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5 results on '"Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré"'

1. Evolutionarily conserved susceptibility of the mitochondrial respiratory chain to SDHI pesticides and its consequence on the impact of SDHIs on human cultured cells

Author

Pierre Rustin, Agathe Kahn, Judith Favier, Paule Bénit, Pierre Gressens, D Chretien, Sylvie Bortoli, Anne Paule Gimenez-Roqueplo, Laurence Huc, Malgorzata Rak, Manuel Schiff, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Contaminants & Stress Cellulaire (ToxAlim-COMICS), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Service de neurologie pédiatrique et maladies métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [CHU HEGP], 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), No specific funding was initially provided for this work. After the work realization, PB and PR received a specific support grant from the French Association POLLINIS (https://www.pollinis.org/). General expenses were covered by grants from AAJI (Association pour l’Aide aux Jeunes Infirmes & aux Personnes Handicapées), AFAF (Association Française de l’Ataxie de Friedreich), Association OLY (Ouvrir Les Yeux), ANR MITOXDRUGS (ANR-16-CE18-0010)., ANR-16-CE18-0010,MITOXDRUGS,Toxicité mitochondriale des médicaments et stéatose hépatique. Généralisation de la relation causale pour le développement de nouveaux tests prédictifs.(2016), 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) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Rustin, Pierre, Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Bodescot, Myriam, and Toxicité mitochondriale des médicaments et stéatose hépatique. Généralisation de la relation causale pour le développement de nouveaux tests prédictifs. - - MITOXDRUGS2016 - ANR-16-CE18-0010 - AAPG2016 - VALID

Subjects
0301 basic medicine, Glutamine, Respiratory chain, Mitochondrion, Toxicology, Biochemistry, Antioxidants, Database and Informatics Methods, 0302 clinical medicine, Animal Cells, Medicine and Health Sciences, Glycolysis, Annelids, Amino Acids, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Energy-Producing Organelles, Cells, Cultured, Connective Tissue Cells, Multidisciplinary, biology, Organic Compounds, Succinate dehydrogenase, Monosaccharides, Acidic Amino Acids, Quinones, Eukaryota, Neurodegenerative Diseases, Bees, Mitochondria, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Insects, Succinate Dehydrogenase, Chemistry, Mitochondrial respiratory chain, [SDV.TOX.TVM] Life Sciences [q-bio]/Toxicology/Vegetal toxicology and mycotoxicology, Connective Tissue, Physical Sciences, Mitochondrial Membranes, Medicine, Cellular Structures and Organelles, Cellular Types, Anatomy, Honey Bees, Sequence Analysis, Research Article, Arthropoda, Bioinformatics, Science, Carbohydrates, Médecine humaine et pathologie, [SDV.TOX.TVM]Life Sciences [q-bio]/Toxicology/Vegetal toxicology and mycotoxicology, Oxidative phosphorylation, Bioenergetics, Research and Analysis Methods, Electron Transport, Fungal Proteins, 03 medical and health sciences, Drug Resistance, Fungal, Animals, Earthworms, Humans, Oligochaeta, Pesticides, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Toxicologie, Organic Chemistry, Chemical Compounds, Organisms, Fungi, Biology and Life Sciences, Proteins, Cell Biology, Fibroblasts, Invertebrates, Hymenoptera, Biological Tissue, Glucose, 030104 developmental biology, Cell culture, biology.protein, Human health and pathology, Sequence Alignment, 030217 neurology & neurosurgery
Abstract

International audience; Succinate dehydrogenase (SDH) inhibitors (SDHIs) are used worldwide to limit the proliferation of molds on plants and plant products. However, as SDH, also known as respiratory chain (RC) complex II, is a universal component of mitochondria from living organisms, highly conserved through evolution, the specificity of these inhibitors toward fungi warrants investigation. We first establish that the human, honeybee, earthworm and fungal SDHs are all sensitive to the eight SDHIs tested, albeit with varying IC50 values, generally in the micromolar range. In addition to SDH, we observed that five of the SDHIs, mostly from the latest generation, inhibit the activity of RC complex III. Finally, we show that the provision of glucose ad libitum in the cell culture medium, while simultaneously providing sufficient ATP and reducing power for antioxidant enzymes through glycolysis, allows the growth of RC-deficient cells, fully masking the deleterious effect of SDHIs. As a result, when glutamine is the major carbon source, the presence of SDHIs leads to time-dependent cell death. This process is significantly accelerated in fibroblasts derived from patients with neurological or neurodegenerative diseases due to RC impairment (encephalopathy originating from a partial SDH defect) and/or hypersensitivity to oxidative insults (Friedreich ataxia, familial Alzheimer's disease).

Published
2019
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2. ARID5B, IKZF1 and non-genetic factors in the etiology of childhood acute lymphoblastic leukemia: the ESCALE study

Author

Rudant, Jérémie, Orsi, Laurent, Bonaventure, Audrey, Goujon-Bellec, Stéphanie, Baruchel, André, Petit, Arnaud, Bertrand, Yves, Nelken, Brigitte, Pasquet, Marlène, Michel, Gérard, Saumet, Laure, Chastagner, Pascal, Ducassou, Stéphane, Réguerre, Yves, Hémon, Denis, Clavel, Jacqueline, 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), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), 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), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Institut d’Hémato-Oncologie Pédiatrique, Université Lille Nord de France (COMUE), Pôle Enfant, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Aix Marseille Université (AMU), Service d'hématologie et oncologie pédiatrique, Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital Pellegrin Tripode, Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Registre National des Hémopathies malignes de l'Enfant (RNHE), Institut de Veille Sanitaire (INVS) - Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche épidémiologies et biostatistique Sorbonne Paris Cité (CRESS), Université Paris Descartes - Paris 5 (UPD5) - Conservatoire National des Arts et Métiers [CNAM] - Université Paris Diderot - Paris 7 (UP7) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Institut National de la Recherche Agronomique (INRA) - Université Paris 13, AP-HP Hôpital universitaire Robert-Debré [Paris], Université Paris Diderot - Paris 7 (UP7), 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), Institut d'Hématologie et d'Oncologie Pédiatrique de Lyon, PRES Université Lille Nord de France, Hématologie pédiatrique U1037 CHU Toulouse, Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU) - Assistance Publique - Hôpitaux de Marseille (APHM) - Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital Arnaud de Villeneuve, Centre hospitalier de Nancy (CHU Nancy), CHU Nancy, CHU de Bordeaux Pellegrin [Bordeaux], CHU Félix Guyon, 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), Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Robert Debré - Université Paris Diderot - Paris 7 (UPD7), Université Lille Nord de France, Hématologie pédiatrique, CHU Toulouse [Toulouse], Hôpital d'Enfants, CHU de Nancy, Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), and HAL AMU, Administrateur

Subjects
Male, Adolescent, Genotype, Science, CHILDREN, [SDV.CAN]Life Sciences [q-bio]/Cancer, VARIANTS, Polymorphism, Single Nucleotide, White People, Ikaros Transcription Factor, [SDV.CAN] Life Sciences [q-bio]/Cancer, PESTICIDES, Risk Factors, Humans, GENERAL-PRACTITIONER RECORDS, Genetic Predisposition to Disease, EXPOSURE, Child, Alleles, RISK, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Infant, Newborn, Infant, Precursor Cell Lymphoblastic Leukemia-Lymphoma, HEMATOPOIETIC MALIGNANCIES, CANCER, EPIGENETICS, DNA-Binding Proteins, INFECTIONS, Case-Control Studies, Child, Preschool, Medicine, Female, Research Article, Genome-Wide Association Study, Transcription Factors
Abstract

International audience; Genome-wide association studies (GWAS) have identified that frequent polymorphisms in ARID5B and IKZF1, two genes involved in lymphoid differentiation, increase the risk of childhood acute lymphoblastic leukemia (ALL). These findings markedly modified the current field of research on the etiology of ALL. In this new context, the present exploratory study investigated the possible interactions between these at-risk alleles and the non-genetic suspected ALL risk factors that were of sufficient prevalence in the French ESCALE study: maternal use of home insecticides during pregnancy, preconception paternal smoking, and some proxies for early immune modulation, i.e. breastfeeding, history of common infections before age one year, and birth order. The analyses were based on 434 ALL cases and 442 controls of European origin, drawn from the nationwide population-based case-control study ESCALE. Information on non-genetic factors was obtained by standardized telephone interview. Interactions between rs10740055 in ARID5B or rs4132601 in IKZF1 and each of the suspected non-genetic factors were tested, with the SNPs coded as counts of minor alleles (trend variable). Statistical interactions were observed between rs4132601 and maternal insecticide use (p = 0.012), breastfeeding p = 0.017) and repeated early common infections (p = 0.0070), with allelic odds ratios (OR) which were only increased among the children not exposed to insecticides (OR = 1.8, 95% CI: 1.3, 2.4), those who had been breastfed (OR = 1.8, 95% CI: 1.3, 2.5) and those who had had repeated early common infections (OR = 2.4, 95% CI: 1.5, 3.8). The allelic ORs were close to one among children exposed to insecticides, who had not been breastfed and who had had no or few common infections. Repeated early common infections interacted with rs10740055 (p = 0.018) in the case-only design. Further studies are needed to evaluate whether these observations of a modification of the effect of the at-risk alleles by non-genetic factors are chance findings or reflect true underlying mechanisms.

Published
2015
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3. Haploinsufficiency of Dmxl2, encoding a synaptic protein, causes infertility associated with a loss of GnRH neurons in mouse

Author

Juliane Leger, Didier Chevenne, Sandrine Jacquier, Vincent Meyer, Sofia Leka, Lukas Huijbregts, Nicolas de Roux, Joëlle Dupont, P. Charles, Emmanuelle Génin, Jean-Claude Carel, Brooke Tata, Zsolt Csaba, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), 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), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Service de génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de biochimie [CHU Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Service d'endocrinologie diabétologie pédiatrique [CHU Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut national de la santé et de la recherche médicale, La société Française d’Endocrinologie, La Fondation Maladies rares, Le département hospitalo-universitaire ‘‘promoting research toward early CNS therapies’’, Domaine d’intérêt majeur ‘‘Cerveau et Pensée’’, 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, Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), HAL UPMC, Gestionnaire, and Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Pituitary gland, Physiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Haploinsufficiency, Gonadotropin-releasing hormone, souris, Biochemistry, Gonadotropin-Releasing Hormone, Mice, chemistry.chemical_compound, Follicle-stimulating hormone, Endocrinology, Testis, Medicine and Health Sciences, Sexual Maturation, Biology (General), Sequence Deletion, Mice, Knockout, Neurons, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, General Neuroscience, Homozygote, Neurochemistry, Syndrome, infertilité, phénotype, medicine.anatomical_structure, Hypothalamus, Pituitary Gland, Synopsis, adn génomique, Neurokinin B, medicine.symptom, General Agricultural and Biological Sciences, Luteinizing hormone, Autre (Sciences du Vivant), Research Article, Delayed puberty, medicine.medical_specialty, Adolescent, QH301-705.5, Molecular Sequence Data, Nerve Tissue Proteins, Biology, General Biochemistry, Genetics and Molecular Biology, Young Adult, Polyneuropathies, neurone à gnrh, Hypothyroidism, Internal medicine, Intellectual Disability, medicine, Animals, Humans, Infertility, Male, Adaptor Proteins, Signal Transducing, Endocrine Physiology, Base Sequence, General Immunology and Microbiology, Puberty, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biology and Life Sciences, Neuroendocrinology, Luteinizing Hormone, Hypoglycemia, Diabetes Mellitus, Type 1, chemistry, hypophyse, génotypage, Follicle Stimulating Hormone, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Rabconnectin-3α and the control of puberty Human genetics shows that low levels of rabconnectin-3α cause a loss of the neurons that produce gonadotropin-releasing hormone, revealing a new mechanism for incomplete puberty and infertility., Characterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3α, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3α was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH) axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3α controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a complex neurological phenotype, with abnormal glucose metabolism and gonadotropic axis deficiency due to a loss of GnRH neurons. Our findings identify rabconectin-3α as a key controller of neuronal and endocrine homeostatic processes., Author Summary Investigation of neurodevelopmental disorders with abnormal puberty can reveal neuronal processes that control the initiation of puberty and subsequent reproductive function. We describe here a new syndrome observed in three brothers with incomplete puberty, central hypothyroidism, peripheral polyneuropathy, mental retardation, and abnormal glucose regulation. Molecular genetic investigation in this consanguineous family revealed an in-frame deletion of 15 nucleotides in the DMXL2 gene, which resulted in lower levels of its expression. We found that rabconnectin-3α, the synaptic protein encoded by DMXL2, is widely expressed in the brain and in the ends of the axons of neurons that produce gonadotropin-releasing hormone (GnRH). We then observed that neuron-specific deletion of one allele of Dmxl2 in mice reproduces the incomplete puberty seen in the human patients and results in decreased numbers of GnRH neurons in the hypothalamus. We also showed that rabconnectin-3α controls glucose-induced insulin secretion. These findings reveal a new mechanism of gonadotropin deficiency and identify rabconnectin-3α as a key controller of neuronal and endocrine homeostasis.

Published
2014
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4. Peer Review of Grant Applications: Criteria Used and Qualitative Study of Reviewer Practices

Author

Florence Tubach, Serge Gottot, Corinne Alberti, Christophe Perrey, Philippe Amiel, Isabelle Durand-Zaleski, Hendy Abdoul, Unité d'Epidémiologie Clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Unité de recherche en sciences humaines et sociales (URSHS), Institut Gustave Roussy (IGR), Modèles et méthodes de l'évaluation thérapeutique des maladies chroniques (U738 / UMR_S738), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Service de Santé Publique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, and PHRC 08 074

Subjects
Institutional Funding of Science, Research design, Non-Clinical Medicine, Economics, Economics of Training and Education, lcsh:Medicine, Social and Behavioral Sciences, 0302 clinical medicine, Science Policy and Economics, Relevance (law), Medicine, MESH: Data Collection, 030212 general & internal medicine, lcsh:Science, MESH: Qualitative Research, Qualitative Research, Reliability (statistics), media_common, Human Capital, [SHS.SOCIO]Humanities and Social Sciences/Sociology, Multidisciplinary, Data Collection, Financing, Organized, Qualitative Studies, Research Assessment, Intellectual Property, MESH: Research, Research Reporting Guidelines, France, Research Article, Typology, Clinical Research Design, Science Policy, media_common.quotation_subject, MEDLINE, Academic Medicine, Research Funding, MESH: Financing, Organized, 03 medical and health sciences, Consistency (negotiation), Originality, Humans, Government Funding of Science, Medical education, MESH: Humans, Research Monitoring, business.industry, Research, lcsh:R, MESH: France, lcsh:Q, MESH: Intellectual Property, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, 030217 neurology & neurosurgery, Qualitative research
Abstract

International audience; BACKGROUND: Peer review of grant applications has been criticized as lacking reliability. Studies showing poor agreement among reviewers supported this possibility but usually focused on reviewers' scores and failed to investigate reasons for disagreement. Here, our goal was to determine how reviewers rate applications, by investigating reviewer practices and grant assessment criteria. METHODS AND FINDINGS: We first collected and analyzed a convenience sample of French and international calls for proposals and assessment guidelines, from which we created an overall typology of assessment criteria comprising nine domains relevance to the call for proposals, usefulness, originality, innovativeness, methodology, feasibility, funding, ethical aspects, and writing of the grant application. We then performed a qualitative study of reviewer practices, particularly regarding the use of assessment criteria, among reviewers of the French Academic Hospital Research Grant Agencies (Programmes Hospitaliers de Recherche Clinique, PHRCs). Semi-structured interviews and observation sessions were conducted. Both the time spent assessing each grant application and the assessment methods varied across reviewers. The assessment criteria recommended by the PHRCs were listed by all reviewers as frequently evaluated and useful. However, use of the PHRC criteria was subjective and varied across reviewers. Some reviewers gave the same weight to each assessment criterion, whereas others considered originality to be the most important criterion (12/34), followed by methodology (10/34) and feasibility (4/34). Conceivably, this variability might adversely affect the reliability of the review process, and studies evaluating this hypothesis would be of interest. CONCLUSIONS: Variability across reviewers may result in mistrust among grant applicants about the review process. Consequently, ensuring transparency is of the utmost importance. Consistency in the review process could also be improved by providing common definitions for each assessment criterion and uniform requirements for grant application submissions. Further research is needed to assess the feasibility and acceptability of these measures.

Published
2012
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5. MRI Findings in 77 Children with Non-Syndromic Autistic Disorder

Author

Catherine Barthélémy, Marie Bourgeois, Anne Philipe, Nadia Bahi-Buisson, Laurence Laurier, Isabelle Desguerre, Marie-Christine Mouren, D. Seidenwurm, M. Zilbovicius, Laurence Robel, Francis Brunelle, Isabelle Meresse, Nathalie Boddaert, Yves Samson, Nadia Chabane, Arnold Munnich, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR de Neuroimagerie Fonctionnelle (IFR 49), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Neuroimagerie en psychiatrie (U1000), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neuropédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de radiologie pédiatrique [CHU Necker], Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), 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 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), 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 psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], 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)-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), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), IFR de Neuroimagerie Fonctionnelle ( IFR 49 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Neuroimagerie en psychiatrie ( U1000 ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Université de Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière ( NEMESIS-CRICM ), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), 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 ) -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 ), 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 ), and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 )

Subjects
Male, medicine.medical_specialty, Pediatrics, Neurology, Neurological Disorders/Developmental and Pediatric Neurology, Science, Fluid-attenuated inversion recovery, Brain mapping, 030218 nuclear medicine & medical imaging, Temporal lobe, 03 medical and health sciences, 0302 clinical medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, medicine, Humans, Clinical significance, Autistic Disorder, Child, Psychiatry, Demography, Brain Mapping, Pediatrics and Child Health/Child and Adolescent Psychiatry, Multidisciplinary, [ INFO.INFO-IM ] Computer Science [cs]/Medical Imaging, medicine.diagnostic_test, business.industry, Radiology and Medical Imaging/Magnetic Resonance Imaging, Magnetic resonance imaging, Syndrome, medicine.disease, Magnetic Resonance Imaging, Neurological Disorders/Neuroimaging, Temporal Lobe, 3. Good health, Autism spectrum disorder, Medicine, Autism, Female, business, 030217 neurology & neurosurgery, Research Article
Abstract

BackgroundThe clinical relevance of MR scanning in children with autism is still an open question and must be considered in light of the evolution of this technology. MRI was judged to be of insufficient value to be included in the standard clinical evaluation of autism according to the guidelines of the American Academy of Neurology and Child Neurology Society in 2000. However, this statement was based on results obtained from small samples of patients and, more importantly, included mostly insufficient MRI sequences. Our main objective was to evaluate the prevalence of brain abnormalities in a large group of children with a non-syndromic autistic disorder (AD) using T1, T2 and FLAIR MRI sequences.MethodologyMRI inspection of 77 children and adolescents with non-syndromic AD (mean age 7.4+/-3.6) was performed. All met the DSM-IV and ADI -R criteria for autism. Based on recommended clinical and biological screenings, we excluded patients with infectious, metabolic or genetic diseases, seizures or any other neurological symptoms. Identical MRI inspections of 77 children (mean age 7.0+/-4.2) without AD, developmental or neurological disorders were also performed. All MRIs were acquired with a 1.5-T Signa GE (3-D T1-FSPGR, T2, FLAIR coronal and axial sequences). Two neuroradiologists independently inspected cortical and sub-cortical regions. MRIs were reported to be normal, abnormal or uninterpretable.Principal findingsMRIs were judged as uninterpretable in 10% (8/77) of the cases. In 48% of the children (33/69 patients), abnormalities were reported. Three predominant abnormalities were observed, including white matter signal abnormalities (19/69), major dilated Virchow-Robin spaces (12/69) and temporal lobe abnormalities (20/69). In all, 52% of the MRIs were interpreted as normal (36/69 patients).ConclusionsAn unexpectedly high rate of MRI abnormalities was found in the first large series of clinical MRI investigations in non-syndromic autism. These results could contribute to further etiopathogenetic research into autism.

Published
2009
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