{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:36:12Z","timestamp":1790775372544,"version":"4.1.0"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,3,30]],"date-time":"2020-03-30T00:00:00Z","timestamp":1585526400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,3,30]],"date-time":"2020-03-30T00:00:00Z","timestamp":1585526400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Children Hospital Funding committee, Tallaght, Dublin","award":["\"CHAMPION\" Award No 1304"],"award-info":[{"award-number":["\"CHAMPION\" Award No 1304"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Neurol"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cytokines are possible mediators of neuroinflammation and associated with adverse outcome in neonatal encephalopathy (NE). Our aim was to explore cytokine response in children with Neonatal Encephalopathy (NE) at school age compared to age-matched controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>Follow up at school age, children who had NE and age-matched controls were assessed for their cytokine responses and neurodevelopment outcome. Pro- and anti-inflammatory cytokines in the serum, [Interleukin (IL)-1\u03b1, IL-1\u03b2, IL-2, IL-6, IL-8, IL-18, Tumor necrosis factor (TNF)-\u03b1, TNF \u03b2, Interferon (IFN)-\u03b3, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), erythropoietin (EPO), IL-10 &amp; IL-1RA] were measured at baseline and in response to in vitro stimulation with lipopolysaccharide (LPS: endotoxin).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>GM-CSF, TNF-\u03b2, IL-2 IL-6 and IL-8 were significantly elevated at school age following NE (n\u2009=\u200940) compared to controls (n\u2009=\u200937). A rise in GM-CSF, IL-8, TNF-\u03b1, IL-1\u03b2, &amp; IL-6 were seen in NE group following LPS stimulation. Relative LPS hypo-responsiveness was also noted in children with severe NE with IL-10, VEGF, EPO and TNF-\u03b2. Elevated TNF-\u03b2 was associated with low gross motor scores on assessment at school age.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>School-age children post-NE had significantly altered cytokine responses to endotoxin compared to controls. TNF-\u03b2 was associated with adverse developmental outcomes. This suggests the inflammatory process may persist into childhood and a longer therapeutic window may be available for neuroprotection therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12883-020-01656-w","type":"journal-article","created":{"date-parts":[[2020,3,30]],"date-time":"2020-03-30T15:04:49Z","timestamp":1585580689000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Cytokine dysregulation persists in childhood post Neonatal Encephalopathy"],"prefix":"10.1186","volume":"20","author":[{"given":"Zunera","family":"Zareen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammy","family":"Strickland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria Mc","family":"Eneaney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynne A.","family":"Kelly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"McDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deirdre","family":"Sweetman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor J.","family":"Molloy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,3,30]]},"reference":[{"issue":"4","key":"1656_CR1","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1002\/ana.22620","volume":"71","author":"H Hagberg","year":"2012","unstructured":"Hagberg H, Gressens P, Mallard C. Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults. Ann Neurol. 2012;71(4):444\u201357.","journal-title":"Ann Neurol"},{"issue":"3","key":"1656_CR2","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1159\/000448702","volume":"111","author":"DU Sweetman","year":"2017","unstructured":"Sweetman DU, Onwuneme C, Watson WR, Murphy JF, Molloy EJ. Perinatal Asphyxia and Erythropoietin and VEGF: Serial Serum and Cerebrospinal Fluid Responses. Neonatology. 2017;111(3):253\u20139.","journal-title":"Neonatology."},{"issue":"4","key":"1656_CR3","doi-asserted-by":"publisher","first-page":"582","DOI":"10.3109\/14767058.2015.1012060","volume":"29","author":"FM O'Hare","year":"2016","unstructured":"O'Hare FM, Watson RW, O'Neill A, Blanco A, Donoghue V, Molloy EJ. Persistent systemic monocyte and neutrophil activation in neonatal encephalopathy. J Matern Fetal Neonatal Med. 2016;29(4):582\u20139.","journal-title":"J Matern Fetal Neonatal Med"},{"issue":"3","key":"1656_CR4","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/pr.2013.238","volume":"75","author":"O Dammann","year":"2014","unstructured":"Dammann O, Leviton A. Intermittent or sustained systemic inflammation and the preterm brain. Pediatr Res. 2014;75(3):376\u201380.","journal-title":"Pediatr Res"},{"issue":"1","key":"1656_CR5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.earlhumdev.2004.04.009","volume":"79","author":"O Dammann","year":"2004","unstructured":"Dammann O, Leviton A. Inflammatory brain damage in preterm newborns--dry numbers, wet lab, and causal inferences. Early Hum Dev. 2004;79(1):1\u201315.","journal-title":"Early Hum Dev"},{"issue":"4","key":"1656_CR6","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1002\/ana.22473","volume":"70","author":"MV Covey","year":"2011","unstructured":"Covey MV, Loporchio D, Buono KD, Levison SW. Opposite effect of inflammation on subventricular zone versus hippocampal precursors in brain injury. Ann Neurol. 2011;70(4):616\u201326.","journal-title":"Ann Neurol"},{"issue":"2","key":"1656_CR7","doi-asserted-by":"publisher","first-page":"F153","DOI":"10.1136\/adc.2006.108837","volume":"93","author":"O Khwaja","year":"2008","unstructured":"Khwaja O, Volpe JJ. Pathogenesis of cerebral white matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed. 2008;93(2):F153\u201361.","journal-title":"Arch Dis Child Fetal Neonatal Ed"},{"issue":"3","key":"1656_CR8","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1159\/000089180","volume":"89","author":"K Okazaki","year":"2006","unstructured":"Okazaki K, Nishida A, Kato M, Kozawa K, Uga N, Kimura H. Elevation of cytokine concentrations in asphyxiated neonates. Biol Neonate. 2006;89(3):183\u20139.","journal-title":"Biol Neonate"},{"issue":"3","key":"1656_CR9","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.pediatrneurol.2008.09.026","volume":"40","author":"V Ramaswamy","year":"2009","unstructured":"Ramaswamy V, Horton J, Vandermeer B, Buscemi N, Miller S, Yager J. Systematic review of biomarkers of brain injury in term neonatal encephalopathy. Pediatr Neurol. 2009;40(3):215\u201326.","journal-title":"Pediatr Neurol"},{"issue":"6","key":"1656_CR10","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1097\/PCC.0b013e318291793f","volume":"14","author":"BH Walsh","year":"2013","unstructured":"Walsh BH, Boylan GB, Livingstone V, Kenny LC, Dempsey EM, Murray DM. Cord blood proteins and multichannel-electroencephalography in hypoxic-ischemic encephalopathy. Pediatr Crit Care Med. 2013;14(6):621\u201330.","journal-title":"Pediatr Crit Care Med"},{"issue":"10","key":"1656_CR11","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1038\/jcbfm.2012.83","volume":"32","author":"DD Jenkins","year":"2012","unstructured":"Jenkins DD, Rollins LG, Perkel JK, Wagner CL, Katikaneni LP, Bass WT, et al. Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy. J Cereb Blood Flow Metab. 2012;32(10):1888\u201396.","journal-title":"J Cereb Blood Flow Metab"},{"key":"1656_CR12","doi-asserted-by":"crossref","unstructured":"Chalak LF, Sanchez PJ, Adams-Huet B, Laptook AR, Heyne RJCytokine dysregulation persists in childhood post Neonatal Encephalopathy, Rosenfeld CR. Biomarkers for severity of neonatal hypoxic-ischemic encephalopathy and outcomes in newborns receiving hypothermia therapy. J Pediatr. 2014;164(3):468\u201374 e1.","DOI":"10.1016\/j.jpeds.2013.10.067"},{"key":"1656_CR13","doi-asserted-by":"publisher","unstructured":"Nair J, Kumar VHS. Current and Emerging Therapies in the Management of Hypoxic Ischemic Encephalopathy in Neonates. Children (Basel). 2018;5(7). https:\/\/doi.org\/10.3390\/children5070099.","DOI":"10.3390\/children5070099"},{"issue":"5","key":"1656_CR14","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1056\/NEJM199907293410504","volume":"341","author":"CC Huang","year":"1999","unstructured":"Huang CC, Wang ST, Chang YC, Lin KP, Wu PL. Measurement of the urinary lactate:creatinine ratio for the early identification of newborn infants at risk for hypoxic-ischemic encephalopathy. N Engl J Med. 1999;341(5):328\u201335.","journal-title":"N Engl J Med"},{"issue":"10","key":"1656_CR15","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1001\/archneur.1976.00500100030012","volume":"33","author":"HB Sarnat","year":"1976","unstructured":"Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976;33(10):696\u2013705.","journal-title":"Arch Neurol"},{"key":"1656_CR16","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/1471-2431-8-17","volume":"8","author":"D Azzopardi","year":"2008","unstructured":"Azzopardi D, Brocklehurst P, Edwards D, Halliday H, Levene M, Thoresen M, et al. The TOBY Study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial. BMC Pediatr. 2008;8:17.","journal-title":"BMC Pediatr"},{"issue":"1","key":"1656_CR17","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/sj.jcbfm.9600496","volume":"28","author":"WR Schabitz","year":"2008","unstructured":"Schabitz WR, Kruger C, Pitzer C, Weber D, Laage R, Gassler N, et al. A neuroprotective function for the hematopoietic protein granulocyte-macrophage colony stimulating factor (GM-CSF). J Cereb Blood Flow Metab. 2008;28(1):29\u201343.","journal-title":"J Cereb Blood Flow Metab"},{"issue":"4","key":"1656_CR18","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1111\/apa.13745","volume":"106","author":"FM O'Hare","year":"2017","unstructured":"O'Hare FM, Watson RW, O'Neill A, Segurado R, Sweetman D, Downey P, et al. Serial cytokine alterations and abnormal neuroimaging in newborn infants with encephalopathy. Acta Paediatr. 2017;106(4):561\u20137.","journal-title":"Acta Paediatr"},{"issue":"8","key":"1656_CR19","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1097\/PCC.0b013e3182975cc9","volume":"14","author":"DD Jenkins","year":"2013","unstructured":"Jenkins DD, Lee T, Chiuzan C, Perkel JK, Rollins LG, Wagner CL, et al. Altered circulating leukocytes and their chemokines in a clinical trial of therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy*. Pediatr Crit Care Med. 2013;14(8):786\u201395.","journal-title":"Pediatr Crit Care Med"},{"issue":"2","key":"1656_CR20","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1016\/j.pharmthera.2007.10.001","volume":"117","author":"D Tracey","year":"2008","unstructured":"Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117(2):244\u201379.","journal-title":"Pharmacol Ther"},{"issue":"2","key":"1656_CR21","first-page":"115","volume":"30","author":"MW Varner","year":"2015","unstructured":"Varner MW, Marshall NE, Rouse DJ, Jablonski KA, Leveno KJ, Reddy UM, et al. The association of cord serum cytokines with neurodevelopmental outcomes. Am J Perinatol. 2015;30(2):115\u201322.","journal-title":"Am J Perinatol"},{"issue":"4","key":"1656_CR22","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1016\/j.clp.2008.07.011","volume":"35","author":"O Dammann","year":"2008","unstructured":"Dammann O, O'Shea TM. Cytokines and perinatal brain damage. Clin Perinatol. 2008;35(4):643\u201363 v.","journal-title":"Clin Perinatol"},{"issue":"6","key":"1656_CR23","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.1378\/chest.113.6.1625","volume":"113","author":"L Doughty","year":"1998","unstructured":"Doughty L, Carcillo JA, Kaplan S, Janosky J. The compensatory anti-inflammatory cytokine interleukin 10 response in pediatric sepsis-induced multiple organ failure. Chest. 1998;113(6):1625\u201331.","journal-title":"Chest."},{"issue":"6","key":"1656_CR24","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1007\/PL00008445","volume":"160","author":"C Romagnoli","year":"2001","unstructured":"Romagnoli C, Frezza S, Cingolani A, De Luca A, Puopolo M, De Carolis MP, et al. Plasma levels of interleukin-6 and interleukin-10 in preterm neonates evaluated for sepsis. Eur J Pediatr. 2001;160(6):345\u201350.","journal-title":"Eur J Pediatr"},{"issue":"2","key":"1656_CR25","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1053\/j.jvca.2006.02.027","volume":"21","author":"E Appachi","year":"2007","unstructured":"Appachi E, Mossad E, Mee RB, Bokesch P. Perioperative serum interleukins in neonates with hypoplastic left-heart syndrome and transposition of the great arteries. J Cardiothorac Vasc Anesth. 2007;21(2):184\u201390.","journal-title":"J Cardiothorac Vasc Anesth"},{"issue":"3","key":"1656_CR26","doi-asserted-by":"publisher","first-page":"e0115083","DOI":"10.1371\/journal.pone.0115083","volume":"10","author":"SJ Korzeniewski","year":"2015","unstructured":"Korzeniewski SJ, Allred E, Logan JW, Fichorova RN, Engelke S, Kuban KC, et al. Elevated endogenous erythropoietin concentrations are associated with increased risk of brain damage in extremely preterm neonates. PLoS One. 2015;10(3):e0115083.","journal-title":"PLoS One"},{"key":"1656_CR27","first-page":"471463","volume":"2014","author":"B Lv","year":"2014","unstructured":"Lv B, Huang J, Yuan H, Yan W, Hu G, Wang J. Tumor necrosis factor-alpha as a diagnostic marker for neonatal sepsis: a meta-analysis. ScientificWorldJournal. 2014;2014:471463.","journal-title":"ScientificWorldJournal."},{"issue":"2","key":"1656_CR28","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1002\/ana.22049","volume":"68","author":"CY Lin","year":"2010","unstructured":"Lin CY, Chang YC, Wang ST, Lee TY, Lin CF, Huang CC. Altered inflammatory responses in preterm children with cerebral palsy. Ann Neurol. 2010;68(2):204\u201312.","journal-title":"Ann Neurol"},{"issue":"4","key":"1656_CR29","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1007\/s001340051169","volume":"26","author":"C Adrie","year":"2000","unstructured":"Adrie C, Pinsky MR. The inflammatory balance in human sepsis. Intensive Care Med. 2000;26(4):364\u201375.","journal-title":"Intensive Care Med"},{"issue":"6","key":"1656_CR30","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1093\/infdis\/174.6.1356","volume":"174","author":"T van der Poll","year":"1996","unstructured":"van der Poll T, Coyle SM, Moldawer LL, Lowry SF. Changes in endotoxin-induced cytokine production by whole blood after in vivo exposure of normal humans to endotoxin. J Infect Dis. 1996;174(6):1356\u201360.","journal-title":"J Infect Dis"},{"issue":"1","key":"1656_CR31","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s12865-017-0231-y","volume":"18","author":"M Kim","year":"2017","unstructured":"Kim M, Kim M, Jeong H, Chae JS, Kim YS, Lee JG, et al. Hyporesponsiveness of natural killer cells and impaired inflammatory responses in critically ill patients. BMC Immunol. 2017;18(1):48.","journal-title":"BMC Immunol"}],"container-title":["BMC Neurology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12883-020-01656-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12883-020-01656-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12883-020-01656-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,2]],"date-time":"2024-08-02T22:58:35Z","timestamp":1722639515000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcneurol.biomedcentral.com\/articles\/10.1186\/s12883-020-01656-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,30]]},"references-count":31,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["1656"],"URL":"https:\/\/doi.org\/10.1186\/s12883-020-01656-w","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.2.16375\/v3","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.2.16375\/v1","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.2.16375\/v2","asserted-by":"object"}]},"ISSN":["1471-2377"],"issn-type":[{"value":"1471-2377","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,30]]},"assertion":[{"value":"2 October 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 February 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 March 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Ethical committee approval was received from the Ethics Committee of the National Maternity Hospital, Dublin and the National Children Hospital, Tallaght, Dublin. Written informed consent was obtained from all parents of children enrolled in the study.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"115"}}