{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T12:57:18Z","timestamp":1792155438086,"version":"4.4.0"},"reference-count":80,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,2]],"date-time":"2023-05-02T00:00:00Z","timestamp":1682985600000},"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. Hum. Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Cerebral malaria is one of the most severe manifestations of malaria and is a leading cause of acquired neurodisability in African children. Recent studies suggest acute kidney injury (AKI) is a risk factor for brain injury in cerebral malaria. The present study evaluates potential mechanisms of brain injury in cerebral malaria by evaluating changes in cerebrospinal fluid measures of brain injury with respect to severe malaria complications. Specifically, we attempt to delineate mechanisms of injury focusing on blood-brain-barrier integrity and acute metabolic changes that may underlie kidney-brain crosstalk in severe malaria.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We evaluated 30 cerebrospinal fluid (CSF) markers of inflammation, oxidative stress, and brain injury in 168 Ugandan children aged 18 months to 12 years hospitalized with cerebral malaria. Eligible children were infected with <jats:italic>Plasmodium falciparum<\/jats:italic> and had unexplained coma. Acute kidney injury (AKI) on admission was defined using the Kidney Disease: Improving Global Outcomes criteria. We further evaluated blood-brain-barrier integrity and malaria retinopathy, and electrolyte and metabolic complications in serum.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The mean age of children was 3.8 years (SD, 1.9) and 40.5% were female. The prevalence of AKI was 46.3% and multi-organ dysfunction was common with 76.2% of children having at least one organ system affected in addition to coma. AKI and elevated blood urea nitrogen, but not other measures of disease severity (severe coma, seizures, jaundice, acidosis), were associated with increases in CSF markers of impaired blood-brain-barrier function, neuronal injury (neuron-specific enolase, tau), excitatory neurotransmission (kynurenine), as well as altered nitric oxide bioavailability and oxidative stress (<jats:italic>p<\/jats:italic> &amp;lt; 0.05 after adjustment for multiple testing). Further evaluation of potential mechanisms suggested that AKI may mediate or be associated with CSF changes through blood-brain-barrier disruption (<jats:italic>p<\/jats:italic> = 0.0014), ischemic injury seen by indirect ophthalmoscopy (<jats:italic>p<\/jats:italic> &amp;lt; 0.05), altered osmolality (<jats:italic>p<\/jats:italic> = 0.0006) and through alterations in the amino acids transported into the brain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In children with cerebral malaria, there is evidence of kidney-brain injury with multiple potential pathways identified. These changes were specific to the kidney and not observed in the context of other clinical complications.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnhum.2023.1177242","type":"journal-article","created":{"date-parts":[[2023,5,2]],"date-time":"2023-05-02T04:58:02Z","timestamp":1683003482000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Cerebrospinal fluid biomarkers provide evidence for kidney-brain axis involvement in cerebral malaria pathogenesis"],"prefix":"10.3389","volume":"17","author":[{"given":"Andrea L.","family":"Conroy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dibyadyuti","family":"Datta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert O.","family":"Opoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Batte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Bangirana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adnan","family":"Gopinadhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kagan A.","family":"Mellencamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayse","family":"Akcan-Arikan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Idro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandy C.","family":"John","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1681\/ASN.V891437","article-title":"Serum levels of NG, NG-dimethyl-L-arginine, a potential endogenous nitric oxide inhibitor in dialysis patients.","volume":"8","author":"Anderstam","year":"1997","journal-title":"J. Am. Soc. Nephrol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1084\/jem.184.2.557","article-title":"Nitric oxide in Tanzanian children with malaria: Inverse relationship between malaria severity and nitric oxide production\/nitric oxide synthase type 2 expression.","volume":"184","author":"Anstey","year":"1996","journal-title":"J. Exp. Med."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0191550","article-title":"Inhaled nitric oxide and cognition in pediatric severe malaria: A randomized double-blind placebo controlled trial.","volume":"13","author":"Bangirana","year":"2018","journal-title":"PLoS One."},{"key":"B4","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1093\/cid\/ciu293","article-title":"Severe malarial anemia is associated with long-term neurocognitive impairment.","volume":"59","author":"Bangirana","year":"2014","journal-title":"Clin. Infect. Dis."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1977","DOI":"10.1093\/infdis\/jiu592","article-title":"Severity of retinopathy parallels the degree of parasite sequestration in the eyes and brains of malawian children with fatal cerebral malaria.","volume":"211","author":"Barrera","year":"2015","journal-title":"J. Infect. Dis."},{"key":"B6","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1086\/595735","article-title":"Perfusion abnormalities in children with cerebral malaria and malarial retinopathy.","volume":"199","author":"Beare","year":"","journal-title":"J. Infect. Dis."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.2009.80.171","article-title":"Malarial retinopathy in cerebral malaria.","volume":"80","author":"Beare","year":"","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1001\/archopht.122.8.1141","article-title":"Prognostic significance and course of retinopathy in children with severe malaria.","volume":"122","author":"Beare","year":"2004","journal-title":"Arch. Ophthalmol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1046\/j.1365-2990.1999.00188.x","article-title":"Evidence of blood-brain barrier dysfunction in human cerebral malaria.","volume":"25","author":"Brown","year":"1999","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"207","DOI":"10.4269\/ajtmh.2001.64.207","article-title":"Blood-brain barrier function in cerebral malaria in Malawian children.","volume":"64","author":"Brown","year":"2001","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"B11","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1089\/ars.2016.6827","article-title":"Reno-cerebral reflex activates the renin-angiotensin system, promoting oxidative stress and renal damage after ischemia-reperfusion injury.","volume":"27","author":"Cao","year":"2017","journal-title":"Antioxid. Redox. Signal."},{"key":"B12","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1136\/jnnp.2004.043893","article-title":"Persistent neurocognitive impairments associated with severe falciparum malaria in Kenyan children.","volume":"76","author":"Carter","year":"2005","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B13","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.brainres.2014.07.030","article-title":"Hippocampal transcriptional dysregulation after renal ischemia and reperfusion.","volume":"1582","author":"Chou","year":"2014","journal-title":"Brain Res."},{"key":"B14","first-page":"1","article-title":"KDIGO clinical practice guideline for acute kidney injury.","volume":"2","year":"2012","journal-title":"Kidney Int. Suppl."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofw046","article-title":"Acute kidney injury is common in pediatric severe malaria and is associated with increased mortality.","volume":"3","author":"Conroy","year":"2016","journal-title":"Open Forum Infect. Dis."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-018-2225-5","article-title":"Chitinase-3-like 1 is a biomarker of acute kidney injury and mortality in paediatric severe malaria.","volume":"17","author":"Conroy","year":"2018","journal-title":"Malar. J."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-019-1332-7","article-title":"Acute kidney injury is associated with impaired cognition and chronic kidney disease in a prospective cohort of children with severe malaria.","volume":"17","author":"Conroy","year":"2019","journal-title":"BMC Med."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-021-02033-1","article-title":"Parenteral artemisinins are associated with reduced mortality and neurologic deficits and improved long-term behavioral outcomes in children with severe malaria.","volume":"19","author":"Conroy","year":"2021","journal-title":"BMC Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"2215","DOI":"10.1093\/infdis\/jiac392","article-title":"Plasma amino acid concentrations in children with severe malaria are associated with mortality and worse long-term kidney and cognitive outcomes.","volume":"226","author":"Conroy","year":"2022","journal-title":"J. Infect. Dis."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.38515","article-title":"Association of plasma tau with mortality and long-term neurocognitive impairment in survivors of pediatric cerebral malaria and severe malarial anemia.","volume":"4","author":"Datta","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1093\/cid\/ciz325","article-title":"Elevated cerebrospinal fluid tau protein concentrations on admission are associated with long-term neurologic and cognitive impairment in Ugandan children with cerebral malaria.","volume":"70","author":"Datta","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.1016\/S0140-6736(10)61924-1","article-title":"Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): An open-label, randomised trial.","volume":"376","author":"Dondorp","year":"2010","journal-title":"Lancet"},{"key":"B23","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1093\/qjmed\/92.9.495","article-title":"Hyperphenylalaninaemia in children with falciparum malaria.","volume":"92","author":"Enwonwu","year":"1999","journal-title":"QJM"},{"key":"B24","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/S0304-3940(01)02242-X","article-title":"Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia.","volume":"313","author":"Erhardt","year":"2001","journal-title":"Neurosci. Lett."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1080\/21505594.2019.1696621","article-title":"New insights into microvascular injury to inform enhanced diagnostics and therapeutics for severe malaria.","volume":"10","author":"Erice","year":"2019","journal-title":"Virulence"},{"key":"B26","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.brainres.2019.05.018","article-title":"Renal ischemia\/reperfusion induced learning and memory deficit in the rat: Insights into underlying molecular and cellular mechanisms.","volume":"1719","author":"Firouzjaei","year":"2019","journal-title":"Brain Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2241","DOI":"10.1097\/CCM.0000000000002007","article-title":"Acute kidney injury in pediatric severe sepsis: An independent risk factor for death and new disability.","volume":"44","author":"Fitzgerald","year":"2016","journal-title":"Crit Care Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1038\/nm1499","article-title":"Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria.","volume":"12","author":"Gramaglia","year":"2006","journal-title":"Nat. Med."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2015.00018","article-title":"Correlation of hemorrhage, axonal damage, and blood-tissue barrier disruption in brain and retina of Malawian children with fatal cerebral malaria.","volume":"5","author":"Greiner","year":"2015","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0175686","article-title":"Extensive alterations of blood metabolites in pediatric cerebral malaria.","volume":"12","author":"Gupta","year":"2017","journal-title":"PLoS One"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens11040436","article-title":"Pathophysiology of acute kidney injury in malaria and non-malarial febrile illness: A prospective cohort study.","volume":"11","author":"Hawkes","year":"2022","journal-title":"Pathogens"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1468","DOI":"10.1016\/S0140-6736(02)11474-7","article-title":"A new NOS2 promoter polymorphism associated with increased nitric oxide production and protection from severe malaria in Tanzanian and Kenyan children.","volume":"360","author":"Hobbs","year":"2002","journal-title":"Lancet"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-017-1954-1","article-title":"Cerebrospinal fluid kynurenine and kynurenic acid concentrations are associated with coma duration and long-term neurocognitive impairment in Ugandan children with cerebral malaria.","volume":"16","author":"Holmberg","year":"2017","journal-title":"Malar. J."},{"key":"B34","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1136\/adc.2005.077784","article-title":"Risk factors for persisting neurological and cognitive impairments following cerebral malaria.","volume":"91","author":"Idro","year":"2006","journal-title":"Arch. Dis. Child."},{"key":"B35","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1203\/PDR.0b013e3181eee738","article-title":"Cerebral malaria: Mechanisms of brain injury and strategies for improved neurocognitive outcome.","volume":"68","author":"Idro","year":"2010","journal-title":"Pediatr. Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"e92","DOI":"10.1542\/peds.2007-3709","article-title":"Cerebral malaria in children is associated with long-term cognitive impairment.","volume":"122","author":"John","year":"2008","journal-title":"Pediatrics"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-021-00284-z","article-title":"Acute kidney injury.","volume":"7","author":"Kellum","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"B38","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/0035-9203(94)90504-5","article-title":"Lactic acidosis and hypoglycaemia in children with severe malaria: Pathophysiological and prognostic significance.","volume":"88","author":"Krishna","year":"1994","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"B39","year":"2021","journal-title":"Albumin, cerebrospinal fluid."},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2018-1026","article-title":"Neurodevelopmental impairments 1 year after cerebral malaria.","volume":"143","author":"Langfitt","year":"2019","journal-title":"Pediatrics"},{"key":"B41","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1053\/j.ajkd.2018.03.028","article-title":"Distant organ dysfunction in acute kidney injury: A review.","volume":"72","author":"Lee","year":"2018","journal-title":"Am. J. Kidney Dis."},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-43044-6","article-title":"Amino acid derangements in adults with severe falciparum malaria.","volume":"9","author":"Leopold","year":"2019","journal-title":"Sci. Rep."},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2012.00217","article-title":"Urea transporter physiology studied in knockout mice.","volume":"3","author":"Li","year":"2012","journal-title":"Front. Physiol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1360","DOI":"10.1681\/ASN.2007080901","article-title":"Acute kidney injury leads to inflammation and functional changes in the brain.","volume":"19","author":"Liu","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"3355","DOI":"10.1128\/IAI.02106-05","article-title":"Elevated plasma phenylalanine in severe malaria and implications for pathophysiology of neurological complications.","volume":"74","author":"Lopansri","year":"2006","journal-title":"Infect. Immun."},{"key":"B46","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1016\/S0140-6736(03)12564-0","article-title":"Low plasma arginine concentrations in children with cerebral malaria and decreased nitric oxide production.","volume":"361","author":"Lopansri","year":"2003","journal-title":"Lancet"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1093\/infdis\/jiaa541","article-title":"How does blood-retinal barrier breakdown relate to death and disability in pediatric cerebral malaria?.","volume":"225","author":"MacCormick","year":"2022","journal-title":"J. Infect. Dis."},{"key":"B48","doi-asserted-by":"publisher","first-page":"315","DOI":"10.23876\/j.krcp.18.0056","article-title":"Brain consequences of acute kidney injury: Focusing on the hippocampus.","volume":"37","author":"Malek","year":"2018","journal-title":"Kidney Res. Clin. Pract."},{"key":"B49","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1016\/j.trstmh.2008.11.003","article-title":"The eye in cerebral malaria: What can it teach us?.","volume":"103","author":"Maude","year":"2009","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"B50","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1086\/377583","article-title":"Metabolites of the kynurenine pathway of tryptophan metabolism in the cerebrospinal fluid of Malawian children with malaria.","volume":"188","author":"Medana","year":"2003","journal-title":"J. Infect. Dis."},{"key":"B51","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1016\/j.ijpara.2006.02.004","article-title":"Human cerebral malaria and the blood-brain barrier.","volume":"36","author":"Medana","year":"2006","journal-title":"Int. J. Parasitol."},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.25481","article-title":"Frequency and risk factors of acute kidney injury during diabetic ketoacidosis in children and association with neurocognitive outcomes.","volume":"3","author":"Myers","year":"2020","journal-title":"JAMA Netw. Open"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-021-03785-0","article-title":"Identifying prognostic factors of severe metabolic acidosis and uraemia in African children with severe falciparum malaria: A secondary analysis of a randomized trial.","volume":"20","author":"Mzumara","year":"2021","journal-title":"Malar. J."},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2022.101292","article-title":"Acute kidney injury, persistent kidney disease, and post-discharge morbidity and mortality in severe malaria in children: A prospective cohort study.","volume":"44","author":"Namazzi","year":"","journal-title":"EClinicalMedicine"},{"key":"B55","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1093\/cid\/ciac229","article-title":"Acute kidney injury interacts with coma, acidosis, and impaired perfusion to significantly increase risk of death in children with severe malaria.","volume":"75","author":"Namazzi","year":"","journal-title":"Clin. Infect. Dis."},{"key":"B56","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1136\/adc.70.4.281","article-title":"Brain swelling and ischaemia in Kenyans with cerebral malaria.","volume":"70","author":"Newton","year":"1994","journal-title":"Arch. Dis. Child."},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-020-03545-6","article-title":"Plasma angiopoietin-2 is associated with age-related deficits in cognitive sub-scales in Ugandan children following severe malaria.","volume":"20","author":"Ouma","year":"2021","journal-title":"Malar. J."},{"key":"B58","doi-asserted-by":"publisher","first-page":"e734","DOI":"10.1097\/CCM.0000000000004469","article-title":"Endothelial activation, acute kidney injury, and cognitive impairment in pediatric severe malaria.","volume":"48","author":"Ouma","year":"2020","journal-title":"Crit. Care Med."},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2022.893993","article-title":"The neglected price of pediatric acute kidney injury: Non-renal implications.","volume":"10","author":"Pande","year":"","journal-title":"Front. Pediatr."},{"key":"B60","doi-asserted-by":"publisher","first-page":"2347","DOI":"10.1016\/j.athoracsur.2022.03.020","article-title":"Neurodevelopmental outcomes in infants with cardiac surgery associated acute kidney injury.","volume":"114","author":"Pande","year":"","journal-title":"Ann. Thorac. Surg."},{"key":"B61","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/j.clinbiochem.2016.06.001","article-title":"Basic concepts and practical equations on osmolality: Biochemical approach.","volume":"49","author":"Rasouli","year":"2016","journal-title":"Clin. Biochem."},{"key":"B62","doi-asserted-by":"publisher","first-page":"e2387","DOI":"10.1093\/cid\/ciaa1647","article-title":"Brain magnetic resonance imaging reveals different courses of disease in pediatric and adult cerebral malaria.","volume":"73","author":"Sahu","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0027714","article-title":"Inhaled nitric oxide reduces endothelial activation and parasite accumulation in the brain, and enhances survival in experimental cerebral malaria.","volume":"6","author":"Serghides","year":"2011","journal-title":"PLoS One"},{"key":"B64","doi-asserted-by":"publisher","first-page":"1126","DOI":"10.1056\/NEJMoa1400116","article-title":"Brain swelling and death in children with cerebral malaria.","volume":"372","author":"Seydel","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1111\/pim.12438","article-title":"Elevated cerebrospinal fluid tumour necrosis factor is associated with acute and long-term neurocognitive impairment in cerebral malaria.","volume":"39","author":"Shabani","year":"2017","journal-title":"Parasite Immunol."},{"key":"B66","doi-asserted-by":"publisher","first-page":"S122","DOI":"10.1053\/ajkd.2001.27419","article-title":"Central nervous dysfunction in uremia.","volume":"38","author":"Smogorzewski","year":"2001","journal-title":"Am. J. Kidney Dis."},{"key":"B67","doi-asserted-by":"publisher","first-page":"e686","DOI":"10.1097\/PCC.0000000000002418","article-title":"Severe acute kidney injury is associated with increased risk of death and new morbidity after pediatric septic shock.","volume":"21","author":"Starr","year":"2020","journal-title":"Pediatr. Crit. Care Med."},{"key":"B68","year":"2021","journal-title":"Stata Statistical Software: Release 17."},{"key":"B69","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.1111\/bph.12230","article-title":"The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders.","volume":"169","author":"Stone","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.3390\/toxins9030092","article-title":"Toxic dimethylarginines: Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA).","volume":"9","author":"Tain","year":"2017","journal-title":"Toxins"},{"key":"B71","first-page":"99","article-title":"Acid-base status in paediatric Plasmodium falciparum malaria.","volume":"86","author":"Taylor","year":"1993","journal-title":"Q. J. Med."},{"key":"B72","doi-asserted-by":"publisher","first-page":"1934","DOI":"10.1046\/j.1523-1755.2003.00924.x","article-title":"Review on uremic toxins: Classification, concentration, and interindividual variability.","volume":"63","author":"Vanholder","year":"2003","journal-title":"Kidney Int."},{"key":"B73","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1093\/jpids\/piz082","article-title":"Retinopathy-Positive cerebral malaria is associated with greater inflammation, blood-brain barrier breakdown, and neuronal damage than retinopathy-negative cerebral malaria.","volume":"9","author":"Villaverde","year":"2020","journal-title":"J. Pediatr. Infect. Dis. Soc."},{"key":"B74","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1093\/cid\/cis034","article-title":"Predicting the clinical outcome of severe falciparum malaria in African children: Findings from a large randomized trial.","volume":"54","author":"von Seidlein","year":"2012","journal-title":"Clin. Infect. Dis."},{"key":"B75","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1111\/tmi.12313_2","article-title":"Severe malaria.","year":"2014","journal-title":"Trop. Med. Int. Health"},{"key":"B76","doi-asserted-by":"publisher","year":"2021","journal-title":"World malaria report 2021.","DOI":"10.30875\/6c551ba0-en"},{"key":"B77","doi-asserted-by":"publisher","first-page":"2693","DOI":"10.1084\/jem.20070819","article-title":"Impaired nitric oxide bioavailability and L-arginine reversible endothelial dysfunction in adults with falciparum malaria.","volume":"204","author":"Yeo","year":"2007","journal-title":"J. Exp. Med."},{"key":"B78","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1086\/590209","article-title":"Recovery of endothelial function in severe falciparum malaria: Relationship with improvement in plasma L-arginine and blood lactate concentrations.","volume":"198","author":"Yeo","year":"2008","journal-title":"J. Infect. Dis."},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000868","article-title":"Increased asymmetric dimethylarginine in severe falciparum malaria: Association with impaired nitric oxide bioavailability and fatal outcome.","volume":"6","author":"Yeo","year":"2010","journal-title":"PLoS Pathog."},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00973","article-title":"Transport of amino acids across the blood-brain barrier.","volume":"11","author":"Zaragoza","year":"2020","journal-title":"Front. Physiol."}],"container-title":["Frontiers in Human Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnhum.2023.1177242\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,2]],"date-time":"2023-05-02T04:58:08Z","timestamp":1683003488000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnhum.2023.1177242\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,2]]},"references-count":80,"alternative-id":["10.3389\/fnhum.2023.1177242"],"URL":"https:\/\/doi.org\/10.3389\/fnhum.2023.1177242","relation":{},"ISSN":["1662-5161"],"issn-type":[{"value":"1662-5161","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,2]]},"article-number":"1177242"}}