larynx, central nervous system and gall-bladder and in females for cervix uteri. The largest part of the incidence associated with deprivation was found for cancer of gall-bladder (30.1%), lips-mouth-pharynx (26.0%), larynx (23.2%) and esophagus (19.6%) in males and for unknown primary sites (18.0%) and lips-mouth-pharynx (12.7%) in females. For prostate cancer and melanoma in males, the sites where incidence increased with affluence, the part associated with affluence was respectively 9.6% and 14.0%. CONCLUSIONS: Beyond identifying cancer sites the most associated with social deprivation, this kind of study points to health care policies that could be undertaken to reduce social inequalities.
Published: 2014

46. Opposite effects of angiotensins receptors type 2 and type 4 on streptozotocin induced diabetes vascular alterations in mice

Author: Nicolas Clere, Nicole Oudart, Sébastien Faure, L. Botelle, Jean-Michel Achard, James Javellaud, Mohamad Nasser, Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), A grant form the Conseil de Région Limousin has supported this work, Département de physiologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), and BMC, Ed.
Subjects: Male, medicine.medical_specialty, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Vasodilation, Angiotensin II Type 2 Receptor Blockers, AT2 receptor, Receptor, Angiotensin, Type 2, Diabetes Mellitus, Experimental, Mice, Organ Culture Techniques, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Diabetes mellitus, medicine, Animals, Endothelial dysfunction, Receptor, Mesenteric arteries, Original Investigation, Mice, Knockout, Receptors, Angiotensin, business.industry, AT4 receptor, Angiotensin II, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, medicine.disease, Receptor antagonist, Streptozotocin, Streptoz otocin-induced diabetes, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Angiotensin IV, Treatment Outcome, medicine.anatomical_structure, Endocrinology, Streptozotocin-induced diabetes, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract: International audience; BACKGROUND: We examined the effect of chronic administration of angiotensin IV (AngIV) on the vascular alterations induced by type 1 diabetes in mice. METHODS: Diabetes was induced in adult Swiss mice with a single injection of streptozotocin (STZ). Mice were treated subcutaneously with AngIV (1.4 mg/kg/day) either immediately following diabetes induction (preventive treatment), or treated with AngIV (0.01 to 1.4 mg/kg), alone or with the AT4 receptor antagonist Divalinal or the AT2 receptor antagonist PD123319, for two weeks after 4 weeks of diabetes duration (rescue treatment). Acetylcholine-induced, endothelium-dependent relaxation (EDR) was measured in isolated aortic rings preparations. Histomorphometric measurements of the media thickness were obtained, and nitric oxide (NO) and superoxide anion production were measured by electron paramagnetic resonance in aorta and mesenteric arteries. The effect of diabetes on mesenteric vascular alterations was also examined in genetically modified mice lacking the AT2 receptor. RESULTS: Induction of diabetes with STZ was associated with a progressive decrease of EDR and an increase of the aortic and mesenteric media thickness already significant after 4 weeks and peaking at week 6. Immediate treatment with AngIV fully prevented the diabetes-induced endothelial dysfunction. Rescue treatment with AngIV implemented after 4 weeks of diabetes dose-dependently restored a normal endothelial function at week 6. AngIV blunted the thickening of the aortic and mesenteric media, and reversed the diabetes-induced changes in NO and O2[bullet] - production by the vessels. The protective effect of AngIV on endothelial function was completely blunted by cotreatment with Divalinal, but not with PD123319. In contrast, both the pharmacological blockade and genetic deletion of the AT2 receptor reversed the diabetes-induced morphologic and endothelial alteration caused by diabetes. CONCLUSIONS: The results suggest an opposite contribution of AT2 and AT4 receptors to the vascular alterations caused by streptozotocin-induced diabetes in mice, since chronic stimulation of AT4 by AngIV and inhibition of AT2 similarly reverse diabetes-induced endothelial dysfunction and hypertrophic remodeling, and increase NO bioavailability.
Published: 2014

47. Noninvasive ventilation reduces energy expenditure in amyotrophic lateral sclerosis

Author: Thomas Similowski, Marjolaine Georges, Capucine Morélot-Panzini, Jésus Gonzalez-Bermejo, Service de Pneumologie Soins Intensifs, Appareillage Respiratoire [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neurophysiologie Respiratoire Expérimentale et Clinique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie et Réanimation Respiratoire, Service de Pneumologie et Réanimation Médicale [CHU Pitié-Salpêtrière] (Département ' R3S '), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), BMC, Ed., and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Diaphragm, Inspiratory neck muscles, Diaphragmatic breathing, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Internal medicine, Humans, Medicine, Resting energy expenditure, Amyotrophic lateral sclerosis, Intensive care medicine, Aged, 2. Zero hunger, business.industry, Middle Aged, medicine.disease, Neck muscles, Diaphragm (structural system), Energy expenditure, Cardiology, Breathing, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Female, Noninvasive ventilation, Energy Metabolism, business, Research Article
Abstract: International audience; BackgroundAmyotrophic lateral sclerosis (ALS) leads to chronic respiratory failure. Diaphragmatic dysfunction, a major driver of dyspnea and mortality, is associated with a shift of the burden of ventilation to extradiaphragmatic inspiratory muscles, including neck muscles. Besides, energy expenditure is often abnormally high in ALS, and this is associated with a negative prognostic value. We hypothesized that noninvasive ventilation (NIV) would relieve inspiratory neck muscles and reduce resting energy expenditure (REE).MethodsUsing indirect calorimetry, we measured REE during spontaneous breathing (REESB) and NIV (REENIV) in 16 ALS patients with diaphragmatic dysfunction, during the first 3 months of NIV. Measured values were compared with predicted REE (REEpred)(Harris-Benedict equation).ResultsNIV abolished inspiratory neck muscle activity. Even though our patients were not hypermetabolic, on the contrary, with a REESB that was lower than REEpred (average 11%), NIV did reduce energy expenditure. Indeed, median REENIV, in this population with a mean body mass index of 21.4 kg.m-2, was 1149 kcal/24 h [interquartile 970-1309], lower than REESB (1197 kcal/24 h, 1054-1402; mean difference 7%; p = 0.03, Wilcoxon). REESB and REENIV were correlated with forced vital capacity and maximal inspiratory pressure.ConclusionsNIV can reduce energy expenditure in ALS patients probably by alleviating the ventilatory burden imposed on inspiratory neck muscles to compensate diaphragm weakness. It remains to be elucidated whether or not, in which population, and to what extent, NIV can be beneficial in ALS through the corresponding reduction in energy expenditure.
Published: 2014

48. Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial

Author: Magali Michaud, Marcel Culcasi, Sylvia Pietri, Yves Donazzolo, Sophie Le Lamer, Jean Afxantidis, Hidayat Rahmouni, Stéphanie Paradis, Didier Morin, Corinne Chaimbault, Patrick Berna, Mathilde Latreille, Rebacca M Pruss, Sophie Schaller, Jean-Louis Abitbol, Alain Berdeaux, Trophos, Luminy Biotech Entreprises, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Optimed Lyon, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), This work was supported in part by the French Agence Nationale de la Recherche [Grant ANR-07-RIB-IRI stop]. S.Pa. was supported by a doctoral grant from the Ministère de la Recherche et de la Technologie, and H.R. by a doctoral Grant from the Agence Universitaire de la Francophonie (AUF)., and BMC, Ed.
Subjects: Male, Sus scrofa, Placebo-controlled study, Myocardial Infarction, Phases of clinical research, Myocardial Reperfusion Injury, Acute myocardial infarction, Phase I clinical tria, Pharmacology, In Vitro Techniques, General Biochemistry, Genetics and Molecular Biology, Translational Research, Biomedical, Pharmacokinetics, Oximes, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, Secosteroids, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Myocardial infarction, Adverse effect, Medicine(all), Mitochondrial permeability transition pore, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Dose-Response Relationship, Drug, Biochemistry, Genetics and Molecular Biology(all), business.industry, Research, Functional recovery, General Medicine, medicine.disease, Healthy Volunteers, 3. Good health, Rats, Disease Models, Animal, Oxidative Stress, Tolerability, Anesthesia, Liposomes, Phase I clinical trial, Myocardial infarction complications, Female, business, Reperfusion injury, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; BACKGROUND: Although reperfusion injury has been shown to be responsible for cardiomyocytes death after an acute myocardial infarction, there is currently no drug on the market that reduces this type of injury. TRO40303 is a new cardioprotective compound that was shown to inhibit the opening of the mitochondrial permeability transition pore and reduce infarct size after ischemia-reperfusion in a rat model of cardiac ischemia-reperfusion injury. METHODS: In the rat model, the therapeutic window and the dose effect relationship were investigated in order to select the proper dose and design for clinical investigations. To evaluate post-ischemic functional recovery, TRO40303 was tested in a model of isolated rat heart. Additionally, TRO40303 was investigated in a Phase I randomized, double-blind, placebo controlled study to assess the safety, tolerability and pharmacokinetics of single intravenous ascending doses of the compound (0.5 to 13 mg/kg) in 72 healthy male, post-menopausal and hysterectomized female subjects at flow rates from 0.04 to 35 mL/min (EudraCT number: 2010-021453-39). This work was supported in part by the French Agence Nationale de la Recherche. RESULTS: In the vivo model, TRO40303 reduced infarct size by 40% at 1 mg/kg and by 50% at 3 and 10 mg/kg given by intravenous bolus and was only active when administered before reperfusion. Additionally, TRO40303 provided functional recovery and reduced oxidative stress in the isolated rat heart model.These results, together with pharmacokinetic based allometry to human and non-clinical toxicology data, were used to design the Phase I trial. All the tested doses and flow rates were well tolerated clinically. There were no serious adverse events reported. No relevant changes in vital signs, electrocardiogram parameters, laboratory tests or physical examinations were observed at any time in any dose group. Pharmacokinetics was linear up to 6 mg/kg and slightly ~1.5-fold, hyper-proportional from 6 to 13 mg/kg. CONCLUSIONS: These data demonstrated that TRO40303 can be safely administered by the intravenous route in humans at doses expected to be pharmacologically active. These results allowed evaluating the expected active dose in human at 6 mg/kg, used in a Phase II proof-of-concept study currently ongoing.
Published: 2014

49. Exploring necrotizing autoimmune myopathies with a novel immunoassay for anti-3-hydroxy-3-methyl-glutaryl-CoA reductase autoantibodies

Author: Drouot , Laurent, Allenbach , Yves, Jouen , Fabienne, Charuel , Jean-Luc, Martinet , Jérémie, Meyer , Alain, Hinschberger , Olivier, Bader-Meunier , Brigitte, Kone-Paut , Isabelle, Campana-Salort , Emmanuelle, Eymard , Bruno, Tournadre , Anne, Musset , Lucile, Sibilia , Jean, Marie , Isabelle, Benveniste , Olivier, Boyer , Olivier, Renseigné , Non, Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Thérapie des maladies du muscle strié, 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 ), Laboratoire d'immunologie et biothérapies [Rouen], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Service d'Immunochimie et Autoimmunité [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Service Physiologie, Les Hôpitaux Universitaires de Strasbourg (HUS)-Nouvel Hôpital Civil, Service Médecine Interne, Centre Hospitalier Emile Muller [Mulhouse] ( CH E.Muller Mulhouse ), Groupe Hospitalier de Territoire Haute Alsace ( GHTHA ) -Groupe Hospitalier de Territoire Haute Alsace ( GHTHA ), Service Immunologie et Hématologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Developpement Normal et Pathologique du Système Immunitaire, 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 Pédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Hôpital de la Timone [CHU - APHM] ( TIMONE ), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service Rhumatologie, CHU Clermont-Ferrand, Service de Médecine Interne [Rouen], This work supported in part by a grant from the Association Française contre les Myopathies, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA)-Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Hôpital de la Timone [CHU - APHM] (TIMONE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Médecine Interne [CHU Rouen], Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), Unité fonctionnelle d’Auto-immunité et Immunochimie [CHU Pitié-Salpêtrière], Service d'Immunologie [CHU Pitié-Salpétrière], 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), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), and BMC, Ed.
Subjects: Male, Pathology, Clinical Biochemistry, Aucun, Fluorescent Antibody Technique, Reductase, Autoantigens, Immunoglobulin G, immunology, chemistry.chemical_compound, Immunology and Allergy, Multiplex, Myositis, Immunoassay, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, biology, medicine.diagnostic_test, Chemistry, General Medicine, Middle Aged, 3. Good health, Acyl coenzyme A, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Biochemistry, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Female, lipids (amino acids, peptides, and proteins), blood, diagnosis, Antibody, Oxidoreductases, Research Article, Adult, medicine.medical_specialty, Immunology, Blotting, Western, Immunofluorescence, Sensitivity and Specificity, methods, Autoimmune Diseases, Glutaryl-CoA, [ SDV.MHEP.RSOA ] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Necrosis, Rheumatology, Muscular Diseases, Internal medicine, medicine, Humans, Immunoprecipitation, Autoantibodies, business.industry, Autoantibody, medicine.disease, biology.protein, Hydroxymethylglutaryl CoA Reductases, Acyl Coenzyme A, business
Abstract: INTRODUCTION: Necrotizing autoimmune myopathies (NAM) have recently been defined as a distinct group of severe acquired myopathies, characterized by prominent myofiber necrosis without significant muscle inflammation. Because of the lack of appropriate biomarkers, these diseases have been long misdiagnosed as atypical forms of myositis. NAM may be associated to autoantibodies directed against signal recognition particle (SRP) or 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR). The objective of this work was to quantify anti-HMGCR autoantibodies in patients with suspicion of NAM through the development of a new addressable laser bead immunoassay (ALBIA). METHODS: Recombinant HMGCR C-domain was bound to fluorescent beads. After incubation with serum, autoantibodies were revealed using class- or subclass-specific anti-human immunoglobulin G (IgG) antibodies. Anti-HMGCR levels were assayed in 150 patients with suspicion of NAM, 142 controls with different inflammatory/autoimmune diseases and 100 healthy donors. Inhibition with free recombinant HMGCR and immunoprecipitation experiments confirmed test specificity. Reproducibility and repeatability were determined from sera with various levels of anti-HMGCR autoantibodies. A multiplex assay (ALBIA-NAM) was also developed to permit the simultaneous quantification of anti-HMGCR and anti-signal recognition particle autoantibodies. RESULTS: No controls scored positive. Of 150 patients with suspicion of NAM, 24% were positive for anti-HMGCR autoantibodies with levels ranging from 24 to 2,656 AU/mL. Anti-HMGCR positivity could be associated to a cytoplasmic pattern in immunofluorescence assay on HEp-2 cells. Anti-HMGCR-positive patients had high creatine kinase (CK) levels (mean 6,630 IU/L) and only 40% of them had been exposed to statins. Multiplex ALBIA-NAM was equally as effective as monoplex anti-HMGCR and anti-SRP ALBIA. CONCLUSIONS: Both monoplex ALBIA-HMGCR and multiplex ALBIA-NAM reliably detect and quantify anti-HMGCR autoantibodies. A positive result allows ascribing patients with a necrotizing myopathy to an autoimmune form. Anti-HMGCR autoantibodies may be found in patients who have not taken statins. journal article research support, non-u.s. gov't 2014 Feb 03 2014 02 03 imported
Published: 2014

50. Estimating time-to-onset of adverse drug reactions from spontaneous reporting databases

Author: Françoise Haramburu, Hélène Théophile, Pascale Tubert-Bitter, Jean-Yves Dauxois, Fanny Leroy, Centre de recherche en épidémiologie et santé des populations (CESP), 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), Institut de Mathématiques de Toulouse UMR5219 (IMT), Université Toulouse Capitole (UT Capitole), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Service de Pharmacologie, CHU Bordeaux [Bordeaux], Pharmacoepidemiologie et évaluation de l'impact des produits de santé sur les populations, Université Bordeaux Segalen - Bordeaux 2-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the Fondation ARC (fellowship DOC20121206119 to Fanny Leroy)., BMC, Ed., 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), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), 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), and Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Simulation study, Exponential distribution, Mean squared error, Databases, Factual, Drug-Related Side Effects and Adverse Reactions, Lymphoma, Epidemiology, Health Informatics, computer.software_genre, Pharmacovigilance, Bias, Statistics, Medicine, Adverse Drug Reaction Reporting Systems, Humans, Right truncation, Computer Simulation, Reporting databases, Truncation (statistics), Weibull distribution, Likelihood Functions, Risk Management, Models, Statistical, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Database, business.industry, Tumor Necrosis Factor-alpha, Estimator, medicine.disease, Maximum likelihood estimation, 3. Good health, Parametric estimation, Sample size determination, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, computer, Adverse drug reaction, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract: International audience; BACKGROUND: Analyzing time-to-onset of adverse drug reactions from treatment exposure contributes to meeting pharmacovigilance objectives, i.e. identification and prevention. Post-marketing data are available from reporting systems. Times-to-onset from such databases are right-truncated because some patients who were exposed to the drug and who will eventually develop the adverse drug reaction may do it after the time of analysis and thus are not included in the data. Acknowledgment of the developments adapted to right-truncated data is not widespread and these methods have never been used in pharmacovigilance. We assess the use of appropriate methods as well as the consequences of not taking right truncation into account (naïve approach) on parametric maximum likelihood estimation of time-to-onset distribution. METHODS: Both approaches, naïve or taking right truncation into account, were compared with a simulation study. We used twelve scenarios for the exponential distribution and twenty-four for the Weibull and log-logistic distributions. These scenarios are defined by a set of parameters: the parameters of the time-to-onset distribution, the probability of this distribution falling within an observable values interval and the sample size. An application to reported lymphoma after anti TNF-¿ treatment from the French pharmacovigilance is presented. RESULTS: The simulation study shows that the bias and the mean squared error might in some instances be unacceptably large when right truncation is not considered while the truncation-based estimator shows always better and often satisfactory performances and the gap may be large. For the real dataset, the estimated expected time-to-onset leads to a minimum difference of 58 weeks between both approaches, which is not negligible. This difference is obtained for the Weibull model, under which the estimated probability of this distribution falling within an observable values interval is not far from 1. CONCLUSIONS: It is necessary to take right truncation into account for estimating time-to-onset of adverse drug reactions from spontaneous reporting databases.
Published: 2014

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