Please use this identifier to cite or link to this item: http://docs.prosentient.com.au/prosentientjspui/handle/1/10204
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dc.contributor.authorYeo, Tsin W-
dc.contributor.authorLampah, Daniel A-
dc.contributor.authorKenangalem, Enny-
dc.contributor.authorTjitra, Emiliana-
dc.contributor.authorPrice, Ric N-
dc.contributor.authorWeinberg, J Brice-
dc.contributor.authorHyland, Keith-
dc.contributor.authorGranger, Donald L-
dc.contributor.authorAnstey, Nicholas M-
dc.date2015-
dc.date.accessioned2018-05-15T23:01:02Z-
dc.date.accessioned2019-06-29T00:36:54Z-
dc.date.available2018-05-15T23:01:02Z-
dc.date.available2019-06-29T00:36:54Z-
dc.date.issued2015-03-
dc.identifier.citationPLoS pathogens 2015-03; 11(3): e1004667-
dc.identifier.urihttp://docs.prosentient.com.au/prosentientjspui/handle/1/10204-
dc.description.abstractTetrahydrobiopterin (BH₄) is a co-factor required for catalytic activity of nitric oxide synthase (NOS) and amino acid-monooxygenases, including phenylalanine hydroxylase. BH4 is unstable: during oxidative stress it is non-enzymatically oxidized to dihydrobiopterin (BH₂), which inhibits NOS. Depending on BH₄ availability, NOS oscillates between NO synthase and NADPH oxidase: as the BH₄/BH₂ ratio decreases, NO production falls and is replaced by superoxide. In African children and Asian adults with severe malaria, NO bioavailability decreases and plasma phenylalanine increases, together suggesting possible BH₄ deficiency. The primary three biopterin metabolites (BH₄, BH₂ and B₀ [biopterin]) and their association with disease severity have not been assessed in falciparum malaria. We measured pterin metabolites in urine of adults with severe falciparum malaria (SM; n=12), moderately-severe malaria (MSM, n=17), severe sepsis (SS; n=5) and healthy subjects (HC; n=20) as controls. In SM, urinary BH₄ was decreased (median 0.16 ¼mol/mmol creatinine) compared to MSM (median 0.27), SS (median 0.54), and HC (median 0.34)]; p<0.001. Conversely, BH₂ was increased in SM (median 0.91 ¼mol/mmol creatinine), compared to MSM (median 0.67), SS (median 0.39), and HC (median 0.52); p<0.001, suggesting increased oxidative stress and insufficient recycling of BH2 back to BH4 in severe malaria. Overall, the median BH₄/BH₂ ratio was lowest in SM [0.18 (IQR: 0.04-0.32)] compared to MSM (0.45, IQR 0.27-61), SS (1.03; IQR 0.54-2.38) and controls (0.66; IQR 0.43-1.07); p<0.001. In malaria, a lower BH₄/BH₂ ratio correlated with decreased microvascular reactivity (r=0.41; p=0.03) and increased ICAM-1 (r=-0.52; p=0.005). Decreased BH4 and increased BH₂ in severe malaria (but not in severe sepsis) uncouples NOS, leading to impaired NO bioavailability and potentially increased oxidative stress. Adjunctive therapy to regenerate BH4 may have a role in improving NO bioavailability and microvascular perfusion in severe falciparum malaria.-
dc.language.isoeng-
dc.subject.meshAdult-
dc.subject.meshBiopterin-
dc.subject.meshCreatinine-
dc.subject.meshEndothelium-
dc.subject.meshFemale-
dc.subject.meshHumans-
dc.subject.meshMalaria, Falciparum-
dc.subject.meshMale-
dc.subject.meshNitric Oxide-
dc.subject.meshSepsis-
dc.subject.meshSeverity of Illness Index-
dc.subject.meshMicrocirculation-
dc.titleImpaired systemic tetrahydrobiopterin bioavailability and increased dihydrobiopterin in adult falciparum malaria: association with disease severity, impaired microvascular function and increased endothelial activation.-
dc.typeClinical Trial-
dc.typeJournal Article-
dc.typeResearch Support, N.I.H., Extramural-
dc.typeResearch Support, Non-U.S. Gov't-
dc.identifier.doi10.1371/journal.ppat.1004667-
dc.identifier.journaltitlePLoS pathogens-
dc.identifier.pubmedurihttps://www.ezpdhcs.nt.gov.au/login?url=https://www.ncbi.nlm.nih.gov/pubmed/25764397-
dc.identifier.pubmedidhttps://www.ezpdhcs.nt.gov.au/login?url=https://www.ncbi.nlm.nih.gov/pubmed/25764397-
dc.identifier.affiliationGlobal and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Institute of Infectious Disease and Epidemiology, Tan Tock Seng Hospital, Singapore..-
dc.identifier.affiliationMenzies School of Health Research-National Institute of Health Research and Development Research Program, and District Ministry of Health, Timika, Papua, Indonesia..-
dc.identifier.affiliationMenzies School of Health Research-National Institute of Health Research and Development Research Program, and District Ministry of Health, Timika, Papua, Indonesia..-
dc.identifier.affiliationNational Institute of Health Research and Development, Jakarta, Indonesia..-
dc.identifier.affiliationGlobal and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia; Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom..-
dc.identifier.affiliationDuke University and VA Medical Centers, Durham, North Carolina, United States of America..-
dc.identifier.affiliationMedical Neurogenetics LLC, Atlanta, Georgia, United States of America..-
dc.identifier.affiliationDivision of Infectious Diseases, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, United States of America..-
dc.identifier.affiliationGlobal and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia; Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia..-
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