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1. Contribution of SLC22A12 on hypouricemia and its clinical significance for screening purposes

Author

Cheryl A. Winkler, Daeui Park, Kyeong Kyu Kim, Hong-Hee Won, Raul Cachau, Do Hyeon Cha, Seungho Ryu, Sung Kweon Cho, Sophie Limou, Heon Yung Gee, Woojae Myung, Sun Ha Jee, Jong Mun Choi, Le Bihan, Sylvie, Department of Pharmacology [Seoul, Republic of Korea] (Brain Korea 21 PLUS Project for Medical Sciences), Yonsei University College of Medicine [Seoul, Republic of Korea], Advanced Biomedical Computational Science [Frederick, MD, USA], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH)-Frederick National Laboratory for Cancer Research (FNLCR), Department of Laboratory Medicine [Gyeonggi-do, Republic of Korea], Green Cross [Gyeonggi-do, Republic of Korea], Department of Predictive Toxicology [Daejeon, Republic of Korea], Korea Institute of Toxicology [Daejeon, Republic of Korea], Department of Epidemiology and Health Promotion [Seoul, Republic of Korea] (Institute for Health Promotion), Yonsei University College of Medicine [Seoul, Republic of Korea]-Graduate School of Public Health [Seoul, Republic of Korea], Center for Cohort Studies - Total Healthcare Center [Seoul, Republic of Korea], Kangbuk Samsung Hospital [Seoul, Republic of Korea]-SKKU School of Medicine [Seoul, Republic of Korea], Sungkyunkwan University [Suwon] (SKKU)-Sungkyunkwan University [Suwon] (SKKU), Department of Health Sciences and Technology [Seoul, Republic of Korea] (SAIHST), Sungkyunkwan University [Suwon] (SKKU), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), École Centrale de Nantes (ECN), Molecular Genetic Epidemiology Section [Frederick, MD, USA] (Basic Research Laboratory/Basic Science Program - NCI/NIH), Frederick National Laboratory for Cancer Research (FNLCR)-Leidos Biomedical Research, Inc [Frederick, MD, USA], Department of Psychiatry [Seongnam, Korea], Seoul National University College of Medicine [Séoul, Corée du Sud] (SNUCM)-Seoul National University Bundang Hospital (SNUBH), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1A6A3A11933380 to S.K.C and 2015R1D1A1A01056685 to H.Y.G) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: HI17C2372 to S.K.C). We thank the Research Division, NEXBiO Co. Ltd for their contribution to our sequencing. We are grateful to Young Sup Cho MD, PhD and Hyekyung Son MD, PhD for their academic advice during this project. This Research was supported partly by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E., and Seoul National University Bundang Hospital-Seoul National University College of Medicine [Séoul, Corée du Sud] (SNUCM)

Subjects
Male, 0301 basic medicine, Heterozygote, medicine.medical_specialty, Renal Tubular Transport, Inborn Errors, Genotype, Organic Cation Transport Proteins, [SDV]Life Sciences [q-bio], Science, Water-Electrolyte Imbalance, Organic Anion Transporters, 030204 cardiovascular system & hematology, Excessive exercise, Predictive markers, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Exome Sequencing, medicine, Humans, Clinical significance, Genetic Testing, Diagnostic screening, Hypouricemia, Aged, Multidisciplinary, biology, business.industry, Diagnostic markers, Middle Aged, medicine.disease, [SDV] Life Sciences [q-bio], 030104 developmental biology, Mutation, Cohort, biology.protein, Medicine, Female, Urinary Calculi, SLC22A12, business, Genetic diagnosis, Primary screening
Abstract

Differentiating between inherited renal hypouricemia and transient hypouricemic status is challenging. Here, we aimed to describe the genetic background of hypouricemia patients using whole-exome sequencing (WES) and assess the feasibility for genetic diagnosis using two founder variants in primary screening. We selected all cases (N = 31) with extreme hypouricemia (SLC22A12 (p.Trp258*, pArg90His) were identified in 24 out of 31 subjects (77.4%). In an independent cohort, we identified 50 individuals with hypouricemia and genotyped the p.Trp258* and p.Arg90His variants; 47 of the 50 (94%) hypouricemia cases were explained by only two mutations. Four novel coding variants in SLC22A12, p.Asn136Lys, p.Thr225Lys, p.Arg284Gln, and p.Glu429Lys, were additionally identified. In silico studies predict these as pathogenic variants. This is the first study to show the value of genetic diagnostic screening for hypouricemia in the clinical setting. Screening of just two ethnic-specific variants (p.Trp258* and p.Arg90His) identified 87.7% (71/81) of Korean patients with monogenic hypouricemia. Early genetic identification of constitutive hypouricemia may prevent acute kidney injury by avoidance of dehydration and excessive exercise.

Published
2019
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2. Standards for practical intravenous rapid drug desensitization & delabeling: A WAO committee statement

Author

Emilio Alvarez-Cuesta, Ricardo Madrigal-Burgaleta, Ana D. Broyles, Javier Cuesta-Herranz, Maria Antonieta Guzman-Melendez, Michelle C. Maciag, Elizabeth J. Phillips, Jason A. Trubiano, Johnson T. Wong, Ignacio Ansotegui, F. Runa Ali, Denisse Angel-Pereira, Aleena Banerji, Maria Pilar Berges-Gimeno, Lorena Bernal-Rubio, Knut Brockow, Ricardo Cardona Villa, Mariana C. Castells, Jean-Christoph Caubet, Yoon-Seok Chang, Luis Felipe Ensina, Manana Chikhladze, Anca Mirela Chiriac, Weng-Hung Chung, Motohiro Ebisawa, Bryan Fernandes, Lene Heise Garvey, Maximiliano Gomez, Javier Gomez Vera, Sandra Gonzalez Diaz, David I. Hong, Juan Carlos Ivancevich, Hye-Ryun Kang, David A. Khan, Merin Kuruvilla, Jose Ignacio Larco Sousa, Patricia Latour-Staffeld, Anne Y. Liu, Eric Macy, Hans Jorgen Malling, Jorge Maspero, Sara M. May, Cristobalina Mayorga, Miguel A. Park, Jonathan Peter, Matthieu Picard, Tito Rodriguez-Bouza, Antonino Romano, Mario Sanchez-Borges, Luciana Kase Tanno, Maria Jose Torres, Alicia Ureña-Tavera, Rocco L. Valluzzi, Gerald W. Volcheck, Masao Yamaguchi, Hospital Universitario Ramón y Cajal [Madrid], Universidad de Alcalá - University of Alcalá (UAH), St Bartholomew's Hospital (London), Barts Health NHS Trust [London, UK], Catalan Institute of Oncology (ICO), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), RETIC ARADyAL, University of Chile Clinical Hospital, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], University of Melbourne, Massachusetts General Hospital [Boston], Hospital Quirónsalud Bizkaia [Bilbao], Hospital Universitario De Canarias, Technische Universität München = Technical University of Munich (TUM), Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Hôpitaux Universitaires de Genève (HUG), Seoul National University Bundang Hospital (SNUBH), Seoul National University [Seoul] (SNU), Federal University of Sao Paulo (Unifesp), Akaki Tsereteli State University, Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service d'allergologie et de pneumologie [Hôpital Arnaud de Villeneuve], Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Chang Gung Memorial Hospital [Taipei] (CGMH), Sagamihara National Hospital [Kanagawa, Japan], Copenhagen University Hospital, IT University of Copenhagen (ITU), Catholic University of Salta, Regional Hospital Lic. Adolfo Lopez Mateos (ISSSTE), Hospital Universitario Dr. José Eleuterio González, Brigham & Women’s Hospital [Boston] (BWH), Servicio de Alergia e ImmunologiaBuenos Aires (Clinica Santa Isabel), Seoul National University College of Medicine [Séoul, Corée du Sud] (SNUCM), University of Texas Southwestern Medical Center [Dallas], Emory University School of Medicine, Emory University [Atlanta, GA], Clinica San Felipe, Centro Avanzado de Alergia y Asma de Santo Domingo, Stanford University Medical Center, University of California Medical Center [San Diego], University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Fundación Cidea Allergy and Respiratory Research Unit, University of Nebraska Medical Center, University of Nebraska System, Hospital Regional Universitario de Málaga = Regional University Hospital of Malaga [Spain], Allergy Unit [Malaga, Spain] (National Network ARADyAL), Mayo Clinic [Rochester], University of Cape Town, Hôpital Maisonneuve-Rosemont, Centro de Patología Alérgica, Oasi Maria Santissima Srl [Troina, Italy], Centro Médico Docente La Trinidad, Clínica Unión Medica del Norte, Bambino Gesù Children’s Hospital [Rome, Italy], Chiba University Hospital, CHIRIAC, Anca Mirela, [Madrigal-Burgaleta, Ricardo] Ramon & Cajal Univ Hosp, Madrid, Spain, and [Madrigal-Burgaleta, Ricardo] St Bartholomews Hosp, Resp Dept, Allergy & Severe Asthma Serv, Barts Hlth NHS Trust, 4th Floor,King George 5 Bldg, London EC1A 7BE, England

Subjects
Pulmonary and Respiratory Medicine, Drug desensitization, Immunology, Basophil activation test, Reported penicillin allergy, Monoclonal-antibodies, Penicillins, In-vitro diagnosis, Antibiotic desensitization, Risk-stratification, Biological agents, Skin test, Antibiotics, Carboplatin hypersensitivity, Immunology and Allergy, Chemotherapy, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Beta-lactam allergy, Drug challenge, Risk stratification, Betalactams, Precision medicine, Cross-reactivity, Drug allergy, Delabeling, Personalized medicine, Drug provocation test, Delabel-ing, Ige-mediated hypersensitivity, Immediate allergic reactions, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology
Abstract

International audience; Drug hypersensitivity reactions (DHRs) to intravenous drugs can be severe and might leave patients and doctors in a difficult position where an essential treatment or intervention has to be suspended. Even if virtually any intravenous medication can potentially trigger a life-threatening DHR, chemotherapeutics, biologics, and antibiotics are amongst the intravenous drugs most frequently involved in these reactions. Admittedly, suspending such treatments may negatively impact the survival outcomes or the quality of life of affected patients. Delabeling pathways and rapid drug desensitization (RDD) can help reactive patients stay on first-choice therapies instead of turning to less efficacious, less cost-effective, or more toxic alternatives. However, these are high-complexity and high-risk techniques, which usually need expert teams and allergy-specific techniques (skin testing, in vitro testing, drug provocation testing) to ensure safety, an accurate diagnosis, and personalized management. Unfortunately, there are significant inequalities within and among countries in access to allergy departments with the necessary expertise and resources to offer these techniques and tackle these DHRs optimally. The main objective of this consensus document is to create a great benefit for patients worldwide by aiding allergists to expand the scope of their practice and support them with evidence, data, and experience from leading groups from around the globe. This statement of the Drug Hypersensitivity Committee of the World Allergy Organization (WAO) aims to be a comprehensive practical guide on the technical aspects of implementing acute-onset intravenous hypersensitivity delabeling and RDD for a wide range of drugs. Thus, the manuscript does not only focus on clinical pathways. Instead, it also provides guidance on topics usually left unaddressed, namely, internal validation, continuous quality improvement, creating a healthy multidisciplinary environment, and redesigning care (including a specific supplemental section on a real-life example of how to design a dedicated space that can combine basic and complex diagnostic and therapeutic techniques in allergy).

Published
2022
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3. Network impact score is an independent predictor of post-stroke cognitive impairment: A multicenter cohort study in 2341 patients with acute ischemic stroke

Author

J. Matthijs Biesbroek, Nick A. Weaver, Hugo P. Aben, Hugo J. Kuijf, Jill Abrigo, Hee-Joon Bae, Mélanie Barbay, Jonathan G. Best, Régis Bordet, Francesca M. Chappell, Christopher P.L.H. Chen, Thibaut Dondaine, Ruben S. van der Giessen, Olivier Godefroy, Bibek Gyanwali, Olivia K.L. Hamilton, Saima Hilal, Irene M.C. Huenges Wajer, Yeonwook Kang, L. Jaap Kappelle, Beom Joon Kim, Sebastian Köhler, Paul L.M. de Kort, Peter J. Koudstaal, Gregory Kuchcinski, Bonnie Y.K. Lam, Byung-Chul Lee, Keon-Joo Lee, Jae-Sung Lim, Renaud Lopes, Stephen D.J. Makin, Anne-Marie Mendyk, Vincent C.T. Mok, Mi Sun Oh, Robert J. van Oostenbrugge, Martine Roussel, Lin Shi, Julie Staals, Maria del C. Valdés-Hernández, Narayanaswamy Venketasubramanian, Frans R.J. Verhey, Joanna M. Wardlaw, David J. Werring, Xu Xin, Kyung-Ho Yu, Martine J.E. van Zandvoort, Lei Zhao, Geert Jan Biessels, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Psychology 5, MUMC+: MA Neurologie (3), Klinische Neurowetenschappen, MUMC+: Hersen en Zenuw Centrum (3), RS: Carim - B05 Cerebral small vessel disease, MUMC+: MA Med Staf Spec Neurologie (9), Psychiatrie & Neuropsychologie, MUMC+: MA Med Staf Spec Psychiatrie (9), Utrecht Brain Center [UMC], University Medical Center [Utrecht], Tweesteden Hospital, The Chinese University of Hong Kong [Hong Kong], Seoul National University College of Medicine [Séoul, Corée du Sud] (SNUCM), Université de Picardie Jules Verne (UPJV), Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), CHU Amiens-Picardie, Institute of Neurology - UCL/Queen Square [London, UK] (IN-UCL-QS), Université de Lille, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Edinburgh, National University Health System [Singapore] (NUHS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), National University of Singapore (NUS), Utrecht University [Utrecht], Hallym University, Maastricht University [Maastricht], CHU Lille, Asan Medical Center [Seoul], University of Ulsan, University of Aberdeen, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Maastricht University Medical Centre (MUMC), DESSAIVRE, Louise, UCL Institute of Neurology, Queen Square [London], École Pratique des Hautes Études (EPHE), and Neurology

Subjects
RISK, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Brain connectomics, Cognitive Neuroscience, ANATOMY, DISEASE, Post-stroke cognitive impairment, Cohort Studies, Stroke, Neurology, HUBS, Infarction, Humans, Radiology, Nuclear Medicine and imaging, Cognitive Dysfunction, Dementia, Neurology (clinical), Diffusion-weighted imaging, LOCATIONS, Ischaemic stroke, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Ischemic Stroke
Abstract

Background: \ud Post-stroke cognitive impairment (PSCI) is a common consequence of stroke. Accurate prediction of PSCI risk is challenging. The recently developed network impact score, which integrates information on infarct location and size with brain network topology, may improve PSCI risk prediction.\ud \ud Aims: \ud To determine if the network impact score is an independent predictor of PSCI, and of cognitive recovery or decline.\ud \ud Methods: \ud We pooled data from patients with acute ischemic stroke from 12 cohorts through the Meta VCI Map consortium. PSCI was defined as impairment in ≥ 1 cognitive domain on neuropsychological examination, or abnormal Montreal Cognitive Assessment. Cognitive recovery was defined as conversion from PSCI < 3 months post-stroke to no PSCI at follow-up, and cognitive decline as conversion from no PSCI to PSCI. The network impact score was related to serial measures of PSCI using Generalized Estimating Equations (GEE) models, and to PSCI stratified according to post-stroke interval (24 months) and cognitive recovery or decline using logistic regression. Models were adjusted for age, sex, education, prior stroke, infarct volume, and study site.\ud \ud Results: \ud We included 2341 patients with 4657 cognitive assessments. PSCI was present in 398/844 patients (47%) 24 months. Cognitive recovery occurred in 64/181 (35%) patients and cognitive decline in 26/287 (9%). The network impact score predicted PSCI in the univariable (OR 1.50, 95%CI 1.34–1.68) and multivariable (OR 1.27, 95%CI 1.10–1.46) GEE model, with similar ORs in the logistic regression models for specified post-stroke intervals. The network impact score was not associated with cognitive recovery or decline.\ud \ud Conclusions: \ud The network impact score is an independent predictor of PSCI. As such, the network impact score may contribute to a more precise and individualized cognitive prognostication in patients with ischemic stroke. Future studies should address if multimodal prediction models, combining the network impact score with demographics, clinical characteristics and other advanced brain imaging biomarkers, will provide accurate individualized prediction of PSCI. A tool for calculating the network impact score is freely available at https://metavcimap.org/features/software-tools/lsm-viewer/.

Published
2022
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4. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Author

Daniel R. Barnes, Matti A. Rookus, Lesley McGuffog, Goska Leslie, Thea M. Mooij, Joe Dennis, Nasim Mavaddat, Julian Adlard, Munaza Ahmed, Kristiina Aittomäki, Nadine Andrieu, Irene L. Andrulis, Norbert Arnold, Banu K. Arun, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Daniel Barrowdale, Javier Benitez, Pascaline Berthet, Katarzyna Białkowska, Amie M. Blanco, Marinus J. Blok, Bernardo Bonanni, Susanne E. Boonen, Åke Borg, Aniko Bozsik, Angela R. Bradbury, Paul Brennan, Carole Brewer, Joan Brunet, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Lise Lotte Christensen, Wendy K. Chung, Kathleen B.M. Claes, Chrystelle Colas, Marie-Agnès Collonge-Rame, Capucine Delnatte, Laurence Faivre, Sophie Giraud, Christine Lasset, Véronique Mari, Noura Mebirouk, Emmanuelle Mouret-Fourme, Hélène Schuster, Dominique Stoppa-Lyonnet, Antonis Antoniou, Jackie Cook, Rosemarie Davidson, Douglas Easton, Ros Eeles, D. Gareth Evans, Debra Frost, Helen Hanson, Louise Izatt, Kai-ren Ong, Lucy Side, Aoife O’Shaughnessy-Kirwan, Marc Tischkowitz, Lisa Walker, Mary B. Daly, Miguel de la Hoya, Robin de Putter, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Cecilia M. Dorfling, Martine Dumont, Bent Ejlertsen, Christoph Engel, Lenka Foretova, Florentia Fostira, Michael Friedlander, Eitan Friedman, Patricia A. Ganz, Judy Garber, Andrea Gehrig, Anne-Marie Gerdes, Paul Gesta, Gord Glendon, Andrew K. Godwin, David E. Goldgar, Anna González-Neira, Mark H. Greene, Daphne Gschwantler-Kaulich, Eric Hahnen, Ute Hamann, Julia Hentschel, Frans B.L. Hogervorst, Maartje J. Hooning, Judit Horvath, Chunling Hu, Peter J. Hulick, Evgeny N. Imyanitov, Georgia Chenevix-Trench, Kelly-Anne Phillips, Amanda Spurdle, Marinus Blok, Frans Hogervorst, Maartje Hooning, Marco Koudijs, Arjen Mensenkamp, Hanne Meijers-Heijboer, Matti Rookus, Klaartje van Engelen, Catherine Noguès, Claudine Isaacs, Angel Izquierdo, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Esther M. John, Vijai Joseph, Beth Y. Karlan, Karin Kast, Torben A. Kruse, Ava Kwong, Yael Laitman, Conxi Lazaro, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Jennifer T. Loud, Jan Lubiński, Phuong L. Mai, Siranoush Manoukian, Hanne E.J. Meijers-Heijboer, Alfons Meindl, Arjen R. Mensenkamp, Austin Miller, Marco Montagna, Semanti Mukherjee, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Dieter Niederacher, Finn Cilius Nielsen, Liene Nikitina-Zake, Edith Olah, Olufunmilayo I. Olopade, Ana Osorio, Claus-Eric Ott, Laura Papi, Sue K. Park, Michael T. Parsons, Inge Sokilde Pedersen, Bernard Peissel, Ana Peixoto, Paolo Peterlongo, Georg Pfeiler, Karolina Prajzendanc, Miquel Angel Pujana, Paolo Radice, Juliane Ramser, Susan J. Ramus, Johanna Rantala, Gad Rennert, Harvey A. Risch, Mark Robson, Karina Rønlund, Ritu Salani, Leigha Senter, Payal D. Shah, Priyanka Sharma, Lucy E. Side, Christian F. Singer, Thomas P. Slavin, Penny Soucy, Melissa C. Southey, Amanda B. Spurdle, Doris Steinemann, Zoe Steinsnyder, Christian Sutter, Yen Yen Tan, Manuel R. Teixeira, Soo Hwang Teo, Darcy L. Thull, Silvia Tognazzo, Amanda E. Toland, Alison H. Trainer, Nadine Tung, Elizabeth J. van Rensburg, Ana Vega, Jeroen Vierstraete, Gabriel Wagner, Shan Wang-Gohrke, Barbara Wappenschmidt, Jeffrey N. Weitzel, Siddhartha Yadav, Xin Yang, Drakoulis Yannoukakos, Dario Zimbalatti, Kenneth Offit, Mads Thomassen, Fergus J. Couch, Rita K. Schmutzler, Jacques Simard, Douglas F. Easton, Antonis C. Antoniou, Pediatric surgery, Human genetics, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, Amsterdam Reproduction & Development (AR&D), Apollo - University of Cambridge Repository, University of Cambridge [UK] (CAM), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Chapel Allerton Hospital, Great Ormond Street Hospital for Children [London] (GOSH), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Université Paris sciences et lettres (PSL), Mount Sinai Hospital [Toronto, Canada] (MSH), University of Toronto (University of Toronto), Christian-Albrechts University of Kiel, The University of Texas M.D. Anderson Cancer Center [Houston], Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Landspitali National University Hospital of Iceland, University of Iceland [Reykjavik], CIBER de Enfermedades Raras (CIBERER), Spanish National Cancer Research Center (CNIO), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Pomeranian Medical University [Szczecin] (PUM), University of California (UC), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], European Institute of Oncology IRCCS [Milan, Italy] (EIO), Zealand University Hospital [Roskilde, Denmark], Lund University [Lund], National Institute of Oncology [Budapest, Hungary], Abramson Cancer Center [philadelphia], University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Institute of Genetic Medicine [Newcastle], Newcastle University [Newcastle], Royal Devon & Exeter Hospital, Exeter, UK, Catalan Institute of Oncology [Barcelone, Espagne], Huntsman Cancer Institute [Salt Lake City], University of Utah, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Pisa University Hospital, Peter MacCallum Cancer Centre [Melbourne, Australie], University of Melbourne, Aarhus University Hospital, Columbia University [New York], Ghent University Hospital, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Sheffield Children's NHS Foundation Trust, Fox Chase Cancer Center, Queen Elizabeth University Hospital (Glasgow), Centre hospitalier universitaire de Nantes (CHU Nantes), Leiden University Medical Center (LUMC), Beckman Research Institute of the City of Hope, Abramson Cancer Center, University of Pretoria [South Africa], Centre Hospitalier Universitaire de Québec Research Center [Canada], Royal Marsden NHS Foundation Trust, Copenhagen University Hospital, Leipzig University, University of Manchester [Manchester], Manchester Academic Health Science Centre (MAHSC), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Masaryk Memorial Cancer Institute (MMCI), Institute of Nuclear and Radiological Sciences and Technology, Energy and Safety (INRASTES), National Center for Scientific Research 'Demokritos' (NCSR), NHMRC Clinical Trials Centre [Camperdown NSW 2050, Australie], Chaim Sheba Medical Center, Tel Aviv University (TAU), Jonsson Comprehensive Cancer Center, University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Dana-Farber Cancer Institute [Boston], University of Würzburg, Rigshospitalet [Copenhagen], Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Hospices Civils de Lyon (HCL), University of Kansas [Kansas City], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Medizinische Universität Wien = Medical University of Vienna, University of Cologne, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Lancashire NHS Foundation Trust, University Hospital Leipzig, Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Mayo Clinic, NorthShore University HealthSystem [Evanston, IL, USA], The University of Chicago Medicine [Chicago], N. N. Petrov Institute of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Guy's and St Thomas' NHS Foundation Trust [London, UK], Peter MacCallum Cancer Center, East Melbourne, Peter MacCallum Cancer Center, Vilnius University [Vilnius], The State Scientific Research Institute Nature Research Centre, Vilnius, Lithuania, Stanford University School of Medicine [CA, USA], Memorial Sloane Kettering Cancer Center [New York], Cedars-Sinai Medical Center, Technische Universität Dresden = Dresden University of Technology (TU Dresden), University Medical Center [Utrecht], Odense University Hospital [Odense, Denmark], The Hong Kong Hereditary Breast Cancer Family Registry, The University of Hong Kong (HKU), Hong Kong Sanatorium and Hospital [Hong Kong] (HKSH), Equipe de prévention et épidémiologie génétique, Centre Léon Bérard [Lyon], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), David Geffen School of Medicine [Los Angeles], Fondation MINES ParisTech, Karolinska Institutet [Stockholm], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Amsterdam UMC - Amsterdam University Medical Center, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Radboud University Medical Center [Nijmegen], Roswell Park Cancer Institute [Buffalo], Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], University of Toronto, University Health Network, University Hospital Düsseldorf, Latvian Biomedical Research and Study Centre [Rīga], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), University of Chicago, Birmingham Women's and Children's NHS Foundation Trust, Cambridge University Hospitals - NHS (CUH), Charité Campus Virchow-Klinikum (CVK), Università degli Studi di Firenze = University of Florence (UniFI), Seoul National University College of Medicine [Séoul, Corée du Sud] (SNUCM), Seoul National University [Seoul] (SNU), QIMR Berghofer Medical Research Institute, Aalborg University [Denmark] (AAU), IRCCS Istituto Nazionale dei Tumori [Milano], Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto (IPO Porto), IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Klinikum rechts der Isar [Munich, Germany], University of New South Wales [Sydney] (UNSW), Garvan Institute of medical research, Technion Faculty of Medicine [Haifa, Israel], Yale School of Medicine [New Haven, Connecticut] (YSM), Vejle Hospital [Danemark], Ohio State University [Columbus] (OSU), Centre de lutte contre le cancer Paul-Strauss, Institut de Cancérologie de Strasbourg Europe (ICANS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Kansas Medical Center [Kansas City, KS, USA], Princess Anne Hospital, City of Hope Comprehensive Cancer Center [Duarte], Monash University [Clayton], Cancer Council Victoria [Melbourne, VIC, Australia], Hannover Medical School [Hannover] (MHH), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Heidelberg University Hospital [Heidelberg], Institute of Biomedical Sciences Abel Salazar - ICBAS [Porto, Portugal], Malaysia and University Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya [Kuala Lumpur, Malaisie], University of Malaya = Universiti Malaya [Kuala Lumpur, Malaisie] (UM), McGill University = Université McGill [Montréal, Canada], Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), Fundación Pública Galega Medicina Xenómica - SERGAS [Santiago de Compostela, Spain] (Grupo de Medicina Xenómica), CIBER de Enfermedades Raras (CIBERER)-Universidade de Santiago de Compostela [Spain] (USC ), Instituto de Investigaciones Sanitarias, Universidade de Santiago de Compostela [Spain] (USC ), Universiteit Gent = Ghent University (UGENT), Oxford University Hospitals NHS Trust, University of Oxford, Universitätsklinikum Ulm - University Hospital of Ulm, University Hospital of Cologne [Cologne], Mayo Clinic [Rochester], Collaborators : Pascaline Berthet, Chrystelle Colas, Marie-Agnès Collonge-Rame, Capucine Delnatte, Laurence Faivre, Sophie Giraud, Christine Lasset, Véronique Mari, Noura Mebirouk, Emmanuelle Mouret-Fourme, Hélène Schuster, Dominique Stoppa-Lyonnet, Julian Adlard, Munaza Ahmed, Antonis Antoniou, Daniel Barrowdale, Paul Brennan, Carole Brewer, Jackie Cook, Rosemarie Davidson, Douglas Easton, Ros Eeles, D Gareth Evans, Debra Frost, Helen Hanson, Louise Izatt, Kai-Ren Ong, Lucy Side, Aoife O'Shaughnessy-Kirwan, Marc Tischkowitz, Lisa Walker, Georgia Chenevix-Trench, Kelly-Anne Phillips, Amanda Spurdle, Marinus Blok, Peter Devilee, Frans Hogervorst, Maartje Hooning, Marco Koudijs, Arjen Mensenkamp, Hanne Meijers-Heijboer, Matti Rookus, Klaartje van Engelen, Nadine Andrieu, Catherine Noguès, Dupuis, Christine, Institut Català de la Salut, [Barnes DR, McGuffog L, Leslie G, Dennis J] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Rookus MA, Mooij TM] The Netherlands Cancer Institute, Department of Epidemiology (PSOE), Amsterdam, The Netherlands. [Balmaña J] High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Barnes, Daniel [0000-0002-3781-7570], Leslie, Goska [0000-0001-5756-6222], Dennis, Joe [0000-0003-4591-1214], Mavaddat, Nasim [0000-0003-0307-055X], RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Universiteit Leiden, Roswell Park Cancer Institute [Buffalo] (RPCI), Medical Oncology, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, Helsinki University Hospital Area, Department of Obstetrics and Gynecology, Biosciences, HUS Gynecology and Obstetrics, University of Helsinki, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Pomeranian Medical University, University of California, University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], University of Leipzig [Leipzig, Allemagne], Masaryk Memorial Cancer Institute (RECAMO), Tel Aviv University [Tel Aviv], University of California-University of California, University of Münster, Amsterdam UMC, Technical University of Munich (TUM), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Garvan Institute of Medical Research [Sydney, Australia], Yale University School of Medicine, Vejle Hospital, University of Kansas Medical Center [Lawrence], Université Paris Descartes (Paris 5), University of Malaya [Kuala Lumpur, Malaisie], Universiteit Gent = Ghent University [Belgium] (UGENT), and University of Oxford [Oxford]

Subjects
0301 basic medicine, Oncology, endocrine system diseases, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], [SDV]Life Sciences [q-bio], Càncer d'ovari, Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], MODIFIERS, Diàtesi, SUSCEPTIBILITY, Carcinoma, Ovarian Epithelial, PRS, 0302 clinical medicine, Breast cancer, 3123 Gynaecology and paediatrics, Risk Factors, Medicine and Health Sciences, Medicine, Genetics(clinical), genetics, Prospective Studies, Prospective cohort study, skin and connective tissue diseases, Genetics (clinical), Ovarian Neoplasms, education.field_of_study, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], BRCA1 Protein, Hazard ratio, Absolute risk reduction, 1184 Genetics, developmental biology, physiology, article, ASSOCIATION, neoplasias::neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas::carcinoma epitelial de ovario [ENFERMEDADES], ddc, 3. Good health, [SDV] Life Sciences [q-bio], ovarian cancer, 030220 oncology & carcinogenesis, Female, Cohort study, medicine.medical_specialty, Heterozygote, Population, 3122 Cancers, Single-nucleotide polymorphism, Breast Neoplasms, MUTATION CARRIERS, Ovaris - Càncer - Aspectes genètics, Càncer de mama, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, Ovarian cancer, BRCA1/2, Internal medicine, Humans, Genetic Predisposition to Disease, education, Retrospective Studies, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], BRCA2 Protein, IDENTIFICATION, business.industry, Neoplasms::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms::Carcinoma, Ovarian Epithelial [DISEASES], Retrospective cohort study, ALLELES, medicine.disease, BRCA1, BRCA2, MODEL, PATHOLOGY, 030104 developmental biology, Mutation, Mama - Càncer - Aspectes genètics, 3111 Biomedicine, business
Abstract

Contains fulltext : 229292.pdf (Publisher’s version ) (Open Access) PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10(-72)). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10(-22)) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10(-12)) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

Published
2020
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5. Synchronization of Isolated Downstates (K-Complexes) May Be Caused by Cortically-Induced Disruption of Thalamic Spindling

Author

Ki-Young Jung, Burke Q. Rosen, Maxim Bazhenov, Sydney S. Cash, Stephen R. Deiss, Terrence J. Sejnowski, Rachel A. Mak-McCully, Eric Halgren, Marc Rey, Hélène Bastuji, Department of Neurosciences [San Diego], University of California [San Diego] (UC San Diego), University of California-University of California, Department of Computer Science and Engineering [San Diego] (CSE-UCSD), Department of Radiology [San Diego], Department of Neurology [Séoul, Corée du Sud], Seoul National University College of Medicine [Séoul, Corée du Sud] (SNUCM), Division of Biological Sciences [San Diego], Howard Hughes Medical Institute (HHMI), The Salk Institute for Biological Studies, Central Integration of Pain [Lyon], Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité d'Hypnologie [Lyon], Service de neurologie fonctionnelle et d'épileptologie [Hôpital Pierre Wertheimer-HCL], Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Sleep Unit [Marseille], Service de neurophysiologie clinique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE)- Hôpital de la Timone [CHU - APHM] (TIMONE), Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Cell Biology and Neuroscience [Riverside] (CBNS), University of California [Riverside] (UCR), Department of Psychiatry [San Diego, CA, États-Unis], This work was funded by NIH R01 MH099645, R01 EB009282 (http://www.nih.gov/), ONR (MURI) N000141310672 (http://www.onr.navy.mil/), NSF GRFP (http://www.nsfgrfp.org/) and Chateaubriand Fellowship (http://www.chateaubriand-fellowship.org/)., European Project: 1059472(2010), Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Department of Computer Science and Engineering [Univ California San Diego] (CSE - UC San Diego), Department of Radiology [Univ California San Diego] (UC San Diego), School of Biological Sciences [Univ California San Diego] (UC San Diego), Central Integration of Pain in Human (NEUROPAIN), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of California [Riverside] (UC Riverside), Graham, Lyle J, Bodescot, Myriam, and NSF GRFP Engineering Innovation Fellows Programs - 2010-10-01 - 2014-09-30 - 1059472 - VALID

Subjects
Male, Physiology, Electroencephalography, Mathematical Sciences, Thalamus, Models, Biology (General), Cortical Synchronization, Electrocorticography, Cerebral Cortex, Neurons, Thalamic reticular nucleus, Ecology, medicine.diagnostic_test, Chemistry, Depolarization, Biological Sciences, Middle Aged, medicine.anatomical_structure, Computational Theory and Mathematics, Modeling and Simulation, Neurological, Excitatory postsynaptic potential, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Sleep Research, Research Article, Adult, Adolescent, QH301-705.5, Bioinformatics, 1.1 Normal biological development and functioning, Models, Neurological, Sleep spindle, Non-rapid eye movement sleep, Young Adult, Cellular and Molecular Neuroscience, Underpinning research, Information and Computing Sciences, Genetics, medicine, Humans, Computer Simulation, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Molecular Biology, Ecology, Evolution, Behavior and Systematics, Aged, Computational Neuroscience, Epilepsy, Neurosciences, Biology and Life Sciences, Computational Biology, eye diseases, Physiological Processes, Sleep, Neuroscience
Abstract

Sleep spindles and K-complexes (KCs) define stage 2 NREM sleep (N2) in humans. We recently showed that KCs are isolated downstates characterized by widespread cortical silence. We demonstrate here that KCs can be quasi-synchronous across scalp EEG and across much of the cortex using electrocorticography (ECOG) and localized transcortical recordings (bipolar SEEG). We examine the mechanism of synchronous KC production by creating the first conductance based thalamocortical network model of N2 sleep to generate both spontaneous spindles and KCs. Spontaneous KCs are only observed when the model includes diffuse projections from restricted prefrontal areas to the thalamic reticular nucleus (RE), consistent with recent anatomical findings in rhesus monkeys. Modeled KCs begin with a spontaneous focal depolarization of the prefrontal neurons, followed by depolarization of the RE. Surprisingly, the RE depolarization leads to decreased firing due to disrupted spindling, which in turn is due to depolarization-induced inactivation of the low-threshold Ca2+ current (IT). Further, although the RE inhibits thalamocortical (TC) neurons, decreased RE firing causes decreased TC cell firing, again because of disrupted spindling. The resulting abrupt removal of excitatory input to cortical pyramidal neurons then leads to the downstate. Empirically, KCs may also be evoked by sensory stimuli while maintaining sleep. We reproduce this phenomenon in the model by depolarization of either the RE or the widely-projecting prefrontal neurons. Again, disruption of thalamic spindling plays a key role. Higher levels of RE stimulation also cause downstates, but by directly inhibiting the TC neurons. SEEG recordings from the thalamus and cortex in a single patient demonstrated the model prediction that thalamic spindling significantly decreases before KC onset. In conclusion, we show empirically that KCs can be widespread quasi-synchronous cortical downstates, and demonstrate with the first model of stage 2 NREM sleep a possible mechanism whereby this widespread synchrony may arise., Author Summary EEG in the most common stage of human sleep is dominated by K-complexes (KCs) and sleep spindles (bursts of 10–14 Hz oscillations) occupying the thalamus and cortex. Recently, we discovered that KCs are brief moments when the cortex becomes almost completely silent. Here, using recordings directly from the cortex of epileptic patients, we show that KCs can be quasi-synchronous across widespread cortical areas, and ask what mechanism could produce such a phenomenon. We created the first network model of realistic cortical and thalamic neurons, which spontaneously generate KCs as well as sleep spindles. We showed that the membrane channels in the reticular nucleus of the thalamus can be inactivated by excitatory inputs from the cortex, and this disrupts the spindle-generating network, which can trigger widespread cortical silence. The model prediction that thalamic spindle disruption occurs prior to KC was then observed in simultaneous recordings from the human thalamus and cortex. Understanding the cellular and network mechanisms whereby KCs arise is crucial to understanding its roles in maintaining sleep and consolidating memories.

Published
2014
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