title: Dimethylarginines: endogenous inhibitors of nitric oxide synthesis in children with falciparum malaria.
abstract: BACKGROUND
  Nitric oxide (NO) bioavailability is impaired in children and adults with severe falciparum malaria (SM). Asymmetric-dimethylarginine (ADMA) limits NO production by inhibiting NO synthase and is increased in adult SM. The role of ADMA in the pathogenesis of childhood SM is unknown.
  
  
  METHODS
  We studied Tanzanian children ages 4-8 years with malaria. Plasma levels of arginine, arginase, cell-free hemoglobin, ADMA, symmetric-dimethylarginine (SDMA), histidine-rich protein-2, and angiopoietin-2 were measured.
  
  
  RESULTS
  ADMA was low in children with SM relative to controls. Nevertheless, arginine and arginine:ADMA ratios were very low in SM. SDMA was high in children with SM. With treatment, arginine and the arginine:ADMA ratio normalized, but SDMA did not. Arginine:ADMA ratios, but not arginine, were significantly and inde-pendent-ly inversely associated with lactate and angiopoietin-2. Plasma arginase was not elevated in those with malaria, and plasma free hemoglobin was elevated only in patients with cerebral malaria.
  
  
  CONCLUSIONS
  In contrast to adults, plasma ADMA is reduced in SM in children, but hypoargininemia is more severe. Arginine bioavailability (reflected by low arginine:ADMA ratios) is therefore comparably low in SM in children as in adults. Therapies to increase NO bioavailability in malaria may be useful as adjunctive treatment of severe malaria in children.
authors.affiliation: Duke University and V.A. Medical Centers, Durham, North Carolina.
authors.forename: Joe Brice
authors.initials: JB
authors.lastname: Weinberg
authors.affiliation: Menzies School of Health Research and Charles Darwin University, Australia.
authors.forename: Tsin W
authors.initials: TW
authors.lastname: Yeo
authors.affiliation: Hubert Karuiki Memorial University, Dar es Salaam, Tanzania.
authors.forename: Jackson P
authors.initials: JP
authors.lastname: Mukemba
authors.affiliation: Hubert Karuiki Memorial University, Dar es Salaam, Tanzania.
authors.forename: Salvatore M
authors.initials: SM
authors.lastname: Florence
authors.affiliation: Duke University and V.A. Medical Centers, Durham, North Carolina.
authors.forename: Alicia D
authors.initials: AD
authors.lastname: Volkheimer
authors.affiliation: Menzies School of Health Research and Charles Darwin University, Australia.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Duke University and V.A. Medical Centers, Durham, North Carolina.
authors.forename: Youwei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Duke University and V.A. Medical Centers, Durham, North Carolina.
authors.forename: Matthew
authors.initials: M
authors.lastname: Rubach
authors.affiliation: University of Utah and V.A. Medical Centers, Salt Lake City.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Granger
authors.affiliation: Hubert Karuiki Memorial University, Dar es Salaam, Tanzania.
authors.forename: Esther D
authors.initials: ED
authors.lastname: Mwaikambo
authors.affiliation: Menzies School of Health Research and Charles Darwin University, Australia.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Anstey
mesh_terms: D000208:Acute Disease; D001119:Arginase / Q000097:blood; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D016778:Malaria, Falciparum / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*
chemical_list: D006454:Hemoglobins; C487735:dimethylarginine; D009569:Nitric Oxide; D001120:Arginine; D001119:Arginase
keywords: angiopoeitin 2; arginase; arginine; asymmetric dimethylarginine; falciparum malaria; lactate; nitric oxide; symmetric dimethylarginine