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13 results on '"Service de Biochimie [Bicêtre]"'

1. Mutation in the AGK gene in two siblings with unusual Sengers syndrome

Author

Catherine Sarret, Sanae Allali, Abdelhamid Slama, Odile Boespflug-Tanguy, Simon Samaan, Charlène Rambaud, Imen Dorboz, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biochemistry Laboratory, Bicêtre Hospital, Assistance Publique - Hôpitaux de Paris, Service de neurologie pédiatrique et maladies métaboliques, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), INSERM U931, Clermont Ferrand, France, Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie [Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut Pascal - Clermont Auvergne (IP), and Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Pediatrics, Cardiomyopathy, Exercise intolerance, Biology, Biochemistry, Cataract, 03 medical and health sciences, Cellular and Molecular Neuroscience, Intellectual Disability, Internal medicine, medicine, Humans, Child, Myopathy, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Siblings, Metabolic disorder, medicine.disease, Hypotonia, Phosphotransferases (Alcohol Group Acceptor), Phenotype, 030104 developmental biology, Endocrinology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Lactic acidosis, Mutation, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), medicine.symptom, Cardiomyopathies, Acylglycerol kinase
Abstract

Sengers syndrome is a rare autosomal recessive metabolic disorder caused by lack of acylglycerol kinase due to mutations in the AGK gene. It is characterized by congenital cataract, hypertrophic cardiomyopathy, myopathy and lactic acidosis. Two clinical forms have been described: a severe neonatal form, and a more benign form displaying exercise intolerance. We describe two siblings with congenital cataract, cardiomyopathy, hypotonia, intellectual disability and lactic acidosis. Whole exome sequencing revealed a homozygous c.1035dup mutation in the two siblings, supporting a diagnosis of Sengers syndrome. Our patients presented an intermediate form with intellectual deficiency, an unusual feature in Sengers syndrome. This permitted a prenatal diagnosis for a following pregnancy.

Published
2017
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2. QIL1 mutation causes MICOS disassembly and early onset fatal mitochondrial encephalopathy with liver disease

Author

Emmanuelle Lacène, Mylène Gilleron, Manuel Schiff, Joao A. Paulo, Eric S. Goetzman, Virginia Guarani, Monique Elmaleh-Bergès, Hélène Ogier de Baulny, Anne Lombès, Clémence Labasse, J. Wade Harper, P. Rustin, Norma B. Romero, Apolline Imbard, Abdelhamid Slama, Pauline Gaignard, Dominique Chrétien, Agnès Bourillon, Paule Bénit, Jean-François Benoist, Imen Dorboz, Claude Jardel, Department of Cell Biology [Boston, MA, USA], Harvard Medical School [Boston] (HMS), 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), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie-hormonologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Department of Pediatrics [Pittsburgh, USA], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE)-Children's Hospital of Pittsburgh of UPMC [Etats-Unis], Service de Biochimie [Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service de Radiologie [AP-HP Hôpital Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Reference Center for Inborn Errors of Metabolism [AP-HP Hôpital Robert Debré], Bos, Mireille, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Harvard Medical School - HMS [Boston, USA], Institut Cochin ( 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 ), Promoting Research Oriented Towards Early Cns Therapies ( PROTECT ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), University of Pittsburgh School of Medicine [USA]-Children's Hospital of Pittsburgh of UPMC [Etats-Unis], and Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre

Subjects
0301 basic medicine, Male, Respiratory chain, Biology (General), Genetics, MICOS complex, biology, General Neuroscience, Liver Diseases, General Medicine, Null allele, Cell biology, MICOS, mitochondrial disease, Medicine, Female, 3-methylglutaconic aciduria, liver disease, Human, QH301-705.5, Mitochondrial disease, Protein subunit, Science, Microbial Sensitivity Tests, General Biochemistry, Genetics and Molecular Biology, Mitochondrial Proteins, 03 medical and health sciences, Mitochondrial Encephalomyopathies, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cytochrome c oxidase, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Human Biology and Medicine, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, General Immunology and Microbiology, Siblings, Infant, Newborn, Membrane Proteins, Cell Biology, medicine.disease, QIL1, 030104 developmental biology, Mutation, biology.protein, early-onset fatal mitochondrial encephalopathy, Cristae formation, Research Advance
Abstract

Previously, we identified QIL1 as a subunit of mitochondrial contact site (MICOS) complex and demonstrated a role for QIL1 in MICOS assembly, mitochondrial respiration, and cristae formation critical for mitochondrial architecture (Guarani et al., 2015). Here, we identify QIL1 null alleles in two siblings displaying multiple clinical symptoms of early-onset fatal mitochondrial encephalopathy with liver disease, including defects in respiratory chain function in patient muscle. QIL1 absence in patients’ fibroblasts was associated with MICOS disassembly, abnormal cristae, mild cytochrome c oxidase defect, and sensitivity to glucose withdrawal. QIL1 expression rescued cristae defects, and promoted re-accumulation of MICOS subunits to facilitate MICOS assembly. MICOS assembly and cristae morphology were not efficiently rescued by over-expression of other MICOS subunits in patient fibroblasts. Taken together, these data provide the first evidence of altered MICOS assembly linked with a human mitochondrial disease and confirm a central role for QIL1 in stable MICOS complex formation.

Published
2016
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3. The Lack of Antitumor Effects of o,p'DDA Excludes Its Role as an Active Metabolite of Mitotane for Adrenocortical Carcinoma Treatment

Author

Hescot, Ségolène, Paci, Angelo, Seck, Atmane, Slama, Abdelhamid, Viengchareun, Say, Trabado, Séverine, Brailly-Tabard, Sylvie, Al Ghuzlan, Abir, Young, Jacques, Baudin, Eric, Lombès, Marc, Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Pharmacologie, Département de biologie et pathologie médicales [Gustave Roussy], Service de Biochimie [Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service de génétique moléculaire, pharmacogénétique et hormonologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service d'endocrinologie, and This work was supported by the Institut National de la Santé et de la Recherche Médicale (Inserm) and Université Paris-Sud. SH is recipient of a fellowship from HRA Pharma Laboratories (Bourse CIFRE).

Subjects
mitotane, Adrenocortical carcinoma, p'-DDA, p'-DDD, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
Abstract

International audience; : Mitotane (o,p'DDD) is the most effective treatment of advanced adrenocortical carcinoma (ACC) but its mechanism of action remains unknown. Previous studies suggested that o,p'DDA may represent the active metabolite of mitotane. We aimed at reevaluating the potential role and pharmacological effects of o,p'DDA. Functional consequences of o,p'DDA exposure were studied on proliferation, steroidogenesis, and mitochondrial respiratory chain in human H295R and SW13 adrenocortical cells. Mitotane and its metabolites were quantified using high-performance liquid chromatography combined to an ultraviolet detection in these cells treated with o,p'DDD or o,p'DDA and in human adrenal tissues. Dose-response curves up to 300 μM showed that, as opposed to o,p'DDD, o,p'DDA did not inhibit cell proliferation nor alter respiratory chain complex IV activity, gene expression nor induce mitochondrial biogenesis, oxidative stress, or apoptosis. However, whereas mitotane drastically decreased expression of genes involved in steroidogenesis, o,p'DDA slightly reduced expression of some steroidogenic enzymes and exerts weak anti-secretory effects only at high doses. While o,p'DDD concentration was significantly reduced by 40 % in H295R cell supernatants after 48 h incubation, o,p'DDA levels remained unchanged suggesting that o,p'DDA was not efficiently transported into the cells. o,p'DDA was not detected in cell homogenates or supernatants after 48 h exposure to o,p'DDD, consistent with the absence of o,p'DDA production in these models. Finally, unlike o'p'DDD, we found that o,p'DDA content was undetectable in two ACC and one normal adrenal gland of mitotane-treated patients, suggesting a lack of cellular uptake and in situ production. Our results demonstrate that o,p'DDD, but not o,p'DDA, induces functional alterations in adrenal cells.

Published
2014
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4. Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect in human adrenocortical cells : Mitotane-induced cytochrome c oxidase defect

Author

Jacques Young, Larbi Amazit, Angelo Paci, Marc Lombès, Ségolène Hescot, Rita Chadarevian, Anne Lombès, Eric Baudin, Sophie Leboulleux, Hervé Remy, Abdelhamid Slama, Séverine Trabado, Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Service de Biochimie [Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, 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), Institut Gustave Roussy (IGR), Laboratoire HRA-Pharma (HRA), HRA Pharma France, Service de génétique moléculaire, pharmacogénétique et hormonologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service d'endocrinologie, Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine Paris-Sud, and a grant from HRA Pharma Laboratories. SH was recipient of a fellowship from the French Endocrine Society (SFE, Société Française d'Endocrinologie)., Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Sud - Paris 11 (UP11) - IFR93 - Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11) - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Bicêtre, Institut Cochin (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), and Institut Gustave Roussy (IGR) - Institut Gustave Roussy (IGR)

Subjects
mitotane, Cancer Research, medicine.medical_specialty, Adrenocortical carcinoma, Antineoplastic Agents, Hormonal, Hydrocortisone, Endocrinology, Diabetes and Metabolism, p'-DDD, Respiratory chain, Mitochondrion, Biology, DNA, Mitochondrial, Cell Line, Electron Transport, Electron Transport Complex IV, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, cytochrome c oxidase, medicine, Humans, Cytochrome c oxidase, Mitotane, Steroid 11-beta-hydroxylase, 030304 developmental biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, 17-alpha-Hydroxyprogesterone, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, mitochondria, Mitochondrial respiratory chain, Oncology, Mitochondrial biogenesis, 030220 oncology & carcinogenesis, Adrenal Cortex, biology.protein, medicine.drug
Abstract

Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane is the most effective medical therapy for adrenocortical carcinoma, but its molecular mechanism of action remains poorly understood. Although mitotane is known to have mitochondrial (mt) effects, a direct link to mt dysfunction has never been established. We examined the functional consequences of mitotane exposure on proliferation, steroidogenesis, and mt respiratory chain, biogenesis and morphology, in two human adrenocortical cell lines, the steroid-secreting H295R line and the non-secreting SW13 line. Mitotane inhibited cell proliferation in a dose- and a time-dependent manner. At the concentration of 50 μM (14 mg/l), which corresponds to the threshold for therapeutic efficacy, mitotane drastically reduced cortisol and 17-hydroxyprogesterone secretions by 70%. This was accompanied by significant decreases in the expression of genes encoding mt proteins involved in steroidogenesis (STAR, CYP11B1, and CYP11B2). In both H295R and SW13 cells, 50 μM mitotane significantly inhibited (50%) the maximum velocity of the activity of the respiratory chain complex IV (cytochrome c oxidase (COX)). This effect was associated with a drastic reduction in steady-state levels of the whole COX complex as revealed by blue native PAGE and reduced mRNA expression of both mtDNA-encoded COX2 (MT-CO2) and nuclear DNA-encoded COX4 (COX4I1) subunits. In contrast, the activity and expression of respiratory chain complexes II and III were unaffected by mitotane treatment. Lastly, mitotane exposure enhanced mt biogenesis (increase in mtDNA content and PGC1α (PPARGC1A) expression) and triggered fragmentation of the mt network. Altogether, our results provide first evidence that mitotane induced a mt respiratory chain defect in human adrenocortical cells.

Published
2014

5. Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect in human adrenocortical cells

Author

Hescot, Ségolène, Slama, Abdelhamid, Lombes, Anne, Paci, Angelo, Remy, Hervé, Leboulleux, Sophie, Chadarevian, Rita, Trabado, Séverine, Amazit, Larbi, Young, Jacques, Baudin, Eric, Lombes, Marc, Lombes, Marc, 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 de Biochimie [Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, 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), Institut Gustave Roussy (IGR), Laboratoire HRA-Pharma (HRA), HRA Pharma France, Service de génétique moléculaire, pharmacogénétique et hormonologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service d'endocrinologie, Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), and This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine Paris-Sud, and a grant from HRA Pharma Laboratories. SH was recipient of a fellowship from the French Endocrine Society (SFE, Société Française d'Endocrinologie).

Subjects
mitotane, mitochondria, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Adrenocortical carcinoma, cytochrome c oxidase, p'-DDD, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
Abstract

Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane (o,p'-DDD) is the most effective medical therapy for adrenocortical carcinoma but its molecular mechanism of action remains poorly understood. Although mitotane is known to have mitochondrial (mt) effects, a direct link to mitochondrial dysfunction has never been established. We examined the functional consequences on proliferation, steroidogenesis, and mitochondrial respiratory chain, biogenesis and morphology, of mitotane exposure in two human adrenocortical cell lines, the steroid-secreting H295R line and the non-secreting SW13 line. Mitotane inhibited cell proliferation in a dose- and a time-dependent manner. At the concentration 50μM (14 mg/L), which corresponds to the threshold for therapeutic efficacy, mitotane drastically reduced cortisol and 17-hydroxyprogesterone secretions by 70%. This was accompanied by significant decreases in the expression of genes encoding mitochondrial proteins involved in steroidogenesis (STAR, CYP11B1, CYP11B2). In both H295R and SW13 cells, 50μM mitotane significantly inhibited (50%) the maximum velocity of the activity of the respiratory chain complex IV (cytochrome c oxidase, COX). This effect was associated with a drastic reduction in steady-state levels of the whole COX complex as revealed by Blue Native PAGE and reduced mRNA expression of both mtDNA-encoded COX2 and nuclear DNA-encoded COX4 subunits. In contrast, the activity and expression of respiratory chain complexes II and III were unaffected by mitotane treatment. Lastly, mitotane exposure enhanced mitochondrial biogenesis (increase in mtDNA content and PGC1α expression) and triggered fragmentation of the mitochondrial network. Altogether, our results provide first evidence that mitotane induced a mitochondrial respiratory chain defect in human adrenocortical cells.

Published
2014

6. Phenotypic diversity associated with the MT-TV gene m.1644GA mutation, a matter of quantity

Author

Anne Lombès, Isabelle Lemière, Frédéric Sedel, Isabelle Nelson, Karine Auré, Stéphane Allouche, Delphine Héron, Abdelhamid Slama, Matthew J. Fraidakis, Jean Baptiste Hamon, Fabien Zagnoli, Claude Jardel, Jean Philippe Thenint, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de biochimie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Signalisation, électrophysiologie et imagerie des lésions d’ischémie-reperfusion myocardique (SEILIRM), Normandie Université (NU)-Normandie Université (NU), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Service de Biochimie [Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service de Neurologie [Alençon], Centre Hospitalier Intercommunal Alençon - Mamers, Service de Neurologie [Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Hôpital d'Instruction des Armées 'Clermont-Tonnerre' (HIA), Unité Fonctionnelle de Génétique Clinique [CHU Pitié Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), The study was supp orted by grants from ANR (Agence Nationale pour la Recherche ( ANR MNP 2008 Mitopark: ANR - 08 - MNPS - 020 - 01 ) , AFM (Association Française contre les Myopathies) and AMMi (Association contre les Maladies Mitochondriales) to AL, Fédération de Neurologie [Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Service de Biochimie [Caen], CHU Caen-Hôpital Côte-de-Nacre (Caen), Signalisation, électrophysiologie et imagerie des lésions d’ischémie-reperfusion myocardique ( SEILIRM ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( 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'Explorations Fonctionnelles, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ) -Hôpital de la Cavale Blanche - CHRU Brest ( CHU - BREST ), Unité Fonctionnelle de Génétique Clinique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP]-Centre de référence 'Déficiences Intellectuelles de Causes Rares' - Paris-Groupe de Recherche Clinique 'Déficience Intellectuelle et Autisme' - Paris, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Bos, Mireille

Subjects
Mitochondrial DNA, Mitochondrial Diseases, Quantitative Trait Loci, [SDV.GEN] Life Sciences [q-bio]/Genetics, mitochondrial DNA, Asymptomatic, medicine, Cytochrome c oxidase, Humans, Point Mutation, heteroplasmy, Respiratory system, Molecular Biology, Gene, RNA, Transfer, Val, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, biology, Spectrum Analysis, Cell Biology, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Phenotype, Molecular biology, Heteroplasmy, clinical diagnosis, Genes, Mitochondrial, Mutation (genetic algorithm), biology.protein, Molecular Medicine, medicine.symptom, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Polarography
Abstract

International audience; We describe four patients from three independent families with the m.1644G>A in the MT-TV gene, previously reported without demonstration of its deleterious impact. Very high mutation proportion co-segregated with cytochrome oxidase defect in single muscle fibers and respiratory defect in cybrids as shown by spectrophotometric assays and polarography. The mutation appeared to have a very steep threshold effect with asymptomatic life up to 70% mutation proportion, progressive encephalopathy above 80% and severe Leigh-like syndrome above 95% mutation. One patient did not fit within that frame but presented with characteristics suggesting the presence of an additional disease.

Published
2013
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7. Value of high-sensitivity C-reactive protein for classification of early axial spondyloarthritis: results from the DESIR cohort

Author

Floris A. van Gaalen, Bernard Combe, Victoria Navarro-Compán, Désirée van der Heijde, Claudine Cosson, Department of Rheumatology (LEIDEN - Rhumato), Leiden University Medical Center (LUMC), Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service de Biochimie [Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Department of Rheumatology ( LEIDEN - Rhumato ), Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - IURC, Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), and Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre

Subjects
Male, [SDV]Life Sciences [q-bio], Cohort Studies, 0302 clinical medicine, Immunology and Allergy, MESH : Female, 030212 general & internal medicine, Axial spondyloarthritis, MESH: Cohort Studies, ComputingMilieux_MISCELLANEOUS, medicine.diagnostic_test, biology, Desir cohort, MESH : Spondylarthritis, MESH : Adult, 3. Good health, C-Reactive Protein, MESH: Young Adult, Female, MESH : Sensitivity and Specificity, Adult, medicine.medical_specialty, MESH : Male, MESH: Spondylarthritis, Immunology, MESH : Young Adult, MESH : Cohort Studies, Sensitivity and Specificity, General Biochemistry, Genetics and Molecular Biology, Disease activity, 03 medical and health sciences, Young Adult, Rheumatology, Internal medicine, MESH: C-Reactive Protein, Spondylarthritis, medicine, Humans, In patient, Symptom onset, 030203 arthritis & rheumatology, MESH: Humans, [ SDV ] Life Sciences [q-bio], business.industry, C-reactive protein, MESH : Humans, MESH: Biological Markers, Magnetic resonance imaging, MESH: Adult, Baseline data, MESH : C-Reactive Protein, MESH: Male, MESH: Sensitivity and Specificity, MESH : Biological Markers, biology.protein, Physical therapy, business, MESH: Female, Biomarkers
Abstract

The average delay in axial spondyloarthritis (axSpA) diagnosis after symptom onset is one of the longest among inflammatory rheumatic diseases.1 New tools, such as magnetic resonance imaging,2 have been developed to reduce this delay. Elevated C-reactive protein (CRP) has been incorporated as one of the features for Assessment of SpondyloArthritis international Society (ASAS) SpA criteria,3 and in the Berlin diagnostic algorithm.4 However, CRP levels are elevated in only a minority of early SpA patients.5 More sensitive tests, so-called high-sensitivity CRP (hsCRP), have been developed and can detect lower concentrations of CRP compared with traditional methods.6 HsCRP levels are increased in other rheumatic chronic inflammatory diseases,7 and show a better correlation with disease activity parameters compared with routine CRP in patients with axSpA.8 Therefore, hsCRP could be more sensitive than traditional CRP in diagnosing axial SpA. The aim of this study was to assess the contribution of hsCRP versus CRP to classification of early axSpA using the ASAS criteria. Baseline data …

Published
2013
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8. Increased susceptibility to liver fibrosis with age is correlated with an altered inflammatory response

Author

Meriem Mahrouf-Yorgov, Claudine Cosson, Elsa Abdoun, Bernard Fromenty, Claudia Mitchell, Alexandra Collin de l'Hortet, Hélène Gilgenkrantz, Jacques-Emmanuel Guidotti, Abdelhamid Slama, 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), Service de Biochimie [Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Cochin ( 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 ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Hépatotoxicité et xénobiotiques, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre

Subjects
MESH : Oxidative Stress, MESH: Inflammation, Liver Cirrhosis, Male, Aging, Necrosis, MESH : Carbon Tetrachloride, MESH : Hepatocytes, medicine.disease_cause, Liver disorder, MESH: Hepatocytes, Mice, 0302 clinical medicine, MESH : Chronic Disease, Fibrosis, MESH : Cell Proliferation, MESH: Aging, MESH: Animals, Carbon Tetrachloride, 0303 health sciences, MESH: Oxidative Stress, 3. Good health, medicine.anatomical_structure, Hepatocyte, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 030211 gastroenterology & hepatology, Disease Susceptibility, medicine.symptom, MESH: Liver Cirrhosis, MESH : Male, Hepatitis C virus, MESH: Disease Susceptibility, Context (language use), Inflammation, MESH : Mice, Inbred C57BL, Biology, MESH : Disease Susceptibility, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH: Cell Proliferation, MESH : Mice, medicine, MESH : Liver Cirrhosis, Animals, Humans, MESH: Mice, 030304 developmental biology, Cell Proliferation, MESH: Necrosis, MESH : Inflammation, MESH: Humans, MESH: Carbon Tetrachloride, MESH: Chronic Disease, MESH : Humans, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, MESH : Aging, MESH: Male, MESH : Necrosis, Mice, Inbred C57BL, Oxidative Stress, Immunology, Chronic Disease, Hepatocytes, MESH : Animals, Geriatrics and Gerontology, Oxidative stress
Abstract

International audience; It has been suggested that increasing age is correlated with an acceleration of the progression of liver fibrosis induced by various agents, such as hepatitis C virus or chronic alcohol consumption. However, the cellular and molecular changes underlying this predisposition are not entirely understood. In the context of an aging population, it becomes challenging to decipher the mechanisms responsible for this higher susceptibility of older individuals to this acquired liver disorder. To address this issue, we induced liver fibrosis by carbon tetrachloride (CCl(4)) chronic administration to 8-week- and 15-month-old mice. We confirmed that susceptibility to fibrosis development increased with age and showed that aging did not affect fibrosis resolution capacity. We then focused on the impairment of hepatocyte proliferation, oxidative stress, and inflammation as potential mechanisms accelerating the development of fibrosis in the elderly. We detected no inhibition of hepatocyte proliferation after CCl(4) injury in 15-month-old mice, whereas it was inhibited after a partial hepatectomy. Finally, we observed that, in a context in which liver oxidative stress was not differentially increased in both experimental groups, there was a higher recruitment of inflammatory cells, including mostly macrophages and lymphocytes, oriented toward a T helper 2 (T(H)2) response in older mice. Our data show that in conditions of equivalent levels of oxidative stress and maintained hepatocyte proliferative capacity, an increased inflammatory reaction mainly composed of CD4(+) lymphocytes and macrophages expressing T(H)2 cytokines is the main factor involved in the higher susceptibility to fibrosis with increasing age.

Published
2011
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9. Vasopressin, ATP and catecholamines differentially control potassium secretion in inner ear cell line

Author

Daniel Butlen, Marie Teixeira, Say Viengchareun, Jérôme Nevoux, Evelyne Ferrary, Marc Lombès, Claudine Cosson, Lombes, Marc, Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Chirurgie otologique mini-invasive robotisée, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie [Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service d'Endocrinologie et Maladies de la reproduction, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service d'ORL, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by grants from Inserm, Université Paris Diderot, Université Paris-Sud, European Section of Aldosterone Council (ESAC) and a fellowship from the Société Française d'Oto-Rhino-Laryngologie (to JN)., and Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11)

Subjects
Vasopressin, Receptors, Vasopressin, Endolymph, Biochemistry, MESH: Receptors, Purinergic P2Y, Menière’s disease, Mice, 0302 clinical medicine, Adenosine Triphosphate, Catecholamines, Structural Biology, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Adenosine Triphosphate, Cyclic AMP, MESH: Animals, MESH: Cyclic AMP, Vasopressin receptor, 0303 health sciences, endolymph, Chemistry, Reverse Transcriptase Polymerase Chain Reaction, Purinergic receptor, Purinergic signalling, 3. Good health, medicine.anatomical_structure, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Receptors, Purinergic P2Y, vestibular cells, MESH: Receptors, Vasopressin, Menière's disease, MESH: Vasopressins, Adenylyl Cyclases, medicine.medical_specialty, Vasopressins, Blotting, Western, Biophysics, Adenylate kinase, MESH: Calcium Signaling, Cell Line, 03 medical and health sciences, vasopressin receptors, Internal medicine, purinergic receptors, MESH: Adenylate Cyclase, Genetics, medicine, otorhinolaryngologic diseases, MESH: Catecholamines, Animals, MESH: Blotting, Western, Inner ear, Calcium Signaling, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Molecular Biology, MESH: Mice, 030304 developmental biology, Phosphoric Diester Hydrolases, Cell Biology, MESH: Cell Line, Endocrinology, Ear, Inner, MESH: Potassium, Potassium, sense organs, MESH: Phosphoric Diester Hydrolases, 030217 neurology & neurosurgery, MESH: Ear, Inner, Low sodium
Abstract

International audience; A strict control of endolymph composition (high potassium, low sodium fluid) and volume is instrumental for a proper functioning of the inner ear. Alteration of endolymph homeostasis is proposed in the pathogenesis of Menière's disease. However, the mechanisms controlling endolymph secretion remain elusive. By using the vestibular EC5v cells, we provide evidence for the presence of vasopressin, catecholamine and purinergic signaling pathways, coupled to adenylate cyclase, phosphoinositidase C and Ca(2+) activation. We demonstrate that vasopressin and catecholamines stimulate while ATP inhibits apical potassium secretion by EC5v cells. These results open new interesting perspectives for the management of inner ear diseases.

Published
2011
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10. High-sensitivity versus conventional troponin in the emergency department for the diagnosis of acute myocardial infarction

Author

Bruno Riou, Patrick Ray, Pascale Bonnet, François Leumani, Yann-Erick Claessens, Camille Chenevier-Gobeaux, Yonathan Freund, Claudine Cosson, Benoit Doumenc, J.-C. Allo, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de médecine d'urgence [CHU Cochin], Service des urgences, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Bichat, Service de Biochimie [Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des urgences et chirurgie, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Hôpital Bichat, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and BMC, Ed.

Subjects
Adult, Male, medicine.medical_specialty, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Myocardial Infarction, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, Chest pain, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Troponin I, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Prospective Studies, 030212 general & internal medicine, Myocardial infarction, cardiovascular diseases, Aged, Aged, 80 and over, biology, Troponin T, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], business.industry, Research, Middle Aged, medicine.disease, Troponin, Confidence interval, 3. Good health, Surgery, Pre- and post-test probability, biology.protein, Cardiology, Female, Myocardial infarction diagnosis, medicine.symptom, Emergency Service, Hospital, business, Biomarkers
Abstract

International audience; INTRODUCTION: Recently, newer assays for cardiac troponin (cTn) have been developed which are able to detect changes in concentration of the biomarker at or below the 99th percentile for a normal population. The objective of this study was to compare the diagnostic performance of a new high-sensitivity troponin T (HsTnT) assay to that of conventional cTnI for the diagnosis of acute myocardial infarction (AMI) according to pretest probability (PTP). METHODS: In consecutive patients who presented to our emergency departments with chest pain suggestive of AMI, levels of HsTnT were measured at presentation, blinded to the emergency physicians, who were asked to estimate the empirical PTP of AMI. The discharge diagnosis was adjudicated by two independent experts on the basis of all available data. RESULTS: A total of 317 patients were included, comprising 149 (47%) who were considered to have low PTP, 109 (34%) who were considered to have moderate PTP and 59 (19%) who were considered to have high PTP. AMI was confirmed in 45 patients (14%), 22 (9%) of whom were considered to have low to moderate PTP and 23 (39%) of whom were considered to have high PTP (P < 0.001). In the low to moderate PTP group, HsTnT levels ≥ 0.014 μg/L identified AMI with a higher sensitivity than cTnI (91%, 95% confidence interval (95% CI) 79 to 100, vs. 77% (95% CI 60 to 95); P = 0.001), but the negative predictive value was not different (99% (95% CI 98 to 100) vs. 98% (95% CI 96 to 100)). There was no difference in area under the receiver operating characteristic (ROC) curve between HsTnT and cTnI (0.93 (95% CI 0.90 to 0.98) vs. 0.94 (95% CI 0.88 to 0.97), respectively). CONCLUSIONS: In patients with low to moderate PTP of AMI, HsTnT is slightly more useful than cTnI. Our results confirm that the use of HsTnT has a higher sensitivity than conventional cTnI.

Published
2011
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11. Influence of alpha-1 glycoprotein acid concentrations and variants on atazanavir pharmacokinetics in HIV-infected patients included in the ANRS 107 trial

Author

Barrail-Tran, Aurélie, Mentré, France, Cosson, Claudine, Piketty, Christophe, Chazallon, Corine, Gérard, Laurence, Girard, Pierre-Marie, Taburet, Anne-Marie, Service de pharmacie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Modèles et méthodes de l'évaluation thérapeutique des maladies chroniques (U738 / UMR_S738), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Service de Biochimie [Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service d'immunologie [HEGP, Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Essais Therapeutiques et Infection Par Le Vih, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Services des Maladies Infectieuses et Tropicales [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), and This study was supported by ANRS (National Agency for AIDS Research), Paris, France

Subjects
MESH: Humans, MESH: Middle Aged, MESH: Pyridines, virus diseases, MESH: Serum Albumin, MESH: Adult, MESH: HIV Infections, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], MESH: Male, MESH: Orosomucoid, MESH: Oligopeptides, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Female, MESH: HIV Protease Inhibitors
Abstract

International audience; Atazanavir is an HIV-1 protease inhibitor with high protein binding in human plasma. The objectives were first to determine the in vitro binding characteristics of atazanavir and second to evaluate whether plasma protein binding to albumin and alpha-1 glycoprotein acid (AAG) influences the pharmacokinetics of atazanavir in HIV-infected patients. For the in vitro study, atazanavir protein binding characteristics were determined in AAG- and albumin-containing purified solutions. Atazanavir was found to bind AAG on a high-affinity saturable site (association constant, 4.61x10(5) liters/mol) and albumin on a low-affinity nonsaturable site. For the in vivo study, blood samples from 51 patients included in trial ANRS 107--Puzzle 2 were drawn prior to drug intake at week 6. For 10 patients included in the pharmacokinetic substudy, five additional blood samples were collected during one dosing interval at week 6. Atazanavir concentrations were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Albumin concentrations, AAG concentrations, and phenotypes were also measured in these patients. Concentrations of atazanavir were modeled using a population approach. A one-compartment model with first-order absorption and elimination best described atazanavir pharmacokinetics. Atazanavir pharmacokinetic parameters and their interindividual variabilities were as follows: absorption rate constant (ka), 0.73 h(-1) (139.3%); apparent clearance (CL/F), 13.3 liters/h (26.7%); and apparent volume of distribution (V/F), 79.7 liters (27.0%). Atazanavir CL/F decreased significantly when alanine aminotransferase and/or AAG levels increased (P

Published
2010
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12. Physiological partial aldosterone resistance in human newborns

Author

Martinerie, Laetitia, Pussard, Eric, Foix-L'Hélias, Laurence, Petit, François, Cosson, Claudine, Boileau, Pascal, Lombès, Marc, Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Service de génétique moléculaire, pharmacogénétique et hormonologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service de Pédiatrie et Réanimations néonatales [Béclère], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biochimie-hormonologie [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Service de Biochimie [Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, and Service d'Endocrinologie et Maladies de la reproduction

Subjects
MESH: Adolescent, MESH: Humans, MESH: Middle Aged, MESH: Renin, MESH: Infant, Newborn, MESH: Aldosterone, MESH: Adult, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Prospective Studies, MESH: Hyperaldosteronism, MESH: Mineralocorticoids, MESH: Renin-Angiotensin System, MESH: Young Adult, MESH: Potassium, MESH: Water-Electrolyte Balance, MESH: Sodium, MESH: Female
Abstract

International audience; In the neonatal period, the human kidney is characterized by an impaired ability to regulate water and sodium homeostasis, resembling partial aldosterone resistance. The aim of our study was to assess this hormonal insensitivity in newborn infants and to determine its relationship with neonatal sodium handling. We conducted a prospective study in 48 healthy newborns and their mothers. Aldosterone, renin, and electrolyte concentrations were measured in umbilical cords and in maternal plasma. Urinary aldosterone concentrations and sodium excretion were determined at urination within 24 h after birth. A significant difference was observed between aldosterone and renin levels in newborn infants compared with their mothers (817 +/- 73 versus 575 +/- 55 pg/mL and 79 +/- 10 versus 15 +/- 2 pg/mL, respectively, p < 0.001). This hyperactivation of the renin-angiotensin-aldosterone system was associated with hyponatremia and hyperkalemia in the newborn infants, and high urinary sodium loss, consistent with a partial aldosterone resistance at birth. Unlike plasma aldosterone, urinary aldosterone concentration was found highly correlated with plasma potassium concentrations, thus representing the best index for accurate evaluation of mineralocorticoid sensitivity. Our study represents a comprehensive characterization of the renin-aldosterone axis in newborn infants and provides evidence for physiologic partial aldosterone resistance in the neonatal period.

Published
2009
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