{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T22:51:38Z","timestamp":1792623098998,"version":"4.5.0"},"reference-count":87,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T00:00:00Z","timestamp":1622160000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T00:00:00Z","timestamp":1622160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pediatr Res"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Perinatal inflammation combined with hypoxia\u2013ischemia (HI) exacerbates injury in the developing brain. Therapeutic hypothermia (HT) is standard care for neonatal encephalopathy; however, its benefit in inflammation-sensitized HI (IS-HI) is unknown.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Twelve newborn piglets received a 2\u2009\u00b5g\/kg bolus and 1\u2009\u00b5g\/kg\/h infusion over 52\u2009h of <jats:italic>Escherichia coli<\/jats:italic> lipopolysaccharide (LPS). HI was induced 4\u2009h after LPS bolus. After HI, piglets were randomized to HT (33.5\u2009\u00b0C 1\u201325\u2009h after HI, <jats:italic>n<\/jats:italic>\u2009=\u20096) or normothermia (NT, <jats:italic>n<\/jats:italic>\u2009=\u20096). Amplitude-integrated electroencephalogram (aEEG) was recorded and magnetic resonance spectroscopy (MRS) was acquired at 24 and 48\u2009h. At 48\u2009h, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive brain cell death, microglial activation\/proliferation, astrogliosis, and cleaved caspase-3 (CC3) were quantified. Hematology and plasma cytokines were serially measured.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Two HT piglets died. aEEG recovery, thalamic and white matter MRS lactate\/<jats:italic>N<\/jats:italic>-acetylaspartate, and TUNEL-positive cell death were similar between groups. HT increased microglial activation in the caudate, but had no other effect on glial activation\/proliferation. HT reduced CC3 overall. HT suppressed platelet count and attenuated leukocytosis. Cytokine profile was unchanged by HT.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>We did not observe protection with HT in this piglet IS-HI model based on aEEG, MRS, and immunohistochemistry. Immunosuppressive effects of HT and countering neuroinflammation by LPS may contribute to the observed lack of HT efficacy. Other immunomodulatory strategies may be more effective in IS-HI.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Impact<\/jats:title>\n                <jats:p><jats:list list-type=\"bullet\">\n                  <jats:list-item>\n                    <jats:p>Acute infection\/inflammation is known to exacerbate perinatal brain injury and can worsen the outcomes in neonatal encephalopathy.<\/jats:p>\n                  <\/jats:list-item>\n                  <jats:list-item>\n                    <jats:p>Therapeutic HT is the current standard of care for all infants with NE, but the benefit in infants with coinfection\/inflammation is unknown.<\/jats:p>\n                  <\/jats:list-item>\n                  <jats:list-item>\n                    <jats:p>In a piglet model of inflammation (LPS)-sensitized HI, we observed no evidence of neuroprotection with cooling for 24\u2009h, based on our primary outcome measures: aEEG, MRS Lac\/NAA, and histological brain cell death.<\/jats:p>\n                  <\/jats:list-item>\n                  <jats:list-item>\n                    <jats:p>Additional neuroprotective agents, with beneficial immunomodulatory effects, require exploration in IS-HI models.<\/jats:p>\n                  <\/jats:list-item>\n                <\/jats:list><\/jats:p>\n              <\/jats:sec>","DOI":"10.1038\/s41390-021-01584-6","type":"journal-article","created":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T09:39:20Z","timestamp":1622194760000},"page":"1416-1427","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Hypothermia is not therapeutic in a neonatal piglet model of inflammation-sensitized hypoxia\u2013ischemia"],"prefix":"10.1038","volume":"91","author":[{"given":"Kathryn A.","family":"Martinello","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Meehan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adnan","family":"Avdic-Belltheus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingran","family":"Lingam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatenda","family":"Mutshiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa Ali","family":"Akin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Price","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Sokolska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Bainbridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariya","family":"Hristova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilias","family":"Tachtsidis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cally J.","family":"Tann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald","family":"Peebles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Hagberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim G. A. M.","family":"Wolfs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris W.","family":"Kramer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bobbi","family":"Fleiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Gressens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Golay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola J.","family":"Robertson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,28]]},"reference":[{"key":"1584_CR1","doi-asserted-by":"publisher","unstructured":"Jacobs, S. E. et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database of Systematic Reviews, CD003311. https:\/\/doi.org\/10.1002\/14651858.CD003311.pub3 (2013).","DOI":"10.1002\/14651858.CD003311.pub3"},{"key":"1584_CR2","doi-asserted-by":"publisher","first-page":"2085","DOI":"10.1056\/NEJMoa1112066","volume":"366","author":"S Shankaran","year":"2012","unstructured":"Shankaran, S. et al. Childhood outcomes after hypothermia for neonatal encephalopathy. N. Engl. J. Med. 366, 2085\u20132092 (2012).","journal-title":"N. Engl. J. Med."},{"key":"1584_CR3","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1111\/apa.13146","volume":"104","author":"S Jary","year":"2015","unstructured":"Jary, S., Smit, E., Liu, X., Cowan, F. M. & Thoresen, M. Less severe cerebral palsy outcomes in infants treated with therapeutic hypothermia. Acta Paediatr. 104, 1241\u20131247 (2015).","journal-title":"Acta Paediatr."},{"key":"1584_CR4","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1136\/archdischild-2018-316509","volume":"105","author":"R Lee-Kelland","year":"2020","unstructured":"Lee-Kelland, R. et al. School-age outcomes of children without cerebral palsy cooled for neonatal hypoxic-ischaemic encephalopathy in 2008-2010. Arch. Dis. Child. Fetal Neonatal Ed. 105, 8\u201313 (2020).","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"1584_CR5","doi-asserted-by":"publisher","first-page":"1549","DOI":"10.1136\/bmj.317.7172.1549","volume":"317","author":"N Badawi","year":"1998","unstructured":"Badawi, N. et al. Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ 317, 1549\u20131553 (1998).","journal-title":"BMJ"},{"key":"1584_CR6","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1016\/j.ajog.2015.05.034","volume":"213","author":"AH MacLennan","year":"2015","unstructured":"MacLennan, A. H., Thompson, S. C. & Gecz, J. Cerebral palsy: causes, pathways, and the role of genetic variants. Am. J. Obstet. Gynecol. 213, 779\u2013788 (2015).","journal-title":"Am. J. Obstet. Gynecol."},{"key":"1584_CR7","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1038\/nrneurol.2015.13","volume":"11","author":"H Hagberg","year":"2015","unstructured":"Hagberg, H. et al. The role of inflammation in perinatal brain injury. Nat. Rev. Neurol. 11, 192\u2013208 (2015).","journal-title":"Nat. Rev. Neurol."},{"key":"1584_CR8","doi-asserted-by":"publisher","first-page":"878","DOI":"10.1542\/peds.2012-0714","volume":"130","author":"KB Nelson","year":"2012","unstructured":"Nelson, K. B. et al. Antecedents of neonatal encephalopathy in the Vermont Oxford Network Encephalopathy Registry. Pediatrics 130, 878\u2013886 (2012).","journal-title":"Pediatrics"},{"key":"1584_CR9","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1046\/j.0953-816x.2001.01474.x","volume":"13","author":"S Eklind","year":"2001","unstructured":"Eklind, S. et al. Bacterial endotoxin sensitizes the immature brain to hypoxic-ischaemia injury. Eur. J. Neurosci. 13, 1101\u20131106 (2001).","journal-title":"Eur. J. Neurosci."},{"key":"1584_CR10","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-46488-y","volume":"9","author":"KA Martinello","year":"2019","unstructured":"Martinello, K. A. et al. Acute LPS sensitization and continuous infusion exacerbates hypoxic brain injury in a piglet model of neonatal encephalopathy. Sci. Rep. 9, 10184 (2019).","journal-title":"Sci. Rep."},{"key":"1584_CR11","doi-asserted-by":"publisher","first-page":"F8","DOI":"10.1136\/archdischild-2014-306192","volume":"100","author":"KB Nelson","year":"2015","unstructured":"Nelson, K. B. & Penn, A. A. Is infection a factor in neonatal encephalopathy? Arch. Dis. Child. Fetal Neonatal Ed. 100, F8\u2013F10 (2015).","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"1584_CR12","first-page":"144","volume":"2","author":"US Bhalala","year":"2014","unstructured":"Bhalala, U. S., Koehler, R. C. & Kannan, S. Neuroinflammation and neuroimmune dysregulation after acute hypoxic-ischemic injury of developing brain. Front. Pediatr. 2, 144 (2014).","journal-title":"Front. Pediatr."},{"key":"1584_CR13","doi-asserted-by":"publisher","first-page":"S173","DOI":"10.1093\/cid\/cix662","volume":"65","author":"CJ Tann","year":"2017","unstructured":"Tann, C. J. et al. Neonatal encephalopathy with Group B Streptococcal disease worldwide: systematic review, investigator group datasets, and meta-analysis. Clin. Infect. Dis. 65, S173\u2013S189 (2017).","journal-title":"Clin. Infect. Dis."},{"key":"1584_CR14","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1016\/j.resuscitation.2013.12.006","volume":"85","author":"D Osredkar","year":"2014","unstructured":"Osredkar, D. et al. Hypothermia is not neuroprotective after infection-sensitized neonatal hypoxic-ischemic brain injury. Resuscitation 85, 567\u2013572 (2014).","journal-title":"Resuscitation"},{"key":"1584_CR15","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1159\/000455838","volume":"39","author":"M Falck","year":"2017","unstructured":"Falck, M. et al. Hypothermic neuronal rescue from infection-sensitised hypoxic-ischaemic brain injury is pathogen dependent. Dev. Neurosci. 39, 238\u2013247 (2017).","journal-title":"Dev. Neurosci."},{"key":"1584_CR16","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1097\/PCC.0b013e3182975cc9","volume":"14","author":"DD Jenkins","year":"2013","unstructured":"Jenkins, D. D. et al. Altered circulating leukocytes and their chemokines in a clinical trial of therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy. Pediatr. Crit. Care Med. 14, 786\u2013795 (2013).","journal-title":"Pediatr. Crit. Care Med."},{"key":"1584_CR17","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1161\/STROKEAHA.114.007330","volume":"46","author":"D Alonso-Alconada","year":"2015","unstructured":"Alonso-Alconada, D. et al. Brain cell death is reduced with cooling by 3.5 degrees C to 5 degrees C but increased with cooling by 8.5 degrees C in a piglet asphyxia model. Stroke 46, 275\u2013278 (2015).","journal-title":"Stroke"},{"key":"1584_CR18","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1038\/jcbfm.2012.83","volume":"32","author":"DD Jenkins","year":"2012","unstructured":"Jenkins, D. D. et al. Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy. J. Cereb. Blood Flow Metab. 32, 1888\u20131896 (2012).","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"1584_CR19","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1136\/adc.2011.214205","volume":"97","author":"K Armstrong","year":"2012","unstructured":"Armstrong, K., Franklin, O., Sweetman, D. & Molloy, E. J. Cardiovascular dysfunction in infants with neonatal encephalopathy. Arch. Dis. Child 97, 372\u2013375 (2012).","journal-title":"Arch. Dis. Child"},{"key":"1584_CR20","doi-asserted-by":"publisher","first-page":"579.e571","DOI":"10.1016\/j.ajog.2010.08.024","volume":"203","author":"P Wintermark","year":"2010","unstructured":"Wintermark, P., Boyd, T., Gregas, M. C., Labrecque, M. & Hansen, A. Placental pathology in asphyxiated newborns meeting the criteria for therapeutic hypothermia. Am. J. Obstet. Gynecol. 203, 579.e571\u2013579.e579 (2010).","journal-title":"Am. J. Obstet. Gynecol."},{"key":"1584_CR21","doi-asserted-by":"publisher","first-page":"e58834","DOI":"10.1371\/journal.pone.0058834","volume":"8","author":"SS Pauliah","year":"2013","unstructured":"Pauliah, S. S., Shankaran, S., Wade, A., Cady, E. B. & Thayyil, S. Therapeutic hypothermia for neonatal encephalopathy in low- and middle-income countries: a systematic review and meta-analysis. PLoS ONE 8, e58834 (2013).","journal-title":"PLoS ONE"},{"key":"1584_CR22","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1016\/S0140-6736(08)61329-X","volume":"372","author":"NJ Robertson","year":"2008","unstructured":"Robertson, N. J. et al. Therapeutic hypothermia for birth asphyxia in low-resource settings: a pilot randomised controlled trial. Lancet 372, 801\u2013803 (2008).","journal-title":"Lancet"},{"key":"1584_CR23","doi-asserted-by":"publisher","first-page":"2174","DOI":"10.1001\/jama.2013.280506","volume":"310","author":"B Mourvillier","year":"2013","unstructured":"Mourvillier, B. et al. Induced hypothermia in severe bacterial meningitis: a randomized clinical trial. JAMA 310, 2174\u20132183 (2013).","journal-title":"JAMA"},{"key":"1584_CR24","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/S2213-2600(18)30004-3","volume":"6","author":"TS Itenov","year":"2018","unstructured":"Itenov, T. S. et al. Induced hypothermia in patients with septic shock and respiratory failure (CASS): a randomised, controlled, open-label trial. Lancet Respir. Med. 6, 183\u2013192 (2018).","journal-title":"Lancet Respir. Med."},{"key":"1584_CR25","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1159\/000487798","volume":"40","author":"M Falck","year":"2018","unstructured":"Falck, M. et al. Hypothermia is neuroprotective after severe hypoxic-ischaemic brain injury in neonatal rats pre-exposed to PAM3CSK4. Dev. Neurosci. 40, 189\u2013197 (2018).","journal-title":"Dev. Neurosci."},{"key":"1584_CR26","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1203\/00006450-198905000-00004","volume":"25","author":"D Azzopardi","year":"1989","unstructured":"Azzopardi, D. et al. Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr. Res. 25, 445\u2013451 (1989).","journal-title":"Pediatr. Res."},{"key":"1584_CR27","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1203\/00006450-199412000-00003","volume":"36","author":"A Lorek","year":"1994","unstructured":"Lorek, A. et al. Delayed (\u201csecondary\u201d) cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy. Pediatr. Res. 36, 699\u2013706 (1994).","journal-title":"Pediatr. Res."},{"key":"1584_CR28","doi-asserted-by":"publisher","first-page":"F201","DOI":"10.1136\/adc.2004.062745","volume":"90","author":"LS de Vries","year":"2005","unstructured":"de Vries, L. S. & Hellstrom-Westas, L. Role of cerebral function monitoring in the newborn. Arch. Dis. Child. Fetal Neonatal Ed. 90, F201\u2013F207 (2005).","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"1584_CR29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/mrm.22579","volume":"65","author":"M Wilson","year":"2011","unstructured":"Wilson, M., Reynolds, G., Kauppinen, R. A., Arvanitis, T. N. & Peet, A. C. A constrained least-squares approach to the automated quantitation of in vivo (1)H magnetic resonance spectroscopy data. Magn. Reson. Med. 65, 1\u201312 (2011).","journal-title":"Magn. Reson. Med."},{"key":"1584_CR30","doi-asserted-by":"publisher","first-page":"883","DOI":"10.3389\/fneur.2020.00883","volume":"11","author":"R Pang","year":"2020","unstructured":"Pang, R. et al. Proton magnetic resonance spectroscopy lactate\/N-acetylaspartate within 48 h predicts cell death following varied neuroprotective interventions in a piglet model of hypoxia\u2013ischemia with and without inflammation-sensitization. Front. Neurol. 11, 883, https:\/\/doi.org\/10.3389\/fneur.2020.00883 (2020).","journal-title":"Front. Neurol."},{"key":"1584_CR31","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1203\/00006450-199505000-00019","volume":"37","author":"M Thoresen","year":"1995","unstructured":"Thoresen, M. et al. Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr. Res. 37, 667\u2013670 (1995).","journal-title":"Pediatr. Res."},{"key":"1584_CR32","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1002\/ana.10402","volume":"53","author":"JR Tooley","year":"2003","unstructured":"Tooley, J. R., Satas, S., Porter, H., Silver, I. A. & Thoresen, M. Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective. Ann. Neurol. 53, 65\u201372 (2003).","journal-title":"Ann. Neurol."},{"key":"1584_CR33","doi-asserted-by":"publisher","first-page":"e131","DOI":"10.1542\/peds.2009-2938","volume":"126","author":"M Thoresen","year":"2010","unstructured":"Thoresen, M., Hellstrom-Westas, L., Liu, X. & de Vries, L. S. Effect of hypothermia on amplitude-integrated electroencephalogram in infants with asphyxia. Pediatrics 126, e131\u2013e139 (2010).","journal-title":"Pediatrics"},{"key":"1584_CR34","doi-asserted-by":"publisher","first-page":"e0201895","DOI":"10.1371\/journal.pone.0201895","volume":"13","author":"MU Huun","year":"2018","unstructured":"Huun, M. U. et al. DHA and therapeutic hypothermia in a short-term follow-up piglet model of hypoxia-ischemia: effects on H+MRS biomarkers. PLoS ONE 13, e0201895 (2018).","journal-title":"PLoS ONE"},{"key":"1584_CR35","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-017-0821-x","volume":"14","author":"E Rocha-Ferreira","year":"2017","unstructured":"Rocha-Ferreira, E. et al. Systemic pro-inflammatory cytokine status following therapeutic hypothermia in a piglet hypoxia-ischemia model. J. Neuroinflamm. 14, 44 (2017).","journal-title":"J. Neuroinflamm."},{"key":"1584_CR36","first-page":"F424","volume":"883","author":"S Mitra","year":"2018","unstructured":"Mitra, S. et al. Proton magnetic resonance spectroscopy lactate\/N-acetylaspartate within 2 weeks of birth accurately predicts 2-year motor, cognitive and language outcomes in neonatal encephalopathy after therapeutic hypothermia. Arch.Dis. Child. Fetal Neonatal Ed. 883, F424\u2013F432 (2018).","journal-title":"Arch.Dis. Child. Fetal Neonatal Ed."},{"key":"1584_CR37","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1038\/pr.2016.198","volume":"81","author":"AJ Gunn","year":"2017","unstructured":"Gunn, A. J. et al. Therapeutic hypothermia translates from ancient history in to practice. Pediatr. Res. 81, 202\u2013209 (2017).","journal-title":"Pediatr. Res."},{"key":"1584_CR38","doi-asserted-by":"publisher","first-page":"40","DOI":"10.3389\/fnins.2014.00040","volume":"8","author":"G Wassink","year":"2014","unstructured":"Wassink, G., Gunn, E. R., Drury, P. P., Bennet, L. & Gunn, A. J. The mechanisms and treatment of asphyxial encephalopathy. Front. Neurosci. 8, 40 (2014).","journal-title":"Front. Neurosci."},{"key":"1584_CR39","doi-asserted-by":"publisher","first-page":"e0199890","DOI":"10.1371\/journal.pone.0199890","volume":"13","author":"E Rocha-Ferreira","year":"2018","unstructured":"Rocha-Ferreira, E., Vincent, A., Bright, S., Peebles, D. M. & Hristova, M. The duration of hypothermia affects short-term neuroprotection in a mouse model of neonatal hypoxic ischaemic injury. PLoS ONE 13, e0199890 (2018).","journal-title":"PLoS ONE"},{"key":"1584_CR40","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1159\/000430860","volume":"37","author":"D Osredkar","year":"2015","unstructured":"Osredkar, D. et al. Hypothermia does not reverse cellular responses caused by lipopolysaccharide in neonatal hypoxic-ischaemic brain injury. Dev. Neurosci. 37, 390\u2013397 (2015).","journal-title":"Dev. Neurosci."},{"key":"1584_CR41","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.bbi.2013.02.005","volume":"32","author":"V Chhor","year":"2013","unstructured":"Chhor, V. et al. Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro. Brain Behav. Immun. 32, 70\u201385 (2013).","journal-title":"Brain Behav. Immun."},{"key":"1584_CR42","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1016\/j.bbi.2012.09.001","volume":"26","author":"S Girard","year":"2012","unstructured":"Girard, S. et al. Postnatal administration of IL-1Ra exerts neuroprotective effects following perinatal inflammation and\/or hypoxic-ischemic injuries. Brain Behav. Immun. 26, 1331\u20131339 (2012).","journal-title":"Brain Behav. Immun."},{"key":"1584_CR43","doi-asserted-by":"publisher","first-page":"129","DOI":"10.4049\/jimmunol.144.1.129","volume":"144","author":"KW Selmaj","year":"1990","unstructured":"Selmaj, K. W., Farooq, M., Norton, W. T., Raine, C. S. & Brosnan, C. F. Proliferation of astrocytes in vitro in response to cytokines. A primary role for tumor necrosis factor. J. Immunol. 144, 129\u2013135 (1990).","journal-title":"J. Immunol."},{"key":"1584_CR44","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1038\/s41390-019-0511-8","volume":"44","author":"I Lingam","year":"2019","unstructured":"Lingam, I. et al. Short-term effects of early initiation of magnesium infusion combined with cooling after hypoxia-ischemia in term piglets. Pediatr. Res. 44, 699\u2013708 (2019).","journal-title":"Pediatr. Res."},{"key":"1584_CR45","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.nbd.2018.10.004","volume":"121","author":"NJ Robertson","year":"2018","unstructured":"Robertson, N. J. et al. Melatonin as an adjunct to therapeutic hypothermia in a piglet model of neonatal encephalopathy: a translational study. Neurobiol. Dis. 121, 240\u2013251 (2018).","journal-title":"Neurobiol. Dis."},{"key":"1584_CR46","doi-asserted-by":"publisher","first-page":"61","DOI":"10.3390\/ijms19010061","volume":"19","author":"C Charriaut-Marlangue","year":"2017","unstructured":"Charriaut-Marlangue, C., Besson, V. C. & Baud, O. Sexually dimorphic outcomes after neonatal stroke and hypoxia-ischemia. Int. J. Mol. Sci. 19, 61, https:\/\/doi.org\/10.3390\/ijms19010061 (2017).","journal-title":"Int. J. Mol. Sci."},{"key":"1584_CR47","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1111\/j.1471-4159.2005.03639.x","volume":"96","author":"C Zhu","year":"2006","unstructured":"Zhu, C. et al. Different apoptotic mechanisms are activated in male and female brains after neonatal hypoxia-ischaemia. J. Neurochem. 96, 1016\u20131027 (2006).","journal-title":"J. Neurochem."},{"key":"1584_CR48","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1111\/j.1471-4159.2004.02547.x","volume":"90","author":"H Hagberg","year":"2004","unstructured":"Hagberg, H. et al. PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury. J. Neurochem. 90, 1068\u20131075 (2004).","journal-title":"J. Neurochem."},{"key":"1584_CR49","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1038\/nature09788","volume":"472","author":"MA Burguillos","year":"2011","unstructured":"Burguillos, M. A. et al. Caspase signalling controls microglia activation and neurotoxicity. Nature 472, 319\u2013324 (2011).","journal-title":"Nature"},{"key":"1584_CR50","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.tcb.2004.03.002","volume":"14","author":"MC Abraham","year":"2004","unstructured":"Abraham, M. C. & Shaham, S. Death without caspases, caspases without death. Trends Cell Biol. 14, 184\u2013193 (2004).","journal-title":"Trends Cell Biol."},{"key":"1584_CR51","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1053\/j.semperi.2008.10.008","volume":"33","author":"M Sola-Visner","year":"2009","unstructured":"Sola-Visner, M., Sallmon, H. & Brown, R. New insights in the mechansims of non-immune thrombocytopenia in neonates. Semin. Perinatol. 33, 43\u201351 (2009).","journal-title":"Semin. Perinatol."},{"key":"1584_CR52","first-page":"122","volume":"5","author":"S Koreti","year":"2018","unstructured":"Koreti, S., Eske, G. S., Gaur, A. & Gupta, A. Study of hematological parameters among newborns with perinatal asphyxia. Pediatr. Rev. 5, 122\u2013129 (2018).","journal-title":"Pediatr. Rev."},{"key":"1584_CR53","doi-asserted-by":"publisher","first-page":"102.110","DOI":"10.4049\/jimmunol.200.Supp.102.10","volume":"200","author":"H-W Yao","year":"2018","unstructured":"Yao, H.-W. & Kuan, C.-Y. Early neutrophil depletion reduces inflammation-sensitized hypoxic-ischemic brain injury in mouse neonates. J. Immunol. 200, 102.110 (2018).","journal-title":"J. Immunol."},{"key":"1584_CR54","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/nri3843","volume":"15","author":"SS Evans","year":"2015","unstructured":"Evans, S. S., Repasky, E. A. & Fisher, D. T. Fever and the thermal regulation of immunity: the immune system feels the heat. Nat. Rev. Immunol. 15, 335\u2013349 (2015).","journal-title":"Nat. Rev. Immunol."},{"key":"1584_CR55","doi-asserted-by":"publisher","first-page":"1499","DOI":"10.1097\/00003246-200207000-00017","volume":"30","author":"A Kimura","year":"2002","unstructured":"Kimura, A., Sakurada, S., Ohkuni, H., Todome, Y. & Kurata, K. Moderate hypothermia delays proinflammatory cytokine production of human peripheral blood mononuclear cells. Crit. Care Med. 30, 1499\u20131502 (2002).","journal-title":"Crit. Care Med."},{"key":"1584_CR56","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1155\/2013\/327604","volume":"35","author":"T Nakamura","year":"2013","unstructured":"Nakamura, T., Yamada, S. & Yoshioka, T. Brain hypothermic therapy dramatically decreases elevated blood concentrations of high mobility group box 1 in neonates with hypoxic-ischemic encephalopathy. Dis. Markers 35, 327\u2013330 (2013).","journal-title":"Dis. Markers"},{"key":"1584_CR57","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1007\/s00011-012-0554-3","volume":"62","author":"A Roka","year":"2013","unstructured":"Roka, A. et al. Changes in serum cytokine and cortisol levels in normothermic and hypothermic term neonates after perinatal asphyxia. Inflamm. Res. 62, 81\u201387 (2013).","journal-title":"Inflamm. Res."},{"key":"1584_CR58","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1038\/jp.2016.132","volume":"36","author":"CJ Moon","year":"2016","unstructured":"Moon, C. J., Youn, Y. A., Yum, S. K. & Sung, I. K. Cytokine changes in newborns with therapeutic hypothermia after hypoxic ischemic encephalopathy. J. Perinatol. 36, 1092\u20131096 (2016).","journal-title":"J. Perinatol."},{"key":"1584_CR59","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1016\/j.jpeds.2013.10.067","volume":"164","author":"LF Chalak","year":"2014","unstructured":"Chalak, L. F. et al. Biomarkers for severity of neonatal hypoxic-ischemic encephalopathy and outcomes in newborns receiving hypothermia therapy. J. Pediatr. 164, 468\u2013474.e461 (2014).","journal-title":"J. Pediatr."},{"key":"1584_CR60","first-page":"4831480","volume":"2017","author":"KK Haase","year":"2017","unstructured":"Haase, K. K., Grelle, J. L., Khasawneh, F. A. & Ike, C. Variability in glycemic control with temperature transitions during therapeutic hypothermia. Crit. Care Res. Pract. 2017, 4831480 (2017).","journal-title":"Crit. Care Res. Pract."},{"key":"1584_CR61","doi-asserted-by":"publisher","first-page":"F149","DOI":"10.1136\/archdischild-2015-308733","volume":"101","author":"SK Basu","year":"2016","unstructured":"Basu, S. K. et al. Hypoglycaemia and hyperglycaemia are associated with unfavourable outcome in infants with hypoxic ischaemic encephalopathy: a post hoc analysis of the CoolCap Study. Arch. Dis. Child. Fetal Neonatal Ed. 101, F149\u2013F155 (2016).","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"1584_CR62","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.jpeds.2018.07.041","volume":"203","author":"SK Basu","year":"2018","unstructured":"Basu, S. K. et al. Early glycemic profile is associated with brain injury patterns on magnetic resonance imaging in hypoxic ischemic encephalopathy. J. Pediatr. 203, 137\u2013143 (2018).","journal-title":"J. Pediatr."},{"key":"1584_CR63","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1007\/s00441-020-03206-9","volume":"380","author":"R Pabst","year":"2020","unstructured":"Pabst, R. The pig as a model for immunology research. Cell Tissue Res. 380, 287\u2013304 (2020).","journal-title":"Cell Tissue Res."},{"key":"1584_CR64","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.nbd.2018.10.004","volume":"121","author":"NJ Robertson","year":"2019","unstructured":"Robertson, N. J. et al. Melatonin as an adjunct to therapeutic hypothermia in a piglet model of neonatal encephalopathy: a translational study. Neurobiol. Dis. 121, 240\u2013251 (2019).","journal-title":"Neurobiol. Dis."},{"key":"1584_CR65","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-60858-x","volume":"10","author":"NJ Robertson","year":"2020","unstructured":"Robertson, N. J. et al. High-dose melatonin and ethanol excipient combined with therapeutic hypothermia in a newborn piglet asphyxia model. Sci. Rep. 10, 3898 (2020).","journal-title":"Sci. Rep."},{"key":"1584_CR66","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1038\/jcbfm.2014.259","volume":"35","author":"JO Davidson","year":"2015","unstructured":"Davidson, J. O. et al. How long is too long for cerebral cooling after ischemia in fetal sheep? J. Cereb. Blood Flow Metab. 35, 751\u2013758 (2015).","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"1584_CR67","doi-asserted-by":"publisher","DOI":"10.1038\/srep25178","volume":"6","author":"JO Davidson","year":"2016","unstructured":"Davidson, J. O. et al. Extending the duration of hypothermia does not further improve white matter protection after ischemia in term-equivalent fetal sheep. Sci. Rep. 6, 25178 (2016).","journal-title":"Sci. Rep."},{"key":"1584_CR68","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1001\/jama.2017.7218","volume":"318","author":"S Shankaran","year":"2017","unstructured":"Shankaran, S. et al. Effect of depth and duration of cooling on death or disability at age 18 months among neonates with hypoxic-ischemic encephalopathy: a randomized clinical trial. JAMA 318, 57\u201367 (2017).","journal-title":"JAMA"},{"key":"1584_CR69","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1177\/0271678X17707671","volume":"38","author":"JO Davidson","year":"2018","unstructured":"Davidson, J. O. et al. How long is sufficient for optimal neuroprotection with cerebral cooling after ischemia in fetal sheep? J. Cereb. Blood Flow Metab. 38, 1047\u20131059 (2018).","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"1584_CR70","doi-asserted-by":"crossref","unstructured":"Davidson, J. O. et al. Limited benefit of slow rewarming after cerebral hypothermia for global cerebral ischemia in near-term fetal sheep. J. Cereb. Blood Flow Metab. 271678X18791631 (2018).","DOI":"10.1177\/0271678X18791631"},{"key":"1584_CR71","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1111\/ped.14215","volume":"62","author":"KH Cho","year":"2020","unstructured":"Cho, K. H., Davidson, J. O., Dean, J. M., Bennet, L. & Gunn, A. J. Cooling and immunomodulation for treating hypoxic-ischemic brain injury. Pediatr. Int. 62, 770\u2013778 (2020).","journal-title":"Pediatr. Int."},{"key":"1584_CR72","doi-asserted-by":"publisher","first-page":"S28","DOI":"10.1016\/j.ajog.2005.10.070","volume":"193","author":"X Wang","year":"2005","unstructured":"Wang, X. et al. Melatonin and N-acetylcysteine reduce brain injury in response to lipopolysaccharide-sensitized hypoxia-ischemia. Am. J. Obstet. Gynecol. 193, S28 (2005).","journal-title":"Am. J. Obstet. Gynecol."},{"key":"1584_CR73","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1002\/ana.21066","volume":"61","author":"X Wang","year":"2007","unstructured":"Wang, X. et al. N-acetylcysteine reduces lipopolysaccharide-sensitized hypoxic-ischemic brain injury. Ann. Neurol. 61, 263\u2013271 (2007).","journal-title":"Ann. Neurol."},{"key":"1584_CR74","doi-asserted-by":"publisher","first-page":"17","DOI":"10.3390\/ijms18010017","volume":"18","author":"B Harding","year":"2016","unstructured":"Harding, B., Conception, K., Li, Y. & Zhang, L. Glucocorticoids protect neonatal rat brain in model of hypoxic-ischemic encephalopathy (HIE. Int. J. Mol. Sci 18, 17, https:\/\/doi.org\/10.3390\/ijms18010017 (2016).","journal-title":"Int. J. Mol. Sci"},{"key":"1584_CR75","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-015-0330-8","volume":"12","author":"A Savard","year":"2015","unstructured":"Savard, A. et al. Neuronal self-injury mediated by IL-1beta and MMP-9 in a cerebral palsy model of severe neonatal encephalopathy induced by immune activation plus hypoxia-ischemia. J. Neuroinflamm. 12, 111 (2015).","journal-title":"J. Neuroinflamm."},{"key":"1584_CR76","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1016\/j.expneurol.2013.01.015","volume":"247","author":"D Yang","year":"2013","unstructured":"Yang, D. et al. Intranasal delivery of cell-penetrating anti-NF-\u03baB peptides (Tat-NBD) alleviates infection-sensitized hypoxic-ischemic brain injury. Exp. Neurol. 247, 447\u2013455 (2013).","journal-title":"Exp. Neurol."},{"key":"1584_CR77","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1093\/cercor\/bhs115","volume":"23","author":"D Yang","year":"2013","unstructured":"Yang, D. et al. Plasminogen activator inhibitor-1 mitigates brain injury in a rat model of infection-sensitized neonatal hypoxia-ischemia. Cereb. Cortex 23, 1218\u20131229 (2013).","journal-title":"Cereb. Cortex"},{"key":"1584_CR78","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-9-70","volume":"9","author":"B Fleiss","year":"2012","unstructured":"Fleiss, B., Nilsson, M. K., Blomgren, K. & Mallard, C. Neuroprotection by the histone deacetylase inhibitor trichostatin A in a model of lipopolysaccharide-sensitised neonatal hypoxic-ischaemic brain injury. J. Neuroinflamm. 9, 70 (2012).","journal-title":"J. Neuroinflamm."},{"key":"1584_CR79","first-page":"290","volume":"16","author":"FL Xu","year":"2014","unstructured":"Xu, F. L. et al. Effects of erythropoietin on neuronal proliferation and apoptosis in neonatal rats after infection-induced brain injury. Zhongguo Dang Dai Er Ke Za Zhi 16, 290\u2013294 (2014).","journal-title":"Zhongguo Dang Dai Er Ke Za Zhi"},{"key":"1584_CR80","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1159\/000355460","volume":"35","author":"CM Traudt","year":"2013","unstructured":"Traudt, C. M. et al. Concurrent erythropoietin and hypothermia treatment improve outcomes in a term nonhuman primate model of perinatal asphyxia. Dev. Neurosci. 35, 491\u2013503 (2013).","journal-title":"Dev. Neurosci."},{"key":"1584_CR81","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1111\/dmcn.13528","volume":"59","author":"N Wagenaar","year":"2017","unstructured":"Wagenaar, N., Nijboer, C. H. & van Bel, F. Repair of neonatal brain injury: bringing stem cell-based therapy into clinical practice. Dev. Med. Child Neurol. 59, 997\u20131003 (2017).","journal-title":"Dev. Med. Child Neurol."},{"key":"1584_CR82","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-45872-y","volume":"9","author":"KHT Cho","year":"2019","unstructured":"Cho, K. H. T. et al. Protective effects of delayed intraventricular TLR7 agonist administration on cerebral white and gray matter following asphyxia in the preterm fetal sheep. Sci. Rep. 9, 9562 (2019).","journal-title":"Sci. Rep."},{"key":"1584_CR83","doi-asserted-by":"publisher","first-page":"2024","DOI":"10.1002\/glia.23212","volume":"65","author":"LR Shiow","year":"2017","unstructured":"Shiow, L. R. et al. Reactive astrocyte COX2-PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury. Glia 65, 2024\u20132037 (2017).","journal-title":"Glia"},{"key":"1584_CR84","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1038\/s41390-019-0408-6","volume":"86","author":"JDE Barks","year":"2019","unstructured":"Barks, J. D. E., Liu, Y., Wang, L., Pai, M. P. & Silverstein, F. S. Repurposing azithromycin for neonatal neuroprotection. Pediatr. Res. 86, 444\u2013451 (2019).","journal-title":"Pediatr. Res."},{"key":"1584_CR85","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1002\/jnr.21890","volume":"87","author":"KM Buller","year":"2009","unstructured":"Buller, K. M., Carty, M. L., Reinebrant, H. E. & Wixey, J. A. Minocycline: a neuroprotective agent for hypoxic-ischemic brain injury in the neonate? J. Neurosci. Res. 87, 599\u2013608 (2009).","journal-title":"J. Neurosci. Res."},{"key":"1584_CR86","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-018-1258-6","volume":"15","author":"M Chevin","year":"2018","unstructured":"Chevin, M., Guiraut, C. & S\u00e9bire, G. Effect of hypothermia on interleukin-1 receptor antagonist pharmacodynamics in inflammatory-sensitized hypoxic-ischemic encephalopathy of term newborns. J. Neuroinflamm. 15, 214 (2018).","journal-title":"J. Neuroinflamm."},{"key":"1584_CR87","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.bbi.2018.02.006","volume":"70","author":"J Herz","year":"2018","unstructured":"Herz, J. et al. Interaction between hypothermia and delayed mesenchymal stem cell therapy in neonatal hypoxic-ischemic brain injury. Brain Behav. Immun. 70, 118\u2013130 (2018).","journal-title":"Brain Behav. Immun."}],"container-title":["Pediatric Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41390-021-01584-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41390-021-01584-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41390-021-01584-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T19:11:41Z","timestamp":1675365101000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41390-021-01584-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,28]]},"references-count":87,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,5]]}},"alternative-id":["1584"],"URL":"https:\/\/doi.org\/10.1038\/s41390-021-01584-6","relation":{},"ISSN":["0031-3998","1530-0447"],"issn-type":[{"value":"0031-3998","type":"print"},{"value":"1530-0447","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,28]]},"assertion":[{"value":"12 February 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 April 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 May 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 May 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}