Although malaria is widely considered a major cause of death in young children born with sickle cell anemia (SCA) in sub-Saharan Africa, this is poorly quantified. We attempted to investigate this question through 4 large case-control analyses involving 7164 children living on the coast of Kenya. SCA was associated with an increased risk of admission to hospital both with nonmalaria diseases in general (odds ratio [OR] ‫؍‬ 4.17; 95% confidence interval [CI], 1.95-8.92; P < .001) and with invasive bacterial diseases in particular (OR ‫؍‬ 8.73; 95% CI, 4.51-16.89; P < .001). We found no evidence for a strongly increased risk of either uncomplicated malaria (OR ‫؍‬ 0.43; 95% CI, 0.09-2.10; P ‫؍‬ .30) or malaria complicated by a range of well-described clinical features of severity (OR ‫؍‬ 0.80; 95% CI, 0.25-2.51; P ‫؍‬ .70) overall; nevertheless, mortality was considerably higher among SCA than non-SCA children hospitalized with malaria. Our findings highlight both the central role that malaria plays in the high early mortality seen in African children with SCA and the urgent need for better quantitative data. Meanwhile, our study confirms the importance of providing all children living with SCA in malaria-endemic areas with effective prophylaxis. (Blood. 2010;116(10):1663-1668) IntroductionThe common causes of morbidity and mortality in children living with sickle cell anemia (SCA) in developed countries have been well documented through projects, such as the Cooperative Study of Sickle Cell Disease in the United States and the Jamaican Cohort study. Nevertheless, surprisingly little research has been conducted in Africa, 1-3 where more than 230 000 children with SCA, approximately 80% of the global burden, are born every year. 4 Although malaria is widely considered a major cause of death in African children with SCA, 1,5-7 this assumption is supported by surprisingly few data. Most reports have involved small, hospital-based studies and have lacked control data that enable comparisons of risk to be made with non-SCA subjects. 1 Perhaps the strongest evidence comes from the Garki project, conducted in northern Nigeria during the 1970s, which reported a nonsignificant trend toward higher survival of children with SCA in an area exposed to intensive malaria control. 8 However, studies suggesting that malaria is an important cause of death in children with SCA are balanced by others that show the opposite: children with SCA might even be less susceptible to malaria than those without the disease. 6,[9][10][11][12][13] Determining the true risk of death from malaria in subjects with SCA is important for several reasons. From a policy perspective, documenting an association between SCA and malaria death would provide strong justification for early-life SCA screening and the targeted prescription of effective malaria prophylaxis. Conversely, if the risk of malaria-specific death was not elevated, alternative approaches to prophylaxis and treatment might be considered. Recently, we reported that malaria was a rare cause...

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In this setting, few children with uncomplicated severe pneumonia fail treatment or die under current guidelines. Deaths mainly occurred early and may be reduced by improving prevention, prehospital care and treatment of sepsis.

Evidence is accumulating that a soluble, secretory form of acetylcholinesterase may have novel, non-cholinergic functions in certain brain regions, such as the substantia nigra. In this study, application of human recombinant acetylcholinesterase (rhAChE) to pars compacta neurons in the rostral substantia nigra resulted in a sustained hyperpolarization that was not only mimicked by application of N-methyl-D-aspartate (NMDA) but also blocked by the NMDA receptor antagonists MK8O1 and 2-amino-5-phosphonopentanoic acid. Neither the rhAChE- nor the NMDA-induced hyperpolarization was seen when the calcium chelator BAPTA was injected into the neuron; hence the effect is mediated by accumulation of intracellular calcium. This intracellular calcium appears sufficient to compromise neuronal metabolism since the rhAChE-induced hyperpolarization was reversed by application of the K-ATP channel antagonist tolbutamide. Butyrylcholinesterase, a protein of similar molecular weight to acetylcholinesterase, which also hydrolyses acetylcholine, had no effect whatsoever. The results suggest that, independent of its normal catalytic function, acetylcholinesterase can act via the NMDA receptor complex to enhance calcium entry into nigral neurons and jeopardize cell metabolism. This non-classical action of acetylcholinesterase might thus be an important factor in the mechanisms underlying parkinsonian neurodegeneration.