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1. Influence of storage and buffer composition on the mechanical behavior of flowing red blood cells

Author: Adlan Merlo, Sylvain Losserand, François Yaya, Philippe Connes, Magalie Faivre, Sylvie Lorthois, Christophe Minetti, Elie Nader, Thomas Podgorski, Céline Renoux, Gwennou Coupier, Emilie Franceschini, Biomécanique et Bioingénierie (BMBI), Université de Technologie de Compiègne (UTC)-Centre National de la Recherche Scientifique (CNRS), Institut de mécanique des fluides de Toulouse (IMFT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT), Laboratoire Interdisciplinaire de Physique [Saint Martin d’Hères] (LIPhy ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), 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]), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut des Nanotechnologies de Lyon (INL), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Aero-Thermo-Mechanics Department, Université libre de Bruxelles (ULB), Laboratoire Rhéologie et Procédés (LRP), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), Hospices Civils de Lyon (HCL), Laboratoire de Mécanique et d'Acoustique [Marseille] (LMA ), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), GDR Mécabio, CNRS, and European Project: 615102,EC:FP7:ERC,ERC-2013-CoG,BRAINMICROFLOW(2014)
Subjects: Biophysics, [PHYS.MECA.MEFL]Physics [physics]/Mechanics [physics]/Fluid mechanics [physics.class-ph], [PHYS.MECA.BIOM]Physics [physics]/Mechanics [physics]/Biomechanics [physics.med-ph]
Abstract: International audience; On-chip study of blood flow has emerged as a powerful tool to assess the contribution of each component of blood to its overall function. Blood has indeed many functions, from gas and nutrient transport to immune response and thermal regulation. Red blood cells play a central role therein, in particular through their specific mechanical properties, that directly influence pressure regulation, oxygen perfusion, or platelet and white cells segregation towards endothelial walls. As the bloom of in-vitro studies has led to the apparition of various storage and sample preparation protocols, we address the question of the robustness of the results involving cell mechanical behavior against this diversity. The effects of three conservation media (EDTA, citrate and glucose-albumin-sodium-phosphate) and storage time on the red blood cell mechanical behavior are assessed under different flow conditions: cell deformability by ektacytometry, shape recovery of cells flowing out of a microfluidic constriction, and cell flipping dynamics under shear flow. The impact of buffer solutions (phosphate-buffered saline and density-matched suspension using iodixanol/Optiprep) are also studied by investigating individual cell flipping dynamics, relative viscosity of cell suspensions and cell structuration under Poiseuille flow. Our results reveal that storing blood samples up to seven days after withdrawal and suspending them in adequate density-matched buffer solutions has in most experiments a moderate effect on the overall mechanical response, with a possible rapid evolution in the first three days after sample collection. SIGNIFICANCE Blood is in intimate contact with all organs in the body, supplying oxygen, nutrients and drugs while removing waste. It carries cells involved in immune response, wound repair and tumor dissemination. Blood is easily collected, revealing the presence of disease through biomarker analysis. It is storable and transfusable. Thus, blood is the subject of many in-vitro studies for research and medical purposes. Guidelines associated to sample preparation or storage conditions have been established, but these may affect its mechanical behavior. In this collaborative study, we provide new guidelines to minimize the impact of specific experimental requirements (e.g. density matching, blood freshness) by focusing on the single or collective motion of red blood cells in a large range of flow conditions.
Published: 2023
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2. HIV-1-Associated Kidney Disease in an Elite Controller

Author: Caroline Charre, Sandrine Lemoine, Vinca Icard, Rabeyrin Maud, Jean-Claude Tardy, Pierre Chiarello, Matthieu Godinot, Véronique Avettand-Fenoel, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Laboratoire de Virologie [HCL, Lyon] (Institut des Agents Infectieux), Hospices civils de Lyon (HCL)-HCL Groupement Hospitalier Nord [Lyon]-Centre National de Reference des virus des Infections Respiratoires France Sud [HCL, Lyon], Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), Hôpital de la Croix-Rousse [CHU - HCL], and CarMeN, laboratoire
Subjects: [SDV.BA] Life Sciences [q-bio]/Animal biology, [SDV.BA]Life Sciences [q-bio]/Animal biology, Public Health, Environmental and Occupational Health, HIV Infections, Kidney Diseases/complications, CD4 Lymphocyte Count, HIV Seropositivity, Infectious Diseases, hiv-1, HIV Infections/complications, HIV-1, Humans, Kidney Diseases, Elite Controllers
Abstract: No abstract available
Published: 2022
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3. Dopaminergic and serotonergic changes in rabbit fetal brain upon repeated gestational exposure to diesel engine exhaust

Author: Karine Badonnel, Pascaline Bouillaud, Jacques Callebert, Henri Schroeder, Christine Baly, Benoit Olivier, Estefania Bernal-Meléndez, Pascale Chavatte-Palmer, Marie-Annick Persuy, Neurobiologie de l'olfaction (NBO), Institut National de la Recherche Agronomique (INRA), Composés Alimentaires : Biofonctionnalités et risques Neurotoxiques (CALBINOTOX), Université de Lorraine (UL), Service de biochimie et biologie moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR139, Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), and ANR-13-CESA-0011,EPPAP,Effets de la Pollution Atmosphérique sur la fonction Placentaire et le développement Post-natal(2013)
Subjects: Male, 0301 basic medicine, Serotonin, Diesel exhaust, medicine.medical_specialty, Time Factors, Dopamine, Gestational exposure, Health, Toxicology and Mutagenesis, Hippocampus, 010501 environmental sciences, Biology, Toxicology, Serotonergic, Synaptic Transmission, 01 natural sciences, Norepinephrine, 03 medical and health sciences, Sex Factors, Pregnancy, Internal medicine, Monoaminergic, medicine, Animals, Vehicle Emissions, 0105 earth and related environmental sciences, Temporal cortex, Tyrosine hydroxylase, [SCCO.NEUR]Cognitive science/Neuroscience, [SDV.BA]Life Sciences [q-bio]/Animal biology, Dopaminergic, Neurotoxicity, Brain, Airborne pollution, General Medicine, Monoaminergic neuromodulation, Tryptophan hydroxylase, medicine.disease, 3. Good health, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, 030104 developmental biology, Endocrinology, Maternal Exposure, Prenatal Exposure Delayed Effects, Female, Rabbits, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: International audience; Limited studies in humans and in animal models have investigated the neurotoxic risks related to a gestational exposure to diesel exhaust particles (DEP) on the embryonic brain, especially those regarding monoaminergic systems linked to neurocognitive disorders. We previously showed that exposure to DEP alters monoaminergic neurotransmission in fetal olfactory bulbs and modifies tissue morphology along with behavioral consequences at birth in a rabbit model. Given the anatomical and functional connections between olfactory and central brain structures, we further characterized their impacts in brain regions associated with monoaminergic neurotransmission. At gestational day 28 (GD28), fetal rabbit brains were collected from dams exposed by nose-only to either a clean air or filtered DEP for 2 h/day, 5 days/week, from GD3 to GD27. HPLC dosage and histochemical analyses of the main monoaminergic systems, i.e., dopamine (DA), noradrenaline (NA), and serotonin (5-HT) and their metabolites were conducted in microdissected fetal brain regions. DEP exposure increased the level of DA and decreased the dopaminergic metabolites ratios in the prefrontal cortex (PFC), together with sex-specific alterations in the hippocampus (Hp). In addition, HVA level was increased in the temporal cortex (TCx). Serotonin and 5-HIAA levels were decreased in the fetal Hp. However, DEP exposure did not significantly modify NA levels, tyrosine hydroxylase, tryptophan hydroxylase or AChE enzymatic activity in fetal brain. Exposure to DEP during fetal life results in dopaminergic and serotonergic changes in critical brain regions that might lead to detrimental potential short-term neural disturbances as precursors of long-term neurocognitive consequences.
Published: 2021
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4. Effect of Recombinant Gonadotropin on Testicular Function and Testicular Sperm Extraction in Five Cases of NR0B1 (DAX1) Pathogenic Variants

Author: Jordan Teoli, Vincent Mezzarobba, Lucie Renault, Delphine Mallet, Hervé Lejeune, Pierre Chatelain, Frédérique Tixier, Marc Nicolino, Noël Peretti, Sandrine Giscard D’estaing, Béatrice Cuzin, Frédérique Dijoud, Florence Roucher-Boulez, Ingrid Plotton, Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), Hospices Civils de Lyon (HCL), Institut cellule souche et cerveau / Stem Cell and Brain Research Institute (U1208 Inserm - UCBL1 / SBRI - USC 1361 INRAE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Fédération d’Endocrinologie, Maladies Métaboliques, Diabète et Nutrition [Bron] (FEMMDN/Hôpital Louis Pradel ), Hospices Civils de Lyon (HCL)-Groupement Hospitalier Est [Bron], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Université de Lyon, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Lyonnais d'Urologie Bellecour [Lyon] (CLUB), and CarMeN, laboratoire
Subjects: [SDV] Life Sciences [q-bio], endocrine system, testicular biopsy, hypogonadotrophic hypogonadism, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, congenital, gonadotropin, adrenal hypoplasia, adrenal insufficiency, male infertility, spermatogenesis
Abstract: BackgroundNR0B1 pathogenic variants can cause congenital adrenal hypoplasia or primary adrenal insufficiency in early childhood usually associated with hypogonadotropic hypogonadism. NR0B1 is necessary for organogenesis of the adrenal cortex and to maintain normal spermatogenesis. In humans, restoration of fertility in patients carrying NR0B1 pathogenic variants is challenging.ObjectiveThe aim of the study was to investigate the clinical, hormonal, histological, spermiological, and molecular genetic characteristics of a cohort of patients with NR0B1 pathogenic variants, monitored for fertility preservation.PatientsWe included five patients, including four teenagers, with NR0B1 pathogenic or likely pathogenic variants. They all had primary adrenal insufficiency and were receiving replacement therapy with glucocorticoids and mineralocorticoids. Patients received recombinant follicle-stimulating hormone and recombinant human chorionic gonadotropin in order to induce spermatogenesis. Combined gonadotropin treatment was initiated between 13 years and 15 years and 6 months for the four teenagers and at 31 years and 2 months for the only adult. Physical and hormonal assessments were performed just before starting gonadotropin treatment. After 12 months of gonadotropin treatment, physical examination and hormonal assessments were repeated, and semen analyses were performed. If no sperm cells were observed in at least 2 semen collections at 3-month interval, testicular biopsy for testicular sperm extraction was proposed.ResultsBilateral testicular volume increased from 8 ml (interquartile range, 6–9) to 12 ml (10–16) after gonadotropin treatment. Inhibin B levels were relatively stable: 110 ng/L (46–139) before and 91 ng/L (20–120) at the end of gonadotropin treatment. Azoospermia was observed in all semen analyses for all cases during gonadotropin treatment. Three patients agreed to testicular biopsy; no mature sperm cells could be retrieved in any.ConclusionWe characterized a cohort of patients with NR0B1 pathogenic or likely pathogenic variants for fertility preservation by recombinant gonadotropin treatment, which began either at puberty or in adulthood. No sperm cells could be retrieved in semen samples or testicular biopsy even after gonadotropin treatment, indicating that gonadotropin treatment, even when started at puberty, is ineffective for restoring fertility.
Published: 2022
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5. Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes

Author: Jérémie Gautheron, Lara Lima, Baris Akinci, Jamila Zammouri, Martine Auclair, Sema Kalkan Ucar, Samim Ozen, Canan Altay, Bridget E. Bax, Ivan Nemazanyy, Véronique Lenoir, Carina Prip-Buus, Cécile Acquaviva-Bourdain, Olivier Lascols, Bruno Fève, Corinne Vigouroux, Esther Noel, Isabelle Jéru, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), 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), Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), Ege university, St George's, University of London, Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), Hospices Civils de Lyon (HCL), Laboratoire commun de biologie et génétique moléculaires [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Strasbourg, and Prip-Buus, Carina
Subjects: TP, Adipose stem cell, Lipodystrophy, Insulins, Expression, ADRA2A, Gene-Mutations, CIDEC, AIRE, Mitochondrial Neurogastrointestinal Encephalomyopathy, CAVIN1, Adipocytes, Genetics, Humans, BANF1, Thymidine phosphorylase, Diabetes Mellitus, Lipoatrophic, AKT2, Tissue, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, DYRK1B, Diabetes, Mngie, Instability, Insulin resistance, General Medicine, Deoxyuridine, Cell Growth-Factor, AGPAT2, Mitochondria, CAV1, Dysfunction, Oxidative stress, Mutation, BSCL2, CRISPR-Cas9, BLM, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background Thymidine phosphorylase (TP), encoded by the TYMP gene, is a cytosolic enzyme essential for the nucleotide salvage pathway. TP catalyzes the phosphorylation of the deoxyribonucleosides, thymidine and 2 '-deoxyuridine, to thymine and uracil. Biallelic TYMP variants are responsible for Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE), an autosomal recessive disorder characterized in most patients by gastrointestinal and neurological symptoms, ultimately leading to death. Studies on the impact of TYMP variants in cellular systems with relevance to the organs affected in MNGIE are still scarce and the role of TP in adipose tissue remains unexplored. Methods Deep phenotyping was performed in three patients from two families carrying homozygous TYMP variants and presenting with lipoatrophic diabetes. The impact of the loss of TP expression was evaluated using a CRISPR-Cas9-mediated TP knockout (KO) strategy in human adipose stem cells (ASC), which can be differentiated into adipocytes in vitro. Protein expression profiles and cellular characteristics were investigated in this KO model. Results All patients had TYMP loss-of-function variants and first presented with generalized loss of adipose tissue and insulin-resistant diabetes. CRISPR-Cas9-mediated TP KO in ASC abolished adipocyte differentiation and decreased insulin response, consistent with the patients' phenotype. This KO also induced major oxidative stress, altered mitochondrial functions, and promoted cellular senescence. This translational study identifies a new role of TP by demonstrating its key regulatory functions in adipose tissue. Conclusions The implication of TP variants in atypical forms of monogenic diabetes shows that genetic diagnosis of lipodystrophic syndromes should include TYMP analysis. The fact that TP is crucial for adipocyte differentiation and function through the control of mitochondrial homeostasis highlights the importance of mitochondria in adipose tissue biology., Mairie de Paris grant [R18139DD]; Societe Francophone du Diabete [R19114DD]; Fondation pour la Recherche Medicale [ARF20170938613, EQU202003010517]; Fondation pour la Recherche Medicale grant [EQU201903007868]; Agence nationale de la recherche grant [ANR-21-CE17-0002-01], Mairie de Paris grant R18139DD (JG) Societe Francophone du Diabete grant R19114DD (JG) Fondation pour la Recherche Medicale grants ARF20170938613 & EQU202003010517 (JG) Agence nationale de la recherche grant ANR-21-CE17-0002-01 (JG) Fondation pour la Recherche Medicale grant EQU201903007868 (IJ, CV, BF)
Published: 2022
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6. A New Approach to Objectively Evaluate Inherited Metabolic Diseases for Inclusion on Newborn Screening Programmes

Author: Alberto Burlina, Simon A. Jones, Anupam Chakrapani, Heather J. Church, Simon Heales, Teresa H. Y. Wu, Georgina Morton, Patricia Roberts, Erica F. Sluys, David Cheillan, Azienda Ospedale Università di Padova = Hospital-University of Padua (AOUP), Manchester University NHS Foundation Trust (MFT), St Mary's Hospital [London], Great Ormond Street Hospital for Children NHS Foundation Trust [London, UK] (GOSHC), University College London Hospitals NHS Foundation Trust [London, UK] (UCLH), ArchAngel MLD Trust [London, UK] (2A), Helvet Health [Nyon, Switzerland] (2H), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), Hospices Civils de Lyon (HCL), and CarMeN, laboratoire
Subjects: congenital disorders, inherited disorder, newborn screening (NBS), Wilson and Jungner, [SDV]Life Sciences [q-bio], public health, Obstetrics and Gynecology, inherited metabolic disease, paediatrics, rare diseases, genetics, methodology, [SDV] Life Sciences [q-bio], Immunology and Microbiology (miscellaneous), Pediatrics, Perinatology and Child Health
Abstract: International audience; Newborn screening (NBS) programmes are essential in the diagnosis of inherited metabolic diseases (IMDs) and for access to disease modifying treatment. Most European countries follow the World Health Organisation (WHO) criteria to determine which disorders are appropriate for screening at birth; however, these criteria are interpreted and implemented by individual countries differently, creating disparities. Advances in research and diagnostics, together with the promise of new treatments, offer new possibilities to accelerate the expansion of evidence-based screening programmes. A novel and robust algorithm was built to objectively assess and prioritise IMDs for inclusion in NBS programmes. The Wilson and Jungner classic screening principles were used as a foundation to develop individual and measurable criteria. The proposed algorithm is a point-based system structured upon three pillars: condition, screening, and treatment. The algorithm was tested by applying the six IMDs currently approved in the United Kingdom NBS programme. The algorithm generates a weight-based score that could be used as the first step in the complex process of evaluating disorders for inclusion on NBS programmes. By prioritising disorders to be further evaluated, individual countries are able to assess the economic, societal and political aspects of a potential screening programme.
Published: 2022
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7. Causes and consequences of impaired methionine synthase activity in acquired and inherited disorders of vitamin B 12 metabolism

Author: David Coelho, Jean-Louis Guéant, Viola J Kosgei, Rosa-Maria Guéant-Rodriguez, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Biochimie et Biologie Moléculaire, Nutrition et Métabolisme [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), The present work was financially supported by FHU ARRIMAGE and the French PIA GEENAGE project of Lorraine Université d’Excellence, reference: ANR-15-IDEX-04-LUE and the OMAGE project granted by Region Grand-Est of France and FEDER., IMPACT GEENAGE, and ANR-15-IDEX-0004,LUE,Isite LUE(2015)
Subjects: Homocysteine, [SDV]Life Sciences [q-bio], peroxisome proliferator-activated receptor-γ coactivator-1α, inborn errors of metabolism, Biochemistry, sirtuin 1, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Methionine synthase, vitamin B12 deficiency, cobalamin, Molecular Biology, 030304 developmental biology, Methionine synthase activity, 2. Zero hunger, 0303 health sciences, Methionine, biology, Chemistry, Methylation, (Methionine synthase) reductase, MMACHC, 3. Good health, fetal programming, biology.protein, Transmethylation, 030217 neurology & neurosurgery
Abstract: International audience; Methyl-Cobalamin (Cbl) derives from dietary vitamin B12 and acts as a cofactor of methionine synthase (MS) in mammals. MS encoded by MTR catalyzes the remethylation of homocysteine to generate methionine and tetrahydrofolate, which fuel methionine and cytoplasmic folate cycles, respectively. Methionine is the precursor of S-adenosyl methionine (SAM), the universal methyl donor of transmethylation reactions. Impaired MS activity results from inadequate dietary intake or malabsorption of B12 and inborn errors of Cbl metabolism (IECM). The mechanisms at the origin of the high variability of clinical presentation of impaired MS activity are classically considered as the consequence of the disruption of the folate cycle and related synthesis of purines and pyrimidines and the decreased synthesis of endogenous methionine and SAM. For one decade, data on cellular and animal models of B12 deficiency and IECM have highlighted other key pathomechanisms, including altered interactome of MS with methionine synthase reductase, MMACHC, and MMADHC, endoplasmic reticulum stress, altered cell signaling, and genomic/epigenomic dysregulations. Decreased MS activity increases catalytic protein phosphatase 2A (PP2A) and produces imbalanced phosphorylation/methylation of nucleocytoplasmic RNA binding proteins, including ELAVL1/HuR protein, with subsequent nuclear sequestration of mRNAs and dramatic alteration of gene expression, including SIRT1. Decreased SAM and SIRT1 activity induce ER stress through impaired SIRT1-deacetylation of HSF1 and hypomethylation/hyperacetylation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), which deactivate nuclear receptors and lead to impaired energy metabolism and neuroplasticity. The reversibility of these pathomechanisms by SIRT1 agonists opens promising perspectives in the treatment of IECM outcomes resistant to conventional supplementation therapies.
Published: 2021
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8. Postprandial triglyceride-rich lipoproteins from type 2 diabetic women activate platelets

Author: Calzada, Catherine, Boulet, M.M., Pettazzoni, Magali, Di Filippo, Mathilde, Moulin, Philippe, Cheillan, D., Michalski, Marie-Caroline, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), Hospices Civils de Lyon (HCL), Fédération d’Endocrinologie, Maladies Métaboliques, Diabète et Nutrition [Bron] (FEMMDN/Hôpital Louis Pradel ), Hospices Civils de Lyon (HCL)-Groupement Hospitalier Est [Bron], CNRS, Université de Bordeaux, and BOGUAIS, SANDRINE
Subjects: [SDV] Life Sciences [q-bio], gas chromatography, [SDV]Life Sciences [q-bio], digestive, oral, and skin physiology, palmitic acid, food and beverages, lipids (amino acids, peptides, and proteins)
Abstract: International audience; Increased concentrations of fasting and post-prandial (PP) triglycerides (TG), carried out in the circulation by triglyceride-rich lipoproteins (TGRL), are a risk factor for atherothrombosis in patients with type 2 diabetes (T2D). The objective of our clinical study was to determine the effects of fasting and PP TGRL from T2D patients on platelet activation while assessing the fatty acid (FA) and sphingolipid (SL) composition of TGRL. Thirty women with T2D were randomly assigned a breakfast containing 20 g lipids from a hazelnut-cocoa spread rich in palm oil (Palm Nut) versus butter. Both breakfasts were rich in palmitic acid, and the Palm Nut breakfast also contained 45% oleic acid. Blood samples were collected at fasting and 4h after the breakfast, and TGRL were isolated from the plasma by ultra-centrifugation at a density equivalent to that of chylomicrons (d
Published: 2021

9. Brain MRI features and scoring of leukodystrophy in adult-onset Krabbe disease

Author: Bruno Law-Ye, Nadya Pyatigorskaya, Fausto Viader, Roseline Froissart, Raili Raininko, Antonio Federico, Seung H. Kim, Louis Cousyn, Kiyotaka Nakamagoe, Monique Piraud, Cornelia Laule, Alfonso Cerase, Xavier Ayrignac, Robert Henderson, Simona Salvatore, Delphine Leclercq, Hiroshi Adachi, Yuwei Da, Karol Jastrzębski, Maria Carmo Macário, Sandra Sirrs, João Durães, Rabab Debs, Ludger Schols, Yann Nadjar, Bertrand Audoin, Roberta La Piana, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Biochimie et Biologie Moléculaire Grand Est Unité Médicale Pathologies Métaboliques, Erythrocytaires et Dépistage Périnatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, Laboratoire de Biologie Tissulaire et d'ingénierie Thérapeutique UMR 5305 (LBTI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Siena = University of Siena (UNISI), Neuroradiology Unit, Azienda Ospedaliera Universitaria Senese, Siena, Department of Neurology, Coimbra Hospital and University Centre, Department of Neurology, College of Medicine, Hanyang University, Seoul, Division of Neurology, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Department of Neurology, La Timone Hospital, Aix-Marseille University, Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Department of Neurology, University Hospital of Montpellier, Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, Department of Neurology, Royal Brisbane Hospital, Brisbane, Laboratory of Neurogenetics of Motion and Department of Neuroradiology, Montréal Neurological Institute and Hospital, McGill University, Montréal, University of British Columbia (UBC), International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, Department of Neurology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Uppsala University, Department of Neurology and Hertie-Institute for Clinical Brain Research, Eberhard-Karls-University, German Center of Neurodegenerative Diseases (DZNE), Tübingen, Department of Neurology, Caen-Normandie University Hospital, Caen, Inserm U1077, EPHE, Caen-Normandie University, Caen, and Department of Neurology and Stroke, Medical University of Lodz
Subjects: Male, 0301 basic medicine, Internal capsule, pathology [Pyramidal Tracts], Pyramidal Tracts, 030105 genetics & heredity, Corpus callosum, Corpus Callosum, methods [Magnetic Resonance Imaging], 0302 clinical medicine, Internal Capsule, pathology [White Matter], Age of Onset, Child, Brain, Middle Aged, Magnetic Resonance Imaging, White Matter, pathology [Corpus Callosum], pathology [Internal Capsule], Female, pathology [Leukodystrophy, Globoid Cell], Radiology, Adult, medicine.medical_specialty, Adolescent, diagnostic imaging [Leukodystrophy, Globoid Cell], Young Adult, 03 medical and health sciences, Corona radiata, medicine, Humans, ddc:610, diagnostic imaging [Brain], Aged, business.industry, Leukodystrophy, Precentral gyrus, medicine.disease, Hyperintensity, Leukodystrophy, Globoid Cell, Corticospinal tract, Krabbe disease, Neurology (clinical), pathology [Demyelinating Diseases], business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, Demyelinating Diseases
Abstract: ObjectiveTo perform a systematic analysis and scoring of brain MRI white matter hyperintensities (WMH) in adult-onset Krabbe disease.MethodsWe retrospectively collected basic clinical data and the first available brain MRI from patients with confirmed Krabbe disease with first clinical manifestations beyond 10 years of age. Data were obtained from our reference center for lysosomal diseases (n = 6) and from contacted authors of published articles describing patients with adult-onset Krabbe disease (n = 15). T2-weighted fluid-attenuated inversion recovery images of each patient were analyzed and scored using a radiologic score of WMH in a single center.ResultsThe corticospinal tract was always affected by WMH (100% of patients), however, with some distinctions along the tract: the precentral gyrus (100%), corona radiata (95%), and posterior internal capsule (81%) were highly abnormal, whereas the mesencephalon (57%), pons (52%), and medulla oblongata (5%) were less affected. WMH were also frequently present in the posterior lateral periventricular white matter (95%), optic radiations (86%), postcentral gyrus (71%), medial lemniscus (62%), and corpus callosum, especially in the isthmus (71%), whereas the genu was always normal. A few patients did not have the classical MRI pattern but extensive hyperintensities (n = 3), or patchy distribution of hyperintensities mimicking an acquired etiology (n = 2), or very subtle hyperintensities of the corticospinal tract (n = 1).ConclusionsWe specified the main locations of WMH, which were observed in the earliest stages of the disease and were also present in patients with atypical MRI pattern, highlighting the importance of radiologic features to guide the diagnosis.
Published: 2019
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10. Regulation of globin-heme balance in Diamond-Blackfan anemia by HSP70/GATA1

Author: Rio, Sarah, Gastou, Marc, Karboul, Narjesse, Derman, Raphaёl, Suriyun, Thunwarat, Manceau, Hana, Leblanc, Thierry, El Benna, Jamel, Schmitt, Caroline, Azouzi, Slim, Larghero, Jérôme, Karim, Zoubida, Macias-Garcia, Alejandra, Chen, Jane-Jane, Puy, Hervé, Gouya, Laurent, Mohandas, Narla, Da Costa, Lydie, Sibon, David, Coman, Tereza, Rossignol, Julien, Lamarque, Mathilde, Kosmider, Olivier, Bayard, Elisa, Fouquet, Guillemette, Rignault, Rachel, Topçu, Selin, Bonneau, Pierre, Bernex, Florence, Dussiot, Michaël, Deroy, Kathy, Laurent, Laetitia, Callebert, Jacques, Launay, Jean-Marie, Georgin-Lavialle, Sophie, COURTOIS, genevieve, Maroteaux, Luc, Vaillancourt, Cathy, Fontenay, Michaela, Hermine, Olivier, Côté, Francine, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de recherche translationnelle, Institut Curie [Paris], Jet Propulsion Laboratory (JPL), NASA-California Institute of Technology (CALTECH), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Français des Porphyries, Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Biotherapie - Saint Louis ((CIC-BT 301)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Génétique et Centre de Référence Maladies Rares Syndrome de Marfan et pathologies apparentées (AP HP, hôpital Bichat), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Red Cell Physiology Laboratory [New York, USA], New York Blood Center, AP-HP, Service d'Hématologie Biologique, Hôpital Robert-Debré, Service d'hématologie-oncologie adultes, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Field Neurosciences Laboratory for Restorative Neurology [Mount Pleasant, MI, USA] (Program in Neuroscience ), Central Michigan University (CMU), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie biologique, Hôpital Cochin [AP-HP], Université Sorbonne Paris Cité (USPC), Hôpital Claude Huriez [Lille], CHU Lille, Cytokines, hématopoïèse et réponse immune (CHRI), 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 de Mathématiques de Toulouse UMR5219 (IMT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Departement /u661 : Endocrinologie, Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Biochimie et Biologie Moleculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Service de biochimie et biologie moléculaire, IFR139-Hôpital Lariboisière-Fernand-Widal [APHP], Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut du Fer à Moulin, 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), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Université Paris Descartes - Paris 5 (UPD5)-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), Hôpital Robert Debré, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Hopital Saint-Louis [AP-HP] (AP-HP), Massachusetts Institute of Technology (MIT), COURTOIS, genevieve, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR139, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)
Subjects: Male, Ribosomal Proteins, Cellular differentiation, Immunology, Haploinsufficiency, Heme, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biochemistry, Small hairpin RNA, 03 medical and health sciences, chemistry.chemical_compound, Red Cells, Iron, and Erythropoiesis, 0302 clinical medicine, Erythroid Cells, hemic and lymphatic diseases, medicine, Humans, GATA1 Transcription Factor, HSP70 Heat-Shock Proteins, Globin, RNA, Small Interfering, Diamond–Blackfan anemia, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Anemia, Diamond-Blackfan, Cell Proliferation, 030304 developmental biology, 0303 health sciences, Chemistry, Cell growth, Infant, Newborn, Infant, Cell Differentiation, GATA1, Cell Biology, Hematology, Prognosis, medicine.disease, Phenotype, Globins, 3. Good health, Cell biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, Mutation, Female, Follow-Up Studies
Abstract: Diamond-Blackfan anemia (DBA) is a congenital erythroblastopenia that is characterized by a blockade in erythroid differentiation related to impaired ribosome biogenesis. DBA phenotype and genotype are highly heterogeneous. We have previously identified 2 in vitro erythroid cell growth phenotypes for primary CD34+ cells from DBA patients and following short hairpin RNA knockdown of RPS19, RPL5, and RPL11 expression in normal human CD34+ cells. The haploinsufficient RPS19 in vitro phenotype is less severe than that of 2 other ribosomal protein (RP) mutant genes. We further documented that proteasomal degradation of HSP70, the chaperone of GATA1, is a major contributor to the defect in erythroid proliferation, delayed erythroid differentiation, increased apoptosis, and decreased globin expression, which are all features of the RPL5 or RPL11 DBA phenotype. In the present study, we explored the hypothesis that an imbalance between globin and heme synthesis may be involved in pure red cell aplasia of DBA. We identified disequilibrium between the globin chain and the heme synthesis in erythroid cells of DBA patients. This imbalance led to accumulation of excess free heme and increased reactive oxygen species production that was more pronounced in cells of the RPL5 or RPL11 phenotype. Strikingly, rescue experiments with wild-type HSP70 restored GATA1 expression levels, increased globin synthesis thereby reducing free heme excess and resulting in decreased apoptosis of DBA erythroid cells. These results demonstrate the involvement of heme in DBA pathophysiology and a major role of HSP70 in the control of balanced heme/globin synthesis.
Published: 2019
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11. [Main biological tools applied to newborn screening: Landscape and future perspectives]

Author: Cheillan, D., Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), Hospices Civils de Lyon (HCL), and CarMeN, laboratoire
Subjects: [SDV] Life Sciences [q-bio], Neonatal Screening, Artificial Intelligence, [SDV]Life Sciences [q-bio], Infant, Newborn, Humans
Abstract: Over the past fifty years, neonatal screening has become essential in the public health programs of a large number of countries. During all these years, the number of detectable diseases has continued to grow, following the possibilities offered by technical advances in clinical biology. The Guthrie test has enabled the miniaturization of blood sampling, opening up the possibilities of biological screening in the newborn population. Fluorimetry, immunoassay and more recently tandem mass spectrometry have subsequently allowed to detect many treatable disorders. The new developments of next generation sequencing and artificial intelligence may open a new era despite many ethical questions that will arise. This review provides an overview of the biological techniques currently used for neonatal screening and opens up perspectives on the place of new technological developments.Les principaux outils biologiques appliqués au dépistage néonatal - État des lieux et perspectives d’avenir.Au cours des cinquante dernières années, le dépistage néonatal est devenu incontournable dans les programmes de santé publique de très nombreux pays. Durant toutes ces années, le nombre de maladies susceptibles d’être dépistées à la naissance n’a cessé de croître grâce aux possibilités offertes par les progrès techniques de la biologie clinique. Le test de Guthrie a permis la miniaturisation du prélèvement de sang, permettant ainsi le dépistage biologique dans la population des nouveau-nés. Par la suite, la fluorimétrie, l’immunoanalyse et, plus récemment, la spectrométrie de masse en tandem ont rendu possible le dépistage de nombreuses maladies qu’il est possible de traiter. Les nouvelles possibilités de séquençage du génome et d’intelligence artificielle vont probablement ouvrir une nouvelle ère, malgré les nombreuses questions éthiques qui se poseront. Cette revue propose de dresser le panorama des techniques biologiques utilisées actuellement pour le dépistage néonatal et de mettre en perspective la place de nouvelles évolutions techniques.
Published: 2021
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12. Inadequate response to treatment reveals persistent osteoclast bone resorption in osteoporotic patients

Author: Agnès Ostertag, Catherine Cormier, Thomas Funck-Brentano, Bernard Jean-Luc, Martine Cohen-Solal, Stéphanie Fabre, Patrice Fardellone, Caroline Marty, Bastien Leger, UCCS Équipe Catalyse Supramoléculaire, Unité de Catalyse et Chimie du Solide - UMR 8181 (UCCS), Université d'Artois (UA)-Centrale Lille-Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université d'Artois (UA)-Centrale Lille-Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), CHU Amiens-Picardie, Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques (BIOSCAR (UMR_S_1132 / U1132)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Diderot - Paris 7 (UPD7), Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de biochimie et biologie moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR139
Subjects: medicine.medical_specialty, Histology, Physiology, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Osteoporosis, Urology, Osteoclasts, Bone resorption, Bone remodeling, Osteoclast, Bone Density, medicine, Humans, Bone Resorption, Aged, Retrospective Studies, Bone mineral, Structure model index, business.industry, X-Ray Microtomography, Middle Aged, medicine.disease, Response to treatment, medicine.anatomical_structure, Hip bone, business, Osteoporotic Fractures
Abstract: International audience; Several drugs are able to reduce fracture risk in osteoporotic patients. Incident fractures occur despite good adherence to treatment. Inadequate response has been found related to high serum bone biomarkers of bone turnover. We here aimed to analyze bone microarchitecture and cellular profiles of inadequate responders. We retrospectively analyzed bone biopsies from patients with major fractures despite long-term treatment (inadequate responder [IR] n = 31) in comparison to patients with untreated osteoporosis (U-OP, n = 31) and controls without osteoporosis (Ctrl, n = 16). Bone samples were analyzed by histomorphometry and micro-computed tomography. Clinical and bone turnover markers and bone mineral density were assessed. As compared with U-OP patients, IRs were older (mean age 69.7 +/- 8.8 vs 63.3 +/- 9.3 years, p = 0.007) and had lower mean hip bone mineral density (0.685 +/- 0.116 vs 0.786 +/- 0.093 g/cm(2)), p = 0.019 and T-score ( 2.3 +/- 0.769 vs 1.6 +/- 0.900, p = 0.032). BV/TV was lower for IRs than U-OP patients and Ctrls (13.9 +/- 3.8% vs 15.2 +/- 5.1 and 17.6 +/- 5.2%, p = 0.044) as was trabecular thickness (145.6 +/- 23.1 vs 160.5 +/- 22.7 and 153.7 +/- 21.4 mu m, p = 0.033). Mean structure model index was lower for IRs than U-OP patients (1.9 +/- 0.806 vs 2.4 +/- 0.687, p = 0.042) and osteoclast number was higher for IRs than U-OP patients and Ctrls (0.721 +/- 0.611 vs 0.394 +/- 0.393 and 0.199 +/- 0.071 mm(-2), p < 0.001). The mean Obl.S/BS was lower for IRs than U-OP patients and Ctrls (1.2 +/- 1.3 vs 1.9 +/- 1.4 and 3.0 +/- 0.638 mm(-2), p < 0.0001), and the mean number of labelled surfaces was lower for IRs than U-OP patients (51.6% vs 87%, p = 0.002). Cortical parameters did not significantly differ. We show an imbalance of bone remodeling in favor of bone resorption in IRs. The persistence of high bone resorption suggests insufficient inhibition of bone resorption that could explain the incident fractures with anti-osteoporotic drug use. Adaptation to treatment should be considered to inhibit bone resorption and prevent further fractures.
Published: 2021
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13. GM3 synthase deficiency in non-Amish patients

Author: Lorita La Selva, Delphine Héron, Diana Rodriguez, Marilyn Tallot, Bénédicte Gérard, Charlotte Poe, David Cheillan, Anne Pervillé, Solveig Heide, Damien Haye, Christel Thauvin-Robinet, Yline Capri, Laurence Faivre, Julien Buratti, Marie-Line Jacquemont, Lionel Arnaud, Michel Renouil, Caroline Nava, Renzo Guerrini, Eric LeGuern, Boris Keren, Françoise Darcel, Amélie Piton, Cyril Mignot, Marc Bintner, Yannis Duffourd, Julien Thevenon, Laurence Perrin, Sandrine Passemard, Annalisa Vetro, Domitille Gras, J. Miquel, Charles E. Schwartz, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), Hospices Civils de Lyon (HCL), The Greenwood Genetic Center, CHU Trousseau [APHP], Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Robert Debré, Les Hôpitaux Universitaires de Strasbourg (HUS), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hopital d'enfants, Institut du Cerveau = Paris Brain Institute (ICM), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 'San Paolo' Hospital, Università degli Studi di Firenze = University of Florence (UniFI), and CarMeN, laboratoire
Subjects: medicine.medical_specialty, Epilepsy, business.industry, [SDV]Life Sciences [q-bio], Homozygote, Intellectual disability, Sialyltransferases, GM3 synthase deficiency, [SDV] Life Sciences [q-bio], Endocrinology, Internal medicine, medicine, Humans, business, Genetics (clinical), GM3 SYNTHASE DEFICIENCY, Movement disorder
Abstract: International audience; PURPOSE: Biallelic loss-of-function variants in ST3GAL5 cause GM3 synthase deficiency (GM3SD) responsible for Amish infantile epilepsy syndrome. All Amish patients carry the homozygous p.(Arg288Ter) variant arising from a founder effect. To date only 10 patients from 4 non-Amish families have been reported. Thus, the phenotypical spectrum of GM3SD due to other variants and other genetic backgrounds is still poorly known. METHODS: We collected clinical and molecular data from 16 non-Amish patients with pathogenic ST3GAL5 variants resulting in GM3SD. RESULTS: We identified 12 families originating from Reunion Island, Ivory Coast, Italy, and Algeria and carrying 6 ST3GAL5 variants, 5 of which were novel. Genealogical investigations and/or haplotype analyses showed that 3 of these variants were founder alleles. Glycosphingolipids quantification in patients' plasma confirmed the pathogenicity of 4 novel variants. All patients (N = 16), aged 2 to 12 years, had severe to profound intellectual disability, 14 of 16 had a hyperkinetic movement disorder, 11 of 16 had epilepsy and 9 of 16 had microcephaly. Other main features were progressive skin pigmentation anomalies, optic atrophy or pale papillae, and hearing loss. CONCLUSION: The phenotype of non-Amish patients with GM3SD is similar to the Amish infantile epilepsy syndrome, which suggests that GM3SD is associated with a narrow and severe clinical spectrum.
Published: 2021
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14. Prevalence and determinants of Transient Congenital Hypothyroidism in children with Eutopic Gland in France: a retrospective cohort study

Author: Nolwenn Regnault, David Cheillan, Régis Coutant, Yaya Barry, Christophe Bonaldi, Juliane Léger, Laurence Mandereau-Bruno, CarMeN, laboratoire, Santé publique France - French National Public Health Agency [Saint-Maurice, France], Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), Hospices Civils de Lyon (HCL), Faculté de Médecine Charles Mérieux, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Robert Debré, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: Male, medicine.medical_specialty, Pediatrics, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Levothyroxine, Thyrotropin, Context (language use), Biochemistry, Infant, Newborn, Diseases, Endocrinology, Neonatal Screening, Metabolic Diseases, Internal medicine, Prevalence, Medicine, Humans, transient hypothyroidism, Child, Retrospective Studies, business.industry, Incidence (epidemiology), Biochemistry (medical), Hazard ratio, Infant, Newborn, congenital hypothyroidism, Retrospective cohort study, determinants, medicine.disease, Congenital hypothyroidism, eutopic gland, [SDV] Life Sciences [q-bio], Low birth weight, Thyroxine, Premature birth, Female, medicine.symptom, business, medicine.drug
Abstract: Context The increase in the incidence of congenital hypothyroidism (CH) reported worldwide may partly be explained by an increase in the transient form of CH. Objective We aimed to estimate the proportion of transient CH (TCH) in France, and to identify associated neonatal and young child characteristics. Methods We used probabilistic record linkage to link children with eutopic gland born between 2006 and 2012 recorded in the national French CH registry and the French national health data system (SNDS). Of the 703 children recorded, 484 (68.8%) were linked. We retrospectively examined reimbursement for oral levothyroxine (LT4) between January 1, 2006, and December 31, 2017. Children who had discontinued treatment for 6 months or more before December 31, 2017, were classified as having TCH. We used a Cox model to examine the factors associated with TCH. Results Among the main study sample (n = 471), 53.5% were female, 14.2% were preterm, and 13.8% had low birth weight. One-quarter (n = 111, 24.3%) had mild CH (thyroid-stimulating hormone [TSH] Conclusion One-third of the children had TCH, and it was associated with several characteristics at birth and postpartum. These data are useful for CH medical management and epidemiological surveillance.
Published: 2021
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15. Anti-Glucosylsphingosine Autoimmunity, JAK2V617F-Dependent Interleukin-1β and JAK2V617F-Independent Cytokines in Myeloproliferative Neoplasms

Author: Edith Bigot-Corbel, Cédric Cleyrat, Eun Ho Eunice Choi, Laura Dufeu, Jean-Marc Gombert, François Girodon, Sophie Allain-Maillet, Nicolas Mennesson, Adrien Bosseboeuf, Yannick Le Bris, Olivier Mansier, Eric Lippert, Magali Pettazzoni, Sylvie Hermouet, Mégane Bostoën, Molecular Mechanisms of Chronic Inflammation in Hematological Diseases (CRCINA-ÉQUIPE 16), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), The University of New Mexico [Albuquerque], Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Hématologie [CHU Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Service d'Hématologie [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'immunologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), Hospices Civils de Lyon (HCL), Laboratoire de Biochimie [Nantes], Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, and Bernardo, Elizabeth
Subjects: 0301 basic medicine, Cancer Research, IL-1Rα, medicine.medical_treatment, Clone (cell biology), interleukin-1β (IL-1β), Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, myeloproliferative neoplasms (MPNs), CALR exon 9 mutants, IP-10, medicine.disease_cause, lcsh:RC254-282, leptin, Article, Autoimmunity, Proinflammatory cytokine, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Polycythemia vera, JAK2V617F, [SDV.CAN] Life Sciences [q-bio]/Cancer, glucolipids, hemic and lymphatic diseases, medicine, article clinique, auto-immunity, antigenic stimulation, business.industry, CRISPR technology, UT-7, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, glucosylsphingosine (GlcSph), cytokines, 3. Good health, Interleukin 33, 030104 developmental biology, Cytokine, Oncology, inflammation, 030220 oncology & carcinogenesis, Immunology, IL-33, medicine.symptom, business
Abstract: Inflammatory cytokines play a major role in myeloproliferative neoplasms (MPNs) as regulators of the MPN clone and as mediators of clinical symptoms and complications. Firstly, we investigated the effect of JAK2V617F on 42 molecules linked to inflammation. For JAK2V617F-mutated patients, the JAK2V617F allele burden (%JAK2V617F) correlated with the levels of IL-1&beta, IL-1R&alpha, IP-10 and leptin in polycythemia vera (PV), and with IL-33 in ET, for all other molecules, no correlation was found. Cytokine production was also studied in the human megakaryocytic cell line UT-7. Wild-type UT-7 cells secreted 27/42 cytokines measured. UT-7 clones expressing 50% or 75% JAK2V617F were generated, in which the production of IL-1&beta, IP-10 and RANTES was increased, other cytokines were not affected. Secondly, we searched for causes of chronic inflammation in MPNs other than driver mutations. Since antigen-driven selection is increasingly implicated in the pathogenesis of blood malignancies, we investigated whether proinflammatory glucosylsphingosine (GlcSph) may play a role in MPNs. We report that 20% (15/75) of MPN patients presented with anti-GlcSph IgGs, distinguished by elevated levels of 11 cytokines. In summary, only IL-1&beta, and IP-10 were linked to JAK2V617F both in patients and in UT-7 cells, other inflammation-linked cytokines in excess in MPNs were not. For subsets of MPN patients, a possible cause of inflammation may be auto-immunity against glucolipids.
Published: 2020
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16. Congenital Hypothyroidism due to a Low Level of Maternal Thyrotropin Receptor-Blocking Antibodies

Author: Véronique Raverot, Juliette Abeillon, Patricia Bretones, Myriam Moret, Solène Castellnou, Karim Chikh, Pauline Perrin, Fédération d’Endocrinologie, Maladies Métaboliques, Diabète et Nutrition [Bron] (FEMMDN/Hôpital Louis Pradel ), Hospices Civils de Lyon (HCL)-Groupement Hospitalier Est [Bron], Service d'endocrinologie pédiatrique [CHU Lyon-Hospices Civils de Lyon], Hospices Civils de Lyon (HCL), Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Biologie et de Pathologie Sud [HCL, Lyon], and CarMeN, laboratoire
Subjects: medicine.medical_specialty, TBAb, endocrine system, endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030209 endocrinology & metabolism, Reference range, Thyrotropin receptor, 03 medical and health sciences, 0302 clinical medicine, Maternal hypothyroidism, TSHR Ab, Internal medicine, medicine, Thyrotropin receptor-blocking antibodies, business.industry, Thyroid, medicine.disease, Thyroid disorder, 3. Good health, Congenital hypothyroidism, [SDV] Life Sciences [q-bio], TRAb, medicine.anatomical_structure, Endocrinology, 030220 oncology & carcinogenesis, Clinical Thyroidology / Case Report, Thyroglobulin, Thyroid function, business, hormones, hormone substitutes, and hormone antagonists
Abstract: Introduction: Maternal TSH receptor antibodies (TRAbs) can cross the placenta and affect fetal and neonatal thyroid function. Maternal TSH receptor-blocking antibodies (TBAbs) are a rare cause of congenital hypothyroidism. Case Report: Following the discovery of a highly elevated TSH on her neonatal screening test, a 10-day-old girl with no familial history of thyroid disorder was referred to the pediatric endocrinology unit. Hypothyroidism was confirmed with a highly elevated TSH (817 mIU/L, reference range 0.4–3.1) and very low levels of FT4 (1.8 pmol/L, reference range 12–22). Anti-TPO antibodies were at 81 IU/mL (reference range Conclusion: We report herein a case of transient congenital hypothyroidism with a normal neonatal TRAbs level. In case of maternal TBAbs, similar activity of maternal TBAbs must be expected in the neonate, independently of the neonatal level of TRAbs.
Published: 2020
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17. Long-term ACE Inhibitor/ARB Use Is Associated With Severe Renal Dysfunction and Acute Kidney Injury in Patients With Severe COVID-19: Results From a Referral Center Cohort in the Northeast of France

Author: Elodie Laugel, Isabelle Aimone-Gastin, Isabelle Clerc Urmes, Antoine Kimmoun, Jean-Louis Guéant, Abderrahim Oussalah, Rosa-Maria Rodriguez-Guéant, F Barbé, Sophie Orlowski, Marc Merten, Nathalie Thilly, Sébastien Gibot, Stanislas Gleye, Catherine Malaplate, Beatrice Maatem Caillierez, Jean-Luc Olivier, Raphaël Kormann, Luc Frimat, Farès Namour, Sybille Bevilacqua, Jonas Callet, Bruno Levy, Evelyne Schvoerer, Elise Jeannesson, Marie-Reine Losser, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Biochimie – Biologie moléculaire et Nutrition [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Virologie [CHRU Nancy], Laboratoire de Chimie Physique et Microbiologie pour les Matériaux et l'Environnement (LCPME), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Stress, Immunité, Pathogènes (SIMPA), Université de Lorraine (UL), Service de Biochimie et Biologie Moléculaire, Nutrition et Métabolisme [CHRU Nancy], Urgences néphrologiques et transplantation rénale [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Composés Alimentaires : Biofonctionnalités et risques Neurotoxiques (CALBINOTOX), Service des Maladies Infectieuses et Tropicales [CHRU Nancy], Service d'anesthésie et réanimation chirurgicale [Nantes], Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Réanimation Médicale [CHRU Nancy], Plateforme d'Aide à la Recherche Clinique [CHRU Nancy] (PARC), and Service de Néphrologie [CHRU Nancy]
Subjects: 0301 basic medicine, Microbiology (medical), medicine.medical_specialty, severe COVID-19, 030204 cardiovascular system & hematology, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, medicine, Major Article, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, cardiovascular diseases, angiotensin receptor blocker, Creatinine, Kidney, business.industry, SARS-CoV-2, Acute kidney injury, Repeated measures design, Odds ratio, medicine.disease, Confidence interval, 3. Good health, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, AcademicSubjects/MED00290, chemistry, angiotensin-converting enzyme inhibitor, acute kidney injury, Cohort, ACE inhibitor, business, medicine.drug
Abstract: Background In patients with severe coronavirus disease 2019 (COVID-19), data are scarce and conflicting regarding whether chronic use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) influences disease outcomes. In patients with severe COVID-19, we assessed the association between chronic ACEI/ARB use and the occurrence of kidney, lung, heart, and liver dysfunctions and the severity of the inflammatory reaction as evaluated by biomarkers kinetics, and their association with disease outcomes. Methods We performed a retrospective longitudinal cohort study on consecutive patients with newly diagnosed severe COVID-19. Independent predictors were assessed through receiver operating characteristic analysis, time-series analysis, logistic regression analysis, and multilevel modeling for repeated measures. Results On the 149 patients included in the study 30% (44/149) were treated with ACEI/ARB. ACEI/ARB use was independently associated with the following biochemical variations: phosphorus >40 mg/L (odds ratio [OR], 3.35, 95% confidence interval [CI], 1.83–6.14), creatinine >10.1 mg/L (OR, 3.22, 2.28–4.54), and urea nitrogen (UN) >0.52 g/L (OR, 2.65, 95% CI, 1.89–3.73). ACEI/ARB use was independently associated with acute kidney injury stage ≥1 (OR, 3.28, 95% CI, 2.17–4.94). The daily dose of ACEI/ARB was independently associated with altered kidney markers with an increased risk of +25 to +31% per each 10 mg increment of lisinopril-dose equivalent. In multivariable multilevel modeling, UN >0.52 g/L was independently associated with the risk of acute respiratory failure (OR, 3.54, 95% CI, 1.05–11.96). Conclusions Patients chronically treated with ACEI/ARB who have severe COVID-19 are at increased risk of acute kidney injury. In these patients, the increase in UN associated with ACEI/ARB use could predict the development of acute respiratory failure., The present retrospective longitudinal cohort study on consecutive patients with newly diagnosed severe COVID-19 provides new evidence on the potentially harmful effect of chronic ACEI/ARB use on kidney outcomes and their possible interaction with the occurrence of acute respiratory failure.
Published: 2020
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18. Coronavirus disease 2019: acute Fanconi syndrome precedes acute kidney injury

Author: Matthieu Garcia Parrilla, Matthieu Koszutski, Paul Voirin, Jean-Louis Guéant, Luc Frimat, Sybille Bevilacqua, Alice Corbel, Asma Alla, Audrey Jacquot, Abderrahim Oussalah, Raphaël Kormann, Bruno Levy, Evelyne Schvoerer, Farès Namour, Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Soins Intensifs [CHRU Nancy], Service des Maladies Infectieuses et Tropicales [CHRU Nancy], Service de Biochimie et Biologie Moléculaire, Nutrition et Métabolisme [CHRU Nancy], Laboratoire de Chimie Physique et Microbiologie pour les Matériaux et l'Environnement (LCPME), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Service de Virologie [CHRU Nancy], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques Nancy, and Cancéropôle du Grand Est-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Glycosuria, medicine.medical_specialty, 030232 urology & nephrology, Renal function, Gastroenterology, acute proximal tubule injury, hypophosphataemia, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Interquartile range, Internal medicine, Medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Kidney, Transplantation, Proteinuria, business.industry, SARS-CoV-2, Acute kidney injury, Fanconi syndrome, COVID-19, medicine.disease, 3. Good health, medicine.anatomical_structure, acute kidney injury, Nephrology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Original Article, medicine.symptom, business, Kidney disease
Abstract: Background Recent data have shown that severe acute respiratory syndrome coronavirus 2 can infect renal proximal tubular cells via Angiotensin Converting Enzyme 2 (ACE2) . Our objective was to determine whether Fanconi syndrome is a frequent clinical feature in coronavirus disease 2019 (COVID-19) patients. Methods A retrospective cohort of 42 laboratory-confirmed COVID-19 patients without history of kidney disease hospitalized in University Hospital of Nancy was investigated. Patients were admitted to the intensive care unit (ICU) (n = 28) or the Medical department (n = 14) and were screened at least once for four markers of proximal tubulopathy. Results The mean (standard deviation) follow-up was 19.7 (±12.2) days. Of the patients, 75% (30/40) showed at least two proximal tubule abnormalities (incomplete Fanconi syndrome). The main disorders were proteinuria (88%, n = 35), renal phosphate leak defined by renal phosphate threshold/glomerular filtration rate (TmPi/GFR) Conclusion Incomplete Fanconi syndrome is highly frequent in COVID-19 patients and precedes AKI or disappears during the recovery phase.
Published: 2020
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19. Bone Disease in Nephropathic Cystinosis: Beyond Renal Osteodystrophy

Author: Cécile Acquaviva-Bourdain, Débora Claramunt-Taberner, Ségolène Gaillard, Irma Machuca-Gayet, Justine Bacchetta, Aurélia Bertholet-Thomas, Thomas Quinaux, Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases (LYOS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Référence des Maladies Rares du Calcium et du Phosphore (HFME - HCL), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), EPICIME-CIC 1407 de Lyon, Inserm, Service de Pharmacologie Clinique, CHU-Lyon, Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), Hospices Civils de Lyon (HCL), and Machuca-Gayet, Irma
Subjects: 0301 basic medicine, Bone disease, [SDV]Life Sciences [q-bio], Cystinosis, 030232 urology & nephrology, mTor signaling, Review, Bioinformatics, Nephropathic cystinosis, lcsh:Chemistry, chemistry.chemical_compound, 0302 clinical medicine, Bone cell, Renal osteodystrophy, lcsh:QH301-705.5, Spectroscopy, 2. Zero hunger, Osteoblast, Renal osteodystrophy (ROD), General Medicine, 3. Good health, Computer Science Applications, [SDV] Life Sciences [q-bio], Cystinosin, Osteoclast, Bone Remodeling, Bone Diseases, Cysteamine, Catalysis, Metabolic bone disease, Inorganic Chemistry, 03 medical and health sciences, Nephropathic Cystinosis, medicine, CKD-MBD, Animals, Humans, Physical and Theoretical Chemistry, Bone, Molecular Biology, Chronic Kidney Disease-Mineral and Bone Disorder, business.industry, Organic Chemistry, medicine.disease, 030104 developmental biology, Amino Acid Transport Systems, Neutral, lcsh:Biology (General), lcsh:QD1-999, chemistry, Orphan disease, Mutation, business
Abstract: International audience; Patients with chronic kidney disease (CKD) display significant mineral and bone disorders (CKD-MBD) that induce significant cardiovascular, growth and bone comorbidities. Nephropathic cystinosis is an inherited metabolic disorder caused by the lysosomal accumulation of cystine due to mutations in the CTNS gene encoding cystinosin, and leads to end-stage renal disease within the second decade. The cornerstone of management relies on cysteamine therapy to decrease lysosomal cystine accumulation in target organs. However, despite cysteamine therapy, patients display severe bone symptoms, and the concept of "cystinosis metabolic bone disease" is currently emerging. Even though its exact pathophysiology remains unclear, at least five distinct but complementary entities can explain bone impairment in addition to CKD-MBD: long-term consequences of renal Fanconi syndrome, malnutrition and copper deficiency, hormonal disturbances, myopathy, and intrinsic/iatrogenic bone defects. Direct effects of both CTNS mutation and cysteamine on osteoblasts and osteoclasts are described. Thus, the main objective of this manuscript is not only to provide a clinical update on bone disease in cystinosis, but also to summarize the current experimental evidence demonstrating a functional impairment of bone cells in this disease and to discuss new working hypotheses that deserve future research in the field.
Published: 2020
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20. Intérêts d’inclure la détermination d’éléments inorganiques à la nomenclature des actes de biologie médicale

Author: Jean Pierre Goullé, Ma’atem Béatrice Fofou-Callierez, Nicolas Beauval, Robert Garnier, Martine Ropert Bouchet, Sarah Romain, Muriel Bost, Souleiman El Balkhi, Bénédicte Lelièvre, Josiane Arnaud, Nourédine Sadeg, Service de biochimie hormonale, métabolique et génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Hospices Civils de Lyon (HCL), Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Biochimie et Biologie Moléculaire, Nutrition et Métabolisme [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Pharmacologie, toxicologie et pharmacovigilance [CHU Limoges], CHU Limoges, Université d'Angers (UA), Laboratoire de Biochimie et Toxicologie [Rennes] = Biochemistry and Toxicology [Rennes], CHU Pontchaillou [Rennes], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Aliments Bioprocédés Toxicologie Environnements (ABTE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)
Subjects: 03 medical and health sciences, 0302 clinical medicine, Health, Toxicology and Mutagenesis, [SDV]Life Sciences [q-bio], 010401 analytical chemistry, 030216 legal & forensic medicine, Toxicology, 01 natural sciences, 3. Good health, 0104 chemical sciences
Abstract: Resume Objectif L’objectif de cette revue est de demontrer que la determination d’elements inorganiques ne figurant pas actuellement a la nomenclature des actes de biologie medicale (NABM), peut etre essentielle au diagnostic et a la prise en charge de patients presentant une carence ou une surcharge. Methodes Une recherche des recommandations concernant la determination d’elements inorganiques dans les matrices biologiques a ete effectuee aupres de differentes agences et organismes de sante publique et de societes savantes. Resultats Ces recommandations sont resumees dans cette revue pour les populations a risque du fait de conditions environnementales, nutritionnelles, metaboliques, genetiques ou en lien avec l’introduction de dispositifs medicaux implantables. Conclusion Afin d’eviter un retard dans le diagnostic ou une prise en charge inadaptee conduisant a une perte de chance pour le patient, nous estimons que plusieurs de ces dosages devraient etre integres rapidement a la NABM.
Published: 2020
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21. Involvement of a homozygous exon 6 deletion of LMF1 gene in intermittent severe hypertriglyceridemia

Author: Mathilde Di Filippo, Muriel Mahl, Sybil Charrière, Anne-Sophie Wozny, Oriane Marmontel, Philippe Moulin, C. Marcais, Thomas Simonet, Marine Serveaux Dancer, Sabrina Dumont, CarMeN, laboratoire, Hospices Civils de Lyon (HCL), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Lyon, Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), 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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), and 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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)
Subjects: medicine.medical_specialty, Severe hypertriglyceridemia, Endocrinology, Diabetes and Metabolism, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Nonsense, Pcr cloning, 030204 cardiovascular system & hematology, 03 medical and health sciences, Exon, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, Multifactorial chylomicronemia syndrome, Humans, 030212 general & internal medicine, Copy-number variation, Gene, media_common, Sequence Deletion, Hypertriglyceridemia, Nutrition and Dietetics, business.industry, Homozygote, Triglyceride, Membrane Proteins, Exons, medicine.disease, Phenotype, 3. Good health, [SDV] Life Sciences [q-bio], Lipolysis, Endocrinology, Familial chylomicronemia syndrome, Female, Cardiology and Cardiovascular Medicine, business, Copy number variation, lmf1
Abstract: International audience; Severe hypertriglyceridemia (HTG), characterized by triglycerides (TG) permanently over 10 mmol/L, may correspond to familial chylomicronemia syndrome (FCS), a rare disorder. However, hypertriglyceridemic patients more often present multifactorial chylomicronemia syndrome (MCS), characterized by highly variable TG. A few nonsense variants of LMF1 gene were reported in literature in FCS patients. In this study, we described a woman with an intermittent severe HTG. NGS analysis and the sequencing of a long range PCR product revealed a homozygous deletion of 6507 base pairs in LMF1 gene, c.730-1528\₈98-3417del, removing exon 6, predicted to create an in-frame deletion of 56 amino acids, p.(Thr244_Gln299del). Despite an exon 6 homozygous deletion of LMF1, the patient's highly variable lipid phenotype was suggestive of MCS diagnosis.
Published: 2020
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22. Application of a Novel Algorithm for Expanding Newborn Screening for Inherited Metabolic Disorders across Europe

Author: Simon A. Jones, David Cheillan, Anupam Chakrapani, Heather J. Church, Simon Heales, Teresa H. Y. Wu, Georgina Morton, Patricia Roberts, Erica F. Sluys, Alberto Burlina, Manchester University NHS Foundation Trust (MFT), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), Hospices Civils de Lyon (HCL), Great Ormond Street Hospital for Children NHS Foundation Trust [London, UK] (GOSHC), University College London Hospitals NHS Foundation Trust [London, UK] (UCLH), ArchAngel MLD Trust [London, UK] (2A), Helvet Health [Nyon, Switzerland] (2H), Azienda Ospedale Università di Padova = Hospital-University of Padua (AOUP), and CarMeN, laboratoire
Subjects: newborn screening (NBS), inherited metabolic disorder (IMD), public health, genetics, congenital disorder, lysosomal storage disorder (LSD), inborn errors of metabolism, rare diseases, methodology, algorithm, [SDV]Life Sciences [q-bio], food and beverages, Obstetrics and Gynecology, [SDV] Life Sciences [q-bio], Immunology and Microbiology (miscellaneous), Pediatrics, Perinatology and Child Health
Abstract: International audience; Inherited metabolic disorders (IMDs) are mostly rare, have overlapping symptoms, and can be devastating and progressive. However, in many disorders, early intervention can improve long-term outcomes, and newborn screening (NBS) programmes can reduce caregiver stress in the journey to diagnosis and allow patients to receive early, and potentially pre-symptomatic, treatment. Across Europe there are vast discrepancies in the number of IMDs that are screened for and there is an imminent opportunity to accelerate the expansion of evidence-based screening programmes and reduce the disparities in screening programmes across Europe. A comprehensive list of IMDs was created for analysis. A novel NBS evaluation algorithm, described by Burlina et al. in 2021, was used to assess and prioritise IMDs for inclusion on expanded NBS programmes across Europe. Forty-eight IMDs, of which twenty-one were lysosomal storage disorders (LSDs), were identified and assessed with the novel NBS evaluation algorithm. Thirty-five disorders most strongly fulfil the Wilson and Jungner classic screening principles and should be considered for inclusion in NBS programmes across Europe. The recommended disorders should be evaluated at the national level to assess the economic, societal, and political aspects of potential screening programmes.
Published: 2022
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23. A new case of SMA phenotype without epilepsy due to biallelic variants in ASAH1

Author: Anne Boland, Tanya Stojkovic, Roseline Froissart, Cécile Masson, Norma B. Romero, Isabelle Nelson, Thierry Levade, Anthony Behin, Virginie Garcia, Emmanuelle Lacène, Gisèle Bonne, Nadine Ame van der Beek, Service de Biochimie et Biologie Moléculaire Grand Est Unité Médicale Pathologies Métaboliques, Erythrocytaires et Dépistage Périnatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, Laboratoire de Biologie Tissulaire et d'ingénierie Thérapeutique UMR 5305 (LBTI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Neurology
Subjects: business.industry, [SDV]Life Sciences [q-bio], Bioinformatics, medicine.disease, SMA, Phenotype, Acid Ceramidase, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, 030225 pediatrics, Genetics, ASAH1, Medicine, business, 030217 neurology & neurosurgery, Genetics (clinical)
Abstract: International audience
Published: 2019
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24. Amyloid PETs are commonly negative in suspected Alzheimer’s disease with an increase in CSF phosphorylated-tau protein concentration but an Aβ42 concentration in the very high range: a prospective study

Author: Pierre-Yves Marie, Antoine Verger, Zohra Lamiral, Gilles Karcher, Catherine Malaplate, Chloé Manca, Thérèse Rivasseau Jonveaux, Véronique Roch, Service de Médecine Nucléaire [Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nancyclotep- Experimental Imaging Platform = Plate-forme d'imagerie moléculaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Lorraine (UL), Laboratoire lorrain de psychologie et neurosciences de la dynamique des comportements (2LPN), Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie et Biologie Moléculaire, Nutrition et Métabolisme [CHRU Nancy], Imagerie Adaptative Diagnostique et Interventionnelle (IADI), and Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, medicine.medical_specialty, Neurology, Amyloid, [SHS.EDU]Humanities and Social Sciences/Education, [SHS.PSY]Humanities and Social Sciences/Psychology, Standardized uptake value, Pilot Projects, tau Proteins, Disease, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Alzheimer Disease, Internal medicine, mental disorders, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Phosphorylation, Prospective cohort study, CSF biomarkers, Neuroradiology, Aged, Aged, 80 and over, Amyloid beta-Peptides, quantitative analysis, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Alzheimer's disease, amyloid PET, Peptide Fragments, 3. Good health, Cross-Sectional Studies, Positron-Emission Tomography, [SCCO.PSYC]Cognitive science/Psychology, Aß42, Female, Neurology (clinical), business, Neurocognitive, 030217 neurology & neurosurgery, Biomarkers
Abstract: International audience; Atypical cerebrospinal fluid (CSF) patterns, involving an increase in the concentration of phosphorylated-tau (P-tau) proteins but normal amyloid-β concentration, are not uncommon in patients with mild neurocognitive disorders and suspected Alzheimer's disease (AD). In these conditions, however, AD diagnosis may be ruled out in the absence of any amyloid deposition at positron emission tomography (PET). This pilot cross-sectional study was aimed to determine whether this negativity of amyloid PET can be predicted by CSF profiles in such patients. Methods: Twenty-five patients (73[68-80] years, 10 women) with mild neurocognitive disorders, suspected AD and an increase in the CSF concentration of P-tau proteins but normal Aβ42 concentration and Aβ42/Aβ40 ratio, were prospectively included and referred to a 18 Fflorbetaben PET. The latter was considered as definitively negative with the conjunction of both visual (brain amyloid plaque load score) and quantified (standard uptake values ratios) criteria. Predictors of a negative PET were searched among current CSF biomarkers (Aß42, Aß40, T-tau, P-tau, Aß42/Aß40, Aß42/p-tau). Results: Amyloid PET was negative in 15 patients (60%) with a CSF Aß42 concentration being the sole independent predictor of this negativity. The criterion of an Aß42 concentration far from the abnormal zone (>843 pg/mL), observed in 60% (15/25) of the study patients, was associated with a negative amyloid PET in 93% (14/15) of cases. Conclusions: In mild neurocognitive disorders patients with suspected AD and showing an increase in CSF P-tau protein level, amyloid PETs are commonly negative, when Aß42 concentration is far from the abnormal zone. In such case, AD diagnosis based on biomarkers can be ruled out with reasonable certainty, without any need of additional CSF second-line assays or results from amyloid PET.
Published: 2019
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25. Age-related changes in regiospecific expression of Lipolysis Stimulated Receptor (LSR) in mice brain

Author: El Hajj, Aseel, Yen, Frances T., Oster, Thierry, Malaplate, Catherine, Pauron, Lynn, Corbier, Catherine, Lanhers, Marie-Claire, Claudepierre, Thomas, Unité de Recherches Animal et Fonctionnalités des Produits Animaux (URAFPA), Institut National de la Recherche Agronomique (INRA)-Université de Lorraine (UL), Service de Biochimie et Biologie Moléculaire, Nutrition et Métabolisme [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), IMPACT Biomolécules, ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), Université de Lorraine (UL)-Institut National de la Recherche Agronomique (INRA), and ANR-15-IDEX-0004,LUE (ISITE),Lorraine Université d'Excellence(2016)
Subjects: Central Nervous System, Male, Aging, Lipoproteins, Lipolysis, Science, Hypothalamus, Biochemistry, Nervous System, Hippocampus, Mice, Animal Cells, Cerebellum, Medicine and Health Sciences, Animals, Homeostasis, Humans, Tissue Distribution, RNA, Messenger, Lipoprotein Receptors, Receptors, Lipoprotein, Neurons, Cerebral Cortex, [SCCO.NEUR]Cognitive science/Neuroscience, Biology and Life Sciences, Proteins, Brain, Cell Biology, Lipids, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Mice, Inbred C57BL, Cholesterol, nervous system, Cellular Neuroscience, Medicine, lipids (amino acids, peptides, and proteins), Anatomy, Cellular Types, Transcriptome, Neuroglia, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Research Article, Neuroscience, Signal Transduction
Abstract: International audience; The regulation of cholesterol, an essential brain lipid, ensures proper neuronal development and function, as demonstrated by links between perturbations of cholesterol metabolism and neurodegenerative diseases, including Alzheimer's disease. The central nervous system (CNS) acquires cholesterol via de novo synthesis, where glial cells provide cholesterol to neurons. Both lipoproteins and lipoprotein receptors are key elements in this intercellular transport, where the latter recognize, bind and endocytose cholesterol containing glia-produced lipoproteins. CNS lipoprotein receptors are like those in the periphery, among which include the ApoB, E binding lipolysis stimulated lipoprotein receptor (LSR). LSR is a multi-meric protein complex that has multiple isoforms including α and α', which are seen as a dou-blet at 68 kDa, and β at 56 kDa. While complete inactivation of murine lsr gene is embryonic lethal, studies on lsr +/-mice revealed altered brain cholesterol distribution and cognitive functions. In the present study, LSR profiling in different CNS regions revealed regiospecific expression of LSR at both RNA and protein levels. At the RNA level, the hippocampus, hypo-thalamus, cerebellum, and olfactory bulb, all showed high levels of total lsr compared to whole brain tissues, whereas at the protein level, only the hypothalamus, olfactory bulb, and retina showed the highest levels of total LSR. Interestingly, major regional changes in LSR expression were observed in aged mice which suggests changes in cholesterol homeostasis in specific structures in the aging brain. Immunocytostaining of primary cultures of mature murine neurons and glial cells isolated from different CNS regions showed that LSR is expressed in both neurons and glial cells. However, lsr RNA expression in the cerebellum was predominantly higher in glial cells, which was confirmed by the immunocytostaining profile of cerebellar neurons and glia. Based on this observation, we would propose that LSR in glial cells may play a key role in glia-neuron cross talk, particularly in the feedback control of cholesterol synthesis to avoid cholesterol overload in neurons and to maintain proper functioning of the brain throughout life.
Published: 2019
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26. High performance of cerebrospinal fluid immunoglobulin G analysis for diagnosis of multiple sclerosis

Author: Marc Debouverie, Simon Gamraoui, Francis Guillemin, René Anxionnat, Guillaume Mathey, Catherine Malaplate, Jonathan A. Epstein, Centre d'investigation clinique - Epidémiologie clinique [Nancy] (CIC-EC), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de neurologie [CHRU Nancy], Université de Lorraine (UL), Service de Biochimie et Biologie Moléculaire, Nutrition et Métabolisme [CHRU Nancy], Département de neuroradiologie diagnostique et thérapeutique [CHRU Nancy], and Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)
Subjects: Adult, Male, medicine.medical_specialty, Neurology, Adolescent, Bayesian analysis, Sensitivity and Specificity, Gastroenterology, Immunoglobulin G, Diagnosis, Differential, Multiple sclerosis, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Internal medicine, Prevalence, medicine, Humans, Latent class model, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, Neuroradiology, Aged, 80 and over, biology, business.industry, Bayes Theorem, McDonald criteria, Gold standard (test), Middle Aged, medicine.disease, 3. Good health, Latent Class Analysis, biology.protein, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), business, Diagnostic test assessment, Biomarkers, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: The 2017 revision of the McDonald criteria highlights the usefulness of cerebrospinal fluid (CSF) immunoglobulin G (IgG) analysis to diagnose multiple sclerosis (MS). The objective of this study was to assess the diagnostic performances of CSF IgG analysis in the absence of a gold standard. All patients who underwent CSF IgG analysis for events suggestive of MS in Nancy University Hospital (France) from 2008 to 2011 were retrospectively included. A latent class analysis with Bayesian approach was used to infer MS prevalence (latent variable) as well as the diagnostic properties of the 2005 and 2010 McDonald criteria and CSF IgG analysis (observed variables). Data from 673 patients were analysed. For CSF IgG analysis, the Bayesian latent class analysis estimated sensitivity of 0.93 (95% CrI 0.89–0.96) and specificity of 0.81 (95% CrI 0.77–0.85). The true prevalence estimate was 36% (95% CrI 0.33–0.40). Sensitivity and specificity estimates for patients with events suggestive of remitting-onset MS were similar to those for the whole sample—0.92 (95% CrI 0.85–0.96) and 0.80 (95% CrI 0.76–0.84), respectively—but higher for patients with signs of progressive-onset MS—0.95 (95% CrI 0.84–0.99) and 0.88 (95% CrI 0.78–0.94), respectively. In the absence of a gold standard, latent class analysis indicates good diagnostic properties of CSF IgG analysis for MS. This test could thus be useful, especially for patients who tested negative for the 2005 and 2010 McDonald criteria. These findings deserve to be confirmed prospectively.
Published: 2019
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27. 2018 Consensus of the French Society of Endocrinology: endocrine toxicities of cancer immunotherapies

Author: Castinetti, Frederic, Borson-Chazot, Francoise, Aibarel, Frederique, Archambeaud, Francoise, Bertherat, Jerome, Bouillet, Benjamin, Buffier, Perrine, Briet, Claire, Cariou, Bertrand, Caron, Philippe, Chabre, Olivier, Chanson, Philippe, Cortet, Christine, Do Cao, Christine, Drui, Delphine, Haissaguerre, Magali, Hescot, Segolene, Illouz, Frederic, Kuhn, Emmanuelle, Lahlou, Najiba, Merlen, Emilie, Raverot, Veronique, Smati, Sarra, Verges, Bruno, 2018, Consensus SFE, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Centre de médecine nucléaire, Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Fédération d'endocrinologie, Service de Médecine interne B, Endocrinologie, Diabète, Maladies métaboliques [CHU Limoges], CHU Limoges, Institut Cochin (IC UM3 (UMR 8104 / U1016)), 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 d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Endocrinology [Nantes], Institut du Thorax [Nantes], Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service d'endocrinologie, CHU Grenoble-Hôpital Michallon, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service d’endocrinologie, diabétologie et maladies métaboliques [CHRU LIlle], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département d'Endocrinologie [CHU Nantes] (Institut du Thorax), Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut du Thorax [Nantes], Service d'endocrinologie, diabétologie et nutrition (CHU de Bordeaux), CHU Bordeaux [Bordeaux], Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Endocrinologie, Diabétologie et Nutrition [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Laboratoire de Biologie hormonale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Saint-Vincent de Paul, Service de Biochimie et Biologie moléculaire [CH Lyon Sud], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Fédération d'endocrinologie-Groupement hospitalier Lyon-Est, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Gall, Valérie
Subjects: Thyroiditis, [SDV.GEN]Life Sciences [q-bio]/Genetics, Diabetes, [SDV.GEN] Life Sciences [q-bio]/Genetics, Immunotherapy, Hypophysitis, Adrenal insufficiency
Abstract: Immunotherapy induced side effects: Are frequent, usually well-tolerated, and can lead to thyroid, pituitary, and less frequently adrenals and pancreas (fulminant diabetes) disease,. Do not contra-indicate immunotherapy, and rarely require high dose glucocorticoids; Need to be screened for, as there are acute manifestations, and replacement treatments can be given lifelong; Require a pre-immunotherapy evaluation; Require a careful follow-up at least during the first 6 months of immunotherapy.
Published: 2019

28. Acute effects of milk polar lipids on intestinal tight junction expression: Towards an impact of sphingomyelin through the regulation of IL-8 secretion?

Author: David Cheillan, Karène Bertrand, Emmanuelle Loizon, Lorna Garnier, Fabienne Laugerette, Florent Joffre, Charline Buisson, Marie-Caroline Michalski, Sébastien Viel, Armelle Penhoat, Marine Milard, Annie Durand, Emmanuelle Meugnier, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), ITERG, Service de Biochimie et Biologie Moléculaire Grand Est, Centre de Biologie et de Pathologie Est[Lyon], Hospices Civils de Lyon (HCL), Département d'allergie et d'immunologie clinique [CHU Lyon Sud], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'immunologie [Centre Hospitalier Lyon Sud - HCL], French Ministry for Higher Education and Research via EDISS, Universite Claude Bernard Lyon 1, CNIEL (French Dairy Interbranch Organization), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National de la Recherche Agronomique (INRA)
Subjects: Male, 0301 basic medicine, Chemokine CXCL1, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Chemokine CXCL2, Clinical Biochemistry, Occludin, Biochemistry, Tight Junctions, Proinflammatory cytokine, 03 medical and health sciences, Gene expression, cytokine, Animals, Humans, Secretion, Molecular Biology, reproductive and urinary physiology, phospholipid, Tight Junction Proteins, 030109 nutrition & dietetics, Nutrition and Dietetics, Dose-Response Relationship, Drug, Tight junction, gut barrier, Chemistry, Interleukin-8, virus diseases, Lipid metabolism, Lipids, Molecular biology, Sphingomyelins, Intestines, Mice, Inbred C57BL, Milk, 030104 developmental biology, Gene Expression Regulation, Caco-2, caco-2, dairy, Caco-2 Cells, Sphingomyelin, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, milk fat globule membrane
Abstract: International audience; Milk polar lipids (MPL) are specifically rich in milk sphingomyelin (MSM) which represents 24% of MPL. Beneficial effects of MPL or MSM have been reported on lipid metabolism, but information on gut physiology is scarce. Here we assessed whether MPL and MSM can impact tight junction expression. Human epithelial intestinal Caco-2/TC7 cells were incubated with mixed lipid micelles devoid of MSM (Control) or with 0.2 or 0.4 mM of MSM via pure MSM or via total MPL. C57Bl/6 mice received 5 or 10 mg of MSM via MSM or via MPL (oral gavage); small intestinal segments were collected after 4 h. Impacts on tight junction and cytokine expressions were assessed by qPCR; IL-8 and IL-8 murine homologs (Cxcl1, Cxcl2) were analyzed. In vitro, MSM increased tight junction expression (Occludin, ZO-1) vs Control, unlike MPL. However, no differences were observed in permeability assays (FITC-dextran, Lucifer yellow). MSM increased the secretion and gene expression of IL-8 but not of other inflammatory cytokines. Moreover, cell incubation with IL-8 induced an overexpression of tight junction proteins. In mice, mRNA level of Cxcl1 and Cxcl2 in the ileum were increased after gavage with MSM vs NaCl but not with MPL. Altogether, these results suggest a specific action of MSM on intestinal tight junction expression, possibly mediated by IL-8. Our study provides clues to shed light on the beneficial effects of MPL on intestinal functions and supports the need for further mechanistic exploration of the direct vs indirect effects of MSM and IL-8 on the gut barrier.
Published: 2019
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29. Milk polar lipids reduce lipid cardiovascular risk factors in overweight postmenopausal women: towards a gut sphingomyelin-cholesterol interplay

Author: Vors, Cécile, Joumard-Cubizolles, Laurie, Lecomte, Manon, Combe, Emmanuel, Ouchchane, Lemlih, Drai, Jocelyne, Raynal, Ketsia, Joffre, Florent, Meiller, Laure, LE BARZ, Mélanie, Gaborit, Patrice, Caille, Aurélie, Sothier, Monique, Domingues-Costa Faria, Carla, Blot, Adeline, Wauquier, Aurélie, Blond, Emilie, Sauvinet, Valérie, Gésan-Guiziou, Geneviève, Bodin, Jean-Pierre, Moulin, Philippe, Cheillan, David, Vidal, Hubert, Morio, Béatrice, Cotte, Eddy, Morel-Laporte, Françoise, Laville, Martine, Bernalier, Annick, Lambert-Porcheron, Stéphanie, Malpuech Brugere, Corinne, Michalski, Marie-Caroline, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Unité de Biostatistique-Informatique Médicale, CHU Clermont-Ferrand, Unité de Nutrition Endocrinologie Métabolisme, Service de Biochimie, Centre de Biologie et de Pathologie Sud, Hospices Civils de Lyon (HCL), ACTALIA Dairy Products and Technologies, Institut des Corps Gras (ITERG), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble, CRNH Auvergne, Microbiologie Environnement Digestif Santé (MEDIS), INRA Clermont-Ferrand-Theix-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Science et Technologie du Lait et de l'Oeuf (STLO), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), ENILIA-ENSMIC, Fédération d’Endocrinologie, Maladies Métaboliques, Diabète et Nutrition, Hôpital Louis Pradel, Unité Maladies Héréditaires du Métabolisme, Service de Biochimie et Biologie Moléculaire Grand Est, Centre de Biologie et de Pathologie Est, Centre Hospitalier Lyon Sud, Service de Chirurgie Digestive, ANR-11-ALID-007-01 (VALOBAB project 'sustainable VALOrization of Buttermilk: nutritionAl Benefits, functional value in food products and consumer perception', Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Actalia - division produits laitiers, Actalia [Saint-Lô], Centre de Recherche en Nutrition Humaine Auvergne [CHU Clermont-Ferrand] (CRNH A), Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-INSTITUT AGRO Agrocampus Ouest, Ciblage thérapeutique en Oncologie (EA3738), Université de Lyon-Université de Lyon, regional hospital clinical research programme (Programme Hospitalier de Recherche Clinique Interregional 2014: VALOBAB) 14-007French Dairy Interbranch Organization (CNIEL) Hospices Civils de Lyon, ProdInra, Archive Ouverte, Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), CNRS, SIGMA Clermont, Institut Pasca, Université Clermont Auvergne (UCA), Centre Hospitalier Universitaire de Clermont-Ferrand, Centre de Recherche en Nutrition Humaine, Hospices Civils de Lyon, CENS, Centre de Recherche en Nutrition Humaine Rhône-Alpes, CRNH Rhône-Alpes, UMR : Microbiologie, Environnement Digestif et Santé, Institut National de la Recherche Agronomique (INRA), Microbiologie Environnement Digestif Santé - Clermont Auvergne (MEDIS), Université Clermont Auvergne (UCA)-INRA Clermont-Ferrand-Theix, CRNH Rhône-Alpes,CENS, Centre de Recherche en Nutrition Humaine Rhône-Alpes, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), and Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-AGROCAMPUS OUEST
Subjects: obesity, sphingomyeline, lipide gras du lait, human health, Feces, fluids and secretions, cardiovascular disease, Risk Factors, maladie cardiovasculaire, lipid metabolism, colonic microflora, Cross-Over Studies, Ileostomy, cholestérol, food and beverages, santé humaine, Middle Aged, Lipids, Sphingomyelins, Cholestanol, Postmenopause, obésité, Cholesterol, Milk, Cardiovascular Diseases, lipoprotein-cholesterol, Apolipoprotein B-100, lipide polaire, lipids (amino acids, peptides, and proteins), Female, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], sphingomyéline, lipid absorption, allégations nutritionnelles et de santé, sphingomyelin, Double-Blind Method, Animals, Humans, Nutrition, Apolipoprotein A-I, [SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT], Cholesterol, HDL, ménopause, lipide du lait, Overweight, Gastrointestinal Microbiome, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Intestinal Absorption, Emulsifying Agents, Dietary Supplements, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Objectives: Nutritional strategies can play a major role in the management of cholesterolemia, notably in postmenopausal women at risk of CVD. Interest has recently grown on the potential health benefitsof milk polar lipids (MPL).We showed that isolipidic enrichment of the diet with MPL improved several lipid CV risk factors but underlying mechanisms remained unclear. We hypothesized that MPL reduceintestinal cholesterol absorption in humans.Methods:We performed a double-blind randomized controlled trial in 58 postmenopausal women with fasting HDL-cholesterol < 1.6 mM.They were subjected to a 4-week dietary intervention with daily consumption of a cream-cheese containing 12 g of milk fat including either 0 g (control, n = 19), 3 g (n = 19) or 5 g (n = 20) of MPL. Before and after each intervention, blood lipids were measured in the whole cohortwhereas fecal lipids and coprostanol were analyzed in a subgroup (n = 7–9 per group). A proof-of-concept mechanistic crossover study was also carried out in 4 ileostomized subjects who performed 8hpostprandial tests after consuming 0g-, 3g- or 5g-MPL enriched cheese labelled with 2H-cholesterol tracer. Plasma, chylomicrons and ilealefflux were analyzed.Results: Milk fat enriched with 3 to 5 g MPL induced doseresponse reductions in serum total cholesterol (up to −6.8% in 5 g group, p < 0.05), LDL-cholesterol (−8.7%, p < 0.05) and HDL/total-cholesterol ratio (p < 0.001), compared to the control that had no effect. Fecal excretion of coprostanol increased after MPL supplementation (p < 0.05, 3g- and 5g-MPL vs control), and the fecal coprostanol/cholesterol ratio was inversely correlated with serum total- and LDL-cholesterol after intervention (r = −0.5, p < 0.05). In ileostomized subjects, postprandial accumulation of 2Hcholesterol in plasma and chylomicrons was reduced after 3 to 5 g MPL consumption (p < 0.05, vs control). Both cholesterol and milk sphingomyelin increased in ileal efflux after MPL enriched cheeses (p < 0.05).Conclusions: Present results suggest that milk polar lipids decrease cholesterol absorption in humans through interactions with sphingomyelin and by increasing conversion of cholesterol to coprostanol.Funding Sources: ANR (French National Research Agency, VALOBAB project, ANR-11-ALID-007–01), PHRC-I (French Clinical Research Program, 14–007), CNIEL (French Dairy Interbranch Organization).
Published: 2018
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30. Analysis of Mucopolysaccharidosis Type VI through Integrative Functional Metabolomics

Author: Stéphane Marret, Monique Piraud, Carine Pilon, Tony Pereira, Soumeya Bekri, Abdellah Tebani, Lenaig Abily-Donval, Farid Zerimech, Isabelle Schmitz-Afonso, Jérôme Ausseil, Carlos Afonso, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Team 4 'NeoVasc' - INSERM U1245, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, CHU Amiens-Picardie, Laboratoire de Biochimie et Biologie Moléculaire [CHRU Lille] (Pôle de Biologie Pathologie Génétique), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), 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)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie générale [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre hospitalier universitaire de Rouen, CHU Lille, Institut Pasteur de Lille, Université de Lille, Université de Rouen Normandie [UNIROUEN], Chimie Organique et Bioorganique : Réactivité et Analyse [COBRA], Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] [Centre de Biologie et de Pathologie], IMPact de l'Environnement Chimique sur la Santé humaine (IMPECS) - ULR 4483, and Service de pédiatrie néonatale et réanimation - neuropédiatrie [CHU Rouen]
Subjects: Arylsulfatase B, Male, [SDV]Life Sciences [q-bio], Mucopolysaccharidosis type VI, Tandem mass spectrometry, lcsh:Chemistry, 0302 clinical medicine, Lysosomal storage disease, Biomarker discovery, skin and connective tissue diseases, Child, lcsh:QH301-705.5, Spectroscopy, mucopolysaccharidosis type VI, mass spectrometry, 0303 health sciences, Mucopolysaccharidosis VI, Chemistry, General Medicine, Middle Aged, metabolomics, Computer Science Applications, Phenotype, Child, Preschool, Metabolome, Female, Metabolic Networks and Pathways, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, In silico, Computational biology, Catalysis, Article, inherited metabolic diseases, Inorganic Chemistry, 03 medical and health sciences, Young Adult, Metabolomics, medicine, Humans, Physical and Theoretical Chemistry, lysosomal storage diseases, Molecular Biology, 030304 developmental biology, Aged, Maroteaux-Lamy syndrome, Maroteaux–Lamy syndrome, Organic Chemistry, nutritional and metabolic diseases, Computational Biology, Molecular Sequence Annotation, medicine.disease, lcsh:Biology (General), lcsh:QD1-999, 030217 neurology & neurosurgery
Abstract: Metabolic phenotyping is poised as a powerful and promising tool for biomarker discovery in inherited metabolic diseases. However, few studies applied this approach to mcopolysaccharidoses (MPS). Thus, this innovative functional approach may unveil comprehensive impairments in MPS biology. This study explores mcopolysaccharidosis VI (MPS VI) or Maroteaux&ndash, Lamy syndrome (OMIM #253200) which is an autosomal recessive lysosomal storage disease caused by the deficiency of arylsulfatase B enzyme. Urine samples were collected from 16 MPS VI patients and 66 healthy control individuals. Untargeted metabolomics analysis was applied using ultra-high-performance liquid chromatography combined with ion mobility and high-resolution mass spectrometry. Furthermore, dermatan sulfate, amino acids, carnitine, and acylcarnitine profiles were quantified using liquid chromatography coupled to tandem mass spectrometry. Univariate analysis and multivariate data modeling were used for integrative analysis and discriminant metabolites selection. Pathway analysis was done to unveil impaired metabolism. The study revealed significant differential biochemical patterns using multivariate data modeling. Pathway analysis revealed that several major amino acid pathways were dysregulated in MPS VI. Integrative analysis of targeted and untargeted metabolomics data with in silico results yielded arginine-proline, histidine, and glutathione metabolism being the most affected. This study is one of the first metabolic phenotyping studies of MPS VI. The findings might shed light on molecular understanding of MPS pathophysiology to develop further MPS studies to enhance diagnosis and treatments of this rare condition.
Published: 2018
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31. A daily gestational exposure to diesel exhaust particles impaired the brain and olfactory dopaminergic pathways of rabbit pups

Author: Estefania Bernal Melendez, Pascaline Bouillaud, Jacques Callebert, Pascale Chavatte-Palmer, Christine Baly, Henri Schroeder, Neurobiologie de l'olfaction (NBO), Institut National de la Recherche Agronomique (INRA), Université Paris Saclay (COmUE), Unité de Recherches Animal et Fonctionnalités des Produits Animaux (URAFPA), Institut National de la Recherche Agronomique (INRA)-Université de Lorraine (UL), Service de Biochimie et Biologie Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biologie du Développement et Reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), ANSES & ADEME (PNR-EST 2014-1-190), and The Nanosafety Platform-CEA..
Subjects: [SDV.TOX]Life Sciences [q-bio]/Toxicology, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS
Abstract: National audience
Published: 2018

32. Endocrine side-effects of new anticancer therapies: Overall monitoring and conclusions

Author: Magali Haissaguerre, Bruno Vergès, Françoise Borson-Chazot, Frédéric Albarel, Sarra Smati, C. Cortet, Benjamin Bouillet, Philippe Caron, Christine Do Cao, Delphine Drui, Philippe Chanson, Frédéric Illouz, Frederic Castinetti, E. Merlen, Perrine Buffier, Emmanuelle Kuhn, Ségolène Hescot, Bertrand Cariou, Véronique Raverot, Olivier Chabre, Claire Briet, Najiba Lahlou, F. Archambeaud, Jérôme Bertherat, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Centre de référence des maladies rares de l'hypophyse (HYPO), Service d'Endocrinologie, Diabète et Maladies Métaboliques, Service de Médecine interne B, Endocrinologie, Diabète, Maladies métaboliques [CHU Limoges], CHU Limoges, Institut Cochin (IC UM3 (UMR 8104 / U1016)), 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 d'endocrinologie et maladies métaboliques (Hôpital Cochin), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, 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), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Service d’Endocrinologie Diabétologie Nutrition [CHU Angers), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service d'Endocrinologie [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'endocrinologie, maladies métaboliques et nutrition (CHU de Toulouse), CHRU Toulouse, Service d'endocrinologie-diabétologie-nutrition [CHU Grenoble-Alpes], Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service d'Endocrinologie et des Maladies de la Reproduction [AP-HP Hôpital de Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service d’endocrinologie, diabétologie et maladies métaboliques [CHRU LIlle], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Physiopathologie de la plasticité neuronale, Université Bordeaux Segalen - Bordeaux 2, Service d'endocrinologie, diabétologie et nutrition (CHU de Bordeaux), CHU Bordeaux [Bordeaux], Institut Curie [Paris], Service d'Endocrinologie, Diabétologie et Nutrition [CHU Angers], Service de Biochimie et Biologie moléculaire [CH Lyon Sud], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Health Service and Performance Research (HESPER), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Fédération d'Endocrinologie, Hospices Civils de Lyon (HCL), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Unité de recherche de l'institut du thorax (ITX-lab), Service Endocrinologie, maladies métaboliques et nutrition [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire [Grenoble] (CHU), and CHU Toulouse [Toulouse]
Subjects: Oncology, medicine.medical_specialty, Consensus, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Antineoplastic Agents, 030209 endocrinology & metabolism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Endocrine System Diseases, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Dysthyroidism, Neoplasms, Internal medicine, Animals, Humans, Medicine, Endocrine system, Hypophysitis, Adverse effect, MTOR inhibitors, Tyrosine kinase inhibitors, Adrenal failure, business.industry, Diabetes, General Medicine, Immunotherapy, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Discovery and development of mTOR inhibitors, 3. Good health, Dyslipidemia, Anticancer treatment, 030220 oncology & carcinogenesis, business
Abstract: IF 0.795 (2017); International audience; The present final consensus statement of the French Society of Endocrinology lays out the assessments that are to be systematically performed before and during anticancer treatment by immunotherapy, tyrosine kinase inhibitors or mTOR inhibitors, even without onset of any endocrinopathy. It also discusses the CTCAE adverse event grading system in oncology and the difficulty of implementing it for endocrine side-effects of these anticancer treatments. Notably, this is why certain treatment steps applied in other side-effects (e.g., high-dose corticosteroids, contraindications to immunotherapy, etc.) need to be discussed before implementation for endocrine side-effects.
Published: 2018
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33. Is circadian rhythmicity a prerequisite to coma recovery? Circadian recovery concomitant to cognitive improvement in two comatose patients

Author: Jacques Luauté, Véronique Raverot, Claude Gronfier, Frédéric Dailler, François Cotton, Fabien Perrin, Florent Gobert, Bruno Claustrat, Médecine Physique et Réadaptation [Hôpital Henry Gabrielle - Lyon], Hôpital Henry Gabrielle [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de Biochimie et Biologie moléculaire [CH Lyon Sud], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), RMN et optique : De la mesure au biomarqueur, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Anesthesia and Intensive Care Medicine, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Division of Sleep Medicine, and Brigham and Women's Hospital [Boston]-Harvard University [Cambridge]
Subjects: 0301 basic medicine, Adult, Male, Consciousness, Hydrocortisone, Traumatic brain injury, [SDV]Life Sciences [q-bio], Physiology, Melatonin, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Cognition, Brain Injuries, Traumatic, medicine, Humans, Circadian rhythm, Longitudinal Studies, Coma, ComputingMilieux_MISCELLANEOUS, Suprachiasmatic nucleus, business.industry, Minimally conscious state, Recovery of Function, medicine.disease, Circadian Rhythm, 030104 developmental biology, Wakefulness, medicine.symptom, business, 030217 neurology & neurosurgery, Biomarkers, medicine.drug
Abstract: Circadian rhythmicity (CR) is involved in the regulation of all integrated functions, from sleep-wake cycle regulation to metabolic function, mood and cognition. However, the interdependence of CR, cognition and consciousness has been poorly addressed. To clarify the state of CR in coma and to determine the chronological relationship between its recovery and consciousness after brain lesions, we conducted a longitudinal observational study investigating how the state of CR was chronologically related with the recovery of behavioural wakefulness, cognition and/or awareness. Among 16 acute comatose patients, we recruited two 37-year-old patients with a persistent disorder of consciousness, presenting diencephalic lesions caused by severe traumatic brain injuries. Two biological urinary markers of CR were explored every 2 hours during 24 hours (6-sulfatoxymelatonin, free cortisol) with a dedicated methodology to extract the endogenous component of rhythmicity (environmental light recording, near-constant-routine protocol, control of beta-blockers). They presented an initial absence of rhythmic secretions and a recovered CR 7-8 months later. This recovery was not associated with the restoration of behavioural wakefulness, but with an improvement of cognition and awareness (up to the minimally conscious state). MRI showed a lesion pattern compatible with the interruption of either the main hypothalamic-sympathetic pathway or the accessory habenular pathway. These results suggest that CR may be a prerequisite for coma recovery with a potential but still unproven favourable effect on brain function of the resorted circadian melatonin secretion and/or the functional recovery of the suprachiasmatic nucleus (SCN). Assessing circadian functions by urinary melatonin should be further explored as a biomarker of cognition reappearance and investigated to prognosticate functional recovery.
Published: 2018
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34. Multifaceted Regulations of the Serotonin Transporter: Impact on Antidepressant Response

Author: Anne Baudry, Mathea Pietri, Jean-Marie Launay, Odile Kellermann, Benoit Schneider, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), 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 biochimie INSERM UMR-S942, Hôpital Lariboisière-APHP, Faculté de Pharmacie, Service de Biochimie et Biologie Moléculaire, hôpital Lariboisière, AP-HP, EA 3621, Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Pharma Research Department, F. Hoffmann-La Roche [Basel], SCHNEIDER, Benoit, Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord
Subjects: 0301 basic medicine, Central nervous system, Review, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, trafficking, medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Serotonin transporter, ComputingMilieux_MISCELLANEOUS, biology, business.industry, phosphorylation, General Neuroscience, SERT, Na/K ATPase, medicine.disease, 3. Good health, Solute carrier family, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], microRNAs, 030104 developmental biology, medicine.anatomical_structure, Autism spectrum disorder, SSRIs, biology.protein, Antidepressant, Anxiety, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Serotonin, medicine.symptom, Reuptake inhibitor, business, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Serotonin transporter, SERT (SLC64A for solute carrier family 6, member A4), is a twelve transmembrane domain (TMDs) protein that assumes the uptake of serotonin (5-HT) through dissipation of the Na+ gradient established by the electrogenic pump Na/K ATPase. Abnormalities in 5-HT level and signaling have been associated with various disorders of the central nervous system (CNS) such as depression, obsessive-compulsive disorder, anxiety disorders, and autism spectrum disorder. Since the 50s, SERT has raised a lot of interest as being the target of a class of antidepressants, the Serotonin Selective Reuptake Inhibitors (SSRIs), used in clinics to combat depressive states. Because of the refractoriness of two-third of patients to SSRI treatment, a better understanding of the mechanisms regulating SERT functions is of priority. Here, we review how genetic and epigenetic regulations, post-translational modifications of SERT, and specific interactions between SERT and a set of diverse partners influence SERT expression, trafficking to and away from the plasma membrane and activity, in connection with the neuronal adaptive cell response to SSRI antidepressants.
Published: 2018
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35. A 1-week extension of a ketogenic diet provides a further decrease in myocardial 18F-FDG uptake and a high detectability of myocarditis with FDG-PET

Author: Alexandra Clément, Jean-Luc Olivier, Allan Kolodziej, Julien Pierson, Gilles Karcher, Henri Boutley, Sylvain Poussier, Pierre-Yves Marie, Mickael Lhuillier, Fatiha Maskali, Nancyclotep- Experimental Imaging Platform = Plate-forme d'imagerie moléculaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Lorraine (UL), Service de Biochimie et Biologie Moléculaire, Nutrition et Métabolisme [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Médecine Nucléaire [Nancy], Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), and Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)
Subjects: medicine.medical_specialty, Myocarditis, Normal diet, medicine.medical_treatment, 030204 cardiovascular system & hematology, 030218 nuclear medicine & medical imaging, 18f fdg uptake, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Medicine, Radiology, Nuclear Medicine and imaging, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, medicine.diagnostic_test, business.industry, Carbohydrate, medicine.disease, 3. Good health, Endocrinology, Positron emission tomography, Ketone bodies, Cardiology and Cardiovascular Medicine, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Ketogenic diet
Abstract: Short periods of fasting and/or low-carbohydrate diet have been proven beneficial for decreasing the myocardial uptake of 18F-fluorodeoxyglucose (18F-FDG) and enhancing the detection of inflammatory heart diseases by 18F-FDG positron emission tomography (PET). This study aimed at determining whether this benefit is increased when a low-carbohydrate ketogenic diet is prolonged up to 7 days. Wistar rats underwent serial 18F-FDG-PET imaging after an 18-hour fasting period and after 2, 4 and 7 days of a ketogenic diet (3% carbohydrate) and they were compared to rats submitted to the same protocol but with normal diet (44% carbohydrate). The 18F-FDG-PET/ketogenic protocol was also applied in rats with immune myocarditis (injection of porcine cardiac myosin). The 7-day ketogenic diet was associated with (1) a sustained increase in circulating ketone bodies at an equivalent level to that reached after 18-hour fasting, (2) a gradual decrease in 18F-FDG uptake within normal myocardium reaching a lower level compared to fasting at the 7th day (myocardium-to-blood ratios: 1.68 ± 1.02 vs 3.25 ± 1.40, P
Published: 2018
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36. Cerebellar compartmentation of prion pathogenesis

Author: Ragagnin, Audrey, Ezpeleta, Juliette, Guillemain, Aurélie, Boudet-Devaud, François, Haeberlé, Anne-Marie, Demais, Valérie, Vidal, Catherine, Demuth, Stanislas, Béringue, Vincent, Kellermann, Odile, Schneider, Benoit, Grant, Nancy, Bailly, Yannick, Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre de Neurochimie, Institut Pasteur [Paris], Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Domaine d’Intérêt Majeur Cerveau Pensée of Région Ile-de-France, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), SCHNEIDER, Benoit, UPR 2356 - Neurotransmission et Secrétion Neuroendocrine, Centre National de la Recherche Scientifique (CNRS), Plateforme d'Imagerie In Vitro, Université Louis Pasteur - Strasbourg I-Institut Fédératif de Recherche 37 des Neurosciences, Pharmacologie, toxicologie et signalisation cellulaire (U747), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA), Faculté de Pharmacie, Service de Biochimie et Biologie Moléculaire, hôpital Lariboisière, AP-HP, EA 3621, Université Paris Descartes - Paris 5 (UPD5), and Université de Franche-Comté (UFC)
Subjects: animal diseases, Green Fluorescent Proteins, Purkinje cell, Mice, Transgenic, Prion Proteins, prion, Cerebellum, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], ComputingMilieux_MISCELLANEOUS, Research Articles, Neurons, zebrin, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], nervous system diseases, Encephalopathy, Bovine Spongiform, Mice, Inbred C57BL, Receptors, Tumor Necrosis Factor, Type I, inflammation, Astrocytes, Synapses, cerebellar compartmentation, Cattle, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Microglia, Excitatory Amino Acid Transporter 4, Scrapie
Abstract: International audience; In prion diseases, the brain lesion profile is influenced by the prion “strain” properties, the invasion route to the brain, and still unknown host cell‐specific parameters. To gain insight into those endogenous factors, we analyzed the histopathological alterations induced by distinct prion strains in the mouse cerebellum. We show that 22L and ME7 scrapie prion proteins (PrP22L, PrPME7), but not bovine spongiform encephalopathy PrP6PB1, accumulate in a reproducible parasagittal banding pattern in the cerebellar cortex of infected mice. Such banding pattern of PrP22L aggregation did not depend on the neuroinvasion route, but coincided with the parasagittal compartmentation of the cerebellum mostly defined by the expression of zebrins, such as aldolase C and the excitatory amino acid transporter 4, in Purkinje cells. We provide evidence that Purkinje cells display a differential, subtype‐specific vulnerability to 22L prions with zebrin‐expressing Purkinje cells being more resistant to prion toxicity, while in stripes where PrP22L accumulated most zebrin‐deficient Purkinje cells are lost and spongiosis accentuated. In addition, in PrP22L stripes, enhanced reactive astrocyte processes associated with microglia activation support interdependent events between the topographic pattern of Purkinje cell death, reactive gliosis and PrP22L accumulation. Finally, we find that in preclinically‐ill mice prion infection promotes at the membrane of astrocytes enveloping Purkinje cell excitatory synapses, upregulation of tumor necrosis factor‐α receptor type 1 (TNFR1), a key mediator of the neuroinflammation process. These overall data show that Purkinje cell sensitivity to prion insult is locally restricted by the parasagittal compartmentation of the cerebellum, and that perisynaptic astrocytes may contribute to prion pathogenesis through prion‐induced TNFR1 upregulation.
Published: 2018
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37. Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant systematic review

Author: Ingrid Terreehorst, Jean-Christoph Roger J-P Caubet, Luciana Kase Tanno, Josefina Cernadas, M. Gotua, M. Atanaskovic, Pascal Demoly, M. Blanca, Abderrahim Oussalah, Alla Nakonechna, Andreas J. Bircher, A. Barbaud, Antonino Romano, Jose Julio Laguna, Knut Brockow, Cristobalina Mayorga, Jean-Louis Guéant, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Biochimie et Biologie Moléculaire, Nutrition et Métabolisme [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Biomedical Research Institute of Málaga (IBIMA), Service de Dermatologie et Allergologie [CHRU Nancy], Allergy and Immunology Clinic [Royal Liverpool and Broadgreen University Hospital], Royal Liverpool and Broadgreen University Hospital NHS Trust, Immunoallergy Department [Porto], Centro Hospitalar São João EPE, Center for Allergy and Immunology Research [Tbilisi], Department of Dermatology and Allergy Biederstein, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Division of Paediatrics [Geneva], University Hospital of Geneva, University Hospital Basel [Basel], Department of Allergology and Pulmonology [Belgrade], University Children's Hospital [Belgrade], Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Hospital Sírio-Libanês [São Paulo, Brazil], Academisch Medisch Centrum bij, Universiteit van Amsterdam (UvA), Allergy Unit [Cruz Roja-Madrid], Hospital Central de la Cruz Roja San Jose y Santa Adela, and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
Subjects: Hypersensitivity, Immediate, Candidate gene, [SDV]Life Sciences [q-bio], Immunology, Human leukocyte antigen, Drug Hypersensitivity, Atopy, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, Genetic predisposition, medicine, Humans, Immunology and Allergy, Genetic Predisposition to Disease, 030212 general & internal medicine, Allele frequency, Aspirin, ddc:618, business.industry, Anti-Inflammatory Agents, Non-Steroidal, Nonsteroidal anti-inflammatory drugs, Genetic Variation, Environmental exposure, Immunoglobulin E, medicine.disease, Anti-Bacterial Agents, 3. Good health, Beta-lactam antibiotics, 030228 respiratory system, Genetic predictors, IgE-mediated drug allergy, business, medicine.drug
Abstract: International audience; Drug hypersensitivity includes allergic (AR) and nonallergic reactions (NARs) influenced by genetic predisposition. We performed a systematic review of genetic predictors of IgE-mediated AR and NAR with MEDLINE and PubMed search engine between January 1966 and December 2014. Among 3110 citations, the search selected 53 studies, 42 of which remained eligible. These eligible studies have evaluated genetic determinants of immediate reactions (IR) to beta-lactams (n = 19), NAR against aspirin (n = 12) and other nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 8), and IR to biologics (n = 3). We reported two genomewide association studies and four case–control studies on candidate genes validated by replication. Genes involved in IR to beta-lactams belonged to HLA type 2 antigen processing, IgE production, atopy, and inflammation, including 4 genes validated by replications, HLA-DRA, ILR4, NOD2, and LGALS3. Genes involved in NAR to aspirin belonged to arachidonic acid pathway, membrane-spanning 4A gene family, histamine production pathway, and pro-inflammatory cytokines, while those involved in NAR to all NSAIDs belonged to arachidonic acid pathway and HLA antigen processing pathway. ALOX5 was a common predictor of studies on NAR to both aspirin and NSAIDs. Although these first conclusions could be drawn, this review highlights also the lack of reliable data and the need for replicating studies in contrasted populations, taking into account worldwide allele frequencies, gene–gene interactions, and contrasted situations of environmental exposure.
Published: 2016
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38. Serum levels of 25(OH)D are not associated with venous thromboembolism in the elderly population

Author: J.-L. Carre, Andro M, Moineau Mp, Cécile Tromeur, Le Gal G, Maelenn Gouillou, Karine Lacut, Aurélien Delluc, Gentric A, Service de Médecine Interne Gériatrique (BREST - SMIG), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Service de Biochimie et Biologie Moléculaire, Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Cachan (ENS Cachan), Service d'angiologie et d'hémostase (MR), and Hôpital Universitaire de Genève
Subjects: Male, Time Factors, [SDV]Life Sciences [q-bio], Walking, 030204 cardiovascular system & hematology, Body Mass Index, chemistry.chemical_compound, 0302 clinical medicine, Odds Ratio, Prevalence, risk factors, Medicine, Prospective Studies, 030212 general & internal medicine, Vitamin D, Aged, 80 and over, education.field_of_study, Incidence, Incidence (epidemiology), Age Factors, Hematology, aged, Female, France, Independent Living, Seasons, case-control, Vitamin, medicine.medical_specialty, venous thromboembolism, Population, Risk Assessment, vitamin D deficiency, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Vitamin D and neurology, Humans, Obesity, cardiovascular diseases, education, Geriatric Assessment, Gynecology, Chi-Square Distribution, business.industry, Case-control study, Odds ratio, Vitamin D Deficiency, equipment and supplies, medicine.disease, Logistic Models, chemistry, Case-Control Studies, Multivariate Analysis, business, Body mass index, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: SummaryThe prevalence of both vitamin D deficiency and venous thromboembolism (VTE) is important in the elderly. Previous studies have provided evidence for a possible association between vitamin D status and the risk of VTE. Thus, we aimed to investigate the association between vitamin D levels and VTE in the population aged 75 and over included in the EDITH case-control study. The association between vitamin D status and VTE was analysed. We also analysed the monthly and seasonal variations of VTE and vitamin D. Between May 2000 and December 2009, 340 elderly patients (mean age 81.5 years, 32 % men) with unprovoked VTE and their controls were included. The univariate and multivariate analysis found no significant association between serum levels of vitamin D and the risk of unprovoked VTE. In the unadjusted analysis, a higher BMI was statistically associated with an increased risk of VTE (OR 1.09; 95 % CI 1.05–1.13) whereas a better walking capacity and living at home were associated with a decreased rate of VTE: OR 0.57; 95 % CI 0.36–0.90 and 0.40; 95 % CI 0.25–0.66, respectively. Although not significant, more VTE events occurred during winter (p=0.09). No seasonal variations of vitamin D levels were found (p=0.11). In conclusion, in contrast with previous reports our findings suggest that vitamin D is not associated with VTE in the elderly population.
Published: 2016
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39. Cross-platform comparison for the detection of RAS mutations in cfDNA (ddPCR Biorad detection assay, BEAMing assay, and NGS strategy)

Author: Garcia, Jessica, Forestier, Julien, Dusserre, Eric, Wozny, Anne-Sophie, Geiguer, Florence, Merle, Patrick, Tissot, Claire, Ferraro-Peyret, Carole, Jones, Frederick S., Edelstein, Daniel L., Cheynet, Valérie, Bardel, Claire, Vilchez, Gaelle, Xu, Zhenyu, Bringuier, Pierre Paul, Barritault, Marc, Brengle-Pesce, Karen, Guillet, Marielle, Chauvenet, Marion, Manship, Brigitte, Brevet, Marie, Rodriguez-Lafrasse, Claire, Hervieu, Valérie, Couraud, Sébastien, Walter, Thomas, Payen, Léa, Manship, Brigitte, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [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), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), Service d'anatomopathologie, and Hospices Civils de Lyon (HCL)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS)
Subjects: [SDV] Life Sciences [q-bio], circulating-free DNA, liquid biopsy, digital PCR, NGS, [SDV]Life Sciences [q-bio], colon and lung cancer, ComputingMilieux_MISCELLANEOUS, Research Paper
Abstract: CfDNA samples from colon (mCRC) and non-small cell lung cancers (NSCLC) (CIRCAN cohort) were compared using three platforms: droplet digital PCR (ddPCR, Biorad); BEAMing/OncoBEAM™-RAS-CRC (Sysmex Inostics); next-generation sequencing (NGS, Illumina), utilizing the 56G oncology panel (Swift Biosciences). Tissue biopsy and time matched cfDNA samples were collected at diagnosis in the mCRC cohort and during 1st progression in the NSCLC cohort. Excellent matches between cfDNA/FFPE mutation profiles were observed. Detection thresholds were between 0.5–1% for cfDNA samples examined using ddPCR and NGS, and 0.03% with BEAMing. This high level of sensitivity enabled the detection of KRAS mutations in 5/19 CRC patients with negative FFPE profiles. In the mCRC cohort, comparison of mutation results obtained by testing FFPE to those obtained by testing cfDNA by ddPCR resulted in 47% sensitivity, 77% specificity, 70% positive predictive value (PPV) and 55% negative predictive value (NPV). For BEAMing, we observed 93% sensitivity, 69% specificity, 78% PPV and 90% NPV. Finally, sensitivity of NGS was 73%, specificity was 77%, PPV 79% and NPV 71%. Our study highlights the complementarity of different diagnostic approaches and variability of results between OncoBEAM™-RAS-CRC and NGS assays. While the NGS assay provided a larger breadth of coverage of the major targetable alterations of 56 genes in one run, its performance for specific alterations was frequently confirmed by ddPCR results.
Published: 2018
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40. Newborn Screening for Severe Combined Immunodeficiency: Analytic and Clinical Performance of the T Cell Receptor Excision Circle Assay in France (DEPISTREC Study)

Author: Sophie Mirallié, David Cheillan, Caroline Hémont, Cécile Dert, M. Audrain, Enora M. Q. Pinel, Maxime A. G. Fournier, Véronique A. Sébille-Rivain, Aurélie M-P. Le Thuaut, Alexandra Léger, Caroline Thomas, Aurore Prat, Marie Rimbert, Eléonore Divry, Laboratoire d'Immunologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Dendritic cells and immunoregulation in transplantation and immunopathology (Team 1 - U1064 Inserm - CRTI), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Laboratoire de dépistage néonatal [CHU Nantes], Service de Biochimie et Biologie Moléculaire Grand Est, Centre de Biologie et de Pathologie Est[Lyon], Hospices Civils de Lyon (HCL), Plateforme de Méthodologie et Biostatistique, Direction de la Recherche [CHU Nantes], Direction de la Recherche, Cellule Innovation [CHU Nantes], Service d'oncologie pédiatrique [CHU Nantes], PRMEN1322265N (French Ministry of Health)., and Le Bihan, Sylvie
Subjects: 0301 basic medicine, Oncology, Newborn screening, medicine.medical_specialty, T cell, Cost-Benefit Analysis, T-Lymphocytes, Immunology, Clinical Decision-Making, Receptors, Antigen, T-Cell, Asymptomatic, 03 medical and health sciences, 0302 clinical medicine, Medical microbiology, Neonatal Screening, 030225 pediatrics, Internal medicine, Immunology and Allergy, Medicine, Humans, Public Health Surveillance, Severe combined immunodeficiency, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, T-cell receptor excision circles, Infant, Newborn, Disease Management, Infant, Reproducibility of Results, analytic performance, medicine.disease, T cell deficiency, 3. Good health, Clinical trial, clinical performance, 030104 developmental biology, medicine.anatomical_structure, Biological Assay, Severe Combined Immunodeficiency, severe combined immunodeficiency (SCID), France, Reagent Kits, Diagnostic, medicine.symptom, business, Biomarkers, T cell receptor excision circle (TREC) quantification, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Severe combined immunodeficiency (SCID) is characterized by a major T cell deficiency. Infants with SCID are asymptomatic at birth but die from infections in the first year of life if not treated. Survival rates are better for early treatment. SCID therefore meets criteria for newborn screening (NBS). T cell receptor excision circle (TREC) quantification is a reliable marker of T cell deficiency and can be performed using Guthrie cards. The DEPISTREC project was designed to study the feasibility, clinical utility, and cost-effectiveness of generalized SCID screening in France. About 200,000 babies from all over the country were screened at birth with a commercial kit. We determined assay performance and proposed a cutoff for classification of results. Our findings suggest that, given clearly established validation rules and decision-making procedures, the TREC assay is a suitably specific and sensitive method for high-throughput SCID screening. Clinical Trials: NCT02244450.
Published: 2018
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41. Brain and olfactory dopaminergic pathways are impaired in rabbit pups daily exposed to diesel exhaust nanoparticules during gestation

Author: Bernal-Meléndez, Estefanía, Bouillaud, P, Callebert, Jacques, Olivier, B, Lacroix, Marie-Christine, Durieux, Didier, Persuy, Marie-Annick, Couturier-Tarrade, Anne, Rousseau-Ralliard, Delphine, Chavatte-Palmer, Pascale, Baly, Christine, Schroeder, Henri, Neurobiologie de l'olfaction (NBO), Institut National de la Recherche Agronomique (INRA), Unité de Recherches Animal et Fonctionnalités des Produits Animaux (URAFPA), Institut National de la Recherche Agronomique (INRA)-Université de Lorraine (UL), Université Paris Saclay (COmUE), Université de Lorraine (UL), Service de Biochimie et Biologie Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biologie du Développement et Reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), and RISE (Rencontres Internationales Santé & Environnement).
Subjects: [SDV]Life Sciences [q-bio], [INFO]Computer Science [cs], ComputingMilieux_MISCELLANEOUS
Abstract: National audience
Published: 2017

42. BCL-XL directly modulates RAS signalling to favour cancer cell stemness

Author: Carné Trécesson, Sophie de, Souazé, Frédérique, Basseville, Agnès, Bernard, Anne-Charlotte, Pécot, Jessie, Lopez, Jonathan, Bessou, Margaux, Sarosiek, Kristopher A., Letai, Anthony, Barillé-Nion, Sophie, Valo, Isabelle, Coqueret, Olivier, Guette, Catherine, Campone, Mario, Gautier, Fabien, Juin, Philippe Paul, Bernardo, Elizabeth, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [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), Service de Biochimie et Biologie moléculaire [CH Lyon Sud], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Dana-Farber Cancer Institute [Boston, USA], Harvard Medical School [Boston] (HMS), Département de Biopathologie [Angers], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Senescence Escape and Soluble Markers of Cancer Progression (CRCINA-ÉQUIPE 12), Dr S. de Carné Trécesson was supported by Institut National du Cancer, Dr J. Pécot by Ministère de la Recherche et de l’Enseignement Supérieur and Dr A. Basseville by Fondation de France. This work was supported by Canceropole Grand Ouest (CIC project 2010–2012, MATURE project 2017–18), ARC (R15083NN), Fondation de France (2015) and INCA PLBio (R12134NN) to PJ, Ligue Grand Ouest (R13137) to SCT and PJ and Fondation de France (2017) to AB., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Proteomics, Science, bcl-X Protein, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Apoptosis, Breast Neoplasms, Article, Mass Spectrometry, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Animals, Humans, lcsh:Science, HMGA2 Protein, Gene Expression Regulation, Neoplastic, Phenotype, Drug Resistance, Neoplasm, MCF-7 Cells, Neoplastic Stem Cells, ras Proteins, lcsh:Q, Female, Neoplasm Recurrence, Local, Proto-Oncogene Proteins c-fos, Plasmids, Signal Transduction
Abstract: In tumours, accumulation of chemoresistant cells that express high levels of anti-apoptotic proteins such as BCL-XL is thought to result from the counter selection of sensitive, low expresser clones during progression and/or initial treatment. We herein show that BCL-XL expression is selectively advantageous to cancer cell populations even in the absence of pro-apoptotic pressure. In transformed human mammary epithelial cells BCL-XL favours full activation of signalling downstream of constitutively active RAS with which it interacts in a BH4-dependent manner. Comparative proteomic analysis and functional assays indicate that this is critical for RAS-induced expression of stemness regulators and maintenance of a cancer initiating cell (CIC) phenotype. Resistant cancer cells thus arise from a positive selection driven by BCL-XL modulation of RAS-induced self-renewal, and during which apoptotic resistance is not necessarily the directly selected trait., BCL-XL provides a survival advantage to cancer cells even in the absence of apoptotic pressures. In this study, the authors show that BCL-XL interacts with RAS in a BH4-dependent manner and regulates RAS-mediated activation of pathways involved in the stemness feature of breast cancer cells.
Published: 2017
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43. Capteur microonde à base de résonateur planaire pour une analyse glycémique in-situ

Author: Srour, Mahdi, Potelon, Benjamin, Quendo, Cédric, Carré, Jean-Luc, Person, Christian, Lab-STICC_UBO_MOM_DIM, Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance (Lab-STICC), École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Service de Biochimie et Biologie Moléculaire, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Lab-STICC_TB_MOM_DIM, Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance (UMR 3192) (Lab-STICC), Université européenne de Bretagne - European University of Brittany (UEB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université européenne de Bretagne - European University of Brittany (UEB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Quendo, Cedric, Université européenne de Bretagne - European University of Brittany (UEB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université européenne de Bretagne - European University of Brittany (UEB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Brestois du Numérique et des Mathématiques (IBNM), and Université de Brest (UBO)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Capteurs, Micro-ondes, [SPI.TRON] Engineering Sciences [physics]/Electronics, [SPI.TRON]Engineering Sciences [physics]/Electronics
Abstract: National audience; Cet article présente les premiers résultats de la conception et du développement d’un capteur microonde basé sur un résonateur à stub quart d’onde. L’idée de ce travail est d’utiliser des tubes à essai standards tels que ceux utilisés au CHRU de Brest remplis d’une solution aqueuse de glucose pour en déterminer sa concentration. L’interaction entre le champ électromagnétique et la solution (eau/glucose) à mesurer peut être observée en mesurant les variations des paramètres S entre 2 et 8 GHz. La technique présentée ci-après peut être utilisée pour d’autres liquides et solutions aqueuses.
Published: 2017

44. Wildtype motoneurons, ALS-Linked SOD1 mutation and glutamate profoundly modify astrocyte metabolism and lactate shuttling

Author: Mavel, Sylvie, Madji Hounoum, Blandine, Coque, Emmanuelle, Patin, Franck, Vourc'H, Patrick, Marouillat, Sylviane, Nadal-Desbarats, Lydie, Emond, Patrick, Corcia, Philippe, Andres, Christian, Raoul, Cédric, Blasco, Hélène, Equipe neurogénétique et neurométabolomique, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie et Biologie Moléculaire, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Research Institute of Organic Agriculture - Forschungsinstitut für biologischen Landbau (FiBL), Développement et pathologie du motoneurone, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie et Biologie Moléculaire, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, and Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2017
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45. Dosage de la thyroglobuline dans les liquides de rinçage d’aiguille de cytoponction ganglionnaire : influence des conditions pré-analytiques [Thyroglobulin assay in fluids from lymph node fine needle-aspiration washout: influence of pre-analytical conditions]

Author: Boux de Casson, Florence, Moal, Valérie, Gauchez, Anne-Sophie, Moineau, Marie-Pierre, Sault, Corinne, Schlageter, Marie-Hélène, Massart, Catherine, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Plateforme de radioactivité [Grenoble], Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Biologie et de Pathologie - IBP [CHU Grenoble]-Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), Service de Biochimie et Biologie Moléculaire, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Unite de Biologie Cellulaire (Biol Cell - ST LOUIS - PARIS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire [Grenoble] (CHU)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Biologie et de Pathologie [CHU Grenoble] (IBP), and Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: washout, [SDV]Life Sciences [q-bio], differentiated thyroid cancer, non-specific adsorption, fine-needle-aspiration, thyroglobulin
Abstract: International audience; The aim of this study was to evaluate the pre-analytical factors contributing to uncertainty in thyroglobulin measurement in fluids from fine-needle aspiration (FNA) washout of cervical lymph nodes. We studied pre-analytical stability, in different conditions, of 41 samples prepared with concentrated solutions of thyroglobulin (FNA washout or certified standard) diluted in physiological saline solution or buffer containing 6% albumin. In this buffer, over time, no changes in thyroglobulin concentrations were observed in all storage conditions tested. In albumin free saline solution, thyroglobulin recovery rates depended on initial sample concentrations and on modalities of their conservation (in conventional storage tubes, recovery mean was 56% after 3 hours-storage at room temperature and 19% after 24 hours-storage for concentrations ranged from 2 to 183 μg/L; recovery was 95%, after 3 hours or 24 hours-storage at room temperature, for a concentration of 5,656 μg/L). We show here that these results are due to non-specific adsorption of thyroglobulin in storage tubes, which depends on sample protein concentrations. We also show that possible contamination of fluids from FNA washout by plasma proteins do not always adequately prevent this adsorption. In conclusion, non-specific adsorption in storage tubes strongly contributes to uncertainty in thyroglobulin measurement in physiological saline solution. It is therefore recommended, for FNA washout, to use a buffer containing proteins provided by the laboratory.
Published: 2017
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46. Comment on ‘Efficacy of daclatasvir-based quadruple therapy in nonresponder patients infected by hepatitis C virus genotype 4: the ANRS HC32 QUATTRO study’

Author: Vincent Leroy, Olivier Schischmanoff, Lawrence Serfaty, Dominique Roulot, Chloé Rousseau, Véronique Loustaud-Ratti, Alain Renault, Eric Bellissant, Fabien Zoulim, Vincent Thibault, Hélène Fontaine, Jean-Pierre Bronowicki, Alpha Diallo, Denis Ouzan, Tarik Asselah, Ventzislava Petrov-Sanchez, Valérie Canva, Marc Bourlière, Claire Laforest, Service de Gastro-entérologie [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pharmacologie [Rennes], Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d’Hépatologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Service d'hépato-gastro-entérologie, Assistance Publique - Hôpitaux de Marseille (APHM), Hôpital Saint-Joseph [Marseille], Hôpital Huriez-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'hépato-gastroentérologie [CHU Grenoble Alpes], Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), Service de Bactériologie, Virologie, Hygiène [CHU Limoges], CHU Limoges, Service de biochimie et biologie moléculaire, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], ANRS France Recherche Nord & sud Sida-hiv hépatites, Service d'hépatologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Liver Cirrhosis, Male, Pyrrolidines, Sustained Virologic Response, [SDV]Life Sciences [q-bio], Pilot Projects, Hepacivirus, medicine.disease_cause, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Pegylated interferon, Treatment Failure, 030212 general & internal medicine, Sulfonamides, Leukopenia, Imidazoles, Valine, Middle Aged, Viral Load, Recombinant Proteins, 3. Good health, Treatment Outcome, RNA, Viral, Drug Therapy, Combination, Female, 030211 gastroenterology & hepatology, medicine.symptom, medicine.drug, Adult, medicine.medical_specialty, Daclatasvir, Genotype, Hepatitis C virus, 030106 microbiology, Neutropenia, Interferon alpha-2, Antiviral Agents, 03 medical and health sciences, Internal medicine, Hepatitis C virus genotype, Ribavirin, medicine, Humans, Adverse effect, Hepatology, business.industry, Interferon-alpha, Hepatitis C, Chronic, medicine.disease, Isoquinolines, Virology, chemistry, Asunaprevir, Carbamates, business
Abstract: International audience; BACKGROUND: A few direct antiviral agents have been studied in difficult-to-treat patients infected by hepatitis C virus (HCV) genotype 4 (GT4). The efficacy of daclatasvir (DCV), asunaprevir (ASV), pegylated interferon and ribavirin (Peg-IFN/RBV) association was investigated in these patients. PATIENTS AND METHODS: This open-label, single-arm, phase 2 study was conducted in HCV GT4 patients who were null or partial responders to Peg-IFN/RBV. Patients received 24 weeks of DCV (60 mg, once daily), ASV (100 mg, twice daily) and Peg-IFN/RBV. The primary endpoint was sustained virologic response at post-treatment week 12 [sustained virologic response (SVR)12]. RESULTS: Sixty patients were included; 45 (75%) were previous null responders and 27 (45%) had cirrhosis. The most frequent subtypes were GT4a (48%) and GT4d (27%) with 25% of the patients being infected with other subtypes such as 4c, 4r, 4f, 4k, 4j and 4q. The global SVR12 was 95% (90% confidence interval: 90.4-99.6) and 96.3% (90% confidence interval: 87.5-99.5) in cirrhotic patients. All patients achieving SVR12 also achieved SVR24. Previous Peg-IFN/RBV response, IL28b genotype, cirrhosis status or GT4 subtypes did not influence SVR12 rates. Serious adverse events occurred in 13% of the patients, four being cirrhotic and four noncirrhotic. Three (5%) patients stopped HCV therapy prematurely: one because of virologic breakthrough and two because of serious adverse events. Grade 3/4 laboratory abnormalities included leukopenia (33%), neutropenia (27%), thrombocytopenia (4%) and transaminases increase (2%). CONCLUSION: Association of DCV plus ASV and peg-IFN/RBV for 24 weeks demonstrated a high rate of SVR12 in HCV GT4-infected prior nonresponders, independently of the cirrhotic status or the GT4 subtype. The safety profile was acceptable, even in cirrhotic patients.
Published: 2018
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47. Advances in the Research of Melatonin in Autism Spectrum Disorders: Literature Review and New Perspectives

Author: Nemat Jaafari, Michel Botbol, Olivier Schischmanoff, George M. Anderson, Sylvie Tordjman, Guillaume Bronsard, Sophie Ribardiere, Solenn Kermarrec, Marianne Barbu-Roth, Eric Bellissant, Claire Fougerou, Julie Vernay-Leconte, David Cohen, Imen Najjar, Remi Fagard, Enas Lagdas, Service Psychiatrie de l'Enfant et de l'Adolescent, CHU Pontchaillou [Rennes]-Centre Hospitalier Guillaume Régnier [Rennes]-CHS (Centre Hospitalier Spécialisé lutte Maladies Mentales), Laboratoire Psychologie de la Perception ( LPP - UMR 8242 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Investigation Clinique [Rennes] ( CIC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Pharmacologie, CHU Pontchaillou [Rennes], Laboratory of Developmental Neurochemistry, Yale Child Study Center, Department of Laboratory Medicine, Yale School of Medicine, Service de psychiatrie de l'enfant et de l'adolescent, CHU Pitié-Salpêtrière [APHP], CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers ( CHU Poitiers ) -Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Adaptateurs de signalisation en hématologie ( ASIH ), Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de biochimie et biologie moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne-Université Paris 13 ( UP13 ), Service Hospitalo-Universitaire de Psychiatrie de l'Enfant et de l'Adolescent, Université de Brest ( UBO ), Santé Publique et maladies Chroniques : Qualité de vie Concepts, Usages et Limites, Déterminants ( SPMC ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ), Maison Départementale de l'Adolescent et Centre Médico-Psycho-Pédagogique, Le Corre, Morgane, Laboratoire Psychologie de la Perception (LPP - UMR 8242), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pharmacologie [Rennes], Yale School of Medicine [New Haven, Connecticut] (YSM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Adaptateurs de signalisation en hématologie (ASIH), Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Brest (UBO), Santé Publique et maladies Chroniques : Qualité de vie Concepts, Usages et Limites, Déterminants (SPMC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Yale University School of Medicine, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: [ SDV.MHEP.PED ] Life Sciences [q-bio]/Human health and pathology/Pediatrics, melatonin, Review, lcsh:Chemistry, Peripheral oscillators, Pineal gland, 0302 clinical medicine, stereotyped behaviors, lcsh:QH301-705.5, Spectroscopy, 0303 health sciences, Social communication, General Medicine, 3. Good health, Computer Science Applications, medicine.anatomical_structure, Communication Disorders, hormones, hormone substitutes, and hormone antagonists, biological clocks, medicine.drug, circadian rhythm, medicine.medical_specialty, endocrine system, autism spectrum disorders, social communication, Catalysis, Inorganic Chemistry, Melatonin, 03 medical and health sciences, Nonverbal communication, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, medicine, Animals, Humans, Circadian rhythm, Physical and Theoretical Chemistry, Psychiatry, Molecular Biology, 030304 developmental biology, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Organic Chemistry, synchrony, medicine.disease, Social relation, lcsh:Biology (General), lcsh:QD1-999, Child Development Disorders, Pervasive, Autism, business, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Abnormalities in melatonin physiology may be involved or closely linked to the pathophysiology and behavioral expression of autistic disorder, given its role in neurodevelopment and reports of sleep-wake rhythm disturbances, decreased nocturnal melatonin production, and beneficial therapeutic effects of melatonin in individuals with autism. In addition, melatonin, as a pineal gland hormone produced from serotonin, is of special interest in autistic disorder given reported alterations in central and peripheral serotonin neurobiology. More specifically, the role of melatonin in the ontogenetic establishment of circadian rhythms and the synchronization of peripheral oscillators opens interesting perspectives to ascertain better the mechanisms underlying the significant relationship found between lower nocturnal melatonin excretion and increased severity of autistic social communication impairments, especially for verbal communication and social imitative play. In this article, first we review the studies on melatonin levels and the treatment studies of melatonin in autistic disorder. Then, we discuss the relationships between melatonin and autistic behavioral impairments with regard to social communication (verbal and non-verbal communication, social interaction), and repetitive behaviors or interests with difficulties adapting to change. In conclusion, we emphasize that randomized clinical trials in autism spectrum disorders are warranted to establish potential therapeutic efficacy of melatonin for social communication impairments and stereotyped behaviors or interests.
Published: 2013
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48. Loss-of-function of PTPR γ and ζ, observed in sporadic schizophrenia, causes brain region-specific deregulation of monoamine levels and altered behavior in mice

Author: Thorsten M. Kranz, Jean-Marie Launay, Sheila Harroch, Françoise Lazarini, Véronique Dubreuil, Sylvie Granon, Arnaud Cressant, Jan Sap, Jing Kong, Jacques Callebert, Dolores Malaspina, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Département de Neuroscience - Department of Neuroscience, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), New York University School of Medicine, NYU System (NYU), Génétique Humaine et Fonctions Cognitives, Service de biochimie et biologie moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR139, Université Paris Diderot - Paris 7 (UPD7), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Paris-Saclay ( Neuro-PSI ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Département de Neuroscience, Institut Pasteur [Paris], Department of psychiatry, New York University Langone School of Medicine, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière-IFR139, and Université Paris Diderot - Paris 7 ( UPD7 )
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Serotonin, Dopamine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Hippocampus, Hippocampal formation, Anxiety, Mental disorders, Amygdala, [ SDV.NEU.PC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, 03 medical and health sciences, [ SDV.NEU.SC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Mice, 0302 clinical medicine, Contactins, Internal medicine, Phosphatase, medicine, Animals, Social behavior, Prefrontal cortex, Swimming, Pharmacology, Mice, Knockout, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Receptor-Like Protein Tyrosine Phosphatases, Class 5, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, medicine.disease, Corpus Striatum, Aggression, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Monoamine neurotransmitter, Schizophrenia, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Psychology, 030217 neurology & neurosurgery, Clinical psychology, medicine.drug
Abstract: The receptor protein tyrosine phosphatase PTPRG has been genetically associated with psychiatric disorders and is a ligand for members of the contactin family, which are themselves linked to autism spectrum disorders. Based on our finding of a phosphatase-null de novo mutation in PTPRG associated with a case of sporadic schizophrenia, we used PTPRG knockout (KO) mice to model the effect of a loss-of-function mutation. We compared the results with loss-of-function in its close paralogue PTPRZ, previously associated with schizophrenia. We tested PTPRG −/− , PTPRZ −/− , and wild-type male mice for effects on social behavior, forced swim test, and anxiety, as well as on regional brain neurochemistry. The most notable behavioral consequences of PTPRG gene inactivation were reduced immobilization in the forced swim test, suggestive of some negative symptoms of schizophrenia. By contrast, PTPRZ −/− mice demonstrated marked social alteration with increased aggressivity, reminiscent of some positive symptoms of schizophrenia. Both knockouts showed elevated dopamine levels in prefrontal cortex, hippocampus, and most particularly amygdala, but not striatum, accompanied by reduced dopamine beta hydroxylase activity only in amygdala. In addition, PTPRG KO elicited a distinct increase in hippocampal serotonin level not observed in PTPRZ KO. PTPRG and PTPRZ gene loss therefore induces distinct patterns of behavioral change and region-specific alterations in neurotransmitters, highlighting their usefulness as models for neuropsychiatric disorder mechanisms and making these receptors attractive targets for therapy.
Published: 2017
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49. Region-specific protein misfolding cyclic amplification reproduces brain tropism of prion strains

Author: Jean-Philippe Brandel, Etienne Levavasseur, Jean-Louis Laplanche, Stéphane Haïk, Samia Hannaoui, Serfildan Yildirim, Danielle Seilhean, Nicolas Privat, Vincent Béringue, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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 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), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Biochimie et Biologie Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Université de Montpellier (UM), Institut national de Veille Sanitaire, Haik, Stephane, Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Protein Folding, mice, Amyloid, PrPSc Proteins, animal diseases, [SDV]Life Sciences [q-bio], Scrapie, Mice, Transgenic, Protein aggregation, Biology, in-vitro, Biochemistry, Creutzfeldt-Jakob Syndrome, 03 medical and health sciences, 0302 clinical medicine, agent strain, propagation, medicine, Animals, Humans, Protein Isoforms, molecules, Proteostasis Deficiencies, Molecular Biology, creutzfeldt-jakob-disease, Tropism, scrapie, transmission, Brain, Molecular Bases of Disease, Cell Biology, Human brain, Virology, Fungal prion, Cell biology, nervous system diseases, 030104 developmental biology, medicine.anatomical_structure, variant, infectious prions, Protein Misfolding Cyclic Amplification, Protein folding, 030217 neurology & neurosurgery
Abstract: International audience; Human prion diseases such as Creutzfeldt-Jakob disease are transmissible brain proteinopathies, characterized by the accumulation of a misfolded isoform of the host cellular prion protein (PrP) in the brain. According to the prion model, prions are defined as proteinaceous infectious particles composed solely of this abnormal isoform of PrP (PrPSc). Even in the absence of genetic material, various prion strains can be propagated in experimental models. They can be distinguished by the pattern of disease they produce and especially by the localization of PrPSc deposits within the brain and the spongiform lesions they induce. The mechanisms involved in this strain-specific targeting of distinct brain regions still are a fundamental, unresolved question in prion research. To address this question, we exploited a prion conversion in vitro assay, protein misfolding cyclic amplification (PMCA), by using experimental scrapie and human prion strains as seeds and specific brain regions from mice and humans as substrates. We show here that region-specific PMCA in part reproduces the specific brain targeting observed in experimental, acquired, and sporadic Creutzfeldt-Jakob diseases. Furthermore, we provide evidence that, in addition to cellular prion protein, other region-and species-specific molecular factors influence the strain-dependent prion conversion process. This important step toward understanding prion strain propagation in the human brain may impact research on the molecular factors involved in protein misfolding and the development of ultrasensitive methods for diagnosing prion disease.
Published: 2017
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50. Undiagnosed phenylketonuria in parents of phenylketonuric patients, is it worthwhile to be checked?

Author: B. Leheup, Arnaud Wiedemann, Shyue-Fang Battaglia-Hsu, P. Jonveaux, Elise Jeannesson, François Feillet, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Biochimie et Biologie Moléculaire, Nutrition et Métabolisme [CHRU Nancy], Service de Génétique [CHRU Nancy], and Centre de référence des maladies héréditaires du métabolisme (MaMEA Nancy-Brabois)
Subjects: Male, Parents, Health Knowledge, Attitudes, Practice, Pediatrics, Turkey, Maternal PKU, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Biochemistry, 0302 clinical medicine, Endocrinology, Hyperphenylalaninemia, Mutation Rate, Mutation Carrier, Pregnancy, Phenylketonurias, Phenylketonuria, MATERNAL PKU, 0303 health sciences, education.field_of_study, biology, 030305 genetics & heredity, Phenylalanine Hydroxylase, Pedigree, 3. Good health, Cohort, Female, Phenylketonuria, Maternal, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Phenylalanine hydroxylase, Genetic counseling, Population, Genetic Counseling, Risk Assessment, 03 medical and health sciences, Neonatal Screening, 030225 pediatrics, Genetics, medicine, Humans, education, Molecular Biology, Mild HPA, Mild PKU, business.industry, Infant, Newborn, nutritional and metabolic diseases, Lithuania, medicine.disease, Mutation, biology.protein, business
Abstract: International audience; In our phenylketonuria (PKU) cohort of 120 patients, we uncovered a couple of cases of undiagnosed mild phenylketonuria (mPKU)/hyperphenylalaninemia (mHPA) in maternal parents of the PKU cohort. This finding prompted us to evaluate the risk of either mild phenylketonuria or mild hyperphenylalaninemia in the parent population whose children were diagnosed with hyperphenylalaninemia (HPA). Taking into account the phenylalanine hydroxylase (PAH) mutation carrier frequency and the PAH mild mutation rate, we estimated that the prevalence of the parental mPKU/mHPA varied widely, from 1/74 in Turkey to 1/708 in Lithuania. The benefits of the parental detection procedure described here are the prevention of further maternal PKU syndrome, the follow-up of the newly detected patients and the accuracy of the genetic counseling provided to these families. This very simple procedure should be incorporated into neonatal PKU management of the hospitals in countries where a routine systematic neonatal screening is operational.
Published: 2013
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