EXCEED THE SPACE PROVIDED. The overall goal of this study is to use the information revealed by autopsies to decrease the mortality rate of pediatric cerebral malaria. Adjunct therapies are required, but in order to be effective, they key pathogenetic mechanisms, and these have yet to be identified. Primary post mortem data from young children in sub-Saharan Africa, the group at highest risk of dying of malaria are required to elucidate these mechanisms; if they can be identified during life, effective treatment could be administered to the patients most likely to benefit. During the first four years of this study, 40 autopsies have been completed. Comparisons of the findings in cases of fatal cerebral malaria (n=25) and controls (8 cases of severe malarial anemia, 7 of non-malaria encephalopathy) reveal considerable heterogeneity in both the gross and histopathological features of fatal cerebral malaria. A sample size re-calculation, based on the variance of key parasitological measures suggests that a total of 100 cases (60 cerebral malaria, 40 controls) would be sufficient address the hypotheses below. We expect to maintain our accrual rate of 10 autopsies/year for the next 6 years (1 year in the current funding cycle, 5 in the next), and thus would be able to reach the target of 100 cases within the projected time frame. Data from the first phase of this study suggest that cerebral malaria, as it is usually defined, encompasses a variety of gross and histopathological features. Although these are dramatic, which (if any of these features) contribute to actual neuropathology has not been established. In addition, the heterogeneity of the pathology observed suggests that multiple pathophysiological processes are converging on the final clinical syndrome of cerebral malaria, i.e., coma in children with P. falciparum parasitemia. Our purpose now is to establish the associations between clinical presentation, disease pathogenesis and pathological findings in children dying of cerebral malaria and controls so that we can address the following hypotheses: The single clinical syndrome of 'fatal cerebral malaria' represents the final common pathway for several distinct pathogenetic processes. The various pathologic features of fatal cerebral malaria are differently associated with neurotoxicity. Specific patterns of endothelial cell receptor expression determine organ-specific patterns of sequestration of parasitized erythrocytes and thus contribute to organ-specific dysfunction. Clinical features, measurable at the time of admission to hospital, can identify cerebral malaria patients in whom specific pathogenetic processes are active. PERFORMANCE SITE ========================================Section End===========================================
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