Malaria remains a major threat to life and the treatment of severe disease is unsatisfactory. Progress in preventing and treating malaria is hampered by our ignorance of pathogenetic mechanisms and of the causes of death. None of the existing animal or in vitro models mimics the human disease adequately, and the most valuable information on pathogenesis has come from autopsy studies of adults. However, 90% of malaria-associated mortality occurs in African children. Because there are important differences in the clinical manifestations of severe malaria between children and adults, the findings of adult post-mortem studies cannot be extrapolated to children. None of the autopsy studies conducted to date contains all of the elements required to describe malaria pathogenesis in African children. These elements are: clinical descriptions prior to death, control groups, and the application of current histological and immunohistochemical techniques. The overall objective of this study is to advance our understanding of the pathogenetic mechanisms in cerebral malaria in order to generate new approaches to prevention and treatment. Data from clinical and laboratory studies of P_. falciparum malaria support several hypotheses regarding the pathogenesis of fatal infections. Ascertaining which, of any, of these is relevant is important because the development of new treatments could then be aimed toward pathogenetically significant processes. The following specific hypotheses will be addressed in Malawian children dying with cerebral malaria, non-malarial encephalopathy and non-cerebral malaria: 1. Cerebral malaria is caused by the sequestration of parasitized red blood cells in the brain. 2. Increased intracranial pressure contributes to death in patients with cerebral malaria. 3. Endothelial receptors to parasitized red blood cells are """"""""up- regulated"""""""" in patients dying of cerebral malaria compared to those with uncomplicated malaria dying of other causes. 4. The intracerebral production of tumor necrosis factor -alpha and nitric oxide is enhanced in patients dying of cerebral malaria compared to patients dying of other causes. 5. The primary pathology in fatal pediatric malaria is within the central nervous system; there are no pathological events in other organs sufficient to account for death in patients with cerebral malaria. By incorporating control groups, making clinical observations and laboratory measurements prior to death, applying current analytical techniques to tissue samples, and studying the group at highest risk of dying from severe malaria (African children), this study would be the first to describe the clinicopathological correlates of pediatric cerebral malaria thoroughly.
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