{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T10:30:16Z","timestamp":1784543416566,"version":"3.55.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T00:00:00Z","timestamp":1698710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Vet. Sci."],"abstract":"<jats:p>Hypoglycemia is a condition associated with neonatal diarrhea in calves, leading to increased mortality and neurological clinical signs. The aim of the present study was to determine the development of brain damage in hypoglycemic calves with neonatal diarrhea and the diagnostic and prognostic significance of these biomarkers. Ten healthy and 50 hypoglycemic calves with diarrhea were included in the study. Clinical examination, blood gases and complete blood count were performed at admission. Blood serum calcium-binding protein B (S100B), neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolysis isoenzyme-1 (UCHL-1), activitin A (ACT), adrenomodullin (AM) concentrations, and creatine kinase-BB (CK-BB) enzyme activity were measured using commercial bovine-specific ELISA kits to assess brain damage. Of the hypoglycemic calves enrolled in the study, 13 (26%) survived and 37 (74%) died. In addition, 32 (64%) of the calves had severe acidosis and 24 (48%) had sepsis. S100B, GFAP, UCHL-1, CK-BB (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.001) and NSE (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.05) concentrations were significantly higher in hypoglycemic calves compared to healthy calves, while ACT concentrations were lower. Blood glucose concentration was negatively correlated with serum S100B, GFAP, UCHL-1, and CK-BB enzyme activity and positively correlated with ACT in hypoglycemic calves (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.01). Brain injury biomarkers were not predictive of mortality (<jats:italic>p<\/jats:italic>\u2009&amp;gt;\u20090.05). Morever, severe hypoglycemia, severe acidosis and sepsis variables were not found to have sufficient capacity to predict mortality when considered alone or together (<jats:italic>p<\/jats:italic>\u2009&amp;gt;\u20090.05). In conclusion, brain damage may develop as a consequence of hypoglycemia in calves. S100B, NSE, GFAP, UCHL-1, ACT, and CK-BB concentrations can be used to diagnose brain damage in hypoglycemic calves. However, the variables of severe hypoglycemia, severe acidosis, and sepsis together with the biomarkers of brain injury have a limited value in predicting the prognosis of neonatal calves with diarrhea.<\/jats:p>","DOI":"10.3389\/fvets.2023.1240846","type":"journal-article","created":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T11:23:44Z","timestamp":1698751424000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Surveilling brain damage using brain biomarkers in hypoglycemic neonatal calves with diarrhea"],"prefix":"10.3389","volume":"10","author":[{"given":"Merve","family":"Ider","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Naseri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmut","family":"Ok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alper","family":"Erturk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murat Kaan","family":"Durgut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suleyman Serhat","family":"Iyigun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,10,31]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1007\/s12602-020-09649-4","article-title":"Properties of a new probiotic candidate and Lactobacterin-Tk2 against diarrhea in calves","volume":"12","author":"Boranbayeva","year":"2020","journal-title":"Probiot Antimicro"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"7234","DOI":"10.3168\/jds.2013-6945","article-title":"Hyperkalemia in neonatal diarrheic calves depends on the degree of dehydration and the cause of the metabolic acidosis but does not require the presence of Acidemia","volume":"96","author":"Trefz","year":"2013","journal-title":"J Dairy Sci"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1111\/jvim.12556","article-title":"Quantitative physicochemical analysis of Acid-Base balance and clinical utility of anion gap and strong ion gap in 806 neonatal calves with diarrhea","volume":"29","author":"Trefz","year":"2015","journal-title":"J Vet Intern Med"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.tvjl.2016.10.001","article-title":"Hypoglycaemia in hospitalised neonatal calves: prevalence, associated conditions and impact on prognosis","volume":"217","author":"Trefz","year":"2016","journal-title":"Vet J"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1016\/B978-0-444-53480-4.00036-9","article-title":"Neurologic damage in hypoglycemia","volume":"126","author":"Mohseni","year":"2014","journal-title":"Handb Clin Neurol"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"e0122358","DOI":"10.1371\/journal.pone.0122358","article-title":"Altered Nrf2 signaling mediates hypoglycemia-induced blood-brain barrier endothelial dysfunction in vitro","volume":"10","author":"Sajja","year":"2015","journal-title":"PLoS One"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1053\/siny.2001.0044","article-title":"Hypoglycemic brain injury","volume":"6","author":"Vannucci","year":"2001","journal-title":"Semin Neonatol"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"4669","DOI":"10.1210\/jc.2010-0805","article-title":"Glucose dysregulation and neurological injury biomarkers in critically ill children","volume":"95","author":"Vanhorebeek","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1002\/jemt.10053","article-title":"Adrenomedullin in the central nervous system","volume":"57","author":"Serrano","year":"2002","journal-title":"Microsc Res Tech"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.3969\/j.issn.1673-5374.2013.11.007","article-title":"Activin a prevents neuron-like Pc12 cell apoptosis after oxygen-glucose deprivation","volume":"8","author":"Xu","year":"2013","journal-title":"Neural Regen Res"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1292\/jvms.19-0502","article-title":"Histopathological and Immunohistochemical analysis of the cerebral white Matter after transient hypoglycemia in rat","volume":"82","author":"Tomita","year":"2020","journal-title":"J Vet Med Sci"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"3223","DOI":"10.3390\/ani12223223","article-title":"The usefulness of serum brain damage biomarkers in detection and evaluation of hypoxic ischemic encephalopathy in calves with perinatal asphyxia","volume":"12","author":"Ok","year":"2022","journal-title":"Animals"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1016\/j.neubiorev.2016.05.009","article-title":"Blood biomarkers for brain injury: what are we measuring?","volume":"68","author":"Kawata","year":"2016","journal-title":"Neurosci Biobehav R"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/j.pneurobio.2009.10.020","article-title":"Uchl1 (Pgp 9.5): Neuronal Biomarker and Ubiquitin System Protein","volume":"90","author":"Day","year":"2010","journal-title":"Prog Neurobiol"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/S0065-2423(06)43004-3","article-title":"Activin a in brain injury","volume":"43","author":"Florio","year":"2007","journal-title":"Adv Clin Chem"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1111\/j.1460-9568.2004.03478.x","article-title":"Distinct cellular expressions of Creatine synthetic enzyme Gamt and Creatine kinases Uck-mi and Ck-B suggest a novel neuron-glial relationship for brain energy homeostasis","volume":"20","author":"Tachikawa","year":"2004","journal-title":"Eur J Neurosci"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/s003800070044","article-title":"Insulin alters cardiac muscle Creatine kinase activity","volume":"15","author":"Mitani","year":"2000","journal-title":"Heart Vessel"},{"key":"ref18","volume-title":"The Merck veterinary manual: Merck & Company","author":"Aiello","year":"2016"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"e0182938","DOI":"10.1371\/journal.pone.0182938","article-title":"Clinical signs, profound Acidemia, hypoglycemia, and hypernatremia are predictive of mortality in 1,400 critically ill neonatal calves with diarrhea","volume":"12","author":"Trefz","year":"2017","journal-title":"PLoS One"},{"key":"ref20","first-page":"303","volume-title":"Manifestations and Management of Disease in neonatal ruminants","author":"Smith","year":"2015"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"9163","DOI":"10.3168\/jds.2017-12690","article-title":"Effects of profound Acidemia on the dynamic glucose and insulin response and plasma potassium and phosphorus concentrations during an intravenous glucose tolerance test in neonatal calves","volume":"100","author":"Trefz","year":"2017","journal-title":"J Dairy Sci"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.rvsc.2019.08.009","article-title":"Echocardiographic assessment of left ventricular systolic function in neonatal calves with naturally occurring Sepsis or septic shock due to diarrhea","volume":"126","author":"Naseri","year":"2019","journal-title":"Res Vet Sci"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.vetimm.2011.02.008","article-title":"Effects of intravenous Escherichia Coli dose on the pathophysiological response of colostrum-fed Jersey calves","volume":"141","author":"Ballou","year":"2011","journal-title":"Vet Immunol Immunopathol"},{"key":"ref24","first-page":"136","article-title":"Hypoglycemia in neonatal calves associated with acute diarrhea","volume":"58","author":"Tennant","year":"1968","journal-title":"Cornell Vet"},{"key":"ref25","first-page":"778","article-title":"Hypoglycemia in sick and moribund farmed elk calves","volume":"43","author":"Klein","year":"2002","journal-title":"Can Vet J"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1113\/jphysiol.1980.sp013065","article-title":"The effects of Hypoglycaemia on cerebral blood flow and metabolism in the new-born calf","volume":"298","author":"Gardiner","year":"1980","journal-title":"J Physiol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1111\/j.1471-4159.1980.tb03701.x","article-title":"Cerebral blood flow and metabolism during hypoglycemia in newborn dogs","volume":"35","author":"Hernandez","year":"1980","journal-title":"J Neurochem"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/S0006-8993(02)02586-6","article-title":"Serum S-100 Beta as a possible marker of blood-brain barrier disruption","volume":"940","author":"Kapural","year":"2002","journal-title":"Brain Res"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cccn.2003.12.008","article-title":"Peripheral markers of blood-brain barrier damage","volume":"342","author":"Marchi","year":"2004","journal-title":"Clin Chim Acta"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.neulet.2004.07.071","article-title":"Astrocytic and neuronal biochemical markers in the sera of subjects with diabetes mellitus","volume":"369","author":"Hovsepyan","year":"2004","journal-title":"Neurosci Lett"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1002\/(sici)1520-7560(199901\/02)15:1<5::aid-dmrr2>3.0.co;2-s","article-title":"Evaluation of serum markers of neuronal damage following severe hypoglycaemia in adults with insulin-treated diabetes mellitus","volume":"15","author":"Strachan","year":"1999","journal-title":"Diabetes Metab Res Rev"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1016\/j.brainresbull.2005.02.026","article-title":"Acute and repeated restraint stress influences cellular damage in rat hippocampal slices exposed to oxygen and glucose deprivation","volume":"65","author":"Fontella","year":"2005","journal-title":"Brain Res Bull"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.1016\/j.neuroscience.2006.05.008","article-title":"Active secretion of S100b from astrocytes during metabolic stress","volume":"141","author":"Gerlach","year":"2006","journal-title":"Neuroscience"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1007\/s11064-009-0075-9","article-title":"Mechanism of S100b release from rat cortical slices determined under basal and stimulated conditions","volume":"35","author":"Gursoy","year":"2010","journal-title":"Neurochem Res"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1080\/080352502753457851","article-title":"Brain damage markers in children","volume":"91","author":"Leviton","year":"2002","journal-title":"Neurobiol Clinical Aspects Acta Paediatr"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1002\/ar.20678","article-title":"Alteration of glial fibrillary acidic proteins immunoreactivity in astrocytes of the spinal cord diabetic rats","volume":"291","author":"Afsari","year":"2008","journal-title":"Anat Rec"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"167","DOI":"10.4172\/2161-0940.1000167","article-title":"Alteration of glial fibrillary acidic protein immunoreactivity in astrocytes of the cerebellum of diabetic rats and potential effect of insulin and ginger","volume":"5","author":"Hashish","year":"2015","journal-title":"Anat Physiol"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1016\/j.lfs.2013.10.009","article-title":"Chromium modulates expressions of neuronal plasticity markers and glial fibrillary acidic proteins in hypoglycemia-induced brain injury","volume":"93","author":"Sahin","year":"2013","journal-title":"Life Sci"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/1471-2377-12-85","article-title":"Ubiquitin Carboxy-terminal hydrolase L1 (Uch-L1) is increased in cerebrospinal fluid and plasma of patients after epileptic seizure","author":"Mondello","year":"2012","journal-title":"BMC Neurol"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1002\/cbf.3527","article-title":"Ubiquitin Carboxy-terminal hydrolase L1- physiology and pathology","volume":"38","author":"Matuszczak","year":"2020","journal-title":"Cell Biochem Funct"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1111\/j.1471-4159.2009.06406.x","article-title":"Delayed Activin a administration attenuates tissue death after transient focal cerebral ischemia and is associated with decreased stress-responsive kinase activation","volume":"111","author":"Mukerji","year":"2009","journal-title":"J Neurochem"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.2337\/db10-1493","article-title":"Activin a levels are associated with abnormal glucose regulation in patients with myocardial infarction: potential counteracting effects of Activin a on inflammation","volume":"60","author":"Andersen","year":"2011","journal-title":"Diabetes"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"e1017226","DOI":"10.1080\/19382014.2015.1017226","article-title":"Effects of Activin a on survival, function and gene expression of pancreatic islets from non-diabetic and diabetic human donors","volume":"6","author":"Brown","year":"2014","journal-title":"Islets"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1007\/s00125-013-3079-6","article-title":"Differential regulation of mouse pancreatic islet insulin secretion and Smad proteins by Activin ligands","volume":"57","author":"Wu","year":"2014","journal-title":"Diabetologia"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/1758-5996-2-12","article-title":"Plasma Adrenomedullin level in Egyptian children and adolescents with type 1 diabetes mellitus: relationship to microvascular complications","volume":"2","author":"El-Habashy","year":"2010","journal-title":"Diabetol Metab Syndr"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1055\/s-0029-1211745","article-title":"High levels of circulating Adrenomedullin in severe illness: correlation with C-reactive protein and evidence against the adrenal medulla as site of origin","volume":"105","author":"Ehlenz","year":"1997","journal-title":"Exp Clin Endocr Diab"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"2505","DOI":"10.1016\/s0024-3205(99)00208-8","article-title":"Secretion and clearance of the mature form of Adrenomedullin in humans","volume":"64","author":"Hirayama","year":"1999","journal-title":"Life Sci"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.1373\/clinchem.2005.051110","article-title":"Measurement of Midregional Proadrenomedullin in plasma with an Immunoluminometric assay","volume":"51","author":"Morgenthaler","year":"2005","journal-title":"Clin Chem"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"999","DOI":"10.2337\/diacare.21.6.999","article-title":"Plasma Adrenomedullin levels in type 1 diabetes-relationship with clinical parameters","volume":"21","author":"Garcia-Unzueta","year":"1998","journal-title":"Diabetes Care"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1507\/endocrj.45.241","article-title":"Plasma Adrenomedullin levels in patients with non-insulin dependent diabetes mellitus: close relationships with diabetic complications","volume":"45","author":"Nakamura","year":"1998","journal-title":"Endocr J"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1097\/00004647-199805000-00007","article-title":"Oligodendrocytes and microglia are selectively vulnerable to combined hypoxia and hypoglycemia injury in vitro","volume":"18","author":"Lyons","year":"1998","journal-title":"J Cereb Blood Flow Metab"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"1472","DOI":"10.1016\/s0026-0495(98)90072-5","article-title":"Muscle damage induced by experimental hypoglycemia","volume":"47","author":"Jiang","year":"1998","journal-title":"Metabolism"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"842937","DOI":"10.3389\/fendo.2022.842937","article-title":"Case report: hypoglycemia due to a novel activating Glucokinase variant in an adult \u2013 a molecular approach","volume":"13","author":"Koneshamoorthy","year":"2022","journal-title":"Front Endocrinol"}],"container-title":["Frontiers in Veterinary Science"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fvets.2023.1240846\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T11:23:52Z","timestamp":1698751432000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fvets.2023.1240846\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,31]]},"references-count":53,"alternative-id":["10.3389\/fvets.2023.1240846"],"URL":"https:\/\/doi.org\/10.3389\/fvets.2023.1240846","relation":{},"ISSN":["2297-1769"],"issn-type":[{"value":"2297-1769","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,31]]},"article-number":"1240846"}}