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Abstract: Microparticles (MPs) resulting from vesiculation of different cell types in Plasmodium falciparum infection correlate with the level of proinflammatory cytokine TNF that may thereby determine the disease severity. Using TruCount tube based flow cytometric method for the exact quantification of MP and enzyme linked immunosorbent assay for the measurement of TNF, we conducted a hospital based case control study on P. falciparum malaria patients to scrutinize and infer the link between the two. In 52 cerebral malaria (CM), 21 multi-organ-dysfunction (MOD), 12 non cerebral severe malaria (NCSM) and 43 uncomplicated malaria patients, the MP level was found to be significantly elevated in febrile malaria patients compared to healthy controls and a striking decrease in MP level was observed with the clearance of the P. falciparum infection in the patients upon follow-up. The lowering of the parasite density with the level of plasma TNF and the positive correlation of the cytokine with the cell derived MPs and negative correlation with the respective cell count in human malaria patients suggests that TNF may be a key stimulant to the cells resulting in the release of MPs in malaria infection. [Copyright &y& Elsevier]

Abstract: In the absence of definite marker for artemisinin (ART) resistance, molecular monitoring of its partner drug sulfadoxine pyrimethamine (SP) in artemisinin based combination therapy (ACTs) together with chloroquine (CQ) for which ART is negatively correlated, may predict the effectiveness of ACT. We analyzed 201 Plasmodium falciparum field isolates for drug resistance markers for CQ (pfcrt and pfmdr1), pyrimethamine (pfdhfr) and sulfadoxine (pfdhps). Our study reveals high prevalence and non-random association of resistant mutants (K76T and N86Y) of CQ markers (pfcrt and pfmdr1). The predominance of highly resistant pfdhfr genotypes for SP with intragenic and intergenic pair-wise linkage disequilibrium between single nucleotide polymorphisms of resistant mutants of pfdhfr (C59R and S108N) and pfdhps (S436A, A437G, K540E) warn on further inclusion of SP in ACT. These findings suggest the replacement of SP in ACT with alternative partner drug for better efficacy. [Copyright &y& Elsevier]

Abstract: The complement receptor 1 (CR1/CD35) protein acts as the major rosetting receptor in Plasmodium falciparum infection and several genetic variants of CR1 gene have been shown to be associated with quantitative expression of erythrocyte CR1 (E-CR1) level. However, CR1 level and gene polymorphisms exhibit differences in clinical manifestation of malaria in regions of varying disease endemicity. The result of the present study which analyzed three SNPs (intron 27 HindIIIA>T, exon 22 3650 A>G, and exon 33 5507 C>G) of the CR1 gene in Orissa, a hyperendemic state in eastern-India showed that a significantly increased risk for cerebral malaria (CM) was associated with AA genotype of both intron 27 and exon 22 when compared with mild, severe malaria anemia (SMA) and CM+SMA group respectively. Further, the overall haplotype analysis for all the three loci showed predominantly two major haplotypes ‘AAC’ coding for higher expression of CR1 and ‘TGG’ haplotype coding for low expression of CR1 level with the former haplotype being significantly associated with CM (P value<0.00619 after Bonferroni correction) compared to mild malaria. The ‘TGG’ haplotype was proportionately more in SMA cases compared to mild malaria though statistically not significant. These findings suggest that the mild malaria group had an intermediate level of E-CR1 and extremely low or high levels of CR1 can cause severity in malaria. Further large scale studies in different endemic regions are needed to explain the epidemiological differences between E-CR1 expression and clinical manifestation of malaria which may contribute to the understanding of malaria pathogenesis. [Copyright &y& Elsevier]

Abstract: To explore the hypothesis that angiotensin II may play a role in the susceptibility to cerebral malaria (CM), we performed a genetic association study of malaria patients in Orissa, India analyzing three SNPs (ACE2 C→T, iNOS C→T, eNOS Glu→Asp) and two I/D polymorphisms (ACE I/D and IL-4 B1/B2). Our results showed that the ‘D’ allele of ACE I/D polymorphism, responsible for increased Ang II production had a significant association with mild malaria and the ACE2 C→T substitution had gender specific effect of possibly reduced expression of ACE2 in presence of ‘T’ allele in women leading to increased level of Ang II and hence protection against CM. Combined genotype analysis of eNOS Glu→Asp substitution responsible for increased NO production in Plasmodium falciparum infected individuals and ACE I/D polymorphism also showed stronger association of (Glu-Asp+Asp-Asp/ID+DD) genotypes with mild malaria (P <0.0001). Whether by its antiplasmodial activity and/or by some unknown mechanisms, Ang II protects from susceptibility to cerebral malaria remains to be investigated. These genetic findings may contribute to the understanding of malaria pathogenesis. [Copyright &y& Elsevier]

Abstract: The role of nitric oxide (NO) in the pathogenesis of cerebral malaria is controversial. Of the three isoforms of nitric oxide synthases (NOS), though iNOS expression is the major source of NO level in vivo, nNOS is the main isoform constitutively expressed in the neural tissues. However, there has been no investigation of the role of polymorphisms of the nNOS gene in the etiology of cerebral malaria. We have analyzed two single nucleotide polymorphisms (SNPs) of nNOS gene (−84G→A and 276C→T), responsible for decreased basal transcriptional activity, in 200 patients with mild Plasmodium falciparum malaria and 170 patients with cerebral malaria. Our results showed a significant association of AG genotype (OR=1.83, 95%CI=1.19–2.78, P =0.007) and AA genotype (OR=3.86, 95%CI=1.42–10.5, P =0.007) of nNOS −84G→A substitution with cerebral malaria. Interestingly, when the nNOS variant genotypes were combined together for analysis, a significantly increased risk of cerebral malaria was associated with −84(AG+AA)/276(CT+TT) genotype (OR=2.59, 95%CI=1.46–4.60, P =0.0016) and −84(AG+AA)/276(CC) genotype (OR=1.89, 95%CI=1.08–3.32, P =0.0334). The −84A seems to be a putative risk allele on the susceptibility to cerebral malaria and low nitric oxide production might have contributed to the development of cerebral malaria. [Copyright &y& Elsevier]