title: Tissue distribution of migration inhibitory factor and inducible nitric oxide synthase in falciparum malaria and sepsis in African children.
abstract: BACKGROUND
  The inflammatory nature of falciparum malaria has been acknowledged since increased circulating levels of tumour necrosis factor (TNF) were first measured, but precisely where the mediators downstream from this prototype inflammatory mediator are generated has not been investigated. Here we report on the cellular distribution, by immunohistochemistry, of migration inhibitory factor (MIF) and inducible nitric oxide synthase (iNOS) in this disease, and in sepsis.
  
  
  METHODS
  We stained for MIF and iNOS in tissues collected during 44 paediatric autopsies in Blantyre, Malawi. These comprised 42 acutely ill comatose patients, 32 of whom were diagnosed clinically as cerebral malaria and the other 10 as non-malarial diseases. Another 2 were non-malarial, non-comatose deaths. Other control tissues were from Australian adults.
  
  
  RESULTS
  Of the 32 clinically diagnosed cerebral malaria cases, 11 had negligible histological change in the brain, and no or scanty intravascular sequestration of parasitised erythrocytes, another 7 had no histological changes in the brain, but sequestered parasitised erythrocytes were present (usually dense), and the remaining 14 brains showed micro-haemorrhages and intravascular mononuclear cell accumulations, plus sequestered parasitised erythrocytes. The vascular walls of the latter group stained most strongly for iNOS. Vascular wall iNOS staining was usually of low intensity in the second group (7 brains) and was virtually absent from the cerebral vascular walls of 8 of the 10 comatose patients without malaria, and also from control brains. The chest wall was chosen as a typical non-cerebral site encompassing a range of tissues of interest. Here pronounced iNOS staining in vascular wall and skeletal muscle was present in some 50% of the children in all groups, including septic meningitis, irrespective of the degree of staining in cerebral vascular walls. Parasites or malarial pigment were rare to absent in all chest wall sections. While MIF was common in chest wall vessels, usually in association with iNOS, it was absent in brain vessels.
  
  
  CONCLUSIONS
  These results agree with the view that clinically diagnosed cerebral malaria in African children is a collection of overlapping syndromes acting through different organ systems, with several mechanisms, not necessarily associated with cerebral vascular inflammation and damage, combining to cause death.
authors.affiliation: Dept of Biochemistry, Australian National University, Canberra, Australia. ian.clark@anu.edu.au
authors.forename: Ian A
authors.initials: IA
authors.lastname: Clark
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Awburn
authors.forename: Richard O
authors.initials: RO
authors.lastname: Whitten
authors.forename: Clive G
authors.initials: CG
authors.lastname: Harper
authors.forename: N George
authors.initials: NG
authors.lastname: Liomba
authors.forename: Malcolm E
authors.initials: ME
authors.lastname: Molyneux
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Taylor
mesh_terms: D000328:Adult; D000349:Africa / Q000453:epidemiology; D000818:Animals; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology / Q000378:metabolism*; D016779:Malaria, Cerebral / Q000201:enzymology / Q000453:epidemiology / Q000378:metabolism; D016778:Malaria, Falciparum / Q000201:enzymology* / Q000453:epidemiology / Q000378:metabolism*; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010963:Plasmodium falciparum / Q000302:isolation & purification; D018805:Sepsis / Q000201:enzymology* / Q000378:metabolism*; D013687:Telencephalon / Q000737:chemistry / Q000473:pathology; D014018:Tissue Distribution
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II