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2. Magnetic Resonance Imaging–Guided Laser Interstitial Therapy for In-Field Recurrence After Stereotactic Radiosurgery: Is Complete Ablation Required for Local Control?

Author

Nicholas B. Dadario, M. Omar Iqbal, Travis Quinoa, Eric Hargreaves, R. Nicholas Hernandez, and Shabbar Danish

Subjects
Surgery, Neurology (clinical)
Abstract

Magnetic resonance imaging-guided laser interstitial therapy (MrLITT) presents a new valuable treatment alternative when the in-field recurrence (IFR) of metastatic brain tumors is difficult to safely access with open surgery or maximum radiation therapy has already been completed.To examine the effects of MrLITT on longevity outcomes based on volume of ablation.A retrospective study was carried out of 35 patients treated with MrLITT for IFR after radiosurgery for metastatic brain tumors at a single institution from 2010 to 2016. Overall survival (OS) and progression-free survival (PFS) were analyzed with Kaplan-Meier and Cox regression analyses according to ablation volume. Univariate and multivariate analyses further assessed risk factors based on ablation volume.Kaplan-Meier analyses showed no significant differences between total and subtotal ablation groups in OS (61.1 vs. 49.7 weeks) and PFS (45.1 and 42.7 weeks), respectively (P0.05). In the subtotal ablation group, independent risk factors included preoperative tumor volume (hazard ratio [HR], 1.24; P = 0.05) for OS and residual tumor volume (HR, 2.62; P = 0.01) for PFS. Multivariate Cox regressions suggested no significant differences in OS (HR, 1.03; P = 0.19) and PFS (HR, 1.02; P = 0.24) between total and subtotal ablation groups, whereas preoperative tumor volume remained a risk factor for decreased OS (HR, 1.23; P = 0.004).MrLITT is an effective treatment option for IFR after radiosurgery for metastatic brain tumors. The benefits of more aggressive gross total ablations of deep targets near eloquent cortices are limited compared with effective subtotal ablations, but the amount of residual tumor volume left must be appropriately balanced.

Published
2022

4. Midterm Results of Contemporary Uncemented Total Hip Arthroplasty in Patients 45 Years or Younger

Author

Nicholas Hernandez, Billy Kim, Niall H. Cochrane, Sean P. Ryan, and Thorsten M. Seyler

Subjects
Orthopedics and Sports Medicine, Surgery
Abstract

Total hip arthroplasty (THA) in young patients has varying results, and some reports show inferior results when compared with those of older patients. This study evaluated the outcomes of contemporary uncemented THA in patients 45 years or younger. This was a retrospective review from 2003 to 2015 at an academic institution. Three hundred one uncemented THAs in 232 patients 45 years or younger were evaluated. All patients had a minimum follow-up of 5 years. Ninety-day complications, survivorship free of revision, and dislocations were evaluated. Mean age was 35.7 years, 43.1% of patients were women, and mean follow-up was 9.3 years. Ninety-day complications included 26 emergency department visits, 11 readmissions, 3 revisions, and 3 dislocations. The rate of 10-year survivorship free of revision was 85.5%, and the rate of 10-year survivorship free of aseptic revision was 87.7%. Excluding metal-on-metal (MOM) THAs, 10-year aseptic survivorship was 93.3%. The most common reasons for revision were adverse local tissue reaction after MOM THA (16 hips) and periprosthetic joint infection (6 hips). In a multivariable logistic regression model, sickle cell disease (SCD) and conversion THA were associated with 90-day readmissions. Both MOM THA and SCD were associated with revision ( P Orthopedics . 2023;46(1):e45–e51.]

Published
2022

6. Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency

Author

Fatima Al Ali, Laurent Abel, Jean-François Emile, Davood Mansouri, Mahbuba Rahman, Franck Rapaport, Stéphanie Boisson-Dupuis, Nicholas Hernandez, Taushif Khan, Anna-Lena Neehus, David Hum, Benedetta Bigio, Vivien Béziat, Nico Marr, Jean-Laurent Casanova, Scott Drutman, Jacinta Bustamante, Emmanuelle Jouanguy, Majid Marjani, Robert Fisch, Ruslana Bryk, Nahal Mansouri, Serkan Belkaya, Lazaro Lorenzo-Diaz, Carl Nathan, and Seyed Alireza Mahdaviani

Subjects
Male, Genotype, Congenital cytomegalovirus infection, Nitric Oxide Synthase Type II, Severe disease, macromolecular substances, 030204 cardiovascular system & hematology, Nitric Oxide, Article, 03 medical and health sciences, Fatal Outcome, 0302 clinical medicine, Loss of Function Mutation, parasitic diseases, Exome Sequencing, medicine, Humans, 030212 general & internal medicine, Frameshift Mutation, business.industry, Homozygote, fungi, food and beverages, virus diseases, General Medicine, Middle Aged, medicine.disease, Pedigree, Multiple infections, Cytomegalovirus infection, Cytomegalovirus Infections, Immunology, Female, business
Abstract

BACKGROUND: Cytomegalovirus (CMV) can cause severe disease in children and adults with a variety of inherited or acquired T-cell immunodeficiencies, who are prone to multiple infections. It can also rarely cause disease in otherwise healthy persons. The pathogenesis of idiopathic CMV disease is unknown. Inbred mice that lack the gene encoding nitric oxide synthase 2 (Nos2) are susceptible to the related murine CMV infection. METHODS: We studied a previously healthy 51-year-old man from Iran who after acute CMV infection had an onset of progressive CMV disease that led to his death 29 months later. We hypothesized that the patient may have had a novel type of inborn error of immunity. Thus, we performed whole-exome sequencing and tested candidate mutant alleles experimentally. RESULTS: We found a homozygous frameshift mutation in NOS2 encoding a truncated NOS2 protein that did not produce nitric oxide, which determined that the patient had autosomal recessive NOS2 deficiency. Moreover, all NOS2 variants that we found in homozygosity in public databases encoded functional proteins, as did all other variants with an allele frequency greater than 0.001. CONCLUSIONS: These findings suggest that inherited NOS2 deficiency was clinically silent in this patient until lethal infection with CMV. Moreover, NOS2 appeared to be redundant for control of other pathogens in this patient. (Funded by the National Center for Advancing Translational Sciences and others.)

Published
2020

7. Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines

Author

Stephen J. Seligman, Serkan Belkaya, Ruben Pholien, Ismail Reisli, Johan Neyts, Yoann Seeleuthner, Leen Moens, Afshin Shirkani, Scott Drutman, Charles M. Rice, Lazaro Lorenzo-Diaz, Isabelle Meyts, Margaret R. MacDonald, Emersom Ciclini Mesquita, Dick Zijlmans, Denise Cristina de Souza Matos, Nicholas Hernandez, Sheila Maria Barbosa de Lima, Maria de Lourdes de Sousa Maia, Alain Lefevre-Utile, Dirk Jochmans, Paul J. Hertzog, Tamiris Azamor da Costa Barros, Marilda M. Siqueira, Esra Hazar Sayar, Hans Heinrich Hoffmann, Xavier Bossuyt, Nico Marr, Qian Zhang, Patrícia Mouta Nunes de Oliveira, Laura Pöyhönen, Emmanuelle Jouanguy, Giorgia Bucciol, Andrea Jurado, Shen-Ying Zhang, Aurélie Cobat, Robbert Boudewijns, Hassan Rokni-Zadeh, Jérémie Le Pen, Ekaterini Goudouris, Rik Gijsbers, Ian Tietjen, Chibuzo U Enemchukwu, Reinaldo de Menezes Martins, Laurent Abel, Majid Changi-Ashtiani, Jean-Laurent Casanova, Mohammad Shahrooei, Mana Momenilandi, and Akira Homma

Subjects
Male, 0301 basic medicine, Adolescent, Measles-Mumps-Rubella Vaccine, Measles Vaccine, Immunology, Inheritance Patterns, Yellow fever vaccine, Receptor, Interferon alpha-beta, Rubella, Measles, Article, 03 medical and health sciences, 0302 clinical medicine, Immunity, medicine, Humans, Immunology and Allergy, Child, Research Articles, Alleles, business.industry, Yellow Fever Vaccine, Yellow fever, Infant, medicine.disease, Virology, Pedigree, 3. Good health, Vaccination, 030104 developmental biology, Interferon Type I, Mutation, Female, Mutant Proteins, Measles vaccine, business, Signal Transduction, 030215 immunology, medicine.drug
Abstract

We describe two unrelated patients with inherited IFNAR1 deficiency who suffered from life-threatening infections following measles or yellow fever virus vaccination and were otherwise healthy., Vaccination against measles, mumps, and rubella (MMR) and yellow fever (YF) with live attenuated viruses can rarely cause life-threatening disease. Severe illness by MMR vaccines can be caused by inborn errors of type I and/or III interferon (IFN) immunity (mutations in IFNAR2, STAT1, or STAT2). Adverse reactions to the YF vaccine have remained unexplained. We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr. The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations. Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN. The patients’ fibroblast phenotypes are rescued with WT IFNAR1. Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals.

Published
2019

8. Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency

Author

Jeremy Manry, Eduardo J. Garcia Reino, Taushif Khan, Romain Lévy, Mary Hasek, Jérémie Rosain, Yoann Seeleuthner, Isabelle Meyts, Lazaro Lorenzo, Laurent Abel, Zhi Li, Omar AbuZaitun, Shai Shrot, Paul Bastard, Jean-Laurent Casanova, Bertrand Boisson, Emmanuelle Jouangy, Flore Rozenberg, Nicholas Hernandez, Raz Somech, Benedetta Bigio, Shen-Ying Zhang, Mélodie Aubart, Vivien Béziat, Nico Marr, Jie Chen, Rik Gijsbers, Peng Zhang, Jacinta Bustamante, Qian Zhang, Yoon-Seung Lee, Sandra Pellegrini, Aurélie Cobat, Soraya Boucherit, Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), Sidra Medicine [Doha, Qatar], Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Chaim Sheba Medical Center, Kfar Saba and Sackler School of Medicine, Service de neurochirurgie pédiatrique [CHU Necker], Faculté de Médecine et Médecine Dentaire [UCLouvain], Université Catholique de Louvain = Catholic University of Louvain (UCL), Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Hamad Bin Khalifa University (HBKU), Precision Immunology Institute [New-York] (PrIISM), Icahn School of Medicine at Mount Sinai [New York] (MSSM), 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), This work was conducted in the two branches of the Laboratory of Human Genetics of Infectious Diseases, and was funded in part by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Clinical and Translational Science Award (CTSA) program, grant UL1TR001866, NIH grants R01AI088364, R01NS072381 and R21AI151663, the National Vaccine Program Office of the US Department of Health and Human Services grant VSRNV000006, grants from the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID) and the French National Research Agency (ANR) under the 'Investments for the future' program (ANR-10-IAHU-01), the ANR grants IEIHSEER (ANR-14-CE14-0008-01), SEAeHostFactors (ANR-18-CE15-0020-02), and CNSVIRGEN (ANR-19-CE15-0009-01), the French Foundation for Medical Research (FRM) (EQU201903007798), the Rockefeller University, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, and the St. Giles Foundation. PB was supported by the French Foundation for Medical Research (FRM, EA20170638020) and the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller). JR was supported by the Inserm PhD program ('poste d’accueil Inserm'). JM was supported by ANR grants BURULIGEN (ANR-12-BSV3-0013-01) and MYCOPARADOX (ANR-16-CE12-0023)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-14-CE14-0008,IEIHSEER,L'encéphalite Herpétique de l'enfant résulte de déficits héréditaires d'immunité contre l'HSV-1: une exception ou une règle?(2014), ANR-18-CE15-0020,SEAe-HostFactors,Facteurs de susceptibilité de l'hôte à l'encéphalite pédiatrique en Asie du Sud Est(2018), and ANR-19-CE15-0009,CNSVIRGEN,Déficits immunitaires innés dans les infections sévères du tronc cérébral(2019)

Subjects
Male, 0301 basic medicine, Untranslated region, Adolescent, [SDV]Life Sciences [q-bio], Immunology, Herpesvirus 1, Human, Receptor, Interferon alpha-beta, Biology, medicine.disease_cause, Rubella, 03 medical and health sciences, Exon, 0302 clinical medicine, Immunity, medicine, Humans, MESH: Receptor, Interferon alpha-beta, MESH: Interferons, Innate immunity, MESH: Adolescent, Infectious disease, MESH: Humans, MESH: Encephalitis, Herpes Simplex, MESH: Child, Preschool, General Medicine, medicine.disease, Virology, MESH: Male, MESH: Herpesvirus 1, Human, HEK293 Cells, 030104 developmental biology, Herpes simplex virus, Tyrosine kinase 2, Child, Preschool, 030220 oncology & carcinogenesis, MESH: HEK293 Cells, Cytokines, Encephalitis, Herpes Simplex, Interferons, Viral disease, Encephalitis, Research Article, Genetic diseases
Abstract

International audience; Inborn errors of TLR3-dependent IFN-α/β– and IFN-λ–mediated immunity in the CNS can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-α/β and IFN-λ are unknown. We report a child homozygous for a genomic deletion of the entire coding sequence and part of the 3′-UTR of the last exon of IFNAR1, who died of HSE at the age of 2 years. An older cousin died following vaccination against measles, mumps, and rubella at 12 months of age, and another 17-year-old cousin homozygous for the same variant has had other, less severe, viral illnesses. The encoded IFNAR1 protein is expressed on the cell surface but is truncated and cannot interact with the tyrosine kinase TYK2. The patient’s fibroblasts and EBV-B cells did not respond to IFN-α2b or IFN-β, in terms of STAT1, STAT2, and STAT3 phosphorylation or the genome-wide induction of IFN-stimulated genes. The patient’s fibroblasts were susceptible to viruses, including HSV-1, even in the presence of exogenous IFN-α2b or IFN-β. HSE is therefore a consequence of inherited complete IFNAR1 deficiency. This viral disease occurred in natural conditions, unlike those previously reported in other patients with IFNAR1 or IFNAR2 deficiency. This experiment of nature indicates that IFN-α/β are essential for anti–HSV-1 immunity in the CNS

Published
2021

9. Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis

Author

Sarah Jill De Jong, Sofie De Schepper, Jean-Laurent Casanova, Jutte van der Werff ten Bosch, David Hum, Emmanuelle Jouanguy, Franklin L. Zhong, Vincent R. Bonagura, Scott Drutman, Nicholas Hernandez, David Creytens, Gérard Orth, Katrien Bonte, Andy Wullaert, Franck Rapaport, Filomeen Haerynck, Laurent Abel, Serkan Belkaya, Xavier Bossuyt, Vivien Béziat, Lazaro Lorenzo-Diaz, Bruno Reversade, Simon Tavernier, Center for Reproductive Medicine, ACS - Diabetes & metabolism, ARD - Amsterdam Reproduction and Development, ACS - Heart failure & arrhythmias, Clinical sciences, Growth and Development, Pediatrics, Reversade, Bruno, Drutman, Scott B., Haerynck, Filomeen, Zhong, Franklin L., Hum, David, Hernandez, Nicholas J., Belkaya, Serkan, Rapaport, Franck, de Jong, Sarah Jill, Creytens, David, Tavernier, Simon J., Bonte, Katrien, De Schepper, Sofie, ten Bosch, Jutte van der Werff, Lorenzo-Diaz, Lazaro, Wullaert, Andy, Bossuyt, Xavier, Orth, Gerard, Bonagura, Vincent R., Beziat, Vivien, Abel, Laurent, Jouanguy, Emmanuelle, Laurent-Casanova, Jean, School of Medicine, and Department of Medical Genetics

Subjects
Medicine(all), Mutation, Human papillomavirus, Multidisciplinary, Medicine, Medical genetics, Genetics, Inflammasome, NLRP1, Recurrent respiratory papillomatosis, Biology, medicine.disease_cause, Phenotype, Pyrin domain, symbols.namesake, inflammasome, Immunology, medicine, Mendelian inheritance, symbols, genetics, Recurrent Respiratory Papillomatosis, Allele, Inflammasome complex, recurrent respiratory papillomatosis, medicine.drug
Abstract

Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1β secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1β at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation., United States Department of Health and Human Services; National Institutes of Health (NIH); NIH National Center for Advancing Translational Sciences (NCATS); French National Research Agency (ANR); Integrative Biology of Emerging Infectious Diseases Laboratoire d'Excellence; French Cancer Institute; Strategic Positioning Fund on Genetic Orphan Diseases from A* STAR, Singapore; Jeffrey Modell Foundation; Bijzonder Onderzoeksfonds-Tenure Grant; Cure-AID; European Union ERA-Net for Research Programmes on Rare Diseases; H2020; European Union (European Union); National Research Foundation; St. Giles Foundation; Rockefeller University; Institut National de la Sante et de la Recherche Medicale (Inserm); Paris Descartes University; Shapiro-Silverberg Fund for the Advancement of Translational Research; American Philosophical Society Daland Fellowship in Clinical Investigation; NIH National Center for Research Resources (NCRR)

Published
2019

10. Genetic basis for yellow fever vaccine-associated viscerotropic disease (YEL-AVD): a preliminary report

Author

Deborah Araújo da Conceição, Reinaldo de Menezes Martins, Qian Zhang, Patrícia Mouta Nunes de Oliveira, Jean-Laurent Casanova, Emmanuelle Jouanguy, Tamiris Azamor da Costa Barros, Maria de Lourdes de Sousa Maia, Emersom Cicilini Mesquita, and Nicholas Hernandez

Subjects
business.industry, Preliminary report, Medicine, Yellow fever vaccine, Disease, business, Virology, medicine.drug
Published
2019

11. Tuberculosis and impaired IL-23–dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant

Author

Durga Sivanesan, Cindy S. Ma, Zafer Caliskaner, Katia Abarca, Jaime Inostroza, Hicham Souhi, Nicholas Hernandez, Stephen W. Michnick, Alix Checchi, Tayfun Ozcelik, Ahmed Abid, Rubén Martínez-Barricarte, Noé Ramírez-Alejo, Adil Zegmout, Esra Hazar Sayar, Nico Marr, Ismail Reisli, Lluis Quintana-Murci, Jamila El-Baghdadi, Bernhard Fleckenstein, Hassan Abolhassani, Jacinta Bustamante, Ingrid Müller-Fleckenstein, Ismail Abderahmani Rhorfi, Antonio Condino-Neto, Jose Antonio Tavares de Albuquerque, Rodrigo Naves, Dimitry N. Krementsov, Beatriz Tavares Costa-Carvalho, Sandra Pellegrini, Aurélie Cobat, Robert Fisch, Michael J. Ciancanelli, Gaspard Kerner, Lorena Orozco, Geetha Rao, Jeanette Mulwa, Hans D. Ochs, Stuart G. Tangye, Fabienne Jabot-Hanin, Patricia García, Frederic Geissmann, Stéphanie Boisson-Dupuis, Humberto García-Ortiz, Zhi Li, Tomi Lazarov, Bertrand Boisson, Hicham Naji Amrani, María Elvira Balcells, Caroline Deswarte, Andrea Guennoun, Alexis Strickler, Carolyn C. Jackson, Sevgi Pekcan, Janet Markle, Joshua Halpern, Jean-Laurent Casanova, Cory Teuscher, Che Kang Lim, Anne Puel, Yuval Itan, Lennart Hammarström, Matthieu Bouaziz, Etienne Patin, Laurent Abel, Qian Zhang, Kathryn Payne, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, Garvan Institute of Medical Research [Darlinghurst, Australia], Laboratory for the Modeling of Biological and Socio-technical Systems [Boston] (MoBS), Northeastern University [Boston], Memorial Sloane Kettering Cancer Center [New York], Laboratory of Genetic Medicine & Immunology, Weill Cornell Medicine [Qatar], Bases de données et traitement des langues naturelles (BDTLN), Laboratoire d'Informatique Fondamentale et Appliquée de Tours (LIFAT), Université de Tours-Institut National des Sciences Appliquées - Centre Val de Loire (INSA CVL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut National des Sciences Appliquées - Centre Val de Loire (INSA CVL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Institute of Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany, Sidra Medicine [Doha, Qatar], Tehran University of Medical Sciences (TUMS), Infectious Diseases Department, School of Medicine, Pontificia Universidad Católica de Chile (UC), Institute of Biomedical Sciences - Department of Immunology [Sao Paulo], University of São Paulo (USP), Hosp Puerto Montt, University of Washington [Seattle], Selcuk University, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Garvan Institute for Medical Research, Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], The Laboratory of Human Genetics of Infectious Diseases was supported, in part, by grants from the French National Agency for Research (ANR) under the 'Investissement d’avenir' program (grant no. ANR-10-IAHU-01), the TBPATHGEN project (grant no. ANR-14-CE14-0007-01), the GENMSMD project (grant no. ANR-16-CE17-0005-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (grant no. ANR-10-LABX-62-IBEID), the European Research Council (ERC, grant no. ERC-2010-AdG-268777), the SCOR Corporate Foundation for Science, the St. Giles Foundation, the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), NIH (grant no. UL1TR001866), the National Institute of Allergy and Infectious Diseases (NIAID) (grant nos. 5R01AI089970, 5R37AI095983, 5U01AI088685, and 5U19AI111143), and The Rockefeller University. Work at the Cytokine Signaling Unit was supported, in part, by a grant from Fondation de la Recherche Médicale to S. Pellegrini (grant no. DEQ20170336741). J.B. was supported by Support of Clinical Research (grant no. SRC2017). C.S.M. and S.G.T. were supported by fellowships and grants from the National Health and Medical Research Council of Australia and the Office of Health and Medical Research of the Government of New South Wales (Australia). M.E.B. was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT, grant no. 1171570) A.C.-N. was supported by Fundação de Amparo a Pesquisa do Estado e de São Paulo (Fapesp) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq). N.R.-A. was supported by fellowships from Consejo Nacional de Ciencia y Tecnología (CONACYT, grant no. 264011) and the Stony Wold-Herbert Fund. Z.L. was supported by the CNRS. J. Markle was supported by the Charles H. Revson Senior Fellowship in Biomedical Sciences and NIAID grant K99AI27932. C.C.J. was the Damon Runyon-Richard Lumsden Foundation Physician Scientist supported by the Damon Runyon Cancer Research Foundation (PST-03-15). H.D.O. was supported by the Jeffrey Modell Foundation. N.H. was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH under award no. T32GM007739 to the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program. The content of this study is the sole responsibility of the authors and does not necessarily represent the official views of the NIH. The Yale Center for Mendelian Genomics (UM1HG006504) is funded by the National Human Genome Research Institute. Funds were also provided by the National Heart, Lung, and Blood Institute. The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-14-CE14-0007,TBPATHGEN,Dissection de la pathogenèse de la tuberculose par l'identification de défauts monogéniques de l'immunité dans les formes pédiatriques sévères de la maladie(2014), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 268777,EC:FP7:ERC,ERC-2010-AdG_20100317,GENTB(2011), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Garvan Institute of medical research, Université de Tours (UT)-Institut National des Sciences Appliquées - Centre Val de Loire (INSA CVL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Tours (UT)-Institut National des Sciences Appliquées - Centre Val de Loire (INSA CVL), Universidade de São Paulo = University of São Paulo (USP), Özçelik, Tayfun, Li, Zhi, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Appel à projets générique - Dissection de la pathogenèse de la tuberculose par l'identification de défauts monogéniques de l'immunité dans les formes pédiatriques sévères de la maladie - - TBPATHGEN2014 - ANR-14-CE14-0007 - Appel à projets générique - VALID, Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme - - GENMSMD2016 - ANR-16-CE17-0005 - AAPG2016 - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Human Genetics of Tuberculosis - GENTB - - EC:FP7:ERC2011-06-01 - 2016-05-31 - 268777 - VALID, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]

Subjects
0301 basic medicine, Tuberculosis, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Immunology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Immunity, medicine, Missense mutation, Allele, Receptor, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, General Medicine, medicine.disease, 3. Good health, 030104 developmental biology, Cytokine, Tyrosine kinase 2, [SDV.IMM]Life Sciences [q-bio]/Immunology, IMUNOGENÉTICA, 030215 immunology
Abstract

International audience; Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common TYK2 P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls (P = 8.37 × 10-8; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of TYK2 selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.

Published
2018

12. Severe influenza pneumonitis in children with inherited TLR3 deficiency

Author

Mary Hasek, Isabelle Meyts, Michael D. Keller, Flore Rozenberg, Fabien G. Lafaille, Priya Luthra, Lazaro Lorenzo, Marie Celard, Jie Chen, Eduardo J. Garcia Reino, Tatiana Kochetkov, Laurent Abel, Catherine Vedrinne, Yuval Itan, Olivier Gilliaux, Hye Kyung Lim, Soraya Boucherit, Benedetta Bigio, Jordan S. Orange, Nicholas Hernandez, Nicolas Goudin, Paul Bastard, Sarah X.L. Huang, Hans-Willem Snoeck, Jean-Laurent Casanova, Michael J. Ciancanelli, Gaspard Kerner, Kerry Dobbs, Shen-Ying Zhang, Luigi D. Notarangelo, Qian Zhang, and Adolfo García-Sastre

Subjects
0301 basic medicine, Male, viruses, NF-KAPPA-B, Inheritance Patterns, STAT2 DEFICIENCY, Research & Experimental Medicine, medicine.disease_cause, RIG-I, 0302 clinical medicine, Fatal Outcome, Loss of Function Mutation, Influenza A virus, Immunology and Allergy, Child, Lung, Research Articles, virus diseases, hemic and immune systems, Penetrance, 3. Good health, VIRUS ENCEPHALITIS, Protein Transport, Medicine, Research & Experimental, Child, Preschool, Female, Life Sciences & Biomedicine, Encephalitis, STRUCTURAL BASIS, Heterozygote, HERPES-SIMPLEX ENCEPHALITIS, Immunology, Induced Pluripotent Stem Cells, Mutation, Missense, chemical and pharmacologic phenomena, DOUBLE-STRANDED-RNA, PANDEMIC INFLUENZA, Article, 03 medical and health sciences, Immunity, Influenza, Human, medicine, Humans, Alleles, Pneumonitis, Science & Technology, business.industry, TOLL-LIKE RECEPTOR-3, Infant, Newborn, Infant, Heterozygote advantage, Epithelial Cells, Pneumonia, Fibroblasts, medicine.disease, Toll-Like Receptor 3, 030104 developmental biology, Poly I-C, IRF7, Interferons, business, 030217 neurology & neurosurgery, GROWTH-RETARDATION
Abstract

The authors report three unrelated children with inherited TLR3 deficiency, impaired TLR3-dependent, IFN-α/β– and/or -λ–mediated, pulmonary epithelial cell–intrinsic immunity to influenza A virus, and life-threatening influenza pneumonitis., Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-β and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients’ iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I and/or III IFN–mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature.

Published
2018

13. Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency

Author

Man Chun Leung, Laurent Abel, Bertrand Boisson, Jeffrey Danielson, Huie Jing, Susie S.Y. Huang, Vimel Rattina, Serkan Belkaya, Lisa S. Mathew, Nicholas Hernandez, Yanick J. Crow, Silvia Giliani, Stephen J. Elledge, Michael J. Ciancanelli, Yoann Rose, Damien Chaussabel, Lazaro Lorenzo-Diaz, Tanwir Habib, Isabelle Melki, Qian Zhang, Helen C. Su, Jean-Laurent Casanova, Shen-Ying Zhang, Marie-Noëlle Lebras, Luigi D. Notarangelo, Nico Marr, Stéphanie Boisson-Dupuis, Mathieu P Rodero, Scott Drutman, Naoki Kitabayashi, Tomasz Kula, Cécile Dumaine, Anais Boulai, Stéphane Blanche, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sidra Medicine [Doha, Qatar], Imagine - Institut des maladies génétiques (IMAGINE - U1163), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Immunology, Pneumonia, Viral, Interferon alpha-2, medicine.disease_cause, Virus, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Immunity, Influenza, Human, Influenza A virus, medicine, Immunology and Allergy, Gene silencing, Humans, STAT1, Research Articles, Alleles, ComputingMilieux_MISCELLANEOUS, biology, Homozygote, virus diseases, Infant, medicine.disease, Orthomyxoviridae, Virology, Interferon-Stimulated Gene Factor 3, gamma Subunit, 3. Good health, Pneumonia, 030104 developmental biology, Viral replication, 030220 oncology & carcinogenesis, biology.protein, Female
Abstract

We report a child with inherited, complete IRF9 deficiency who suffered from life-threatening influenza pneumonitis. IRF9 deficiency disrupts the activation of ISGF3 and impairs but does not abolish cellular responses to type I IFNs, as some ISGs are induced., Life-threatening pulmonary influenza can be caused by inborn errors of type I and III IFN immunity. We report a 5-yr-old child with severe pulmonary influenza at 2 yr. She is homozygous for a loss-of-function IRF9 allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not IFN-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-α2b. The transcriptome induced by IFN-α2b in the patient’s cells is much narrower than that of control cells; however, induction of a subset of IFN-stimulated gene transcripts remains detectable. In vitro, the patient’s cells do not control three respiratory viruses, influenza A virus (IAV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV). These phenotypes are rescued by wild-type IRF9, whereas silencing IRF9 expression in control cells increases viral replication. However, the child has controlled various common viruses in vivo, including respiratory viruses other than IAV. Our findings show that human IRF9- and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling IAV.

Published
2018

14. Determining Defeat: The PRC, the ICCPR, and the Interim Obligation

Author

Nicholas Hernandez

Subjects
Vienna Convention on the Law of Treaties, Scholarship, Scope (project management), Interim, media_common.quotation_subject, Law, Political science, Obligation, Treaty, Ratification, Duty, media_common
Abstract

The Vienna Convention on the Law of Treaties codifies in Article 18 the duty not to defeat the object and purpose of a treaty after signature but before ratification. This duty has become known as the interim obligation and has undergone substantial scholarship evaluating its scope and extent. In fact several tests have been developed to identify the enigmatic nature of this obligation, which in the forthcoming paper are addressed. More specifically however, this paper evaluates the actions of the PRC since signature of the ICCPR to determine defeat of the interim obligation.

Published
2010

15. Inherited IL-18BP deficiency in human fulminant viral hepatitis

Author

Emmanuelle Jouanguy, Julie Bruneau, Yoon Seung Lee, Jean-Laurent Casanova, Lazaro Lorenzo-Diaz, Mohammad Kabbani, Eleftherios Michailidis, Serkan Belkaya, Scott Drutman, Laurent Abel, Soraya Boucherit, Cecilia B. Korol, Mylène Sebagh, Vivien Béziat, Aurélie Cobat, Ype P. de Jong, Bertrand Boisson, Nicholas Hernandez, Charles M. Rice, Paul Bastard, Jean-François Emile, Eric Vivier, Emmanuel Jacquemin, Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'anatomie et cythologie pathologique, CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, Département de Pathologie [Villejuif], Hôpital Paul Brousse, Physiopathogenèse et Traitement des Maladies du Foie [Villejuif], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Génétique Humaine des Maladies Infectieuses (Inserm U980), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Laboratory of Virology and Infectious Disease [New York], Rockefeller University [New York], Université Paris Descartes - Paris 5 (UPD5), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Physiopathogénèse et Traitement des Maladies du Foie, and Hôpital Paul Brousse-Université Paris-Saclay

Subjects
0301 basic medicine, Hepatitis, Mutation, business.industry, Fulminant, Immunology, medicine.disease, medicine.disease_cause, Virology, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Immunity, 030220 oncology & carcinogenesis, Immunology and Allergy, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Interleukin 18, business, Viral hepatitis, Exome sequencing, IL18BP
Abstract

Fulminant viral hepatitis (FVH) is a devastating and unexplained condition that strikes otherwise healthy individuals during primary infection with common liver-tropic viruses. We report a child who died of FVH upon infection with hepatitis A virus (HAV) at age 11 yr and who was homozygous for a private 40-nucleotide deletion in IL18BP, which encodes the IL-18 binding protein (IL-18BP). This mutation is loss-of-function, unlike the variants found in a homozygous state in public databases. We show that human IL-18 and IL-18BP are both secreted mostly by hepatocytes and macrophages in the liver. Moreover, in the absence of IL-18BP, excessive NK cell activation by IL-18 results in uncontrolled killing of human hepatocytes in vitro. Inherited human IL-18BP deficiency thus underlies fulminant HAV hepatitis by unleashing IL-18. These findings provide proof-of-principle that FVH can be caused by single-gene inborn errors that selectively disrupt liver-specific immunity. They also show that human IL-18 is toxic to the liver and that IL-18BP is its antidote.

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