What people with Down Syndrome can teach us about cardiopulmonary disease

Down syndrome is the most common chromosomal abnormality among live-born infants. Through full or partial trisomy of chromosome 21, Down syndrome is associated with cognitive impairment, congenital malformations (particularly cardiovascular) and dysmorphic features. Immune disturbances in Down syndrome account for an enormous disease burden ranging from quality-of-life issues (autoimmune alopecia) to more serious health issues (autoimmune thyroiditis) and life-threatening issues (leukaemia, respiratory tract infections and pulmonary hypertension). Cardiovascular and pulmonary diseases account for ∼75% of the mortality seen in persons with Down syndrome. This review summarises the cardiovascular, respiratory and immune challenges faced by individuals with Down syndrome, and the genetic underpinnings of their pathobiology. We strongly advocate increased comparative studies of cardiopulmonary disease in persons with and without Down syndrome, as we believe these will lead to new strategies to prevent and treat diseases affecting millions of people worldwide. This review summarises the cardiopulmonary and immune challenges faced by individuals with Down syndrome http://ow.ly/tlGU306iMkG

[1]  R. Köhler,et al.  Emerging roles of calcium‐activated K channels and TRPV4 channels in lung oedema and pulmonary circulatory collapse , 2017, Acta physiologica.

[2]  S. Abman,et al.  Increased Lung Expression of Anti-Angiogenic Factors in Down Syndrome: Potential Role in Abnormal Lung Vascular Growth and the Risk for Pulmonary Hypertension , 2016, PloS one.

[3]  Ahwan Pandey,et al.  Trisomy 21 consistently activates the interferon response , 2016, eLife.

[4]  Giuseppina Stifano,et al.  miR-155 in the progression of lung fibrosis in systemic sclerosis , 2016, Arthritis Research & Therapy.

[5]  Jie Su,et al.  Macrophage micro-RNA-155 promotes lipopolysaccharide-induced acute lung injury in mice and rats. , 2016, American journal of physiology. Lung cellular and molecular physiology.

[6]  S. Varga,et al.  Altered Treg and cytokine responses in RSV-infected infants , 2016, Pediatric Research.

[7]  A. Goldfine,et al.  Clinical Update: Cardiovascular Disease in Diabetes Mellitus Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes Mellitus – Mechanisms, Management, and Clinical Considerations , 2016, Circulation.

[8]  P. Saavalainen,et al.  Expanded CD4+ Effector/Memory T Cell Subset in APECED Produces Predominantly Interferon Gamma , 2016, Journal of Clinical Immunology.

[9]  Matheus C. Bürger,et al.  Differential Expression of Inflammation-Related Genes in Children with Down Syndrome , 2016, Mediators of inflammation.

[10]  L. Groop,et al.  A Syntenic Cross Species Aneuploidy Genetic Screen Links RCAN1 Expression to β-Cell Mitochondrial Dysfunction in Type 2 Diabetes , 2016, PLoS genetics.

[11]  C. Maslen,et al.  Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier , 2016, Genetics.

[12]  Mark S. Anderson,et al.  AIRE expands: new roles in immune tolerance and beyond , 2016, Nature Reviews Immunology.

[13]  A. Hall,et al.  The Divergent Cardiovascular Effects of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Myocardial Infarction and Death. , 2016, Progress in cardiovascular diseases.

[14]  H. Petri,et al.  Morbidity and medication in a large population of individuals with Down syndrome compared to the general population , 2016, Developmental medicine and child neurology.

[15]  L. Ding,et al.  Overexpression of microRNA-99a Attenuates Cardiac Hypertrophy , 2016, PloS one.

[16]  W. Clement,et al.  The prevalence of airway problems in children with Down's syndrome. , 2016, International journal of pediatric otorhinolaryngology.

[17]  J. Araya,et al.  miR-101-2, miR-125b-2 and miR-451a act as potential tumor suppressors in gastric cancer through regulation of the PI3K/AKT/mTOR pathway , 2016, Cellular Oncology.

[18]  Thomas Braun,et al.  The Ubiquitin-Like SUMO System and Heart Function: From Development to Disease. , 2016, Circulation research.

[19]  T. Mayadas,et al.  The many faces of Mac‐1 in autoimmune disease , 2016, Immunological reviews.

[20]  V. Tybulewicz,et al.  Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel , 2015, eLife.

[21]  M. Castrucci,et al.  Generation of switched memory B cells in response to vaccination in Down syndrome children and their siblings. , 2015, Vaccine.

[22]  B. Nagy,et al.  Elevated hsa-miR-99a levels in maternal plasma may indicate congenital heart defects. , 2015, Biomedical reports.

[23]  M. Yeager,et al.  Biomarkers for pediatric pulmonary arterial hypertension: challenges and recommendations. , 2015, Paediatric respiratory reviews.

[24]  S. Chandran,et al.  Risk factors for mortality in Down syndrome. , 2015, Journal of intellectual disability research : JIDR.

[25]  S. Antonarakis,et al.  DNA-Methylation Patterns in Trisomy 21 Using Cells from Monozygotic Twins , 2015, PloS one.

[26]  C. Campos,et al.  Oxidative stress, thyroid dysfunction & Down syndrome , 2015, The Indian journal of medical research.

[27]  P. McNamara,et al.  Persistent pulmonary hypertension of the newborn: Advances in diagnosis and treatment. , 2015, Seminars in fetal & neonatal medicine.

[28]  S. Camper,et al.  The pattern of congenital heart defects arising from reduced Tbx5 expression is altered in a Down syndrome mouse model , 2015, BMC Developmental Biology.

[29]  Michael E Zwick,et al.  Genome-Wide Association Study of Down Syndrome-Associated Atrioventricular Septal Defects , 2015, G3: Genes, Genomes, Genetics.

[30]  J. A. López,et al.  Families of microRNAs Expressed in Clusters Regulate Cell Signaling in Cervical Cancer , 2015, International journal of molecular sciences.

[31]  S. Bhalla,et al.  Pulmonary vascular diseases. , 2015, Clinics in chest medicine.

[32]  Zhijian Yang,et al.  MicroRNA let-7c Inhibits Cell Proliferation and Induces Cell Cycle Arrest by Targeting CDC25A in Human Hepatocellular Carcinoma , 2015, PloS one.

[33]  O. Franco,et al.  Subclinical Hypothyroidism and the Risk of Stroke Events and Fatal Stroke: An Individual Participant Data Analysis. , 2015, The Journal of clinical endocrinology and metabolism.

[34]  V. Rodríguez-Sureda,et al.  Intracellular Oxidant Activity, Antioxidant Enzyme Defense System, and Cell Senescence in Fibroblasts with Trisomy 21 , 2015, Oxidative medicine and cellular longevity.

[35]  A. Danser,et al.  Hypertension Renin–Angiotensin–Aldosterone System Alterations , 2015 .

[36]  Thomas Danner,et al.  Phosphodiesterase 9A Controls Nitric-oxide Independent cGMP and Hypertrophic Heart Disease , 2015, Nature.

[37]  H. Ghofrani,et al.  Pathophysiology and Treatment of High-Altitude Pulmonary Vascular Disease , 2015, Circulation.

[38]  M. Yeager,et al.  Proteomics of pulmonary hypertension: Could personalized profiles lead to personalized medicine? , 2015, Proteomics. Clinical applications.

[39]  S. Nobs,et al.  The development and function of lung-resident macrophages and dendritic cells , 2014, Nature Immunology.

[40]  M. Gatzoulis,et al.  Pulmonary arterial hypertension associated with congenital heart disease: recent advances and future directions. , 2014, International journal of cardiology.

[41]  M. Scarsella,et al.  Reduced numbers of switched memory B cells with high terminal differentiation potential in Down syndrome , 2014, European journal of immunology.

[42]  Dolly Mehta,et al.  Mechanisms Regulating Endothelial Permeability , 2014, Pulmonary circulation.

[43]  P. Scarborough,et al.  CardioPulse, Cardiovascular disease in Europe 2014: epidemiological update, Heart disease and stroke decline in Europe, Estimating an individual person's course of coronary artery calcification, The CardioScape Project, In memoriam , 2014 .

[44]  C. Dani,et al.  The role of genetic polymorphisms in antioxidant enzymes and potential antioxidant therapies in neonatal lung disease. , 2014, Antioxidants & redox signaling.

[45]  L. Gaman,et al.  The regulator of calcineurin (RCAN1) an important factor involved in atherosclerosis and cardiovascular diseases development , 2014, Journal of medicine and life.

[46]  L. Spaggiari,et al.  Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β–SMAD3 pathway in non-small cell lung adenocarcinoma , 2014, Proceedings of the National Academy of Sciences.

[47]  J. Dupuis,et al.  Lung capillary injury and repair in left heart disease: a new target for therapy? , 2014, Clinical science.

[48]  T. Saji.  Clinical characteristics of pulmonary arterial hypertension associated with Down syndrome , 2014, Pediatrics international : official journal of the Japan Pediatric Society.

[49]  Stylianos E. Antonarakis,et al.  Domains of genome-wide gene expression dysregulation in Down’s syndrome , 2014, Nature.

[50]  S. Antonarakis,et al.  Cardiomyogenesis is controlled by the miR-99a/let-7c cluster and epigenetic modifications. , 2014, Stem cell research.

[51]  C. O'Gorman,et al.  Thyroid dysfunction in children with Down syndrome: a literature review , 2014, Irish Journal of Medical Science.

[52]  Domènec Farré,et al.  The Vertebrate RCAN Gene Family: Novel Insights into Evolution, Structure and Regulation , 2014, PloS one.

[53]  G. Castellani,et al.  Identification of a DNA methylation signature in blood cells from persons with Down Syndrome , 2014, Aging.

[54]  B. D. de Jong,et al.  Functionality of the pneumococcal antibody response in Down syndrome subjects. , 2013, Vaccine.

[55]  J. Redondo,et al.  A major role for RCAN1 in atherosclerosis progression , 2013, EMBO molecular medicine.

[56]  H. Vyas,et al.  An overview of respiratory problems in children with Down's syndrome , 2013, Archives of Disease in Childhood.

[57]  C. McCormick,et al.  Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections , 2013, The Journal of Immunology.

[58]  S. Sinha,et al.  Down Syndrome Related Muscle Hypotonia: Association with COL6A3 Functional SNP rs2270669 , 2013, Front. Genet..

[59]  C. Vizza,et al.  Therapy for pulmonary arterial hypertension due to congenital heart disease and Down's syndrome. , 2013, International journal of cardiology.

[60]  G. Annéren,et al.  Changes in mortality and causes of death in the Swedish Down syndrome population , 2013, American journal of medical genetics. Part A.

[61]  C. Martínez-Cué,et al.  Apoptosis in Down’s syndrome: lessons from studies of human and mouse models , 2013, Apoptosis.

[62]  Alan D. Lopez,et al.  A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010 , 2012, The Lancet.

[63]  Alan D. Lopez,et al.  A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010 , 2012, The Lancet.

[64]  M. V. Capela,et al.  Expression of interferon-γ, interferon-α and related genes in individuals with Down syndrome and periodontitis. , 2012, Cytokine.

[65]  V. Mahadevan,et al.  Pulmonary arterial hypertension associated with congenital heart diseases , 2018, ESC CardioMed.

[66]  S. Buitendijk,et al.  Prevalence of Overweight in Dutch Children With Down Syndrome , 2012, Pediatrics.

[67]  R. Lutter,et al.  Effect of oxidative stress on respiratory epithelium from children with Down syndrome , 2012, European Respiratory Journal.

[68]  V. Coates,et al.  Management and quality indicators of diabetes mellitus in people with intellectual disabilities. , 2012, Journal of intellectual disability research : JIDR.

[69]  R. Hardison,et al.  Trisomy 21-associated defects in human primitive hematopoiesis revealed through induced pluripotent stem cells , 2012, Proceedings of the National Academy of Sciences.

[70]  Lora J. H. Bean,et al.  An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects. , 2012, American journal of human genetics.

[71]  D. Nižetić,et al.  Tumorigenesis in Down's syndrome: big lessons from a small chromosome , 2012, Nature Reviews Cancer.

[72]  M. V. Capela,et al.  Expression of the interleukin-10 signaling pathway genes in individuals with Down syndrome and periodontitis. , 2012, Journal of periodontology.

[73]  C. Maslen,et al.  Genetic Modifiers Predisposing to Congenital Heart Disease in the Sensitized Down Syndrome Population , 2012, Circulation. Cardiovascular genetics.

[74]  C. Wellington,et al.  Sterol Lipid Metabolism in Down Syndrome Revisited: Down Syndrome Is Associated with a Selective Reduction in Serum Brassicasterol Levels , 2012, Current gerontology and geriatrics research.

[75]  Mark S. Anderson,et al.  Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection , 2012, Proceedings of the National Academy of Sciences.

[76]  M. Eren,et al.  Long-term effect of bosentan therapy on cardiac function and symptomatic benefits in adult patients with Eisenmenger syndrome. , 2012, Journal of cardiac failure.

[77]  A. Bos,et al.  Pulmonary Epithelial Apoptosis in Fetal down Syndrome: Not Higher than Normal , 2012, Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society.

[78]  D. Fitzgerald,et al.  Respiratory problems in children with Down syndrome , 2012, Journal of paediatrics and child health.

[79]  B. Hanna,et al.  Pulmonary complications of congenital heart disease. , 2012, Paediatric respiratory reviews.

[80]  G. Daley,et al.  Altered hematopoiesis in trisomy 21 as revealed through in vitro differentiation of isogenic human pluripotent cells , 2011, Proceedings of the National Academy of Sciences.

[81]  B. Fernhall,et al.  Heart rate complexity in response to upright tilt in persons with Down syndrome. , 2011, Research in developmental disabilities.

[82]  P. L. Ramos,et al.  Decreased AIRE Expression and Global Thymic Hypofunction in Down Syndrome , 2011, The Journal of Immunology.

[83]  R. Friedman,et al.  Outcomes of hospitalization in adults in the United States with atrial septal defect, ventricular septal defect, and atrioventricular septal defect. , 2011, The American journal of cardiology.

[84]  J. Ryan,et al.  Rodent models of pulmonary hypertension: harmonisation with the world health organisation’s categorisation of human PH , 2011, International journal of clinical practice. Supplement.

[85]  C. Campos,et al.  Evaluation of urinary biomarkers of oxidative/nitrosative stress in adolescents and adults with Down syndrome. , 2011, Biochimica et biophysica acta.

[86]  K. Moore,et al.  Macrophages in the Pathogenesis of Atherosclerosis , 2011, Cell.

[87]  M. Griksaitis,et al.  Acute altitude induced hypoxia in a child with Down’s syndrome following postoperative repair of complete atrioventricular septal defect , 2011, BMJ Case Reports.

[88]  J. Chinen,et al.  Infections and immunodeficiency in Down syndrome , 2011, Clinical and experimental immunology.

[89]  D. Craven,et al.  Pulmonary complications of Down syndrome during childhood. , 2011, The Journal of pediatrics.

[90]  Justin R. Geijer,et al.  Comparison of intima-media thickness of the carotid artery and cardiovascular disease risk factors in adults with versus without the Down syndrome. , 2010, The American journal of cardiology.

[91]  N. Schork,et al.  Altered DNA Methylation in Leukocytes with Trisomy 21 , 2010, PLoS genetics.

[92]  Claudia Grosse,et al.  CT findings in diseases associated with pulmonary hypertension: a current review. , 2010, Radiographics : a review publication of the Radiological Society of North America, Inc.

[93]  D. Radford,et al.  Endothelin receptor antagonists are an effective long term treatment option in pulmonary arterial hypertension associated with congenital heart disease with or without trisomy 21. , 2010, Heart, lung & circulation.

[94]  L. Bont,et al.  Increased risk of respiratory tract infections in children with Down syndrome: the consequence of an altered immune system. , 2010, Microbes and infection.

[95]  M. Cunningham,et al.  Pediatric sleep apnea and craniofacial anomalies: A population‐based case–control study , 2010, The Laryngoscope.

[96]  K. Kosaki,et al.  Mechanisms underlying early development of pulmonary vascular obstructive disease in Down syndrome: An imbalance in biosynthesis of thromboxane A2 and prostacyclin , 2010, American journal of medical genetics. Part A.

[97]  C. Fonatsch.  The role of chromosome 21 in hematology and oncology , 2010, Genes, chromosomes & cancer.

[98]  R. Verstegen,et al.  Down Syndrome B-Lymphocyte Subpopulations, Intrinsic Defect or Decreased T-Lymphocyte Help , 2010, Pediatric Research.

[99]  Michael W. Beets,et al.  Autonomic response to upright tilt in people with and without Down syndrome. , 2010, Research in developmental disabilities.

[100]  M. Weijerman,et al.  Prevalence of congenital heart defects and persistent pulmonary hypertension of the neonate with Down syndrome , 2010, European Journal of Pediatrics.

[101]  D. Mozaffarian,et al.  Executive summary: heart disease and stroke statistics--2010 update: a report from the American Heart Association. , 2010, Circulation.

[102]  G. Iotti,et al.  Down syndrome fibroblasts and mouse Prep1-overexpressing cells display increased sensitivity to genotoxic stress , 2010, Nucleic acids research.

[103]  B. Mulder,et al.  Down patients with Eisenmenger syndrome: is bosentan treatment an option? , 2009, International journal of cardiology.

[104]  B. Mulder,et al.  Effect of bosentan on exercise capacity and quality of life in adults with pulmonary arterial hypertension associated with congenital heart disease with and without Down's syndrome. , 2009, The American journal of cardiology.

[105]  M. Kusters,et al.  Intrinsic defect of the immune system in children with Down syndrome: a review , 2009, Clinical and experimental immunology.

[106]  B. Mulder,et al.  Down syndrome: a cardiovascular perspective. , 2009, Journal of intellectual disability research : JIDR.

[107]  George Q. Daley,et al.  Down syndrome suppression of tumor growth and the role of the calcineurin inhibitor DSCR1 , 2009, Nature.

[108]  A. Contestabile,et al.  Widespread impairment of cell proliferation in the neonate Ts65Dn mouse, a model for Down syndrome , 2009, Cell proliferation.

[109]  W. Alexander,et al.  Hematopoietic defects in the Ts1Cje mouse model of Down syndrome. , 2009, Blood.

[110]  M. Weiss,et al.  Trisomy 21 enhances human fetal erythro-megakaryocytic development. , 2008, Blood.

[111]  M. Davidson.  Primary care for children and adolescents with Down syndrome. , 2008, Pediatric clinics of North America.

[112]  C. Stefanadis,et al.  Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials. , 2008, European heart journal.

[113]  M. Thase.  Longevity and mortality in Down's syndrome. , 2008, Journal of mental deficiency research.

[114]  R. Nisihara,et al.  Autoantibodies in patients with Down Syndrome: Early senescence of the immune system or precocious markers for immunological diseases? , 2008, Journal of paediatrics and child health.

[115]  Lora J. H. Bean,et al.  Ethnicity, sex, and the incidence of congenital heart defects: a report from the National Down Syndrome Project , 2008, Genetics in Medicine.

[116]  T. Altes,et al.  Subpleural lung cysts in Down syndrome: prevalence and association with coexisting diagnoses , 2008, Pediatric Radiology.

[117]  M. L. Le Beau,et al.  Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome. , 2008, Blood.

[118]  R. Hodapp,et al.  Hospitalizations of infants and young children with Down syndrome: evidence from inpatient person-records from a statewide administrative database. , 2007, Journal of intellectual disability research : JIDR.

[119]  R. Byard.  Forensic issues in Down syndrome fatalities. , 2007, Journal of forensic and legal medicine.

[120]  L. Bont,et al.  Down Syndrome: A Novel Risk Factor for Respiratory Syncytial Virus Bronchiolitis— A Prospective Birth-Cohort Study , 2007, Pediatrics.

[121]  J M Delabar,et al.  Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes. , 2007, American journal of human genetics.

[122]  A. Bos,et al.  High incidence of acute lung injury in children with Down syndrome , 2007, Intensive Care Medicine.

[123]  Praveen Sethupathy,et al.  Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3' untranslated region: a mechanism for functional single-nucleotide polymorphisms related to phenotypes. , 2007, American journal of human genetics.

[124]  L. Nelin,et al.  Increased Incidence of Idiopathic Persistent Pulmonary Hypertension in Down Syndrome Neonates , 2007, Pediatric Cardiology.

[125]  C. Naspitz,et al.  Antibody response to pneumococcal capsular polysaccharide vaccine in Down syndrome patients. , 2006, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[126]  G. Annéren,et al.  Autoantibodies linked to autoimmune polyendocrine syndrome type I are prevalent in Down syndrome , 2006, Acta paediatrica.

[127]  E. Porcellini,et al.  Does Down's syndrome support the homocysteine theory of atherogenesis? Experience in elderly subjects with trisomy 21. , 2006, Archives of gerontology and geriatrics.

[128]  S. Shott.  Down syndrome: Common otolaryngologic manifestations , 2006, American journal of medical genetics. Part C, Seminars in medical genetics.

[129]  M. van den Akker,et al.  Cardiac diseases in people with intellectual disability. , 2006, Journal of intellectual disability research : JIDR.

[130]  Rachel Akers,et al.  Obstructive sleep apnea: Should all children with Down syndrome be tested? , 2006, Archives of otolaryngology--head & neck surgery.

[131]  F. Pociot,et al.  Increased prevalence of Down’s syndrome in individuals with type 1 diabetes in Denmark: a nationwide population-based study , 2006, Diabetologia.

[132]  L. Nespoli,et al.  Interferon-γ- and interleukin-4-producing T cells in Down's syndrome , 2006, Neuroscience Letters.

[133]  R. Franklin,et al.  Saddle Arterial Embolus in a Patient with Down Syndrome , 2006, Pediatric Cardiology.

[134]  R. Reeves,et al.  Perinatal Loss of Ts65Dn Down Syndrome Mice , 2006, Genetics.

[135]  W. Hop,et al.  Intrinsic abnormalities of lymphocyte counts in children with down syndrome. , 2005, The Journal of pediatrics.

[136]  S. Day,et al.  Mortality and causes of death in persons with Down syndrome in California. , 2005, Developmental medicine and child neurology.

[137]  C. Melville,et al.  Obesity in adults with Down syndrome: a case-control study. , 2005, Journal of intellectual disability research : JIDR.

[138]  Takahide Kohro,et al.  Vascular Endothelial Growth Factor- and Thrombin-induced Termination Factor, Down Syndrome Critical Region-1, Attenuates Endothelial Cell Proliferation and Angiogenesis*♦ , 2004, Journal of Biological Chemistry.

[139]  Junying Yuan,et al.  Dual Role of Sumoylation in the Nuclear Localization and Transcriptional Activation of NFAT1* , 2004, Journal of Biological Chemistry.

[140]  Tien Hsu,et al.  Ets proteins in biological control and cancer , 2004, Journal of cellular biochemistry.

[141]  J. Hellmann,et al.  Clinical characteristics and follow up of Down syndrome infants without congenital heart disease who presented with persistent pulmonary hypertension of newborn , 2004, Journal of perinatal medicine.

[142]  K. Yutzey,et al.  DSCR1 gene expression is dependent on NFATc1 during cardiac valve formation and colocalizes with anomalous organ development in trisomy 16 mice. , 2004, Developmental biology.

[143]  R. Grosschedl,et al.  SUMO modification of a novel MAR-binding protein, SATB2, modulates immunoglobulin mu gene expression. , 2003, Genes & development.

[144]  I. Sánchez,et al.  Airway anomalies in children with Down syndrome: endoscopic findings , 2003, Pediatric pulmonology.

[145]  M. Dyken,et al.  Prospective polysomnographic analysis of obstructive sleep apnea in down syndrome. , 2003, Archives of pediatrics & adolescent medicine.

[146]  J. Kelly,et al.  Diagnosis and therapy for airway obstruction in children with Down syndrome. , 2003, Archives of otolaryngology--head & neck surgery.

[147]  N. Roizen,et al.  Down's syndrome , 2003, The Lancet.

[148]  T. Martin,et al.  Science review: Apoptosis in acute lung injury , 2003, Critical care.

[149]  T. Martin,et al.  The role of apoptosis in acute lung injury , 2003, Critical care medicine.

[150]  I. Kola,et al.  ETS2 overexpression in transgenic models and in Down syndrome predisposes to apoptosis via the p53 pathway. , 2003, Human molecular genetics.

[151]  A. Boening,et al.  Long-term results after surgical correction of atrioventricular septal defects. , 2002, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[152]  R. Glanville,et al.  Identification, genomic organization and mRNA expression of CRELD1, the founding member of a unique family of matricellular proteins. , 2002, Gene.

[153]  C. Draheim,et al.  Differences in cardiovascular disease risk between nondiabetic adults with mental retardation with and without Down syndrome. , 2002, American journal of mental retardation : AJMR.

[154]  S. Rasmussen,et al.  Mortality associated with Down's syndrome in the USA from 1983 to 1997: a population-based study , 2002, The Lancet.

[155]  B. Tüysüz,et al.  Thyroid dysfunction in children with Down's syndrome , 2001, Acta paediatrica.

[156]  A. Durmowicz.  Pulmonary edema in 6 children with Down syndrome during travel to moderate altitudes. , 2001, Pediatrics.

[157]  G. Piatti,et al.  Nasal Ciliary Function and Ultrastructure in Down Syndrome , 2001, The Laryngoscope.

[158]  I. Pogribny,et al.  Homocysteine metabolism in children with Down syndrome: in vitro modulation. , 2001, American journal of human genetics.

[159]  P. Hirth,et al.  Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death‐dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[160]  M. Farrer,et al.  Heterotrisomy, a significant contributing factor to ventricular septal defect associated with Down syndrome? , 2000, Human Genetics.

[161]  S. Shott.  Down Syndrome: Analysis of Airway Size and a Guide for Appropriate Intubation , 2000, The Laryngoscope.

[162]  J T Richtsmeier,et al.  Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse. , 2000, Human molecular genetics.

[163]  H. Hasle,et al.  Risks of leukaemia and solid tumours in individuals with Down's syndrome , 2000, The Lancet.

[164]  E. Malec,et al.  Results of Surgical Treatment of Congenital Heart Defects in Children with Down's Syndrome , 1999, Pediatric Cardiology.

[165]  D. Fitzgerald,et al.  Respiratory morbidity of hospitalized children with Trisomy 21 , 1999, Journal of paediatrics and child health.

[166]  F. Rasmussen,et al.  Mortality in Down's syndrome in relation to congenital malformations. , 1999, Journal of intellectual disability research : JIDR.

[167]  F. Okamoto,et al.  Long term follow-up of atrioventricular valve function after repair of atrioventricular septal defect. , 1999, Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia.

[168]  M. Rocchi,et al.  PKNOX1, a gene encoding PREP1, a new regulator of Pbx activity, maps on human chromosome 21q22.3 and murine chromosome 17B/C. , 1998, Genomics.

[169]  S. O’Brien,et al.  In search of AIDS-resistance genes. , 1997, Scientific American.

[170]  G. Pearlson,et al.  Cerebellar volume in adults with Down syndrome. , 1997, Archives of neurology.

[171]  William Arbuthnot Sir Lane,et al.  Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth , 1997, Cell.

[172]  I. Kola,et al.  Elevation in the ratio of Cu/Zn-superoxide dismutase to glutathione peroxidase activity induces features of cellular senescence and this effect is mediated by hydrogen peroxide. , 1996, Human molecular genetics.

[173]  M. Farrer,et al.  Genetic variation in the COL6A1 region is associated with congenital heart defects in trisomy 21 (Down's syndrome) , 1995, Annals of human genetics.

[174]  A. McElduff,et al.  Medical disorders of adults with mental retardation: a population study. , 1995, American journal of mental retardation : AJMR.

[175]  Marilyn J Bull,et al.  Health Supervision for Children With Down Syndrome , 2001, Pediatrics.

[176]  S. Leeder,et al.  A population based study , 1993, The Medical journal of Australia.

[177]  E. Cuadrado,et al.  Differential expression of lymphocyte function‐associated antigen (LFA‐1) on peripheral blood leucocytes from individuals with Down's syndrome , 1992, Clinical and experimental immunology.

[178]  D. Southall,et al.  Sleep related upper airway obstruction in a cohort with Down's syndrome. , 1991, Archives of disease in childhood.

[179]  G. Vawter,et al.  Down syndrome: patterns of disturbed lung growth. , 1991, Human pathology.

[180]  Y. Thong,et al.  Immunoglobulin G subclass deficiency and predisposition to infection in Down's syndrome , 1990, The Pediatric infectious disease journal.

[181]  L. Epstein,et al.  Down syndrome (trisomy 21) thymuses have a decreased proportion of cells expressing high levels of TCR alpha, beta and CD3. A possible mechanism for diminished T cell function in Down syndrome. , 1990, Clinical immunology and immunopathology.

[182]  H. Hirano,et al.  Changes in Pulmonary Tissue of Patients with Congenital Heart Disease and Down Syndrome: A Morphological and Histochemical Study , 1990, Acta paediatrica Japonica : Overseas edition.

[183]  F. Baciewicz,et al.  Congenital Heart Disease in Down's Syndrome Patients: A Decade of Surgical Experience , 1989, The Thoracic and cardiovascular surgeon.

[184]  T. Nikkari,et al.  Down's syndrome and atherosclerosis. , 1989, Atherosclerosis.

[185]  T. Sharav,et al.  Growth studies in infants and children with Down's syndrome and elevated levels of thyrotropin. , 1988, American journal of diseases of children.

[186]  A. Sadovnick,et al.  Causes of death to age 30 in Down syndrome. , 1988, American journal of human genetics.

[187]  J. Lintermans,et al.  [Congenital heart diseases and obstructive pulmonary vascular diseases in Down's syndrome. Apropos of 142 children with trisomy 21]. , 1988, Archives des maladies du coeur et des vaisseaux.

[188]  G. M. Taylor,et al.  The expression of CD18 is increased on Trisomy 21 (Down syndrome) lymphoblastoid cells. , 1988, Clinical and experimental immunology.

[189]  A. Brun,et al.  DOES DOWN SYNDROME SUPPORT HOMOCYSTEINE THEORY OF ARTERIOSCLEROSIS? , 1987, The Lancet.

[190]  D. Roberts,et al.  EXACERBATION OF RHEUMATOID SYNOVTTIS BY IRON-DEXTRAN INFUSION , 1987, The Lancet.

[191]  F. J. Mclaughlin,et al.  Tracheal bronchus: association with respiratory morbidity in childhood. , 1985, The Journal of pediatrics.

[192]  K. Schumann,et al.  Cholesterol fractions and triglycerides in children and adults with Down's syndrome. , 1984, Clinica chimica acta; international journal of clinical chemistry.

[193]  W. Thurlbeck,et al.  Pulmonary hypoplasia in Down's syndrome. , 1982, The New England journal of medicine.

[194]  C. Fletcher,et al.  Down's syndrome: an atheroma-free model? , 1977, British medical journal.

[195]  A. Nadas,et al.  The clinical course of cardiac disease in Down's syndrome. , 1976, Pediatrics.

[196]  J. Trela,et al.  Deoxyribonucleic acid polymerase from the extreme thermophile Thermus aquaticus , 1976, Journal of bacteriology.

[197]  D. Segal,et al.  Studies on Down's syndrome in tissue culture. I. Growth rates protein contents of fibroblast cultures , 1974, Journal of cellular physiology.

[198]  E. Niebuhr,et al.  Down's syndrome , 1974, Humangenetik.

[199]  S. Abman,et al.  Prominent Intrapulmonary Bronchopulmonary Anastomoses and Abnormal Lung Development in Infants and Children with Down Syndrome , 2017, The Journal of pediatrics.

[200]  E. Montoya-Diaz,et al.  Innate immune system cells in atherosclerosis. , 2014, Archives of medical research.

[201]  I. Žitňanová,et al.  Oxidative stress and Down syndrome. Do antioxidants play a role in therapy? , 2014, Physiological research.

[202]  Peter Scarborough,et al.  Cardiovascular disease in Europe 2014: epidemiological update. , 2013, European heart journal.

[203]  The Lancet Respiratory Medicine.  Rates of lung disease in Europe: an uncomfortable equilibrium. , 2013, The Lancet. Respiratory medicine.

[204]  B. Marino,et al.  Better surgical prognosis for patients with Down syndrome. , 2008, The Journal of thoracic and cardiovascular surgery.

[205]  M. Weijerman,et al.  Prevalence, neonatal characteristics, and first-year mortality of Down syndrome: a national study. , 2008, The Journal of pediatrics.

[206]  T. Oka,et al.  Comparison of hemodynamic data before and after corrective surgery for Down's syndrome and ventricular septal defect , 2005, Heart and Vessels.

[207]  I. Kola,et al.  An altered antioxidant balance occurs in Down syndrome fetal organs: implications for the "gene dosage effect" hypothesis. , 2003, Journal of neural transmission. Supplementum.

[208]  American Academy of Pediatrics: Health supervision for children with Down syndrome. , 2001, Pediatrics.

[209]  H. Meisner,et al.  Atrioventricular Septal Defect , 1998, Pediatric Cardiology.

[210]  B. Landing,et al.  Postnatal development of the cystic lung lesion of Down syndrome: suggestion that the cause is reduced formation of peripheral air spaces. , 1991, Pediatric Pathology.

[211]  A. Ferrante,et al.  Immunoglobulin G subclass deficiency in children with high levels of immunoglobulin E and infection proneness. , 1990, International archives of allergy and applied immunology.

[212]  J. Lintermans,et al.  [Congenital Heart-disease and Pulmonary Obstructive Vascular-disease in Downs-syndrome - Report of 142 Children With Trisomy-21] , 1988 .

[213]  C. Epstein,et al.  Abnormalities in the interferon response and immune systems in Down syndrome: studies in human trisomy 21 and mouse trisomy 16. , 1987, Progress in clinical and biological research.

[214]  R. Philip,et al.  Abnormalities of the immune response to influenza antigen in Down syndrome (trisomy 21). , 1987, Progress in clinical and biological research.