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223 results on '"Texas Children's Hospital [Houston, USA]"'

1. Macrophage PPARγ, a Lipid Activated Transcription Factor Controls the Growth Factor GDF3 and Skeletal Muscle Regeneration

Author

Szilárd Póliska, Gergely Nagy, Sylvain Cuvellier, Attila Horvath, Laszlo Nagy, Tamas Varga, Sabrina Ben Larbi, Attila Pap, Bence Daniel, Matthew Peloquin, Bénédicte Chazaud, Eva Pintye, Brian E. Sansbury, Chester W. Brown, Matthew Spite, Rémi Mounier, Andreas Patsalos, Péter Gogolák, Chazaud, Benedicte, Department of Biochemistry and Molecular Biology [Debrecen, Hungary], University of Debrecen [Hungary], Institut NeuroMyoGène (INMG), 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), Department of Immunology [Debrecen, Hungary], Sanford Burnham Prebys Medical Discovery Institute, MTA - DE 'Lendület' Immunogenomics Research Group [Debrecen, Hungary], Université de Debrecen [Hungary], Department of Radiation Therapy [Debrecen, Hungary], 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), Department of Anesthesiology, Perioperative and Pain Medicine [Boston], Harvard Medical School [Boston] (HMS)-Brigham and Women's Hospital [Boston], Department of Molecular and Human Genetics [Houston, USA], Baylor College of Medecine, Department of Pediatrics [Houston, USA], Baylor College of Medecine-Texas Children's Hospital [Houston, USA], Institut NeuroMyoGène ( INMG ), 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 ), Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, 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 ), Harvard Medical School [Boston] ( HMS ) -Brigham and Women's Hospital [Boston], Baylor College of Medicine, Baylor College of Medicine [Houston, USA]-Texas Children's Hospital [Houston, USA], 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
0301 basic medicine, Chromatin Immunoprecipitation, medicine.medical_treatment, Blotting, Western, Immunology, Peroxisome proliferator-activated receptor, Cell Separation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Myoblasts, Mice, 03 medical and health sciences, Growth Differentiation Factor 3, medicine, Animals, Regeneration, Immunology and Allergy, Myocyte, Elméleti orvostudományok, Muscle, Skeletal, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Transcription factor, Oligonucleotide Array Sequence Analysis, chemistry.chemical_classification, Wound Healing, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Effector, Regeneration (biology), Growth factor, Skeletal muscle, Orvostudományok, Cell biology, Mice, Inbred C57BL, PPAR gamma, Disease Models, Animal, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, Gene Expression Regulation, chemistry, Wound healing
Abstract

International audience; Tissue regeneration requires inflammatory and reparatory activity of macrophages. Macrophages detect and eliminate the damaged tissue and subsequently promote regeneration. This dichotomy requires the switch of effector functions of macrophages coordinated with other cell types inside the injured tissue. The gene regulatory events supporting the sensory and effector functions of macrophages involved in tissue repair are not well understood. Here we show that the lipid activated transcription factor, PPARγ is required for proper skeletal muscle regeneration, acting in repair macrophages. PPARγ controls the expression of the transforming growth factor-b family member, GDF3, which in turn regulates the restoration of skeletal muscle integrity by promoting muscle progenitor cell fusion. This work establishes PPARγ as a required metabolic sensor and transcriptional regulator of repair macrophages. Moreover, this work also establishes GDF3 as a secreted extrinsic effector protein acting on myoblasts and serving as an exclusively macrophage-derived regeneration factor in tissue repair.

Published
2016

2. Lumasiran for Advanced Primary Hyperoxaluria Type 1: Phase 3 ILLUMINATE-C Trial

Author

Michael, M., Groothoff, J. W., Shasha-Lavsky, H., Lieske, J. C., Frishberg, Y., Simkova, E., Sellier-Leclerc, A. L., Devresse, A., Guebre-Egziabher, F., Bakkaloglu, S. A., Mourani, C., Saqan, R., Singer, R., Willey, R., Habtemariam, B., Gansner, J. M., Bhan, I., Mcgregor, T., Magen, D., Paediatric Nephrology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ARD - Amsterdam Reproduction and Development, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, CarMeN, laboratoire, Texas Children's Hospital [Houston, USA], Baylor College of Medicine (BCM), Baylor University, Emma Children’s Hospital, Amsterdam UMC - Amsterdam University Medical Center, Galilee Medical Center [Nahariya, Israel], Bar-Ilan University [Israël], Mayo Clinic [Rochester], Shaare Zedek Medical Center [Jerusalem, Israel], Al Jalila Children's Specialty Hospital, Filières Maladies Rares ORKID et ERK-Net, Centre d'Investigation Clinique [Bron] (CIC1407), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupement Hospitalier Est [Bron], Cliniques Universitaires Saint-Luc [Bruxelles], 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), Gazi University, Hôpital Hôtel Dieu de France [Beirut, Lebanon] (2HDF), Jordan University of Science and Technology [Irbid, Jordan] (JUST), Canberra Health Services [Garran, ACT, Australia] (CHS), Alnylam Pharmaceuticals [Cambridge, MA, USA], and Rambam Health Care Campus [Haifa, Israel]

Subjects
Adult, Male, RNA interference (RNAi), safety, Lumasiran, urinary oxalate (UOx), Adolescent, [SDV]Life Sciences [q-bio], kidney disease, efficacy, Young Adult, nephrocalcinosis, glycolate, pharmacodynamics, Humans, Child, Hyperoxaluria, Oxalates, systemic oxalosis, hemodialysis, cardiac dysfunction, phase 3 clinical trial, Infant, Newborn, Infant, Middle Aged, adverse events, primary hyperoxaluria type 1 (PH1), [SDV] Life Sciences [q-bio], plasma oxalate (POx), anti-drug antibodies, pediatric, Nephrology, Child, Preschool, Hyperoxaluria, Primary, Female, Kidney Diseases, pharmacokinetics
Abstract

Rationale & Objective: Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease. Study Design: Phase 3, open-label, single-arm trial. Setting & Participants: Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate ≤45 mL/min/1.73 m2 (if age ≥12 months) or increased serum creatinine level (if age

Published
2023

3. Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability

Author

Philippe M. Campeau, Katherine Agre, Vernon R. Sutton, Kirsty McWalter, Bertrand Isidor, Øystein L. Holla, Anna Lehman, Megha Desai, Jonathan Berg, Stéphane Bézieau, Rolph Pfundt, Jennifer Tarpinian, Jennifer B. Humberson, Holly A.F. Stessman, Madeleine R. Geisheker, Emma Bedoukian, Shalini N. Jhangiani, Marine I. Murphree, Annapurna Poduri, Anne-Sophie Denommé-Pichon, Christian Gilissen, Yaping Yang, Eliane Beauregard-Lacroix, Claude Férec, Francesca Filippini, Anne Guimier, Daryl A. Scott, Stephen Sanders, Julie C. Sapp, Ralitza H. Gavrilova, Slavé Petrovski, Ann Nordgren, Sylvia Redon, Ernie M.H.F. Bongers, Shelagh Joss, Jill A. Rosenfeld, Wallid Deb, Ingrid M. Wentzensen, Usha Kini, Vandana Shashi, Mindy H. Li, Stanislas Lyonnet, Thomas Garcia, Øyvind L. Busk, Christoffer Nellåker, Amber Begtrup, Brigitte Gilbert-Dussardier, Thomas Besnard, Francois V. Bolduc, Patrick R. Blackburn, Justine Rousseau, Frédéric Bilan, Eric W. Klee, Christopher T. Gordon, Pavel N. Pichurin, Peggy Kulch, Kevin P. Lally, Laurie Robak, Arnaud Picard, Kristian Tveten, Meredith Park, Sébastien Küry, Jaya Punetha, Moira Blyth, Asbjørg Stray-Pedersen, Jacqueline Harris, Erin L. Heinzen, Nicholas Stong, Cara M. Skraban, Julie S. Cohen, Aida Telegrafi, Xenia Latypova, Zeynep Coban Akdemir, Jacob Zyskind, Caitlin Troyer, Xiang-Jiao Yang, Tuula Rinne, Leslie G. Biesecker, Jennifer E. Posey, Kyle Retterer, Jeanne Amiel, Rui Xiao, Magnus Nordenskjöld, Tammie Dewan, Jennifer A. Sullivan, Charlotte von der Lippe, Evan E. Eichler, Anna Lindstrand, Dominique Bonneau, Yuri A. Zarate, Elaine H. Zackai, Fayth M. Kalb, Daniel H. Lowenstein, Shiri Avni, Benjamin Cogné, Jennifer J. Johnston, Kerri H. Whitlock, Catherine Shain, Séverine Audebert-Bellanger, Malin Kvarnung, Oana Caluseriu, David Goldstein, Annick Toutain, Andres Hernandez-Garcia, Brina Daniels, Sophie Ehresmann, James R. Lupski, Julie McGaughran, Ashley H Ebanks, Kévin Uguen, Marine Legendre, Sylvie Odent, Richard Redon, Erica H. Gerkes, Xiaofei Song, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), 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)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Sainte Justine [Montréal], Université du Québec à Montréal = University of Québec in Montréal (UQAM), University of Oxford [Oxford], GeneDx [Gaithersburg, MD, USA], Mayo Clinic [Rochester], University of California [San Francisco] (UCSF), University of California, 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), Etablissement Français du Sang Bretagne, EFS, Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Johns Hopkins University School of Medicine [Baltimore], Kennedy Krieger Institute [Baltimore], Chapel Allerton Hospital, University of British Columbia (UBC), University of Dundee, Rush University Medical Center [Chicago], Oxford University Hospitals NHS Trust, Queen Elizabeth University Hospital (Glasgow), Trondheim University, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Virginia [Charlottesville], Texas Children's Hospital [Houston, USA], Baylor College of Medicine (BCM), Baylor University, University of Pennsylvania [Philadelphia], National Human Genome Research Institute (NHGRI), Harvard Medical School [Boston] (HMS), Karolinska University Hospital [Stockholm], Duke University Medical Center, University of Groningen [Groningen], University of Arkansas for Medical Sciences (UAMS), McGovern Medical School [Houston, Texas], The University of Texas Health Science Center at Houston (UTHealth), Phoenix Children's Hospital, Columbia University [New York], University of Southern Queensland (USQ), Telemark Hospital Trust [Skien, Norway], University of Washington [Seattle], Oslo University Hospital [Oslo], Children’s Hospital of Philadelphia (CHOP ), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Radboud University Medical Center [Nijmegen], Ann & Robert H. Lurie Children's Hospital of Chicago, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], 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), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre hospitalier universitaire de Poitiers (CHU Poitiers), University of Alberta, Boston Children's Hospital, McGill University Health Center [Montreal] (MUHC), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Creighton University Medical School [Omaha, NE, USA], Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), National Institute of Neurological Disorders and Stroke, K08 HG008986, National Human Genome Research Institute, BC Children’s Hospital Foundation, Genome British Columbia, Fonds de Recherche du Québec - Santé, Canadian Institutes of Health Research, Center for Individualized Medicine, Mayo Clinic, Health Regional Agency from Poitou-Charentes, French Ministry of Health, RC14_0107, HUGODIMS, NS053998, The Epilepsy Phenome/Genome Project, NS077303, Epi4K, Duke Genome Sequencing Clinic, NINDS R35 NS105078, National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, HG200328 12, intramural research program of the NHGRI, Dart NeuroScience, Kids Brain Health Network, Mining for Miracles, UM1 HG006542, National Heart, Lung, and Blood Institute, CIM Investigative and Functional Genomics Program, R01MH101221, National Institute of Mental Health, 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), University of Oxford, University of California [San Francisco] (UC San Francisco), University of California (UC), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Virginia, University of Pennsylvania, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), CCSD, Accord Elsevier, Faculteit Medische Wetenschappen/UMCG, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
CHROMATIN, Male, 0301 basic medicine, Autism, Sequence Homology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Medical and Health Sciences, 0302 clinical medicine, SCHIZOPHRENIA, Gene expression, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Child, de novo variants, Genetics (clinical), Pediatric, Genetics & Heredity, Genetics, biology, neurodevelopmental disorders, histone acetylation, Adaptor Proteins, Nuclear Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Syndrome, Biological Sciences, Prognosis, Phenotype, Chromatin, Mental Health, Histone, intellectual disability, Child, Preschool, Female, REGULATOR, congenital malformations, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], BRAIN-DEVELOPMENT, Adult, Adolescent, Histone acetyltransferase complex, Intellectual and Developmental Disabilities (IDD), Mutation, Missense, Deciphering Developmental Disorders study, autism spectrum disorder, KAT6B, RNAI SCREEN, Young Adult, 03 medical and health sciences, CAUSES Study, Rare Diseases, Intellectual Disability, Report, COFACTOR, medicine, RUBINSTEIN-TAYBI-SYNDROME, Humans, Amino Acid Sequence, Autistic Disorder, Preschool, Gene, Genetic Association Studies, Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Rubinstein–Taybi syndrome, Signal Transducing, Neurosciences, Infant, medicine.disease, TRRAP, Brain Disorders, SELF-RENEWAL, 030104 developmental biology, DE-NOVO MUTATIONS, Mutation, biology.protein, Missense, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 202928.pdf (Publisher’s version ) (Open Access) Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

Published
2019

4. The human gut microbiome and health inequities

Author

Erika C. Claud, Erin C. Hanlon, Carlijn E Bruggeling, Katherine R. Amato, Corinne F. Maurice, Meghan B. Azad, Christopher W. Kuzawa, Liping Zhao, Ali Keshavarzian, Geoffrey A. Preidis, Michael T. Bailey, Bas E. Dutilh, Elizabeth K. Costello, Laure Ségurel, Josiane L. Broussard, Burton H. Singer, Wrenetha Julion, Holly A. Swain Ewald, Marie-Claire Arrieta, Gregory E. Miller, Paul W. Ewald, Emily R. Davenport, Sathish Subramanian, Northwestern University [Evanston], University of Calgary, Children's Hospital Research Institute of Manitoba [Winnipeg, Canada], University of Manitoba [Winnipeg], Center for Microbial Pathogenesis [Columbus], Ohio State University [Columbus] (OSU), Colorado State University [Fort Collins] (CSU), Radboud University Medical Centre [Nijmegen, The Netherlands], University of Chicago, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Huck Institutes of the Life Sciences [University Park], Utrecht University [Utrecht], Centre for Molecular and Biomolecular Informatics, Radboud University Medical Centre, University of Louisville, Rush University [Chicago], Rush University Medical Center [Chicago], McGill University = Université McGill [Montréal, Canada], Baylor College of Medicine (BCM), Baylor University, Texas Children's Hospital [Houston, USA], Éco-Anthropologie (EAE), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), University of Florida [Gainesville] (UF), Massachusetts General Hospital [Boston], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Shanghai Jiao Tong University [Shanghai], Rutgers, The State University of New Jersey [New Brunswick] (RU), Rutgers University System (Rutgers), Theoretical Biology and Bioinformatics, and Sub Bioinformatics

Subjects
Population health, Structural racism|health disparities|chronic disease|DOHad|policy, 03 medical and health sciences, Race (biology), 0302 clinical medicine, Human gut, Development economics, Taverne, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Humans, Disease, Microbiome, General, Socioeconomic status, Health policy, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, Sexual identity, Multidisciplinary, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Publications, Health Status Disparities, Health equity, 3. Good health, Gastrointestinal Microbiome, Mental Health, Health, Perspective, Psychology, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 235695.pdf (Publisher’s version ) (Closed access) Individuals who are minoritized as a result of race, sexual identity, gender, or socioeconomic status experience a higher prevalence of many diseases. Understanding the biological processes that cause and maintain these socially driven health inequities is essential for addressing them. The gut microbiome is strongly shaped by host environments and affects host metabolic, immune, and neuroendocrine functions, making it an important pathway by which differences in experiences caused by social, political, and economic forces could contribute to health inequities. Nevertheless, few studies have directly integrated the gut microbiome into investigations of health inequities. Here, we argue that accounting for host-gut microbe interactions will improve understanding and management of health inequities, and that health policy must begin to consider the microbiome as an important pathway linking environments to population health.

Published
2021

5. Mutations in the KIF21B kinesin gene cause neurodevelopmental disorders through imbalanced canonical motor activity

Author

Petra J. G. Zwijnenburg, Kirsty McWalter, Sonal Mahida, Delphine Héron, Frédéric Saudou, Hélène Vitet, Anna Chassevent, José Rivera Alvarez, Carlos A. Bacino, Juliette D. Godin, Christel Thauvin-Robinet, Chantal Weber, Laure Asselin, Caroline Nava, Christelle Golzio, Neil A. Hanchard, Christel Depienne, Peggy Tilly, Camille S. Bonnet, Cyril Mignot, Gladys Zapata, Amy Dameron, Marjan M. Weiss, Solveig Heide, Laurence Faivre, Haley Streff, Agnès Rastetter, Kristin W. Barañano, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Référence des Déficiences Intellectuelles de Causes Rares, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Baylor College of Medicine (BCM), Baylor University, Texas Children's Hospital [Houston, USA], Kennedy Krieger Institute [Baltimore], GeneDx [Gaithersburg, MD, USA], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Université de Bourgogne (UB), 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), Boston Children's Hospital, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Vrije Universiteit Amsterdam [Amsterdam] (VU), and University of Duisburg-Essen

Subjects
Male, 0301 basic medicine, Microcephaly, Organogenesis, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Medizin, Kinesins, General Physics and Astronomy, medicine.disease_cause, Mice, 0302 clinical medicine, Neurodevelopmental disorder, Cell Movement, Gene duplication, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Missense mutation, lcsh:Science, Zebrafish, Cerebral Cortex, Neurons, Mutation, Multidisciplinary, Neurodevelopmental disorders, Gene Expression Regulation, Developmental, Organ Size, Pedigree, 3. Good health, Kinesin, Female, Haploinsufficiency, Science, Mutation, Missense, Motor Activity, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Animals, Humans, RNA, Messenger, Cell Proliferation, Corpus Callosum Agenesis, General Chemistry, medicine.disease, Axons, HEK293 Cells, 030104 developmental biology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Neuronal development, lcsh:Q, Nerve Net, Neuroscience, 030217 neurology & neurosurgery
Abstract

KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients’ neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mRNA decay. Although we demonstrate that Kif21b haploinsufficiency leads to an impaired neuronal positioning, the duplication variant might not be pathogenic. Altogether, our data indicate that impaired KIF21B autoregulation and function play a critical role in the pathogenicity of human neurodevelopmental disorder., Kinesins regulate intracellular transport and microtubule dynamics. Here, the authors show that KIF21B variants in humans associate with corpus callosum agenesis and microcephaly. Using mice and zebrafish, they showed the cellular mechanisms altered by the missense KIF21B variants.

Published
2020

6. Insufficient Evidence for 'Autism-Specific' Genes

Author

Kevin J. Mitchell, David T. Miller, John N. Constantino, Wendy K. Chung, Raphael Bernier, Christa Lese Martin, David H. Ledbetter, Thomas Bourgeron, Evan E. Eichler, Thomas D. Challman, Sébastien Jacquemont, Scott M. Myers, Huda Y. Zoghbi, Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), University of Washington [Seattle], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Columbia University Irving Medical Center (CUIMC), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Université de Montréal (UdeM), Boston Children's Hospital, Trinity College Dublin, Texas Children's Hospital [Houston, USA], Baylor College of Medicine (BCM), Baylor University, This work was supported, in part, by the National Institute of Mental Health (NIMH) and Eunice Kennedy Shriver National Institute of Child Health and Human Development of the US National Institutes of Health (NIH), under award numbers R01MH074090, R01MH107431, and U01MH11970510 (D.H.L., C.L.M., S.M.M.), Institut Pasteur, Université de Paris, Fondation Bettencourt-Schueller (T.B.), the Simons Foundation Autism Research Initiative (W.K.C.), the Eunice Kennedy Shriver National Institute of Child Health and Human Development award number U54 HD087011 (J.N.C.), NIH grant MH101221 (E.E.E.), and the Canadian Institute of Health Research Canada Research Chair, Canadian Institute of Health Research award number 400528, and NIMH award number U01 MH119690-01 (S.J.). E.E.E. is an investigator of the Howard Hughes Medical Institute. D.T.M. receives an honorarium to serve on the Medical Genetics Committee of the Simons Foundation Powering Autism Research (SPARK) project and receives salary support from NIH grant U41 HG006834 (a Unified Clinical Genomics Database). H.Y.Z. is an investigator of the Howard Hughes Medical Institute., and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
0301 basic medicine, Computational biology, MESH: Genotype, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Genetics, medicine, Gene, MESH: Cohort Studies, Genetics (clinical), MESH: Autism Spectrum Disorder, MESH: Humans, MESH: Genetic Testing, Large effect size, [SCCO.NEUR]Cognitive science/Neuroscience, medicine.disease, Phenotype, MESH: Reproducibility of Results, 030104 developmental biology, Autism spectrum disorder, ▪▪▪, Commentary, Autism, Psychology, 030217 neurology & neurosurgery, MESH: Uncertainty
Abstract

International audience; Despite evidence that deleterious variants in the same genes are implicated across multiple neurodevelopmental and neuropsychiatric disorders, there has been considerable interest in identifying genes that, when mutated, confer risk that is largely specific for autism spectrum disorder (ASD). Here, we review the findings and limitations of recent efforts to identify relatively "autism-specific" genes, efforts which focus on rare variants of large effect size that are thought to account for the observed phenotypes. We present a divergent interpretation of published evidence; discuss practical and theoretical issues related to studying the relationships between rare, large-effect deleterious variants and neurodevelopmental phenotypes; and describe potential future directions of this research. We argue that there is currently insufficient evidence to establish meaningful ASD specificity of any genes based on large-effect rare-variant data.

Published
2020

7. A framework for an evidence-based gene list relevant to autism spectrum disorder

Author

Peter Szatmari, Mayada Elsabbagh, Wendy K. Chung, Helen V. Firth, Ny Hoang, Jacques L. Michaud, Catalina Betancur, Janet A. Buchanan, Jennifer L. Howe, Jacob A. S. Vorstman, Louise Gallagher, Christian P. Schaaf, Edwin H. Cook, Joseph D. Buxbaum, Kira A. Dies, Olivia Rennie, Stephen W. Scherer, Raphael Bernier, Jeremy R. Parr, Ryan K. C. Yuen, Patrick Bolton, Thomas W. Frazier, Christian R. Marshall, Chun-An Chen, David Skuse, Betancur, Catalina, Institute of Human Genetics [Heidelberg, Germany], Universität Heidelberg [Heidelberg], Baylor College of Medicine (BCM), Baylor University, Texas Children's Hospital [Houston, USA], Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), The Hospital for sick children [Toronto] (SickKids), University of Toronto, Newcastle University [Newcastle], University College of London [London] (UCL), Trinity College Dublin, University of Washington [Seattle], Children's Autism Center [Seattle, WA, USA], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Neurology, Children's Hospital [Boston], Boston Children's Hospital, Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), The Wellcome Trust Sanger Institute [Cambridge], Autism Speaks [Cleveland, OH, USA], Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Centre for Addiction and Mental Health [Toronto] (CAMH), Columbia University Medical Center (CUMC), Columbia University [New York], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, University of Illinois [Chicago] (UIC), University of Illinois System, McLaughlin Centre for Population Health Risk Assessment, University of Ottawa [Ottawa], Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche du CHU Sainte-Justine [Montreal], and CHU Sainte Justine [Montréal]-Université de Montréal (UdeM)

Subjects
Evidence-based practice, Research groups, Autism Spectrum Disorder, MEDLINE, MESH: Cognition, Computational biology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, behavioral disciplines and activities, MESH: Intellectual Disability, 03 medical and health sciences, MESH: Brain, Cognition, 0302 clinical medicine, Intellectual Disability, mental disorders, Genetics, medicine, Humans, Molecular Biology, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, MESH: Genetic Association Studies, MESH: Autism Spectrum Disorder, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Evidence-Based Medicine, MESH: Humans, Extramural, Brain, Evidence-based medicine, medicine.disease, Clinical Practice, Autism spectrum disorder, Gene list, 030217 neurology & neurosurgery, MESH: Evidence-Based Medicine
Abstract

International audience; Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.

Published
2020

8. Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders

Author

Charles E. Schwartz, Marjolein H. Willemsen, Saadet Mercimek-Andrews, Amy B. Wilfert, Hugo J. Bellen, Alexander P.A. Stegmann, Tjitske Kleefstra, Pawel Stankiewicz, Benjamin Büttner, Hailun Ni, Rongjuan Zhao, Rami Abou Jamra, Mariëtte J.V. Hoffer, Kristin Herman, Marjan M. Weiss, Heather C Mefford, Huidan Wu, Deanna J. Erwin, Zhengmao Hu, Claudia A. L. Ruivenkamp, Helger G. Yntema, Cindy Colson, Alessandra Murgia, Maria Bottitta, Jane Juusola, Tianyun Wang, Stephen M. Malone, Kun Xia, Baosheng Zhu, Nicolas Richard, Jozef Gecz, Elisa Bettella, Tuula Rinne, Raphael Bernier, Emilia K. Bijlsma, Michael F. Wangler, Shinya Yamamoto, Brigid M. Regan, Sharayu Jangam, Bregje W.M. van Bon, Jill A. Rosenfeld, Kendra Hoekzema, Cenying Liu, Shweta U. Dhar, Stefano Sartori, Boris Keren, Hui Guo, Lucia Castiglia, Servi J. C. Stevens, Corrado Romano, Min Long, Tomasz J. Nowakowski, Evan E. Eichler, Jan Maarten Cobben, Alison M. Muir, Lisa Emrick, Quinten Waisfisz, Wenjing Zhao, Jonathan C. Andrews, Ingrid E. Scheffer, Bing Bai, Madelyn A. Gillentine, Paul C. Marcogliese, Fan Xia, Han G. Brunner, Alexandra Afenjar, Academic Medical Center, MUMC+: DA KG Polikliniek (9), MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Klinische Genetica, Chinese Academy of Forestry, University Hospital of Padua, Baylor College of Medicine (BCM), Baylor University, Texas Children's Hospital [Houston, USA], Central South University [Changsha], University of California, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Department of Genome Sciences [Seattle] (GS), University of Washington [Seattle], Radboud University Medical Center [Nijmegen], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Ecosystèmes méditerranéens et risques (UR EMAX), Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF), Service de Génétique [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), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), The Greenwood Genetic Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Kunming University of Science and Technology (KMUST), The Hospital for sick children [Toronto] (SickKids), University of Toronto, GeneDx [Gaithersburg, MD, USA], Universität Leipzig [Leipzig], University of Melbourne, Queensland Institute of Medical Research, University of Adelaide, Emma Children’s Hospital, Vrije Universiteit Amsterdam [Amsterdam] (VU), Leiden University Medical Center (LUMC), The Chinese University of Hong Kong [Hong Kong], and Human genetics

Subjects
0301 basic medicine, Proband, Male, Genetics of the nervous system, Developmental Disabilities, General Physics and Astronomy, Muscle Proteins, medicine.disease_cause, ANNOTATION, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Whole Exome Sequencing, Craniofacial Abnormalities, Epilepsy, 0302 clinical medicine, Postsynaptic potential, Intellectual disability, Drosophila Proteins, lcsh:Science, Child, SYNAPTIC DEVELOPMENT, Neurons, Mutation, Multidisciplinary, Behavior, Animal, Mental Disorders, Brain, Drosophila melanogaster, Child, Preschool, Behavioural genetics, Excitatory postsynaptic potential, Female, Neuroglia, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, medicine.medical_specialty, GENES, Adolescent, Science, Nerve Tissue Proteins, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Young Adult, All institutes and research themes of the Radboud University Medical Center, RESOURCE, Intellectual Disability, Exome Sequencing, medicine, Animals, Humans, Language Development Disorders, Autistic Disorder, Psychiatry, Preschool, [SDV.GEN]Life Sciences [q-bio]/Genetics, Behavior, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Animal, MEMORY, Membrane Proteins, Proteins, General Chemistry, medicine.disease, FRAMEWORK, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, DE-NOVO MUTATIONS, Neurodevelopmental Disorders, Neuronal development, Autism, lcsh:Q, business, Postsynaptic density, 030217 neurology & neurosurgery
Abstract

Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2—whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes., Neurodevelopmental disorders (NDDs) are a heterogeneous group of diseases for which the genetic basis is still unknown in more than half of the cases. Here, the authors report a NDD associated with disruptive variants in the TANC2 gene and show that rols, the TANC2 homolog in flies, is required for synapse growth and function.

Published
2019

9. The Effect of Age on the Progression and Severity of Type 1 Diabetes: Potential Effects on Disease Mechanisms

Author

Jay M. Sosenko, Pia Leete, Sarah J. Richardson, Maria J. Redondo, Roberto Mallone, Carmella Evans-Molina, Islet Biology Exeter [Exeter, UK] (IBEx), University of Exeter Medical School [UK]-Institute of Biomedical and Clinical Sciences [Exeter, UK], 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 de diabétologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Sorbonne Paris Cité (USPC), Hôpital Cochin [AP-HP], Department of Medicine [Miami, FL, USA] (Diabetes Research Institute), University of Miami Leonard M. Miller School of Medicine (UMMSM)-University of Miami [Coral Gables], Department of Pediatrics [Houston, TX, USA] (Baylor College of Medicine), Texas Children's Hospital [Houston, USA], Departments of Medicine and Pediatrics [Indianapolis, IN, USA], Indiana University School of Medicine, Indiana University System-Indiana University System-Herman B Wells Center for Pediatric Research [Indianapolis, IN, USA]-Roudebush VA Medical Center [Indianapolis, IN, USA], This study was financially supported by the European Union’s Seventh Framework Programme PEVNET ([FP7/2007-2013)] under grant agreement number 261441. The participants of the PEVNET consortium are described at http://www.uta.fi/med/pevnet/publications.html. Additional support was from a JDRF research grants awarded to the network of Pancreatic Organ Donors–Virus (nPOD-V) consortium (JDRF 25-2012-516 and JDRF-3-SRA-2017-492-A-N) and a JDRF Career Development Award (5-CDA-2014-221-A-N), an MRC Project Grant (MR/P010695/1) and project grant from Diabetes UK (16/0005480) all to SJR. This work was also supported by NIH grants R01 DK093954 and UC4 DK 104166 (to C.E.M.), U01 DK103180 (toM.R.), VA Merit Award I01BX001733 (to C.E.M.), a JDRF Strategic Research Agreement (2-SRA-2018-493-A-B), and gifts from the Sigma Beta Sorority, the Ball Brothers Foundation, the George and Frances Ball Foundation, and the Holiday Management Foundation, all to C.E.M. R.M. received grants from the JDRF (1-PNF-2014-155-A-V, 2-SRA-2016-164-Q-R), the Agence Nationale de la Recherche (ANR-2015-CE17-0018-01) and by the Innovative Medicines Initiative 2 Joint Undertaking (INNODIA, 115797), which receives support from the EU Horizon 2020 program, the European Federation of Pharmaceutical Industries and Associations, JDRF, and the Helmsley Charitable Trust., ANR-15-CE17-0018,TIBET,LA PRESSION ENVIRONNEMENTALE SUR UNE IMAGE ALTEREE DU SOI IMMUNITAIRE : VERS LA PREDICTION ET LA PREVENTION DU DIABETE DE TYPE 1(2015), European Project: 261441,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,PEVNET(2011), University of Exeter-Institute of Biomedical and Clinical Sciences [Exeter, UK], Mallone, Roberto, LA PRESSION ENVIRONNEMENTALE SUR UNE IMAGE ALTEREE DU SOI IMMUNITAIRE : VERS LA PREDICTION ET LA PREVENTION DU DIABETE DE TYPE 1 - - TIBET2015 - ANR-15-CE17-0018 - AAPG2015 - VALID, and Persistent virus infection as a cause of pathogenic inflammation in type 1 diabetes - an innovative research program of biobanks and expertise - PEVNET - - EC:FP7:HEALTH2011-01-01 - 2015-12-31 - 261441 - VALID

Subjects
0301 basic medicine, endocrine system diseases, [SDV.IMM] Life Sciences [q-bio]/Immunology, Endocrinology, Diabetes and Metabolism, β cell, 030209 endocrinology & metabolism, Autoimmunity, Human leukocyte antigen, medicine.disease_cause, Article, 03 medical and health sciences, Genetic Heterogeneity, 0302 clinical medicine, Immune system, Age, Diabetes mellitus, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, Autoimmune disease, Type 1 diabetes, business.industry, Autoantibody, Age Factors, medicine.disease, 3. Good health, 030104 developmental biology, Diabetes Mellitus, Type 1, Immune System, Immunology, Disease Progression, [SDV.IMM]Life Sciences [q-bio]/Immunology, Age of onset, C-peptide, business
Abstract

International audience; PURPOSE OF REVIEW:To explore the impact of age on type 1 diabetes (T1D) pathogenesis.RECENT FINDINGS:Children progress more rapidly from autoantibody positivity to T1D and have lower C-peptide levels compared to adults. In histological analysis of post-mortem pancreata, younger age of diagnosis is associated with reduced numbers of insulin containing islets and a hyper-immune CD20hi infiltrate. Moreover compared to adults, children exhibit decreased immune regulatory function and increased engagement and trafficking of autoreactive CD8+ T cells, and age-related differences in β cell vulnerability may also contribute to the more aggressive immune phenotype observed in children. To account for some of these differences, HLA and non-HLA genetic loci that influence multiple disease characteristics, including age of onset, are being increasingly characterized. The exception of T1D as an autoimmune disease more prevalent in children than adults results from a combination of immune, metabolic, and genetic factors. Age-related differences in T1D pathology have important implications for better tailoring of immunotherapies.

Published
2018

10. Switching-Off Adora2b in Vascular Smooth Muscle Cells Halts the Development of Pulmonary Hypertension

Author

Tinne C. J. Mertens, Ankit Hanmandlu, Ly Tu, Carole Phan, Scott D. Collum, Ning-Yuan Chen, Tingting Weng, Jonathan Davies, Chen Liu, Holger K. Eltzschig, Soma S. K. Jyothula, Keshava Rajagopal, Yang Xia, Ashrith Guha, Brian A. Bruckner, Michael R. Blackburn, Christophe Guignabert, Harry Karmouty-Quintana, Department of Biochemistry and Molecular Biology [Houston, TX, USA], The University of Texas Medical School at Houston, Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anesthésie et de Soins Intensifs [Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Université Paris-Saclay, Department of Pediatrics [Houston, TX, USA] (Baylor College of Medicine), Texas Children's Hospital [Houston, USA], Department of Anesthesiology [Houston, TX, USA] (McGovern Medical School), The University of Texas Health Science Center at Houston (UTHealth), Department of Internal Medicine [Houston, TX, USA] (McGovern Medical School), Methodist Debakey Heart and Vascular Center [Houston, TX, USA], Houston Methodist Hospital [Houston, TX, USA], We would like to acknowledge the funding of the following organizations: American Heart Association 14SDG18550039 to HK-Q, American Lung Association RG-414673 to HK-Q, National Institutes of Health (NIH) 1R01 HL138510-01 to HK-Q. NIH 1P01 HL114457-02 to MB, HE, and YX., Guignabert, Christophe, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre chirurgical Marie Lannelongue

Subjects
0301 basic medicine, Vascular smooth muscle, Physiology, vascular remodeling, [SDV]Life Sciences [q-bio], tissue transglutaminase, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Pharmacology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, lcsh:Physiology, hyaluronan, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Fibrosis, Physiology (medical), Medicine, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Lung, lcsh:QP1-981, business.industry, lung fibrosis, Group III PH, Hypoxia (medical), Group I PH, medicine.disease, Adenosine receptor, Adenosine, Pulmonary hypertension, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, medicine.symptom, business, Adenosine A2B receptor, medicine.drug
Abstract

International audience; Background: Pulmonary hypertension (PH) is a devastating and progressive disease characterized by excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) and remodeling of the lung vasculature. Adenosine signaling through the ADORA2B receptor has previously been implicated in disease progression and tissue remodeling in chronic lung disease. In experimental models of PH associated with chronic lung injury, pharmacological or genetic inhibition of ADORA2B improved markers of chronic lung injury and hallmarks of PH. However, the contribution of ADORA2B expression in the PASMC was not fully evaluated. Hypothesis: We hypothesized that adenosine signaling through the ADORA2B receptor in PASMC mediates the development of PH. Methods: PASMCs from controls and patients with idiopathic pulmonary arterial hypertension (iPAH) were characterized for expression levels of all adenosine receptors. Next, we evaluated the development of PH in ADORA2Bf/f-Transgelin (Tagln)cre mice. These mice or adequate controls were exposed to a combination of SUGEN (SU5416, 20 mg/kg/b.w. IP) and hypoxia (10% O2) for 28 days (HX-SU) or to chronic low doses of bleomycin (BLM, 0.035U/kg/b.w. IP). Cardiovascular readouts including right ventricle systolic pressures (RVSPs), Fulton indices and vascular remodeling were determined. Using PASMCs we identified ADORA2B-dependent mediators involved in vascular remodeling. These mediators: IL-6, hyaluronan synthase 2 (HAS2) and tissue transglutaminase (Tgm2) were determined by RT-PCR and validated in our HX-SU and BLM models. Results: Increased levels of ADORA2B were observed in PASMC from iPAH patients. ADORA2Bf/f-Taglncre mice were protected from the development of PH following HX-SU or BLM exposure. In the BLM model of PH, ADORA2Bf/f- Taglncre mice were not protected from the development of fibrosis. Increased expression of IL-6, HAS2 and Tgm2 was observed in PASMC in an ADORA2B-dependent manner. These mediators were also reduced in ADORA2Bf/f- Taglncre mice exposed to HX-SU or BLM. Conclusions: Our studies revealed ADORA2B-dependent increased levels of IL-6, hyaluronan and Tgm2 in PASMC, consistent with reduced levels in ADORA2Bf/f- Taglncre mice exposed to HX-SU or BLM. Taken together, our data indicates that ADORA2B on PASMC mediates the development of PH through the induction of IL-6, hyaluronan and Tgm2. These studies point at ADORA2B as a therapeutic target to treat PH.

Published
2018

11. Argasid and ixodid systematics: Implications for soft tick evolution and systematics, with a new argasid species list

Author

Minique H. de Castro, Ronel Pienaar, Esther G. Kanduma, Daniel G. de Klerk, Ben J. Mans, Job E. Lopez, Ali Bouattour, Marija Kvas, Pete D. Teel, Daniel E. Sonenshine, Kerry-Anne Pillay, Jonathan Featherston, Tom G. Schwan, Adalberto A. Pérez de León, Abdalla A. Latif, Nkululeko Nyangiwe, Deon K. Bakkes, Heloise Heyne, Noble I. Egekwu, Epidemiology, Parasites and Vectors, Agricultural Research Council-Onderstepoort Veterinary Research, Onderstepoort 0110, South Africa., University of South Africa (UNISA), National Institute of Allergy and Infectious Diseases, Hamilton, Department of Pediatrics [Houston, TX, USA] (Baylor College of Medicine), Texas Children's Hospital [Houston, USA], Texas A&M University [College Station], Livestock Insects Research Laboratory and Veterinary Pest Genomics Center, Kerrville, TX, United States., Old Dominion University [Norfolk] (ODU), USDA Agricultural Research Service [Maricopa, AZ] (USDA), United States Department of Agriculture (USDA), Department of Biochemistry, School of Medicine, University of Nairobi, P.O BOX 30197, 00100, Nairobi, Kenya., Döhne Agricultural Development Institute, Private Bag X15, Stutterheim, 4930, South Africa., Laboratoire d'Entomologie Médicale [Tunis, Tunisie], Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), and University of KwaZulu-Natal (UKZN)

Subjects
0301 basic medicine, Paraphyly, Systematics, Species complex, Genetic Speciation, [SDV]Life Sciences [q-bio], 030231 tropical medicine, Argas, Context (language use), Microbiology, DNA, Ribosomal, 03 medical and health sciences, 0302 clinical medicine, Nuttalliella, RNA, Ribosomal, 28S, RNA, Ribosomal, 18S, Animals, DNA Barcoding, Taxonomic, Ornithodoros, Phylogeny, biology, Argasidae, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, biology.organism_classification, Classification, 030104 developmental biology, Infectious Diseases, Evolutionary biology, Insect Science, Genome, Mitochondrial, Parasitology
Abstract

International audience; The systematics of the genera and subgenera within the soft tick family Argasidae is not adequately resolved. Different classification schemes, reflecting diverse schools of scientific thought that elevated or downgraded groups to genera or subgenera, have been proposed. In the most recent classification scheme, Argas and Ornithodoros are paraphyletic and the placement of various subgenera remains uncertain because molecular data are lacking. Thus, reclassification of the Argasidae is required. This will enable an understanding of soft tick systematics within an evolutionary context. This study addressed that knowledge gap using mitochondrial genome and nuclear (18S and 28S ribosomal RNA) sequence data for representatives of the subgenera Alectorobius, Argas, Chiropterargas, Ogadenus, Ornamentum, Ornithodoros, Navis (subgen. nov.), Pavlovskyella, Persicargas, Proknekalia, Reticulinasus and Secretargas, from the Afrotropical, Nearctic and Palearctic regions. Hard tick species (Ixodidae) and a new representative of Nuttalliella namaqua (Nuttalliellidae), were also se-quenced with a total of 83 whole mitochondrial genomes, 18S rRNA and 28S rRNA genes generated. The study confirmed the utility of next-generation sequencing to retrieve systematic markers. Paraphyly of Argas and Ornithodoros was resolved by systematic analysis and a new species list is proposed. This corresponds broadly with the morphological cladistic analysis of Klompen and Oliver (1993). Estimation of divergence times using molecular dating allowed dissection of phylogeographic patterns for argasid evolution. The discovery of cryptic species in the subgenera Chiropterargas, Ogadenus and Ornithodoros, suggests that cryptic speciation is common within the Argasidae. Cryptic speciation has implications for past biological studies of soft ticks. These are discussed in particular for the Ornithodoros (Ornithodoros) moubata and Ornithodoros (Ornithodoros) savignyi groups.

Published
2018

12. Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations

Author

Maria del Pilar Trelles, François Muratet, Alexander Kolevzon, Yitzchak Frank, Reymundo Lozano, Allison Durkin, J. Lloyd Holder, Catalina Betancur, Paige M. Siper, Silvia De Rubeis, Danielle Halpern, A. Ting Wang, Jordana Weissman, Joseph D. Buxbaum, Betancur, Catalina, Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Psychiatry, Department of Neurology, Department of Pediatircs, Department of Genetics and Genomic Sciences, Division of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medecine-Texas Children's Hospital [Houston, USA], Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Molecular Neuropsychiatry, Department of Neuroscience, Friedman Brain Institute, The Mindich Child Health and Development Institute, This work was supported by grants from the Beatrice and Samuel A. SeaverFoundation, the Phelan-McDermid Syndrome Foundation, NIMH (R34MH100276-01 to AK and R21 MH107839 to JDB), and NINDS (U54 NS092090-01 to AK and K08 NS091381 to JLH). SDR is a Seaver fellow. JLH is funded bythe Robbins Foundation. CB is a Research Director at INSERM., Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, Chromosomes, Human, Pair 22, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Intellectual disability, Chromosome Disorders, Haploinsufficiency, [SDV.GEN] Life Sciences [q-bio]/Genetics, lcsh:RC346-429, 0302 clinical medicine, Neurodevelopmental disorder, Autism spectrum disorder, Child, SHANK3, Genetics, Phenotype, Hypotonia, 3. Good health, Psychiatry and Mental health, 22q13 deletion syndrome, Child, Preschool, Female, Allelic heterogeneity, Chromosome Deletion, medicine.symptom, Adult, Adolescent, Nerve Tissue Proteins, Sequence variants, 03 medical and health sciences, Developmental Neuroscience, medicine, Humans, Point Mutation, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Research, Point mutation, medicine.disease, 030104 developmental biology, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Phelan-McDermid syndrome, business, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Background Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by psychiatric and neurological features. Most reported cases are caused by 22q13.3 deletions, leading to SHANK3 haploinsufficiency, but also usually encompassing many other genes. While the number of point mutations identified in SHANK3 has increased in recent years due to large-scale sequencing studies, systematic studies describing the phenotype of individuals harboring such mutations are lacking. Methods We provide detailed clinical and genetic data on 17 individuals carrying mutations in SHANK3. We also review 60 previously reported patients with pathogenic or likely pathogenic SHANK3 variants, often lacking detailed phenotypic information. Results SHANK3 mutations in our cohort and in previously reported cases were distributed throughout the protein; the majority were truncating and all were compatible with de novo inheritance. Despite substantial allelic heterogeneity, four variants were recurrent (p.Leu1142Valfs*153, p.Ala1227Glyfs*69, p.Arg1255Leufs*25, and c.2265+1G>A), suggesting that these are hotspots for de novo mutations. All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%). Severe speech deficits were common, but in contrast to individuals with 22q13.3 deletions, the majority developed single words, including 41% with at least phrase speech. Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems. Conclusions Haploinsufficiency of SHANK3 resulting from point mutations is sufficient to cause a broad range of features associated with PMS. Our findings expand the molecular and phenotypic spectrum of PMS caused by SHANK3 point mutations and suggest that, in general, speech impairment and motor deficits are more severe in the case of deletions. In contrast, renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of SHANK3. Electronic supplementary material The online version of this article (10.1186/s13229-018-0205-9) contains supplementary material, which is available to authorized users.

Published
2018

13. Human adaptive immunity rescues an inborn error of innate immunity

Author

Maya Chrabieh, Ying Wang, Sandra K. Weller, Elisabeth Israelsson, Katarzyna Bulek, Damien Chaussabel, Nicole Lemmens, Vincent Pedergnana, Laura Israel, Michael Levin, Jethro Herberg, Théo Lasseau, Carolina Prando, Andrew Moran, Vanessa Sancho-Shimizu, Zhao Zhang, François Vandenesch, Leonard E. Weisman, Jean-Laurent Casanova, Ling Yun, Erika Della Mina, Aziz Belkadi, Yuval Itan, Marc Descatoire, Lazaro Lorenzo, Willem J. B. van Wamel, Bruce Beutler, Avinash Abhyankar, Capucine Picard, Xiaoxia Li, Anne Puel, Peter D. Arkwright, Laurent Abel, Frédéric Batteux, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Texas Southwestern Medical Center [Dallas], Cleveland Clinic, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Imperial College London, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Benaroya Research Institute [Seattle] (BRI), Manchester Royal Infirmary, University of Manchester [Manchester], Texas Children's Hospital [Houston, USA], Hospices Civils de Lyon (HCL), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], CHU Necker - Enfants Malades [AP-HP], Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), Herrada, Anthony, and Medical Microbiology & Infectious Diseases

Subjects
incomplete clinical penetrance, Lipopolysaccharides, Male, 0301 basic medicine, Proband, TIRAP, [SDV]Life Sciences [q-bio], MESH: Membrane Glycoproteins, MESH: Protein Isoforms, Adaptive Immunity, MESH: Monocytes, MESH: Phagocytes, Monocytes, MESH: Antibodies, Monoclonal, 0302 clinical medicine, MESH: Child, TLR2, Protein Isoforms, CRYSTAL-STRUCTURE, Child, PYOGENIC BACTERIAL-INFECTIONS, Phagocytes, Membrane Glycoproteins, Toll-Like Receptors, MESH: Toll-Like Receptor 2, Antibodies, Monoclonal, 11 Medical And Health Sciences, Staphylococcal Infections, respiratory system, Acquired immune system, Penetrance, Pedigree, [SDV] Life Sciences [q-bio], MYD88 DEFICIENCY, lipoteichoic acid, LTA, MESH: Immunity, Innate, Female, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, MESH: Toll-Like Receptors, MESH: Myeloid Differentiation Factor 88, staphylococcus aureus, Biochemistry & Molecular Biology, MESH: Pedigree, MESH: Staphylococcal Infections, SIGNAL-TRANSDUCTION, Biology, MESH: Receptors, Interleukin-1, primary immunodeficiency, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immunity, TIR DOMAIN, medicine, Humans, Point Mutation, MESH: Point Mutation, STAPHYLOCOCCUS-AUREUS, MESH: Humans, Science & Technology, CUTTING EDGE, PRIMARY IMMUNODEFICIENCIES, Macrophages, MESH: Macrophages, Receptors, Interleukin-1, Cell Biology, 06 Biological Sciences, Fibroblasts, medicine.disease, GENE, MESH: Male, Immunity, Innate, Toll-Like Receptor 2, Teichoic Acids, carbohydrates (lipids), stomatognathic diseases, 030104 developmental biology, toll-like receptors, MESH: Fibroblasts, MESH: Teichoic Acids, Myeloid Differentiation Factor 88, Immunology, anti-LTA antibodies, Primary immunodeficiency, TLR4, MESH: Lipopolysaccharides, MESH: Female, MESH: Adaptive Immunity, Developmental Biology, 030215 immunology
Abstract

International audience; The molecular basis of the incomplete penetrance of monogenic disorders is unclear. We describe here eight related individuals with autosomal recessive TIRAP deficiency. Life-threatening staphylococcal disease occurred during childhood in the proband, but not in the other seven homozygotes. Responses to all Toll-like receptor 1/2 (TLR1/2), TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes of all TIRAP-deficient individuals. However, the whole-blood response to the TLR2/6 agonist staphylococcal lipoteichoic acid (LTA) was abolished only in the index case individual, the only family member lacking LTA-specific antibodies (Abs). This defective response was reversed in the patient, but not in interleukin-1 receptor-associated kinase 4 (IRAK-4)-deficient individuals, by anti-LTA monoclonal antibody (mAb). Anti-LTA mAb also rescued the macrophage response in mice lacking TIRAP, but not TLR2 or MyD88. Thus, acquired anti-LTA Abs rescue TLR2-dependent immunity to staphylococcal LTA in individuals with inherited TIRAP deficiency, accounting for incomplete penetrance. Combined TIRAP and anti-LTA Ab deficiencies underlie staphylococcal disease in this patient.

Published
2017

14. Two-year outcomes after diagnostic and therapeutic fetal cystoscopy for lower urinary tract obstruction

Author

Sananès, Nicolas, Cruz-Martinez, Rogelio, Favre, Romain, Ordorica-Flores, Ricardo, Moog, Raphaël, Zaloszy, Ariane, Giron, Amilcar Martins, Ruano, Rodrigo, Biomatériaux et Bioingénierie (BB), Université de Strasbourg (UNISTRA)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Texas Children's Hospital [Houston, USA], Instituto de Neurobiologia, Instituto Politecnico Nacional [Mexico] (IPN), CHU Strasbourg, and Faculdade de Medicina da Universidade de São Paulo [São Paulo, Brésil]

Subjects
embryonic structures, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Objectives: Our objective is to report long-term outcome after fetal cystoscopy for lower urinary tract obstruction (LUTO), as well as to investigate the accuracy of fetal cystoscopy in diagnosing the cause of bladder outlet obstruction. Methods: This is a retrospective cohort study of all fetuses who underwent cystoscopy for prenatal diagnosis of LUTO in three tertiary referral centers. Fetal diagnostic cystoscopy was performed to determine prenatally the cause of LUTO and to ablate the posterior urethral valves (PUV). Results: A total of 50 fetal cystoscopies were performed, revealing PUV in 31 (62%) fetuses, urethral atresia (UA) in 14 (28%) fetuses, and urethral stenosis (US) in 5 (10%) fetuses. Two fetuses had trisomy 18 diagnosed after fetal cystoscopy and were excluded from the present analysis. Fetal cystoscopy was accurate in the diagnosis of the etiology of LUTO in 32/35 (91.4%). There were no survivors in the UA group. One fetus with US underwent urethral stenting and survived with normal renal function at 2 years of life. Among the infants with PUV, 17/30 (56.7%) infants survived, and 13/17 (76.5%) had normal renal function at 1 year of life; 15/28 (53.6%) infants survived, and 11/15 (73.3%) had normal renal function at 2 years. Conclusions: Fetal cystoscopy is accurate in the diagnosis of the etiology of LUTO and serves as a guide to the specific prenatal treatment. This procedure is associated with modest long-term survival (54%) but with adequate preserved normal renal function in two thirds of the infants among fetuses with PUV.

Published
2016

15. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

Author

Laurent Pasquier, Anne V. Snow, David T. Miller, Louise Harewood, Christina Triantafallou, Timothy P.L. Roberts, Leighton B. Hinkley, Zili Chu, Louis Vallée, Alyss Lian Cavanagh, Evica Rajcan-Separovic, Patricia Blanchet, Fiona Miller, Robin P. Goin-Kochel, Beau Reilly, Bettina Cerban, Vanessa Siffredi, Bridget A. Fernandez, Roger Vaughan, Brianna M. Paul, Fanny Morice-Picard, Elisabeth Flori, Dominique Campion, Gérard Didelot, Anne Philippe, Christa Lese Martin, Srikantan S. Nagarajan, Joris Andrieux, Jacques Puechberty, Marie Pierre Cordier, Jill V. Hunter, Ellen van Binsbergen, Catherine Vincent-Delorme, Vivek Swarnakar, Jean Marie Cuisset, Monica Proud, Patrick Callier, Bert B.A. de Vries, Jeffrey I. Berman, Sarah J. Spence, Alexandra Bowe, Wendy K. Chung, Katy Ankenman, Katherine Hines, Sarah E. Gobuty, Philippe Jonveaux, Lisa Blaskey, Alice Goldenberg, Sylvie Jaillard, Alessandra Renieri, Anne M. Maillard, Tracy Luks, Lee Anne Green Snyder, Elliott H. Sherr, Sarah Y. Khan, Fabienne Prieur, Simon A. Zwolinski, Andres Metspalu, Ghislaine Plessis, Jean Chiesa, Rita J. Jeremy, Valérie Malan, Michèle Mathieu-Dramard, Loyse Hippolyte, Bethanny Smith-Packard, Andrea M. Paal, Bénédicte Duban Bedu, Claudine Rieubland, Jordan Burko, Sylvie Joriot, Philippe Conus, Dominique Bonneau, Benoit Arveiler, Nicole de Leeuw, Allison G. Dempsey, John E. Spiro, Julia Wenegrat, Bertrand Isidor, Cédric Le Caignec, Kyle J. Steinman, Bruno Delobel, Ashlie Llorens, Jacques S. Beckmann, Kelly Johnson, Sean Ackerman, Polina Bukshpun, Silvia Garza, Alexandre Reymond, Damien Sanlaville, Ellen Hanson, Martine Doco-Fenzy, Jacques Thonney, Mari Wakahiro, Juliane Hoyer, Jacqueline Vigneron, Katrin Õunap, Arthur L. Beaudet, Mandy Barker, Nicole Visyak, Sonia Bouquillon, W. Andrew Faucett, Raphael Bernier, Sudha Kilaru Kessler, Audrey Lynn Bibb, Dennis Shaw, R. Frank Kooy, Suzanne M E Lewis, Anna L. Laakman, Nicholas J. Pojman, Hubert Journel, Laura Bernardini, Arianne Stevens, Julia P. Owen, Rebecca Mc Nally Keehn, Stéphanie Selmoni, Sébastien Lebon, Aurélien Macé, Bruno Leheup, Saba Qasmieh, Zoltán Kutalik, Anita Rauch, Yiping Shen, Elysa J. Marco, Nathalie Van der Aa, Carina Ferrari, Noam D. Beckmann, Delphine Héron, Jennifer Tjernage, Benjamin Aaronson, Albert David, Marie Pierre Lemaitre, Muriel Holder, Eve Õiglane-Shlik, Anneke T. Vulto-van Silfhout, Flore Zufferey, Constance Atwell, Marta Benedetti, Ellen Grant, Jenna Elgin, Patricia Z. Page, Caroline Rooryck, Randy L. Buckner, Qixuan Chen, Laurence Faivre, Sébastien Jacquemont, Kerri P. Nowell, Florence Fellmann, Disciglio Vittoria, Katharina Magdalena Rötzer, Hana Lee, Alastair J. Martin, Marion Greenup, David H. Ledbetter, Katrin Männik, Morgan W. Lasala, Jennifer Gerdts, Hanalore Alupay, Florence Petit, Elizabeth Aylward, Gerald D. Fischbach, Mafalda Mucciolo, Maxwell Cheong, Gabriela Marzano, Frédérique Béna, Danielle Martinet, Timothy J. Moss, Odile Boute, Jennifer Olson, Marco Belfiore, Christina Fagerberg, Corby L. Dale, Robert M. Witwicki, Yolanda L. Evans, Melissa B. Ramocki, Marie-Claude Addor, Christèle Dubourg, Mariken Ruiter, Tuhin K. Sinha, Mieke M. van Haelst, Alan Packer, Kathleen E. McGovern, Christie M. Brewton, Stephen M. Kanne, Richard I. Fisher, Tracey Ward, Sophie Dupuis-Girod, Pratik Mukherjee, Simons VIP Consortium, 16p11.2 European Consortium, Addor, MC., Arveiler, B., Belfiore, M., Bena, F., Bernardini, L., Blanchet, P., Bonneau, D., Boute, O., Callier, P., Campion, D., Chiesa, J., Cordier, MP., Cuisset, JM., David, A., de Leeuw, N., de Vries, B., Didelot, G., Doco-Fenzy, M., Bedu, BD., Dubourg, C., Dupuis-Girod, S., Fagerberg, CR., Faivre, L., Fellmann, F., Fernandez, BA., Fisher, R., Flori, E., Goldenberg, A., Heron, D., Holder, M., Hoyer, J., Isidor, B., Jaillard, S., Jonveaux, P., Joriot, S., Journel, H., Kooy, F., le Caignec, C., Leheup, B., Lemaitre, MP., Lewis, S., Malan, V., Mathieu-Dramard, M., Metspalu, A., Morice-Picard, F., Mucciolo, M., Oiglane-Shlik, E., Ounap, K., Pasquier, L., Petit, F., Philippe, A., Plessis, G., Prieur, F., Puechberty, J., Rajcan-Separovic, E., Rauch, A., Renieri, A., Rieubland, C., Rooryck, C., Rötzer, KM., Ruiter, M., Sanlaville, D., Selmoni, S., Shen, Y., Siffredi, V., Thonney, J., Vallée, L., van Binsbergen, E., Van der Aa, N., van Haelst MM., Vigneron, J., Vincent-Delorme, C., Vittoria, D., Vulto-van Silfhout AT., Witwicki, RM., Zwolinski, SA., Bowe, A., Beaudet, AL., Brewton, CM., Chu, Z., Dempsey, AG., Evans, YL., Garza, S., Kanne, SM., Laakman, AL., Lasala, MW., Llorens, AV., Marzano, G., Moss, TJ., Nowell, KP., Proud, MB., Chen, Q., Vaughan, R., Berman, J., Blaskey, L., Hines, K., Kessler, S., Khan, SY., Qasmieh, S., Bibb, AL., Paal, AM., Page, PZ., Smith-Packard, B., Buckner, R., Burko, J., Cavanagh, AL., Cerban, B., Snow, AV., Snyder, LG., Keehn, RM., Miller, DT., Miller, FK., Olson, JE., Triantafallou, C., Visyak, N., Atwell, C., Benedetti, M., Fischbach, GD., Greenup, M., Packer, A., Bukshpun, P., Cheong, M., Dale, C., Gobuty, SE., Hinkley, L., Jeremy, RJ., Lee, H., Luks, TL., Marco, EJ., Martin, AJ., McGovern, KE., Nagarajan, SS., Owen, J., Paul, BM., Pojman, NJ., Sinha, T., Swarnakar, V., Wakahiro, M., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Elgin, J., Gerdts, J., Johnson, K., Reilly, B., Shaw, D., Stevens, A., Ward, T., Wenegrat, J., Other departments, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), CHU Pontchaillou [Rennes], Department of Medical Genetics, Université de Lausanne (UNIL), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-GHICL, Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Texas Children's Hospital [Houston, USA], Department of pediatrics, Primary palliative Care Research Group, Community Health Sciences, General Practice Section, University of Edinburgh, Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Developmental Brain and Behaviour Unit, University of Southampton, Institute of Molecular and Cell Biology, University of Tartu, Department of Human Genetics, UCLA, University of California [Los Angeles] (UCLA), University of California-University of California-Semel Institute, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Lausanne = University of Lausanne (UNIL), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), University of California (UC)-University of California (UC)-Semel Institute, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and Kooy, Frank

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Heterozygote, Adolescent, [SDV]Life Sciences [q-bio], Developmental Disabilities, Biology, Body Mass Index, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Gene Order, Genetics, medicine, Humans, Copy-number variation, Clinical genetics, Obesity, Young adult, Child, Genetics (clinical), 030304 developmental biology, Child Development Disorders, Pervasive/diagnosis, Child Development Disorders, Pervasive/genetics, Chromosome Deletion, Chromosomes, Human, Pair 16, Developmental Disabilities/diagnosis, Developmental Disabilities/genetics, Female, Intelligence Tests, Phenotype, Syndrome, 2. Zero hunger, Psychiatry, 0303 health sciences, Intelligence quotient, Neuropsychology, Complex traits, medicine.disease, Comorbidity, 3. Good health, Autism spectrum disorder, Child Development Disorders, Pervasive, Autism, Medical genetics, Human medicine, Copy-Number Variation, 030217 neurology & neurosurgery
Abstract

Background The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. Methods We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. Results When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. Conclusions The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Published
2012

16. Activation of the constitutive androstane receptor decreases HDL in wild-type and human apoA-I transgenic mice

Author

Jean Paul Pais de Barros, Anne Laure Sberna, Rui Xiao, David Masson, David D. Moore, Philippe Gambert, Anne Athias, Mohammed Qatanani, Laurent Lagrost, Mahfoud Assem, Jacques Grober, Valérie Deckert, 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), Santé - STIC, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Baylor College of Medicine (BCM), Baylor University, Department of Pediatrics [Houston, TX, USA] (Baylor College of Medicine), and Texas Children's Hospital [Houston, USA]

Subjects
Apolipoprotein B, Pyridines, [SDV]Life Sciences [q-bio], Receptors, Cytoplasmic and Nuclear, Biochemistry, Mice, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Constitutive androstane receptor, Promoter Regions, Genetic, 0303 health sciences, biology, Chemistry, 3. Good health, 030220 oncology & carcinogenesis, lipids (amino acids, peptides, and proteins), Multidrug Resistance-Associated Proteins, Lipoproteins, HDL, Agonist, Genetically modified mouse, medicine.medical_specialty, medicine.drug_class, apolipoprotein A-I, Down-Regulation, Mice, Transgenic, QD415-436, 5-dichloropyridyloxy)]benzene, 03 medical and health sciences, Downregulation and upregulation, Internal medicine, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Constitutive Androstane Receptor, 030304 developmental biology, bile acids, Base Sequence, Cholesterol, Cholesterol, HDL, Wild type, nutritional and metabolic diseases, cholesterol, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, Cell Biology, Dietary Fats, 4-bis[2-(3, Nuclear receptor, biology.protein, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, human activities, Transcription Factors
Abstract

International audience; The nuclear hormone receptor constitutive androstane receptor (CAR, NR1I3) regulates detoxification of xenobiotics and endogenous molecules, and has been shown to be involved in the metabolism of hepatic bile acids and cholesterol. The goal of this study was to address potential effects of CAR on the metabolism of HDL particles, key components in the reverse transport of cholesterol to the liver. Wild-type (WT) mice, transgenic mice expressing human apolipoprotein A-I (HuAITg), and CAR-deficient (CAR(-/-)) mice were treated with the specific CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP). CAR activation decreased HDL cholesterol and plasma apolipoprotein A-I (apoA-I) levels in both WT and HuAITg mice, but not CAR(-/-) mice. Both mouse apoA-I and human apoA-I were decreased by more than 40% after TCPOBOP treatment, and kinetic studies revealed that the production rate of HDL is reduced in TCPOBOP-treated WT mice. In transient transfections, TCPOBOP-activated CAR decreased the activity of the human apoA-I promoter. Although loss of CAR function did not alter HDL levels in normal chow-fed mice, HDL cholesterol, apoA-I concentration, and apoA-I mRNA levels were increased in CAR(-/-) mice relative to WT mice when both were fed a high-fat diet. We conclude that CAR activation in mice induces a pronounced decrease in circulating levels of plasma HDL, at least in part through downregulation of apoA-I gene expression.

Published
2008

17. Endovascular Treatment of Wide-neck Bifurcation Aneurysms: Short- and Midterm Results in a European Study

Author

Pierot, L, Klisch, J, Gauvrit, J, Szikora, I, Leonardi, M, Liebig, T, Nunzi, N, Boccardi, B, Di Paola, F, Holtmanspötter, M, Weber, W, Calgliari, E, Lubicz, B, Université de Reims Champagne-Ardenne (URCA), Texas Children's Hospital [Houston, USA], Vision, Action et Gestion d'informations en Santé (VisAGeS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Service de radiologie et imagerie médicale [Rennes] = Radiology [Rennes], CHU Pontchaillou [Rennes], Neuroradiology, National Institute of Neurosciences, Budapest, Hungary, Ospedale Bellaria [Bologna, Italy], Imperial College London, Universitaetsklinikum Koeln, Ospedale Niguarda, Laboratoire de mécanique des sols, structures et matériaux (MSSMat), CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Institut de Physique et Chimie des Matériaux de Strasbourg (IPCMS), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Neuroradiology, Ospedale dell'Angelo, Mestre, Italy, Department of Neuroradiology (B.L., B.M.), Erasme University Hospital, Brussels, Belgium., CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Molecular Medicine, National Heart and Lung Institute, Imperial College London., United Kingdom, Université de Strasbourg (UNISTRA)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, and Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
[INFO.INFO-IM]Computer Science [cs]/Medical Imaging, cardiovascular diseases
Abstract

International audience; Background and purpose Flow disruption with the WEB-DL device has been used safely for the treatment of wide-necked bifurcation aneurysms but the stability of aneurysm occlusion after this treatment is unknown. This retrospective multicenter European study analyzed short- and midterm data in patients treated with WEB-DL.Methods Twelve European neurointerventional centers participated to the study. Clinical data, pre- and post-operative, short-, and midterm images were collected. An experienced interventional neuroradiologist independently analyzed images. Aneurysm occlusion was classified in 4 grades: complete occlusion, opacification of the proximal recess of the device, neck remnant, and aneurysm remnant.Results Forty-five patients (34 females and 11 males) aged 35 to 74 years (mean: 56.3 +/- 9.6 years) harbouring 45 aneurysms treated with the WEB device were included. Aneurysm locations were middle cerebral artery in 26 patients, posterior circulation in 13, anterior communicating artery in 5, and internal carotid artery terminus in 1. Forty-two aneurysms were unruptured. Good clinical outcome (mRS < 2) was observed in 93.3% of patients. Adequate occlusion (Complete occlusion, opacification of the proximal recess, or neck remnant) was observed in 30/37 patients (81.1%) in short-term follow-up (median 6 months) and in 26/29 patients (89.7%) in midterm follow-up (median 13 months). Worsening of aneurysm occlusion was observed in 2/28 patients (7.1%) in midterm follow-up.Conclusions The results suggest WEB treatment of wide-neck bifurcation aneurysms offers stable occlusion in aneurysms that are usually unstable. Additionally, our data show that opacification of the WEB recess can be delineated from true neck or aneurysm remnant.

Published
2014

18. WEB-DL endovascular treatment of wide-neck bifurcation aneurysms: short- and midterm results in a European study

Author

Vojtech Sychra, F. D. Paola, Joachim Klisch, Boris Lubicz, Marco Leonardi, Laurent Pierot, Thomas Liebig, Benjamin Mine, Werner Weber, Nunzio Paolo Nuzzi, E. Calgliari, Markus Holtmannspötter, Jean-Yves Gauvrit, Edoardo Boccardi, István Szikora, Department of Neuroradiology (B.L., B.M.), Erasme University Hospital, Brussels, Belgium., Texas Children's Hospital [Houston, USA], Service de radiologie et imagerie médicale [Rennes] = Radiology [Rennes], CHU Pontchaillou [Rennes], Vision, Action et Gestion d'informations en Santé (VisAGeS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Neuroradiology, National Institute of Neurosciences, Budapest, Hungary, Department of Life, Health and Environmental Sciences, L'Aquila University, L'Aquila, Italy, Molecular Medicine, National Heart and Lung Institute, Imperial College London., United Kingdom, Radiodiagnostic and Interventional Radiology Institute, University of Eastern Piedmont, Novara, Italy., Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli studi di Bari Aldo Moro (UNIBA), Division of Interventional Neuroradiology (M.H.), Københavns Universitet, Copenhagen, Denmark, Neuroradiology, Ospedale dell'Angelo, Mestre, Italy, Institute of Diagnostic und Interventional Radiology and Neuroradiology (J.K., V.S., C.S.), Helios Klinikum, Erfurt, Germany, and Departments of Neuroradiology (C.A.T., H.U., S.M.) and Neurology (M.R.), University Hospital Freiburg, Freiburg, Germany, Erasme University Hospital, Department of Diagnostic and Interventional Neuroradiology, Route de Lennik, 808, 1070 Brussels, Belgium, Hôpital Maison Blanche, Centre Hospitalier Universitaire de Reims (CHU Reims), Neuroadiology, Knappschaftskrankenhaus, Recklinghausen, Germany, Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Università degli Studi dell'Aquila = University of L'Aquila (UNIVAQ), Imperial College London, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Gauvrit, Jean-Yves, Lubicz B, Klisch J, Gauvrit JY, Szikora I, Leonardi M, Liebig T, Nuzzi NP, Boccardi E, Paola FD, Holtmannspötter M, Weber W, Calgliari E, Sychra V, Mine B, and Pierot L.

Subjects
FLOW-DISRUPTION, medicine.medical_specialty, [SDV]Life Sciences [q-bio], education, MULTICENTER, INTRACRANIAL ANEURYSMS, Aneurysm, Text mining, medicine.artery, Occlusion, medicine, Radiology, Nuclear Medicine and imaging, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], cardiovascular diseases, Endovascular treatment, COILING, [SDV.IB] Life Sciences [q-bio]/Bioengineering, business.industry, Retrospective cohort study, Sciences bio-médicales et agricoles, medicine.disease, 3. Good health, Surgery, [SDV] Life Sciences [q-bio], Anterior communicating artery, Middle cerebral artery, cardiovascular system, TRIAL, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.IB]Life Sciences [q-bio]/Bioengineering, Neurology (clinical), Radiology, Internal carotid artery, FOLLOW-UP, business
Abstract

BACKGROUND AND PURPOSE:Flow disruption with the WEB-DL device has been used safely for the treatment of wide-neck bifurcation aneurysms, but the stability of aneurysm occlusion after this treatment is unknown. This retrospective multicenter European study analyzed short- and midterm data in patients treated with WEB-DL.MATERIALS AND METHODS:Twelve European neurointerventional centers participated in the study. Clinical data and pre- and postoperative short- and midterm images were collected. An experienced interventional neuroradiologist independently analyzed the images. Aneurysm occlusion was classified into 4 grades: complete occlusion, opacification of the proximal recess of the device, neck remnant, and aneurysm remnant.RESULTS:Forty-five patients (34 women and 11 men) 35-74 years of age (mean, 56.3 ± 9.6 years) with 45 aneurysms treated with the WEB device were included. Aneurysm locations were the middle cerebral artery in 26 patients, the posterior circulation in 13 patients, the anterior communicating artery in 5 patients, and the internal carotid artery terminus in 1 patient. Forty-two aneurysms were unruptured. Good clinical outcome (mRS < 2) was observed in 93.3% of patients at the last follow-up. Adequate occlusion (complete occlusion, opacification of the proximal recess, or neck remnant) was observed in 30/37 patients (81.1%) in short-term follow-up (median, 6 months) and in 26/29 patients (89.7%) in midterm follow-up (median, 13 months). Worsening of the aneurysm occlusion was observed in 2/28 patients (7.1%) at midterm follow-up.CONCLUSIONS:The results suggest that the WEB endovascular treatment of wide-neck bifurcation aneurysms offers stable occlusion in a class of aneurysms that are historically unstable. Additionally, our data show that opacification of the WEB recess can be delineated from true neck or aneurysm remnants., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2014

19. Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling

Author

Stefano Confalonieri, Edoardo Nusco, Dorien J.M. Peters, Carmine Settembre, Marco Salvatore, Eric Verschuren, Andrea Ballabio, Giovanni Bertalot, Emile de Heer, Nicolina Zampelli, Gabriel G. Malouf, Alessia Calcagni, Jaklien C. Leemans, Salvatore Pece, Rossella De Cegli, Pier Paolo Di Fiore, Lotte Kors, TIGEM (Telethon Institute of Genetics and Medicine), Telethon Institute of Genetics and Medicine = Istituto Telethon di Genetica e Medicina (TIGEM), Academical Medical Center, Leiden University Medical Center (LUMC), European Institute of Oncology [Milan] (ESMO), FIRC Institute of Molecular Oncology Foundation, IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Università degli Studi di Milano [Milano] (UNIMI), Baylor College of Medicine (BCM), Baylor University, Texas Children's Hospital [Houston, USA], Università degli studi di Napoli Federico II, Service d'Oncologie médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Universitaire de Cancérologie [Paris] (IUC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), SDN - Istituto di Ricerca Diagnostica e Nucleare, AII - Amsterdam institute for Infection and Immunity, Graduate School, Pathology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Universiteit Leiden, Università degli Studi di Milano = University of Milan (UNIMI), University of Naples Federico II = Università degli studi di Napoli Federico II, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Universitaire de Cancérologie [Sorbonne Université] (IUC), Calcagnì, Alessia, Kors, Lotte, Verschuren, Eric, DE CEGLI, Rossella, Zampelli, Nicolina, Nusco, Edoardo, Confalonieri, Stefano, Bertalot, Giovanni, Pece, Salvatore, Settembre, Carmine, Malouf, Gabriel G., Leemans, Jaklien C., de Heer, Emile, Salvatore, Marco, Peters, Dorien J. M., Di Fiore, Pier Paolo, and Ballabio, Andrea

Subjects
0301 basic medicine, Genetically modified mouse, renal cell carcinoma, Mouse, WNT pathway, Immunology and Microbiology (all), QH301-705.5, Science, Cell, TFE3, Chromosomal translocation, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Renal cell carcinoma, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Biology (General), Human Biology and Medicine, Cancer Biology, TFEB, Kidney, Neuroscience (all), Biochemistry, Genetics and Molecular Biology (all), General Immunology and Microbiology, Medicine (all), General Neuroscience, Wnt signaling pathway, human biology, General Medicine, medicine.disease, 3. Good health, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Cancer research, Medicine, Research Article
Abstract

TFE-fusion renal cell carcinomas (TFE-fusion RCCs) are caused by chromosomal translocations that lead to overexpression of the TFEB and TFE3 genes (Kauffman et al., 2014). The mechanisms leading to kidney tumor development remain uncharacterized and effective therapies are yet to be identified. Hence, the need to model these diseases in an experimental animal system (Kauffman et al., 2014). Here, we show that kidney-specific TFEB overexpression in transgenic mice, resulted in renal clear cells, multi-layered basement membranes, severe cystic pathology, and ultimately papillary carcinomas with hepatic metastases. These features closely recapitulate those observed in both TFEB- and TFE3-mediated human kidney tumors. Analysis of kidney samples revealed transcriptional induction and enhanced signaling of the WNT β-catenin pathway. WNT signaling inhibitors normalized the proliferation rate of primary kidney cells and significantly rescued the disease phenotype in vivo. These data shed new light on the mechanisms underlying TFE-fusion RCCs and suggest a possible therapeutic strategy based on the inhibition of the WNT pathway.

Published
2016

20. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism

Author

Stephen Sanders, Rui Luo, Patrícia B. S. Celestino-Soper, Frédéric M. Vaz, Ronald J.A. Wanders, Anath C. Lionel, Robin P. Goin-Kochel, Edwin H. Cook, Richard J. Schroer, Arthur L. Beaudet, Roger E. Stevenson, Peter Szatmari, Richard E. Person, Marwan Shinawi, Stephen W. Scherer, Suzanne M. Leal, Kwanghyuk Lee, Ni Huang, Sara Violante, Guiqing Cai, Catalina Betancur, Bekim Sadikovic, Wendy Roberts, Kun Gao, Diane Treadwell-Deering, Daniel H. Geschwind, Chad A. Shaw, Joseph D. Buxbaum, Timothy J. Moss, Bridget A. Fernandez, Elsa Delaby, Emily L. Crawford, Charlene Lo, James S. Sutcliffe, Matthew E. Hurles, Jennifer R. German, Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Laboratory Genetic Metabolic Disease, University of Amsterdam [Amsterdam] (UvA)-Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Metabolism and Genetics Group, Universidade de Lisboa (ULISBOA)-Research Institute for Medicines and Pharmaceutical Sciences, Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Department of Human Genetics, UCLA, University of California [Los Angeles] (UCLA), University of California-University of California-Semel Institute, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Physiopathologie des Maladies du Système Nerveux Central, 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), Human Genetics Center, The University of Texas Health Science Center at Houston (UTHealth), Department of Neurology, Johns Hopkins University (JHU), Texas Children's Hospital [Houston, USA], Department of psychiatry, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, Disciplines of Genetics and Medicine, Memorial University of Newfoundland [St. John's], The Greenwood Genetic Center, Departments of Psychiatry and Genetics, Yale University School of Medicine, Department of Psychiatry, Institute for Juvenile Research-University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Department of pediatrics, The AGRE is a program of Autism Speaks and is supported, in part, by Grant 1U24MH081810 from the National Institute of Mental Health (to Clara M. Lajonchere). Part of this work was supported by Grant SFARI 124827 from the Simons Foundation (to the investigators of the SSC Genetic Consortium) and Grant HD-37283 (to A.L.B) and Grant P30HD-0240640 from the National Institutes of Health. Part of this work was financially supported by the Fundação para a Ciência e Tecnologia, Lisbon, Portugal, by Grant SFRH/BD/38074/2007 (to. S.V.). Part of this work was supported by National Institutes of Health Grants R01 MH061009 and R01 NS049261 (to J.S.S.). Funding for part of this work was provided by the Wellcome Trust under Award 076113 and by Grant 077014/Z/05/Z. Funding for the Paris Autism Research International Sibpair study was provided, in part, by the Institut National de la Santé et de la Recherche Médicale, Fondation de France, Fondation Orange, Fondation pour la Recherche Médicale, Assistance Publique- Hôpitaux de Paris, and the Swedish Science Council., Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Universidade de Lisboa = University of Lisbon (ULISBOA)-Research Institute for Medicines and Pharmaceutical Sciences, University of California (UC)-University of California (UC)-Semel Institute, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Yale School of Medicine [New Haven, Connecticut] (YSM), AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Genetic Metabolic Diseases, Betancur, Catalina, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Mazalérat, Charlotte

Subjects
Male, Proband, Penetrance, MESH: Cognition, [SDV.GEN] Life Sciences [q-bio]/Genetics, Mixed Function Oxygenases, Cognition, 0302 clinical medicine, Genes, X-Linked, Risk Factors, MESH: Penetrance, MESH: Risk Factors, Heritability of autism, X chromosome, Genetics, 0303 health sciences, Multidisciplinary, MESH: Carnitine, Exons, Biological Sciences, MESH: Mixed Function Oxygenases, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.drug, MESH: Metabolism, Inborn Errors, TMLHE, MESH: Autistic Disorder, Biology, MESH: Chromosomes, Human, X, 03 medical and health sciences, Carnitine, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Autistic Disorder, 030304 developmental biology, Chromosomes, Human, X, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Siblings, medicine.disease, MESH: Male, MESH: Siblings, MESH: Genes, X-Linked, MESH: Gene Deletion, Carnitine biosynthesis, Autism, MESH: Exons, Gene Deletion, Metabolism, Inborn Errors, 030217 neurology & neurosurgery
Abstract

We recently reported a deletion of exon 2 of the trimethyllysine hydroxylase epsilon ( TMLHE ) gene in a proband with autism. TMLHE maps to the X chromosome and encodes the first enzyme in carnitine biosynthesis, 6- N -trimethyllysine dioxygenase. Deletion of exon 2 of TMLHE causes enzyme deficiency, resulting in increased substrate concentration (6- N -trimethyllysine) and decreased product levels (3-hydroxy-6- N -trimethyllysine and γ-butyrobetaine) in plasma and urine. TMLHE deficiency is common in control males (24 in 8,787 or 1 in 366) and was not significantly increased in frequency in probands from simplex autism families (9 in 2,904 or 1 in 323). However, it was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 or 1 in 130; P = 0.023). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (metaanalysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2–4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism.

Published
2012

21. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission

Author

Blümcke, Ingmar, Thom, Maria, Aronica, Eleonora, Armstrong, Dawna, Vinters, Harry, Palmini, Andre, Jacques, Thomas, Avanzini, Giuliano, Barkovich, James, Battaglia, Giorgio, Becker, Albert, Cepeda, Carlos, Cendes, Fernando, Colombo, Nadia, Peter, Crino, Cross, Helen, Delalande, Olivier, Dubeau, François, Duncan, John, Guerrini, Renzo, Kahane, Philippe, Mathern, Gary, Najm, Imad, Ozkara, Ciğdem, Raybaud, Charles, Represa, Alfonso, Roper, Steven, Salamon, Noriko, Schulze-Bonhage, Andreas, Tassi, Laura, Vezzani, Annamaria, Spreafico, Roberto, Department of Neuropathology, University Hospital Erlangen = Uniklinikum Erlangen, University College of London [London] (UCL)-Institute of Neurology, Department of (Neuro)Pathology, Academic Medisch Centrum, University of Amsterdam [Amsterdam] (UvA)-Stichting Epilepsie Instellingen Nederland (SEIN), Texas Children's Hospital [Houston, USA], Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, UCLA Medical Center-David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Servico de Neurologia, Universidade Catolica do Rio Grande do Sul-Hospital Sao Lucas da Pontifica, UCL-Institute of Child Health (ICH), Great Ormond Street Hospital for Children [London] (GOSH)-Institute of Child Health, Department of Epilepsy Clinic and Experimental Neurophysiology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Department of Neuroradiology, University of California [San Francisco] (UC San Francisco), Molecular Neuroanatomy and Pathogenesis Unit, University of Bonn Medical Center, Intellectual and Developmental Disabilities Research Center (IDDRC), UCLA Medical Center-Semel Institute, Department of Neurology, Universidade Estadual de Campinas = University of Campinas (UNICAMP), Ospedale Niguardia, PENN Epilepsy Center, University of Pennsylvania, The Prince of Wales's Chair of Childhood Epilepsy, Great Ormond Street Hospital for Children [London] (GOSH)-UCL-Institute of Child Health-National Centre for Young People with Epilepsy, Service de Neurochirurgie Pediatrique, Fondation Ophtalmologique Rotschild, Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Department of Clinical and Experimental Epilepsy, Pediatric Neurology Unit and Laboratories, Università degli Studi di Firenze = University of Florence (UniFI)-Children's Hospital A. Meyer, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de neurologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Departments of Neurosurgery, Psychiatry and Behavioral Science, David Geffen School of Medicine [Los Angeles], Neurological Institute, Cleveland Clinic, Cerrahpasa Medical Faculty-Istanbul University, Division of Neuroradiology, Hospital for Sick Children-Department of Diagnostic Imaging, Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Neurosurgery, University of Florida [Gainesville] (UF), Departement of Radiology, Epilepsy Centre, University Hospital Freiburg, Centre « Claudio-Munari » pour la chirurgie de l'épilepsie et du Parkinson, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Department of Neuroscience, Mario Negri Institute for Pharmacological Research - Milan, Janssen- Cilag, UCB, GSK, NIH R01 NS38992, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Neurology, Pathology, University Hospital Erlangen, University of Amsterdam [Amsterdam] (UvA)-Stichting Epilepsie Instellingen Nederland, University of California-University of California-University of California [Los Angeles] (UCLA), University of California-University of California, University of California [San Francisco] (UCSF), University of Campinas [Campinas] (UNICAMP), University of Pennsylvania [Philadelphia], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-Children's Hospital A. Meyer, Istanbul University -Cerrahpasa Medical Faculty, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and Deransart, Colin

Subjects
Cerebral Cortex, clinicopathologic spectrum, MESH: Humans, Advisory Committees, MESH: Societies, Medical, Global Health, Article, MESH: Cerebral Cortex, Malformations of Cortical Development, MESH: Malformations of Cortical Development, epilepsy, Humans, MESH: Advisory Committees, cortical dysplasia, Societies, Medical, MESH: World Health
Abstract

Focal cortical dysplasias (FCDs) are localized regions of malformed cerebral cortex and are very frequently associated with epilepsy in both children and adults. A broad spectrum of histopathology has been included in the diagnosis of FCD. Characteristic findings include aberrant radial or tangential lamination of the neocortex (FCD Type I) and cytological abnormalities (FCD Type II). An ILAE task force has re-evaluated available data and proposes a clinico-pathologic classification system of FCDs. The major change since a prior classification represents the introduction of FCD Type III, which occurs in combination with Hippocampal Sclerosis (FCD Type IIIa), or with epilepsy-associated tumors (FCD Type IIIb). FCD Type IIIc is found adjacent to vascular malformations, whereas FCD Type IIId can be diagnosed in association with epileptogenic lesions acquired in early life (i.e., traumatic injury, ischemic injury or encephalitis). Hence, FCD Type I will now refer to isolated lesions, which present either as radial (FCD Type Ia) or tangential (FCD Type Ib) dyslamination of the neocortex, microscopically identified in one or multiple lobes. FCD Type II is an isolated lesion characterized by cortical dyslamination and dysmorphic neurons without (Type IIa) or with balloon cells (Type IIb). Architectural abnormalities adjacent to or within gross malformations of cortical development are frequently observed and not distinguished as a specific FCD variant. This three-tiered classification system will help to better characterize specific clinico-pathological entities and is an important basis to further explore imaging, electro-clinical features, and postsurgical seizure control as well as underlying molecular pathomechanisms.

Published
2011

22. A high-resolution anatomical atlas of the transcriptome in the mouse embryo

Author

Graciana Diez-Roux, Sandro Banfi, Marc Sultan, Lars Geffers, Santosh Anand, David Rozado, Alon Magen, Elena Canidio, Massimiliano Pagani, Ivana Peluso, Nathalie Lin-Marq, Muriel Koch, Marchesa Bilio, Immacolata Cantiello, Roberta Verde, Cristian De Masi, Salvatore A Bianchi, Juliette Cicchini, Elodie Perroud, Shprese Mehmeti, Emilie Dagand, Sabine Schrinner, Asja Nürnberger, Katja Schmidt, Katja Metz, Christina Zwingmann, Norbert Brieske, Cindy Springer, Ana Martinez Hernandez, Sarah Herzog, Frauke Grabbe, Cornelia Sieverding, Barbara Fischer, Kathrin Schrader, Maren Brockmeyer, Sarah Dettmer, Christin Helbig, Violaine Alunni, Marie-Annick Battaini, Carole Mura, Charlotte N Henrichsen, Raquel Garcia-Lopez, Diego Echevarria, Eduardo Puelles, Elena Garcia-Calero, Stefan Kruse, Markus Uhr, Christine Kauck, Guangjie Feng, Nestor Milyaev, Chuang Kee Ong, Lalit Kumar, MeiSze Lam, Colin A Semple, Attila Gyenesei, Stefan Mundlos, Uwe Radelof, Hans Lehrach, Paolo Sarmientos, Alexandre Reymond, Duncan R Davidson, Pascal Dollé, Stylianos E Antonarakis, Marie-Laure Yaspo, Salvador Martinez, Richard A Baldock, Gregor Eichele, Andrea Ballabio, Telethon Institute for Genetics and Medicine, Telethon Institute, Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, Genes and Behavior Department [Göttingen], Max Planck Institute for Biophysical Chemistry (MPI-BPC), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Primm, Department of Genetic Medicine and Development [Geneva], Université de Genève (UNIGE), Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Experimental Embryology Lab, Universidad Miguel Hernández [Elche] (UMH)-Instituto de Neurociencias, ORGARAT, Human Genetics Unit, Medical Research Council, Deutsches Ressourcenzentrum für Genomforschung (RZPD), Deutsches Ressourcenzentrum für Genomforschung, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Medical Genetics, Università degli studi di Napoli Federico II, Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital [Houston, USA], This work was supported by the EC VI Framework Programme contract number LSHG-CT-2004-512003. The authors also acknowledge the support of: the Italian Telethon Foundation (AB, SB, and GD-R), the Swiss National Science Foundation (AR and SEA), the Max Planck Society (GE, M-LY, HL), MRC (RB, DD), Association pour la Recherche sur le Cancer (PD), and Ingenio 2010 MEC-CONSOLIDER CSD2007-00023, DIGESIC-MEC BFU2008-00588, CIBERSAM/ISCIII (SM)., Université de Genève = University of Geneva (UNIGE), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), University of Naples Federico II = Università degli studi di Napoli Federico II, Autard, Delphine, Diez Roux, G, Banfi, Sandro, Sultan, M, Geffers, L, Anand, S, Rozado, D, Magen, A, Canidio, E, Pagani, M, Peluso, I, Lin Marq, N, Koch, M, Bilio, M, Cantiello, I, Verde, R, De Masi, C, Bianchi, Sa, Cicchini, J, Perroud, E, Mehmeti, S, Dagand, E, Schrinner, S, Nürnberger, A, Schmidt, K, Metz, K, Zwingmann, C, Brieske, N, Springer, C, Martinez Hernandez, A, Herzog, S, Grabbe, F, Sieverding, C, Fischer, B, Schrader, K, Bürsing, M, Schubert, S, Helbig, C, Alunni, V, Battaini, Ma, Mura, C, Henrichsen, Cn, Garcia Lopez, R, Echevarria, D, Puelles, E, Garcia Calero, E, Kruse, S, Uhr, M, Kauck, C, Feng, G, Milyaev, N, Ong, Ck, Kumar, L, Lam, M, Semple, Ca, Gyenesei, A, Mundlos, S, Radelof, U, Lehrach, H, Sarmientos, P, Reymond, A, Davidson, Dr, Dollé, P, Antonarakis, Se, Yaspo, Ml, Martinez, M, Baldock, Ra, Eichele, G, Ballabio, A., Banfi, S, Reymond, R, Martinez, S, Ballabio, Andrea, and Reymond, Alexandre

Subjects
Transcriptome, Mice, 0302 clinical medicine, Databases, Genetic, Gene expression, Animals, Atlases as Topic, Embryo, Mammalian, Gene Expression Profiling, Internet, Mice/anatomy & histology, Mice/embryology, Mice, Inbred C57BL, Organ Specificity, ddc:576.5, MESH: Animals, Biology (General), [SDV.BDD]Life Sciences [q-bio]/Development Biology, MESH: Databases, Genetic, MESH: Organ Specificity, Genetics, 0303 health sciences, Agricultural and Biological Sciences(all), General Neuroscience, Wnt signaling pathway, Genetics and Genomics/Gene Expression, Genome project, MESH: Internet, General Agricultural and Biological Sciences, Research Article, Genetics and Genomics/Animal Genetics, QH301-705.5, Neuroscience(all), education, MESH: Atlases as Topic, In situ hybridization, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, MESH: Gene Expression Profiling, Mice/anatomy & histology/embryology/genetics, MESH: Mice, Inbred C57BL, Immunology and Microbiology(all), microRNA, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Gene, MESH: Mice, 030304 developmental biology, General Immunology and Microbiology, Biochemistry, Genetics and Molecular Biology(all), MESH: Embryo, Mammalian, Gene expression profiling, Genetics and Genomics/Genome Projects, 030217 neurology & neurosurgery, Developmental Biology
Abstract

The manuscript describes the “digital transcriptome atlas” of the developing mouse embryo, a powerful resource to determine co-expression of genes, to identify cell populations and lineages and to identify functional associations between genes relevant to development and disease., Ascertaining when and where genes are expressed is of crucial importance to understanding or predicting the physiological role of genes and proteins and how they interact to form the complex networks that underlie organ development and function. It is, therefore, crucial to determine on a genome-wide level, the spatio-temporal gene expression profiles at cellular resolution. This information is provided by colorimetric RNA in situ hybridization that can elucidate expression of genes in their native context and does so at cellular resolution. We generated what is to our knowledge the first genome-wide transcriptome atlas by RNA in situ hybridization of an entire mammalian organism, the developing mouse at embryonic day 14.5. This digital transcriptome atlas, the Eurexpress atlas (http://www.eurexpress.org), consists of a searchable database of annotated images that can be interactively viewed. We generated anatomy-based expression profiles for over 18,000 coding genes and over 400 microRNAs. We identified 1,002 tissue-specific genes that are a source of novel tissue-specific markers for 37 different anatomical structures. The quality and the resolution of the data revealed novel molecular domains for several developing structures, such as the telencephalon, a novel organization for the hypothalamus, and insight on the Wnt network involved in renal epithelial differentiation during kidney development. The digital transcriptome atlas is a powerful resource to determine co-expression of genes, to identify cell populations and lineages, and to identify functional associations between genes relevant to development and disease., Author Summary In situ hybridization (ISH) can be used to visualize gene expression in cells and tissues in their native context. High-throughput ISH using nonradioactive RNA probes allowed the Eurexpress consortium to generate a comprehensive, interactive, and freely accessible digital gene expression atlas, the Eurexpress transcriptome atlas (http://www.eurexpress.org), of the E14.5 mouse embryo. Expression data for over 15,000 genes were annotated for hundreds of anatomical structures, thus allowing us to systematically identify tissue-specific and tissue-overlapping gene networks. We illustrate the value of the Eurexpress atlas by finding novel regional subdivisions in the developing brain. We also use the transcriptome atlas to allocate specific components of the complex Wnt signaling pathway to kidney development, and we identify regionally expressed genes in liver that may be markers of hematopoietic stem cell differentiation.

Published
2011
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23. Transmission of Bordetella pertussis to young infants

Author

Michael A. Gerber, David P. Greenberg, Aaron M. Wendelboe, Johannes G. Liese, Annelies Van Rie, Rémy Teyssou, Daniel Floret, Emmanuel Grimprel, Nicole Guiso, Joel Gaudelus, Flor Munoz-Rivas, Elisabeth Njamkepo, Scott A. Halperin, Antoine Bourillon, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Centre National de Référence de la Coqueluche et autres bordetelloses (CNR), Institut Pasteur [Paris], Hôpital Robert Debré Paris, Hôpital Robert Debré, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cincinnati Children's Hospital Medical Center, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Children's Hospital of Pittsburgh of UPMC [Etats-Unis], Dalhousie University [Halifax], Ludwig-Maximilians-Universität München (LMU), Baylor College of Medicine (BCM), Baylor University, Texas Children's Hospital [Houston, USA], Sanofi Pasteur [Lyon, France], Etude ET501, and Institut Pasteur [Paris] (IP)

Subjects
Parents, Pediatrics, Bordetella pertussis, diagnosis, Whooping Cough, Polymerase Chain Reaction, Serology, MESH: Bordetella pertussis, 0302 clinical medicine, sensitivity analysis, MESH: Child, MESH: Antibodies, Bacterial, Medicine, 030212 general & internal medicine, Child, MESH: Aged, MESH: Middle Aged, biology, transmission, Grandparent, MESH: Whooping Cough, Middle Aged, MESH: Infant, Antibodies, Bacterial, 3. Good health, Vaccination, Infectious Diseases, Child, Preschool, Population study, medicine.symptom, Developed country, Microbiology (medical), Adult, medicine.medical_specialty, Adolescent, source case, Asymptomatic, MESH: Contact Tracing, 03 medical and health sciences, 030225 pediatrics, asymptomatic, Humans, Whooping cough, Aged, MESH: Adolescent, MESH: Parents, MESH: Humans, business.industry, Siblings, MESH: Child, Preschool, Infant, MESH: Adult, MESH: Polymerase Chain Reaction, biology.organism_classification, medicine.disease, MESH: Siblings, Pediatrics, Perinatology and Child Health, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Contact Tracing, business
Abstract

International audience; BACKGROUND:Pertussis vaccination has reduced the number of notified cases in industrialized countries from peak years by more than 95%. The effect of recently recommended adult and adolescent vaccination strategies on infant pertussis depends, in part, on the proportion of infants infected by adults and adolescents. This proportion, however, remains unclear, because studies have not been able to determine the source case for 47%-60% of infant cases.METHODS:A prospective international multicenter study was conducted of laboratory confirmed infant pertussis cases (aged

Published
2007

24. Interobserver agreement of peritoneal dialysis exit site scoring: Results from the Standardizing Care to Improve Outcomes in Pediatric End Stage Kidney Disease (SCOPE) collaborative.

Author

Keswani M, Mallet K, Richardson T, Swartz SJ, Neu A, and Warady BA

Subjects
Humans, Child, Female, Male, Catheters, Indwelling, Adolescent, Peritonitis etiology, Peritonitis epidemiology, Child, Preschool, Catheter-Related Infections epidemiology, Catheter-Related Infections etiology, Peritoneal Dialysis, Kidney Failure, Chronic therapy, Observer Variation
Abstract

Background: Exit site infections are a risk factor for the development of peritonitis in patients on long-term peritoneal dialysis. Visual assessments of an exit site utilising currently available tools (Twardowski and Mid-European Pediatric Peritoneal Dialysis Study Group (MEPPS)) are necessary to objectively characterise the appearance of an exit site. The aim of this study was to assess the interobserver agreement of exit site evaluations utilising both exit site scoring tools., Methods: Exit site evaluations were independently performed by two evaluators during outpatient visits at 13 sites within the Standardizing Care to Improve Outcomes in Pediatric End Stage Kidney Disease collaborative. The frequency and percentage of evaluations where both reviewers agreed were calculated. A sub-analysis was performed looking at evaluations where disagreement occurred., Results: A total of 371 paired exit site evaluations were collected over 6 months. For the majority of evaluations (range: 78%-97% Twardowski, 78%-97% MEPPS), both reviewers agreed that no abnormality was present across all domains. When the analysis was restricted to evaluations where at least one reviewer noted an abnormality, interobserver agreement fell across all domains (range: 31%-61% Twardowski, 56%-66% MEPPS). Disagreements more commonly occurred regarding the presence versus absence of an abnormality, rather than a difference in the severity of an abnormality., Conclusions: Whereas interobserver agreement is high when the appearance of a peritoneal dialysis catheter exit site is characterised as 'normal', interobserver disagreement is common when the appearance of the exit site is 'abnormal'. Further work is warranted to improve interobserver agreement of exit site assessments and to identify domains conferring an increased risk of infection., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Published
2024
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25. Do androids dream of informed consent? The need to understand the ethical implications of experimentation on simulated beings.

Author

Gariti A

Abstract

Creating simulations of the world can be a valuable way to test new ideas, predict the future, and broaden our understanding of a given topic. Presumably, the more similar the simulation is to the real world, the more transferable the knowledge generated in the simulation will be and, therefore, the more useful. As such, there is an incentive to create more advanced and representative simulations of the real world. Simultaneously, there are ethical and practical limitation to what can be done in human and animal research, so creating simulated beings to stand in their place could be a way of advancing research while avoiding some of these issues. However, the value of representativeness implies that there will be an incentive to create simulated beings as similar to real-world humans as possible to better transfer the knowledge gained from that research. This raises important ethical questions related to how we ought to treat advanced simulated beings and consider if they might have autonomy and wellbeing concerns that ought to be respected. As such, the uncertainty and potential of this line of research should be carefully considered before the simulation begins., (© 2024. The Author(s) under exclusive licence to Monash University.)

Published
2024
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26. Something Seems Fishy: Hepatic Abscess Due to Foreign Body Ingestion in a Pediatric Patient.

Author

Rhodes J, Macias A, Cooke E, Jacob J, Devoll A, Young C, and Nguyen B

Abstract

Pediatric hepatic abscesses are uncommon in children. They are usually preceded by intra-abdominal infections or caused by acute or chronic biliary disease. Cases of hepatic abscesses secondary to foreign body ingestion are even rarer but are most reported in countries such as China, where ingestion of fish and chicken bones is common. We report a rare case of an adolescent patient who developed a hepatic abscess after ingestion of a fishbone foreign body. He presented to the emergency department with emesis, abdominal pain, and subjective fevers of unknown etiology. Initial imaging of the abdomen was pertinent for a heterogeneous hepatic mass with evidence of fluid collection, concerning for malignancy. Subsequent incision and drainage then confirmed fluid collection to be pus. However, his cryptogenic hepatic abscess was not responsive to broad-spectrum intravenous antibiotics. After imaging was re-reviewed and repeated, a 4.3 cm thin curvilinear hyperdensity was identified embedded in the liver parenchyma. Eventually, the patient underwent exploratory laparoscopy where a fishbone foreign body was removed. To our knowledge, this is one of the few reported pediatric cases of hepatic abscess formation caused by a foreign body ingestion. Hepatic abscesses that do not resolve with antibiotics and ultrasound-guided drainage via catheter should prompt reassessment of other uncommon etiologies, specifically migrated foreign bodies as a rare but important differential diagnosis. Compared to pyogenic hepatic abscesses, hepatic abscesses secondary to foreign bodies require expedited surgical intervention for source control; thus, timely recognition and prompt intervention are crucial to minimize morbidity and mortality., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Rhodes et al.)

Published
2024
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27. TFEB activation hallmarks antigenic experience of B lymphocytes and directs germinal center fate decisions.

Author

Münchhalfen M, Görg R, Haberl M, Löber J, Willenbrink J, Schwarzt L, Höltermann C, Ickes C, Hammermann L, Kus J, Chapuy B, Ballabio A, Reichardt SD, Flügel A, Engels N, and Wienands J

Subjects
Animals, Mice, Mice, Inbred C57BL, Lymphocyte Activation immunology, Cell Differentiation immunology, Signal Transduction, Antigen Presentation immunology, Germinal Center immunology, Germinal Center cytology, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, B-Lymphocytes immunology, B-Lymphocytes metabolism, Apoptosis, CD40 Antigens metabolism, CD40 Antigens immunology, Receptors, Antigen, B-Cell metabolism, Receptors, Antigen, B-Cell immunology
Abstract

Ligation of the B cell antigen receptor (BCR) initiates humoral immunity. However, BCR signaling without appropriate co-stimulation commits B cells to death rather than to differentiation into immune effector cells. How BCR activation depletes potentially autoreactive B cells while simultaneously primes for receiving rescue and differentiation signals from cognate T lymphocytes remains unknown. Here, we use a mass spectrometry-based proteomic approach to identify cytosolic/nuclear shuttling elements and uncover transcription factor EB (TFEB) as a central BCR-controlled rheostat that drives activation-induced apoptosis, and concurrently promotes the reception of co-stimulatory rescue signals by supporting B cell migration and antigen presentation. CD40 co-stimulation prevents TFEB-driven cell death, while enhancing and prolonging TFEB's nuclear residency, which hallmarks antigenic experience also of memory B cells. In mice, TFEB shapes the transcriptional landscape of germinal center B cells. Within the germinal center, TFEB facilitates the dark zone entry of light-zone-residing centrocytes through regulation of chemokine receptors and, by balancing the expression of Bcl-2/BH3-only family members, integrates antigen-induced apoptosis with T cell-provided CD40 survival signals. Thus, TFEB reprograms antigen-primed germinal center B cells for cell fate decisions., (© 2024. The Author(s).)

Published
2024
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29. Effects of ganaxolone on non-seizure outcomes in CDKL5 Deficiency Disorder: Double-blind placebo-controlled randomized trial.

Author

Downs J, Jacoby P, Specchio N, Cross H, Amin S, Bahi-Buisson N, Rajaraman R, Suter B, Devinsky O, Aimetti A, Busse G, Olson HE, Demarest S, Benke TA, and Pestana-Knight E

Subjects
Humans, Female, Male, Double-Blind Method, Child, Child, Preschool, Adolescent, Young Adult, Treatment Outcome, Epileptic Syndromes drug therapy, Seizures drug therapy, Seizures etiology, Pregnanolone analogs & derivatives, Spasms, Infantile, Quality of Life
Abstract

CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy. Ganaxolone, a neuroactive steroid, reduces the frequency of major motor seizures in children with CDD. This analysis explored the effect of ganaxolone on non-seizure outcomes. Children (2-19 years) with genetically confirmed CDD and ≥ 16 major motor seizures per month were enrolled in a double-blind randomized placebo-controlled trial. Ganaxolone or placebo was administered three times daily for 17 weeks. Behaviour was measured with the Anxiety, Depression and Mood Scale (ADAMS), daytime sleepiness with the Child Health Sleep Questionnaire, and quality of life with the Quality of Life Inventory-Disability (QI-Disability) scale. Scores were compared using ANOVA, adjusted for age, sex, number of anti-seizure mediations, baseline 28-day major motor seizure frequency, baseline developmental skills, and behaviour, sleep or quality of life scores. 101 children with CDD (39 clinical sites, 8 countries) were randomized. Median (IQR) age was 6 (3-10) years, 79.2 % were female, and 50 received ganaxolone. After 17 weeks of treatment, Manic/Hyperactive scores (mean difference 1.27, 95%CI -2.38,-0.16) and Compulsive Behaviour scores (mean difference 0.58, 95%CI -1.14,-0.01) were lower (improved) in the ganaxolone group compared with the placebo group. Daytime sleepiness scores were similar between groups. The total change in QOL score for children in the ganaxolone group was 2.6 points (95%CI -1.74,7.02) higher (improved) than in the placebo group but without statistical significance. Along with better seizure control, children who received ganaxolone had improved behavioural scores in select domains compared to placebo., Competing Interests: Declaration of competing interest Jenny Downs: Consultancy for Marinus, Ultragenyx, Orion and Taysha; Clinical Trials with Anavex; All remuneration has been made to her department. Peter Jacoby: No conflicts of interest to report. Nicola Specchio: served on scientific advisory boards for GW Pharma, BioMarin, Arvelle, Marinus and Takeda; has received speaker honoraria from Eisai, Biomarin, Livanova, Sanofi; has served as an investigator for Zogenix, Marinus, Biomarin, UCB, Roche. Helen Cross: acted as an investigator for studies with GW Pharma, Ovid Therapeutics, Zogenix, Vitaflo, Marinius and Stoke Therapeutics. She has been a speaker and on advisory boards for GW Pharma, Zogenix, UCB and Nutricia; all remuneration has been paid to her department. She holds an endowed chair at UCL Great Ormond Street Institute of Child Health; she holds grants from NIHR, EPSRC, GOSH Charity, ERUK, the Waterloo Foundation and the National Institute of Health Research (NIHR) Biomedical Research Centre at Great Ormond Street Hospital. Sam Amin: SA has received funding from GW Pharmaceuticals, Novartis, PTC Therapeutics, Boston Scientific, Nutricia, UCB, BioMarin, LivaNova, Medtronic, Desitin, Ipsen, Orion, CDKL5 UK, TSA and the National Institute for Health Research. Nadia Bahi-Buisson: Consultancy for Marinus, Orion. Rajsekar Rajaraman: Consultancy for Marinus, Ultragenyx, Zogenix. Bernard Suter: Consultancy for Neurogene and Taysha; all remuneration has been paid to his department. Acted as investigator for clinical trials with Acadia, Marinus and Newron. Orrin Devinsky: Orrin Devinsky has equity and/or compensation from the following companies: Tilray, Receptor Life Sciences, Qstate Biosciences, Hitch Biosciences, Tevard Biosciences, Regel Biosciences, Script Biosciences, Actio Biosciences, Empatica, SilverSpike, and California Cannabis Enterprises (CCE). He has received consulting fees from Zogenix, Ultragenyx, BridgeBio, GeneMedicine and Marinus. He holds patents for the use of cannabidiol in treating neurological disorders and others in molecular biology. He is the managing partner of PhiFund Ventures. Alex Aimetti: Employee of Marinus Pharmaceuticals. Gregory Busse: Previously an employee of Marinus Pharmaceuticals. Heather Olson: Dr. Olson received consulting fees from Takeda Pharmaceuticals and Zogenix regarding clinical trial design, Ovid Therapeutics regarding clinical trial results, Marinus Pharmaceuticals regarding CDKL5 Deficiency Disorder, and has done consulting for the FOXG1 Research Foundation. Scott Demarest: Consulted for Biomarin, Neurogene, Marinus, Tysha, Ultragenyx, Zogenix and Ovid Therapeutics. He has funding from project 8P and Mila's Miracle Foundation. He also serves on the advisory board for the non-profit foundations SLC6A1 Connect, Project 8P, Ring14 USA and FamilieSCN2A. Tim Benke: Consultancy for Acadia, CUREGRI, GRINtherapeutics, GW, IRSF, Marinus, Neurogene, Taysha, Ultragenyx and Zogenix; Clinical Trials with Acadia, RSRT and GW; all remuneration has been made to his department. Elia Pestana-Knight: Scientific Advisory Board, Marinus Pharmaceuticals., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2024
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30. Diagnosis and management of primary hyperoxalurias: best practices.

Author

Michael M, Harvey E, Milliner DS, Frishberg Y, Sas DJ, Calle J, Copelovitch L, Penniston KL, Saland J, Somers MJG, and Baum MA

Subjects
Humans, Liver Transplantation, Kidney Transplantation, Algorithms, Early Diagnosis, Renal Dialysis, Hyperoxaluria, Primary therapy, Hyperoxaluria, Primary diagnosis, Hyperoxaluria, Primary genetics, Hyperoxaluria, Primary complications
Abstract

The primary hyperoxalurias (PH 1, 2, and 3) are rare autosomal recessive disorders of glyoxylate metabolism resulting in hepatic overproduction of oxalate. Clinical presentations that should prompt consideration of PH include kidney stones, nephrocalcinosis, and kidney failure of unknown etiology, especially with echogenic kidneys on ultrasound. PH1 is the most common and severe of the primary hyperoxalurias with a high incidence of kidney failure as early as infancy. Until the recent availability of a novel RNA interference (RNAi) agent, PH care was largely supportive of eventual need for kidney/liver transplantation in PH1 and PH2. Together with the Oxalosis and Hyperoxaluria Foundation, the authors developed a diagnostic algorithm for PH1 and in this report outline best clinical practices related to its early diagnosis, supportive treatment, and long-term management, including the use of the novel RNAi. PH1-focused approaches to dialysis and kidney/liver transplantation for PH patients with progression to chronic kidney disease/kidney failure and systemic oxalosis are suggested. Therapeutic advances for this devastating disease heighten the importance of early diagnosis and informed treatment., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Published
2024
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31. New clinical decision tool to assist physical therapists with joint mobilization application to the pediatric population.

Author

Henderson VK and Brismée JM

Subjects
Humans, Child, Physical Therapy Modalities education, Pediatrics education, Pediatrics methods, Musculoskeletal Manipulations methods, Musculoskeletal Manipulations education, Physical Therapists education
Abstract

Joint mobilizations are well-established and extensively researched treatment modality for adults. However, it remains largely unexplored in the pediatric population. Physical therapists hesitate to perform joint mobilization on children because of lack of knowledge, concern for the developing skeletal system, and the paucity of research on the topic. The aim of this article is to present a decision tool created for a continuing education course with the purpose to instruct pediatric therapists in the safe and effective use of joint mobilizations in children. It is based on the pediatric paradigm of developmental and functional assessment to best address the concerns and preferences of physical therapists (PTs). To advance research in pediatric joint mobilization, PTs should listen to the concerns of pediatric therapists and respond to those concerns with effective, evidence-supported training. This decision tree will serve as a resource for the education of pediatric therapists in the safe and effective use of joint mobilizations.

Published
2024
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32. Tolerance development in cow's milk-allergic children receiving amino acid-based formula with synbiotics: 36-Months follow-up of a randomized controlled trial (PRESTO Study).

Author

Chatchatee P, Nowak-Wegrzyn A, Lange L, Benjaponpitak S, Chong KW, Sangsupawanich P, Eussen SRBM, van Ampting MTJ, Oude Nijhuis MM, Langford JE, Trendelenburg V, Pesek R, Davis CM, Muraro A, Erlewyn-Lajeunesse M, Fox AT, Michaelis LJ, and Beyer K

Subjects
Child, Female, Animals, Cattle, Humans, Infant, Child, Preschool, Milk, Follow-Up Studies, Amino Acids, Infant Formula, Allergens, Synbiotics, Milk Hypersensitivity prevention & control
Abstract

The objective of the present study is to assess the rates of acquired tolerance to cow's milk (CM) after 36 months in subjects who consumed amino acid-based formula with synbiotics (AAF-S) or amino acid-based formula without synbiotics (AAF) during a 1-year intervention period in early life as part of the PRESTO study (Netherlands Trial Register number NTR3725). Differences in CM tolerance development between groups were analysed using a logistic regression model. Results show that the proportion of subjects (mean [±SD] age, 3.8 ± 0.27 years) who developed CM tolerance after 36 months was similar in the group receiving AAF-S (47/60 [78%]) and in the group receiving AAF (49/66 [74%]) (p = 0.253), that is, figures comparable to natural outgrowth of CM allergy. Our data suggest that the consumption of AAF and absence of exposure to CM peptides do not slow down CM tolerance acquisition., (© 2024 The Authors. Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Published
2024
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33. Tuberculosis in people of Ukrainian origin in the European Union and the European Economic Area, 2019 to 2022.

Author

Stoycheva K, Cristea V, Ködmön C, Rosales-Klintz S, Zenner D, Vasiliu A, van der Werf M, and Lange C

Subjects
Humans, European Union, Population Surveillance, Eastern European People, Tuberculosis diagnosis, Tuberculosis epidemiology, Tuberculosis, Multidrug-Resistant
Abstract

Approximately five million Ukrainians were displaced to the EU/EEA following the Russian invasion of Ukraine. While tuberculosis (TB) notification rates per 100,000 Ukrainians in the EU/EEA remained stable, the number of notified TB cases in Ukrainians increased almost fourfold (mean 2019-2021: 201; 2022: 780). In 2022, 71% cases were notified in three countries, and almost 20% of drug-resistant TB cases were of Ukrainian origin. Targeted healthcare services for Ukrainians are vital for early diagnosis and treatment, and preventing transmission.

Published
2024
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34. The Perfect Storm: A Case of Rapid-Onset Obesity With Hypoventilation, Hypothalamic, Autonomic Dysregulation, Neuroendocrine Tumor (ROHHADNET) With Heart Failure, Narcolepsy, and a Rare Location of a Pelvic Neuroendocrine Tumor.

Author

Roby P, Smith Beltran G, Finch C, Malhotra S, Reiling K, Dayyat E, Birkemeier K, Raju M, Macmurdo C, Hernandez E, and Sagar M

Abstract

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome is a rare disease of concurrent respiratory dysfunction and autonomic dysregulation with endocrine abnormalities. ROHHADNET includes ROHHAD plus coexisting neuroendocrine tumors (NETs). We describe an eight-year-old boy, who originally presented at four years of age with rapid weight gain and hyperhidrosis and who developed mild obstructive sleep apnea (OSA). His clinical course was eventually complicated by hypoxic respiratory failure requiring admission to the pediatric intensive care unit (PICU). Echocardiogram at that time demonstrated dilated cardiomyopathy left ventricular ejection fraction (LVEF) of 28% at time of admission. His respiratory failure persisted despite average volume-assured pressure support (AVAPS) around the clock leading to tracheostomy placement for cardiopulmonary support. He also demonstrated autonomic instability with multiple pituitary hormone deficiencies. Computed tomography (CT) imaging of the abdomen and pelvis demonstrated a presacral soft tissue mass consistent with a tumor of neural crest origin. Daytime somnolence and confusion progressed and a low cerebrospinal fluid hypocretin level revealed a diagnosis of narcolepsy type 1., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Roby et al.)

Published
2023
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35. Phone-based psychosocial counseling for people living with HIV: Feasibility, acceptability and impact on uptake of psychosocial counseling services in Malawi.

Author

Cox CM, Masiano S, Mazenga A, Stark M, Udedi M, Simon KR, Ahmed S, Nyasulu P, and Kim MH

Abstract

People living with HIV experience psychosocial needs that often are not addressed. We designed an innovative low-resource model of phone-based psychosocial counseling (P-PSC). We describe cohort characteristics, acceptability, feasibility and utilization of P-PSC at health facilities supported by Baylor Foundation Malawi. Staff were virtually oriented at 120 sites concurrently. From facility-based phones, people with new HIV diagnosis, high viral load, treatment interruption or mental health concerns were referred without identifiable personal information to 13 psychosocial counselors via a WhatsApp group. Routine program data were retrospectively analyzed using univariate approaches and regressions with interrupted time series analyses. Clients utilizing P-PSC were 63% female, 25% youth (10-24 y) and 9% children (<10 y). They were referred from all 120 supported health facilities. Main referral reasons included new HIV diagnosis (32%), ART adherence support (32%) and treatment interruption (21%). Counseling was completed for 99% of referrals. Counseling sessions per month per psychosocial counselor increased from 77 before P-PSC to 216 in month 1 (95% CI = 82, 350, p = 0.003). Total encounters increased significantly to 31,642 in year 1 from ~6,000 during the 12 prior months, an over fivefold increase. P-PSC implementation at 120 remote facilities was acceptable and feasible with immediate, increased utilization despite few psychosocial counselors in Malawi., Competing Interests: The authors declare no competing interests exist., (© The Author(s) 2023.)

Published
2023
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36. Ewing's Sarcoma of the Hand: An Unusual Presentation in a Young Hispanic Male.

Author

McBee DB, Bentley HA, and Toledanes G

Abstract

Ewing's sarcoma is a neuroectodermal malignancy classically associated with innocuous and chronic symptomatology. Although tumors typically involve the axial skeleton, some malignancies may be confined to extraosseous tissue only. This report presents the case of a 15-year-old Hispanic male with a tender, slow-growing mass of seven months in the subcutaneous tissue of the right hand. Core needle biopsy and fine needle aspiration confirmed the diagnosis of high-grade extraosseous Ewing's sarcoma and the patient was treated via surgical resection and chemotherapy. Nonspecific findings of Ewing's sarcoma may mimic infection or trauma and contribute to a delay in diagnosis. However, social and economic influences including limited English proficiency and insurance status also critically affect the timing of presentation., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, McBee et al.)

Published
2023
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37. Unveiling Peripherally Inserted Central Catheter Fractures and Related Complications in the Neonatal Intensive Care Unit: A Concise Review.

Author

Balasundaram P, Lucena MH, Jiang L, and Nafday S

Abstract

Peripherally inserted central catheters (PICCs) have become popular over tunneled catheters in neonatal intensive care units (NICUs) due to their ease of use and convenience. Although rare, a PICC fracture can be a severe and potentially fatal complication. This narrative review aims to identify factors predisposing neonates to PICC fracture and related complications, such as catheter jamming, and explore strategies for preventing and detecting this complication. A thorough search of PubMed and Google Scholar was conducted using relevant keywords to identify articles discussing PICC fracture in neonates. The review encompassed English-language literature on PICC fracture in neonates, with additional pertinent publications identified through citation searching. The incidence of PICC fracture in neonates varies from less than 1% to 10%, with a higher risk associated with prolonged catheterization, lower gestational age and lower birth weight, and the use of multi-lumen catheters. PICC fractures can occur during insertion, maintenance, or removal. Factors such as catheter duration, gestational age, birth weight, and catheter type increase the risk of PICC fracture. Excessive syringe pressure, securement failure, and excessive force during removal are contributing factors. Catheter fatigue and thin-walled catheter design are common causes of breakage. Preventive measures include proper training of healthcare providers, regular monitoring, early recognition, and prompt catheter removal upon fracture. Preventing and detecting PICC fractures is crucial for neonatal safety. Vigilance during insertion, maintenance, and removal, along with care to avoid excessive force during removal and high pressure during flushing, can help prevent catheter breakage. More research is required to improve prevention strategies for PICC fractures in neonates., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Balasundaram et al.)

Published
2023
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38. Anesthetic Management for a Child With a Newly Identified Mitochondrial Disease SLC25A46 Mutation: A Case Report.

Author

Nguyen T, Shabot S, Yngve D, and Abouleish A

Abstract

SLC25A46 mutation is a newly recognized mitochondrial mutation causing neurological and muscular abnormalities. We describe a first-ever report of the anesthetic management of a seven-year-old boy with an SLC25A46 mutation during a major orthopedic procedure. The patient was nonverbal and presented with cerebral visual impairment, torticollis, and lower extremity contractures. Because of his new diagnosis of mitochondrial disease and history of delayed awakening after anesthesia, we performed general anesthesia with sevoflurane, a low-dose ketamine infusion, and small doses of fentanyl while avoiding propofol and maintaining normoglycemia and normothermia. No postoperative complications were noted during the recovery period., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Nguyen et al.)

Published
2023
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39. Presentation of External Ear Rosai-Dorfman Disease With Laryngeal Involvement.

Author

Kobayashi KR, Hajiyev Y, Fuller MY, Orman G, and Lambert EM

Subjects
Female, Humans, Adolescent, Neck pathology, Lymph Nodes pathology, Ear, External pathology, Histiocytosis, Sinus diagnosis, Histiocytosis, Sinus pathology, Lymphadenopathy
Abstract

Rosai-Dorfman disease (RDD) is a rare benign systemic histiocytic proliferation characterized by massive lymph node enlargement and sometimes associated with extranodal involvement. Even though it is considered to be benign, death can occur depending on the extent and location. Our case highlights a primary extranodal site of the right pinna with extension through the Eustachian tube to the subglottis. A previously healthy 15-year-old female presented with 1-year right pinna swelling, slowly enlarging and becoming more bothersome. An incisional biopsy was performed on the ear along with S100 staining yielding a diagnosis. After multidisciplinary case discussion, clofarabine monotherapy and systemic therapy for Langerhans cell histiocytosis has started. Rosai-Dorfman disease can be a general disorder, often affecting the lymph nodes. Unlike a nodal disease, extranodal disease could involve any site on the patient's anatomy. Head and neck lesions are the most common extranodal lesions. Rosai-Dorfman disease is self-limited in more than 20% of the cases with spontaneous regression without intervention; 70% of the patients have noticeable symptoms and vital organ involvement requiring treatments such as surgery, steroids, radiation, and chemotherapy. In our case, the patient had wide involvement and presented without any serious breathing difficulties; we decided to start with monotherapy with chemotherapy and systematic glucocorticoid treatment.

Published
2023
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40. The Novel Use of the Lateral Scanogram to Detect Cruciate Deficiency in Children With Congenital Femoral Deficiency.

Author

Taylor TN, Bridges CS, Martin BM, McKay S, and Hill JF

Abstract

Congenital femoral deficiency (CFD) is often associated with cruciate ligament deficiency. The lateral scanogram may be a potential solution to some limitations for detecting instability associated with cruciate ligament deficiency. This qualitative case study identified two children with congenital femoral deficiency who were assessed with a lateral scanogram and had their results correlated to the clinical examination and MRI. Both cases identified a child with congenital femoral deficiency, one with a total leg length discrepancy (LLD) of 12 cm and the next with 6.5 cm. The weight-bearing lateral scanogram revealed anterior tibial translation, indicating knee instability. Both patients will undergo anterior cruciate ligament (ACL) reconstruction prior to limb lengthening. The lateral scanogram is a useful imaging modality that is capable of detecting anterior tibial translation, and thereby knee instability, in children with congenital femoral deficiency. Larger studies utilizing and evaluating the benefits of lateral scanograms are warranted., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Taylor et al.)

Published
2023
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41. Integrated clinical genomic analysis reveals xenobiotic metabolic genes are downregulated in meningiomas of current smokers.

Author

Khan AB, Patel R, McDonald MF, Goethe E, English C, Gadot R, Shetty A, Nouri SH, Harmanci AO, Harmanci AS, Klisch TJ, and Patel AJ

Subjects
Humans, Xenobiotics, Smoking adverse effects, Smoking genetics, Mutation, Genomics, Glucuronosyltransferase genetics, Meningioma genetics, Meningioma pathology, Meningeal Neoplasms pathology
Abstract

Introduction: Meningiomas are the most common primary intracranial tumor. Recently, various genetic classification systems for meningioma have been described. We sought to identify clinical drivers of different molecular changes in meningioma. As such, clinical and genomic consequences of smoking in patients with meningiomas remain unexplored., Methods: 88 tumor samples were analyzed in this study. Whole exome sequencing (WES) was used to assess somatic mutation burden. RNA sequencing data was used to identify differentially expressed genes (DEG) and genes sets (GSEA)., Results: Fifty-seven patients had no history of smoking, twenty-two were past smokers, and nine were current smokers. The clinical data showed no major differences in natural history across smoking status. WES revealed absence of AKT1 mutation rate in current or past smokers compared to non-smokers (p = 0.046). Current smokers had increased mutation rate in NOTCH2 compared to past and never smokers (p < 0.05). Mutational signature from current and past smokers showed disrupted DNA mismatch repair (cosine-similarity = 0.759 and 0.783). DEG analysis revealed the xenobiotic metabolic genes UGT2A1 and UGT2A2 were both significantly downregulated in current smokers compared to past (Log2FC = - 3.97, padj = 0.0347 and Log2FC = - 4.18, padj = 0.0304) and never smokers (Log2FC = - 3.86, padj = 0.0235 and Log2FC = - 4.20, padj = 0.0149). GSEA analysis of current smokers showed downregulation of xenobiotic metabolism and enrichment for G2M checkpoint, E2F targets, and mitotic spindle compared to past and never smokers (FDR < 25% each)., Conclusion: In this study, we conducted a comparative analysis of meningioma patients based on their smoking history, examining both their clinical trajectories and molecular changes. Meningiomas from current smokers were more likely to harbor NOTCH2 mutations, and AKT1 mutations were absent in current or past smokers. Moreover, both current and past smokers exhibited a mutational signature associated with DNA mismatch repair. Meningiomas from current smokers demonstrate downregulation of xenobiotic metabolic enzymes UGT2A1 and UGT2A2, which are downregulated in other smoking related cancers. Furthermore, current smokers exhibited downregulation xenobiotic metabolic gene sets, as well as enrichment in gene sets related to mitotic spindle, E2F targets, and G2M checkpoint, which are hallmark pathways involved in cell division and DNA replication control. In aggregate, our results demonstrate novel alterations in meningioma molecular biology in response to systemic carcinogens., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2023
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42. Novel Use of an Internal Distractor for Metacarpal Lengthening.

Author

Bashour LE, Hill C, Frommer SA, and Henry SL

Subjects
Humans, Child, Adolescent, Young Adult, Adult, Fingers surgery, Range of Motion, Articular, Metacarpal Bones surgery, Metacarpal Bones abnormalities, Osteogenesis, Distraction
Abstract

Background: In patients who have had proximal digit amputation, metacarpal distraction osteogenesis is an option to improve digital length and function. One drawback is that traditional external distraction devices are large and cumbersome; the option of a low-profile internal device is therefore appealing. Internal distractors are commonly used in craniofacial reconstruction, but use in the hand has not been reported. We describe a case series of the novel use of an internal distractor in metacarpal lengthening., Methods: In this single-center case series, patients who underwent metacarpal distraction by the senior author using a uniplanar internal distractor were reviewed, and indications, outcomes, and complications were analyzed., Results: There were 5 cases in 4 patients (age range: 7-33 years). Indications were traumatic amputation in 4 cases and congenital hypoplasia in 1. All were successfully distracted, with a mean final length gain of 1.3 cm (range: 1.0-1.7 mm). Mean time from device placement to consolidation was 3.5 months. Complications included activation arm site infection in 2 cases, both occurring after the distraction period, necessitating device removal before full consolidation. In these cases, the device was removed after the distraction period and replaced with a Kirschner wire for stabilization through the consolidation period., Conclusions: Metacarpal distraction was successfully achieved with an internal distraction device. Although infection was common, it occurred after the distraction period and did not preclude length gain. We feel that this low-profile device offers advantages over cumbersome external devices typically used for metacarpal lengthening.

Published
2023
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44. Thoracolumbar Scoliosis in Pediatric Patients With Loeys-Dietz Syndrome: A Case Series.

Author

LoPresti MA, Athukuri P, Khan AB, Prablek M, Patel R, Mayer R, Bauer DF, Gerow FT, Morris SA, Lam S, and Ravindra V

Abstract

Background Loeys-Dietz syndrome (LDS) is a genetic connective tissue disorder that predominantly affects cardiovascular, skeletal, and craniofacial structures. Associated thoracolumbar scoliosis in LDS can be challenging to manage, though other etiologies of pediatric scoliosis have better-defined management guidelines. We examined our institutional experience regarding the treatment of pediatric patients with LDS and scoliosis. Methodology In this retrospective study, all patients seen at our pediatric tertiary care center from 2004 through 2018 with a diagnosis of LDS were reviewed, and those with radiographic diagnoses of scoliosis (full-length scoliosis X-rays) were included. Demographic, clinical, and radiographic parameters were collected, and management strategies were reported. Results A total of 39 LDS patients whose ages ranged between seven and 13 years were identified. A total of nine patients were radiographically diagnosed with scoliosis, but three patients were excluded due to incomplete medical records, leaving six patients. The median age at scoliosis diagnosis was 11.5 years, with a median follow-up of 51 months. Two patients were successfully managed with observation (average initial Cobb angle (CA): 14°, average final CA: 20.5°). Two were braced, one successfully (initial CA: 15°, final CA: 30°) and one with a progressive disease requiring surgery (initial CA: 40°, final CA: 58°). Of the two who were offered surgical correction, one underwent surgery with a durable correction of spinal deformity (CA: 33° to 19°). One patient underwent a recent correction of aortic root dilatation and was not a candidate for scoliosis surgery. Conclusions Principles of adolescent idiopathic scoliosis management such as bracing for CA of 20-50° and surgery for CA of >50° can be applied to LDS patients with good outcomes. This augments our understanding of the treatment algorithm for pediatric patients with LDS., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, LoPresti et al.)

Published
2023
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45. Unraveling Spatial Gene Associations with SEAGAL: a Python Package for Spatial Transcriptomics Data Analysis and Visualization.

Author

Wang L, Liu C, and Liu Z

Abstract

Summary: In the era where transcriptome profiling moves towards single-cell and spatial resolutions, the traditional co-expression analysis lacks the power to fully utilize such rich information to unravel spatial gene associations. Here we present a Python package called Spatial Enrichment Analysis of Gene Associations using L-index (SEAGAL) to detect and visualize spatial gene correlations at both single-gene and gene-set levels. Our package takes spatial transcriptomics data sets with gene expression and the aligned spatial coordinates as input. It allows for analyzing and visualizing spatial correlations at both single-gene and gene-set levels. The output could be visualized as volcano plots and heatmaps with a few lines of code, thus providing an easy-yet-comprehensive tool for mining spatial gene associations., Availability and Implementation: The Python package SEAGAL can be installed using pip: https://pypi.org/project/seagal/ . The source code and step-by-step tutorials are available at: https://github.com/linhuawang/SEAGAL ., Contact: linhuaw@bcm.edu.

Published
2023
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46. scGREAT: Graph-based regulatory element analysis tool for single-cell multi-omics data.

Author

Liu C, Wang L, and Liu Z

Abstract

Motivation: With the development in single-cell multi-omics sequencing technology and data integration algorithms, we have entered the single-cell multi-omics era. Current multi-omics analysis algorithms failed to systematically dissect the heterogeneity within the datasets when inferring cis-regulatory events. Thus, there is a need for cis-regulatory element inferring algorithms that considers the cellular heterogeneity., Results: Here, we propose scGREAT, a single-cell multi-omics regulatory state analysis Python package with a rapid graph-based correlation measurement L . The graph-based correlation method assigns each cell a local L index, pinpointing specific cell groups of certain regulatory states. Such single-cell resolved regulatory state information enables the heterogeneity analysis equipped in the package. Applying scGREAT to the 10X Multiome PBMC dataset, we demonstrated how it could help subcluster cell types, infer regulation-based pseudo-time trajectory, discover feature modules, and find cluster-specific regulatory gene-peak pairs. Besides, we showed that global L index, which is the average of all local L values, is a better replacement for Pearson's r in ruling out confounding regulatory relationships that are not of research interests., Availability: https://github.com/ChaozhongLiu/scGREAT.

Published
2023
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47. Efficient Recognition and Closed Reduction of Locked Lateral Patella Dislocation.

Author

Aflatooni J and McKay SD

Abstract

Patellar dislocation is not an uncommon injury in the general population that can often be managed in the emergency room with a closed reduction. However, rarely, the patella can become impacted on the lateral femoral condyle and become resistant to closed reduction techniques, which is known as a locked patellar dislocation. This injury is reported in the literature as requiring advanced imaging with a costly workup, operative intervention, or extensive manipulation under general anesthesia, and, to our knowledge, has never been documented to be closed reduced outside the operating room. In this report, we present a 17-year-old male with a locked lateral patella dislocation and describe a new approach to efficiently diagnose and close reduce this injury in the ER under conscious sedation without advanced pre-treatment studies or urgent treatment in the operating room (OR)., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Aflatooni et al.)

Published
2023
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48. Single-cell multi-omics integration for unpaired data by a siamese network with graph-based contrastive loss.

Author

Liu C, Wang L, and Liu Z

Subjects
Humans, Transcriptome, Neural Networks, Computer, Single-Cell Analysis methods, Multiomics, COVID-19
Abstract

Background: Single-cell omics technology is rapidly developing to measure the epigenome, genome, and transcriptome across a range of cell types. However, it is still challenging to integrate omics data from different modalities. Here, we propose a variation of the Siamese neural network framework called MinNet, which is trained to integrate multi-omics data on the single-cell resolution by using graph-based contrastive loss., Results: By training the model and testing it on several benchmark datasets, we showed its accuracy and generalizability in integrating scRNA-seq with scATAC-seq, and scRNA-seq with epitope data. Further evaluation demonstrated our model's unique ability to remove the batch effect, a common problem in actual practice. To show how the integration impacts downstream analysis, we established model-based smoothing and cis-regulatory element-inferring method and validated it with external pcHi-C evidence. Finally, we applied the framework to a COVID-19 dataset to bolster the original work with integration-based analysis, showing its necessity in single-cell multi-omics research., Conclusions: MinNet is a novel deep-learning framework for single-cell multi-omics sequencing data integration. It ranked top among other methods in benchmarking and is especially suitable for integrating datasets with batch and biological variances. With the single-cell resolution integration results, analysis of the interplay between genome and transcriptome can be done to help researchers understand their data and question., (© 2023. The Author(s).)

Published
2023
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49. Exploring Latino Perspectives in Childhood Fever: Beliefs, Practices, and Needs.

Author

Acorda DE, Engebretson J, DesOrmeaux C, Cuccaro P, and Rozmus C

Subjects
Humans, Parents, Qualitative Research, Health Knowledge, Attitudes, Practice, Hispanic or Latino
Abstract

Introduction: Latino parents have significant knowledge gaps and misconceptions about fever. In this study, we explored Latino beliefs and practices around fever and its impact on their care decisions., Methods: A qualitative-focused ethnography was conducted with 21 Latino parents. Semi-structured interviews were completed, and inductive thematic analysis was used to identify themes and subthemes., Results: Three major themes emerged: (a) the meaning of fever; (b) seeking guidance; and (c) navigating fever. Subthemes included: a sign of folk illness, a sign of infection, trust in health care providers, watchful waiting, and barriers and needs., Discussion: Latino parents have significant knowledge gaps about the role of fever in illness. They engage multiple systems of care but rarely share their fears with health care providers. Culturally-sensitive interventions incorporating traditional and biomedical approaches are needed. Findings can help inform future interventions targeting knowledge gaps in this population.

Published
2022
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50. Aortic tortuosity in Turner syndrome is associated with larger ascending aorta.

Author

Srinivasan R, Shanbhag S, Pezzini A, Olivieri L, and Morris SA

Subjects
Child, Humans, Female, Adult, Retrospective Studies, Prospective Studies, Predictive Value of Tests, Aorta diagnostic imaging, Aorta pathology, Turner Syndrome complications, Turner Syndrome diagnosis, Turner Syndrome pathology, Aortic Dissection etiology, Aortic Dissection complications
Abstract

Turner syndrome (TS) is associated with aortic coarctation, dissection and dilation/aneurysm. Predictors of dissection are not well delineated, making decisions regarding prophylactic root replacement challenging. In other disorders, arterial tortuosity is an imaging biomarker associated with increased risk for aortic dissection and adverse cardiovascular events. We aimed to determine if, in TS, arterial tortuosity was associated with aortic dilation or aortic events. We performed a retrospective cohort analysis of unselected women and children with TS who underwent cardiovascular magnetic resonance angiography (MRA) for a prior prospective study. We calculated tortuosity indices including vertebral artery tortuosity index, aortic arch tortuosity index, thoracic aortic tortuosity index (ATI-D), and aortic tortuosity index to the celiac artery (ATI-C). We compared tortuosity in TS patients against age and gender matched controls. We evaluated univariable and multivariable associations between the tortuosity indices and aortic root and ascending aorta size as defined by z-scores, which give a sense of how far a measurement deviates from the mean. We also studied associations between tortuosity and need for aortic root replacement or aortic dissection. Of 184 subjects, with median age 34 years, mean general aortic root z-score was 0.1 ± 1.2 and mean general ascending aortic z-score was 0.4 ± 1.5. Three patients had aortic dissection, and one had prophylactic root replacement, which all occurred prior to first MRA. Vertebral tortuosity index, ATI-D, and ATI-C all increased with age (p < 0.0001) for all. ATI-C was associated with larger general ascending z-score. In multivariable analysis, ATI-C remained independently associated with larger ascending aortic z-scores. The relationship between aortic indices and surgery/dissection could not be evaluated since all were collected post-surgery/dissection. Thoracic aortic tortuosity as measured by ATI-C is independently associated with larger ascending aortic dimensions. In this population with only three aortic dissections occurring prior to imaging assessment, we could not assess for associations between aortic tortuosity and dissection. Studies including more patients with aortic dissection are needed to draw further conclusions., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Published
2022
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