Burden, features, and outcome of neurological involvement in acute falciparum malaria in Kenyan children

Context  Plasmodium falciparum appears to have a particular propensity to involve the brain but the burden, risk factors, and full extent of neurological involvement have not been systematically described. Objectives  To determine the incidence and describe the clinical phenotypes and outcomes of neurological involvement in African children with acute falciparum malaria. Design, Setting, and Patients  A review of records of all children younger than 14 years admitted to a Kenyan district hospital with malaria from January 1992 through December 2004. Neurological involvement was defined as convulsive seizures, agitation, prostration, or impaired consciousness or coma. Main Outcome Measures  The incidence, pattern, and outcome of neurological involvement. Results  Of 58 239 children admitted, 19 560 (33.6%) had malaria as the primary clinical diagnosis. Neurological involvement was observed in 9313 children (47.6%) and manifested as seizures (6563/17 517 [37.5%]), agitation (316/11 193 [2.8%]), prostration (3223/15 643 [20.6%]), and impaired consciousness or coma (2129/16 080 [13.2%]). In children younger than 5 years, the mean annual incidence of admissions with malaria was 2694 per 100 000 persons and the incidence of malaria with neurological involvement was 1156 per 100 000 persons. However, readmissions may have led to a 10% overestimate in incidence. Children with neurological involvement were older (median, 26 [interquartile range {IQR}, 15-41] vs 21 [IQR, 10-40] months; P<.001), had a shorter duration of illness (median, 2 [IQR, 1-3] vs 3 [IQR, 2-3] days; P<.001), and a higher geometric mean parasite density (42.0 [95% confidence interval {CI}, 40.0-44.1] vs 30.4 [95% CI, 29.0-31.8] x 10³/µL; P<.001). Factors independently associated with neurological involvement included past history of seizures (adjusted odds ratio [AOR], 3.50; 95% CI, 2.78-4.42), fever lasting 2 days or less (AOR, 2.02; 95% CI, 1.64-2.49), delayed capillary refill time (AOR, 3.66; 95% CI, 2.40-5.56), metabolic acidosis (AOR, 1.55; 95% CI, 1.29-1.87), and hypoglycemia (AOR, 2.11; 95% CI, 1.31-3.37). Mortality was higher in patients with neurological involvement (4.4% [95% CI, 4.2%-5.1%] vs 1.3% [95% CI, 1.1%-1.5%]; P<.001). At discharge, 159 (2.2%) of 7281 patients had neurological deficits. Conclusions  Neurological involvement is common in children in Kenya with acute falciparum malaria, and is associated with metabolic derangements, impaired perfusion, parasitemia, and increased mortality and neurological sequelae. This study suggests that falciparum malaria exposes many African children to brain insults.      

Physical and functional interactions between Stat5 and the tyrosine- phosphorylated receptors for erythropoietin and interleukin-3

Erythropoietin (Epo) and interleukin-3 (IL-3) stimulate activation of the Jak2 tyrosine kinase and induce tyrosine phosphorylation and activation of Stat5. In the present study, we have shown that Epo or IL- 3 stimulation induces binding of Stat5 to the tyrosine-phosphorylated Epo receptor (EpoR) or IL-3 receptor beta subunit (betaIL3), respectively, in IL-3-dependent 32D cells expressing the EpoR. The binding of Stat5 to these cytokine receptors was shown to be rapid and transient, occurring within 1 minute of stimulation of cells and significantly decreasing after 5 minutes of cell treatment. In vivo binding experiments in COS cells showed that binding of Stat5 to the EpoR was mediated through the Stat5 Src homology 2 (SH2) domain. In vitro binding studies further showed that Stat5, but not other Stats examined, bound specifically to tyrosine-phosphorylated recombinant EpoR fusion proteins. In these in vivo and in vitro binding studies, Stat5 bound, albeit to a lesser degree, to truncated EpoR mutants in which all the intracellular tyrosines except Y-343 were removed. Furthermore, EpoR-derived synthetic phosphotyrosine peptides corresponding to Y-343, Y-401, Y-431, and Y-479 inhibited the in vitro binding of Stat5. When expressed in 32D cells, a mutant EpoR in which all the intracellular tyrosines were removed by carboxy-terminal truncation showed a significantly impaired ability to induce tyrosine phosphorylation of Stat5, particularly at low concentrations of Epo, but exhibited an increased sensitivity to Epo for growth signaling as compared with the wild-type EpoR. These results indicate that Stat5 specifically and transiently binds to the EpoR through the interaction between the Stat5 SH2 domain and specific phosphorylated tyrosines, including Y-343, in the EpoR cytoplasmic domain. It was implied that betaIL3 may also have similar Stat5 docking sites. The Stat5 docking sites in the EpoR were shown to facilitate specific activation of Stat5, which, however, may not be required for the EpoR-mediated growth signaling.     

Detection of high risk coronary artery disease by thallium imaging.

One hundred and three patients who underwent coronary arteriography were studied by thallium imaging and the results analysed by Bayesian principles to assess the usefulness of semiquantitative stress thallium imaging for predicting the presence or absence of multivessel coronary disease. Significant disease was found in 80 patients, of whom 77 had abnormal thallium scans (sensitivity 96%). Thallium images were normal in 15 of 23 patients with no significant disease (specificity 65%). Multiple thallium segmental defects were found to be 90% sensitive and 65% specific for multivessel coronary artery disease and were present in 80% of patients with left main stem disease and in 93% of patients with triple vessel disease. A single thallium defect or normal scan excluded multivessel, left main, and triple vessel disease with 81%, 94%, and 91% predictive accuracy respectively. By Bayesian analysis the predictive accuracy for excluding multivessel disease was greater than 90% in patients with a pretest probability of multivessel disease of less than or equal to 40%. Coronary arteriography to exclude multivessel disease is therefore unnecessary in a high proportion of patients with known or suspected coronary artery disease.     

The haemostatic role of tissue factor pathway inhibitor

Under normal conditions the blood circulates freely within the confines of the vascular system, carrying oxygen, nutrients, and hormonal information around the body and removing metabolic waste. If blood gains access to extravascular sites, or the vasculature becomes pathologically challenged, hemostasis may be activated. This process is finely regulated by positive and negative feedback loops that modulate fibrin clot formation. Blood coagulation revolves around the activation and assembly of the components of the prothrombinase complex, which converts the inactive zymogen, prothrombin, into its active form, thrombin. This serine protease catalyzes the conversion of fibrinogen to fibrin, the structural scaffold that stabilizes platelet aggregates at sites of vascular injury. The extent of the hemostatic response is controlled by the action of inhibitory pathways, which ensure that thrombin activity and the spread of the hemostatic plug is limited to the site of vessel damage. This review article focuses on the major physiological regulator of tissue factor-induced coagulation, tissue factor pathway inhibitor, its expression, anticoagulant function, and its role in normal hemostasis.