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Genetic variations in toll-like receptors and cytokine genes of the innate immune pathways have been implicated in controlling parasite growth and the pathogenesis of Plasmodium falciparum mediated malaria. We previously published genetic association of TLR4 non-synonymous and TNF-α promoter polymorphisms with P.falciparum blood infection level and here we extend the study considerably by (i) investigating genetic dependence of parasite-load on interleukin-12B polymorphisms, (ii) reconstructing gene-gene interactions among candidate TLRs and cytokine loci, (iii) exploring genetic and functional impact of epistatic models and (iv) providing mechanistic insights into functionality of disease-associated regulatory polymorphisms. Our data revealed that carriage of AA (P = 0.0001) and AC (P = 0.01) genotypes of IL12B 3′UTR polymorphism was associated with a significant increase of mean log-parasitemia relative to rare homozygous genotype CC. Presence of IL12B+1188 polymorphism in five of six multifactor models reinforced its strong genetic impact on malaria phenotype. Elevation of genetic risk in two-component models compared to the corresponding single locus and reduction of IL12B (2.2 fold) and lymphotoxin-α (1.7 fold) expressions in patients'peripheral-blood-mononuclear-cells under TLR4Thr399Ile risk genotype background substantiated the role of Multifactor Dimensionality Reduction derived models. Marked reduction of promoter activity of TNF-α risk haplotype (C-C-G-G) compared to wild-type haplotype (T-C-G-G) with (84%) and without (78%) LPS stimulation and the loss of binding of transcription factors detected in-silico supported a causal role of TNF-1031. Significantly lower expression of IL12B+1188 AA (5 fold) and AC (9 fold) genotypes compared to CC and under-representation (P = 0.0048) of allele A in transcripts of patients' PBMCs suggested an Allele-Expression-Imbalance. Allele (A+1188C) dependent differential stability (2 fold) of IL12B-transcripts upon actinomycin-D treatment and observed structural modulation (P = 0.013) of RNA-ensemble were the plausible explanations for AEI. In conclusion, our data provides functional support to the hypothesis that de-regulated receptor-cytokine axis of innate immune pathway influences blood infection level in P. falciparum malaria.

Scrub meningoencephalitis, with a notably higher incidence, showed favorable therapeutic response. Prompt and empiric doxycycline therapy could be lifesaving.

BackgroundDespite its immunogenicity, the polymorphic nature of merozoite surface protein 1, an important vaccine candidate for Plasmodium falciparum malaria, remains a concern. This study analyses the impact of genetic variability and parasite population structure on epitope organization of different MSP1 segments.MethodsAltogether 98 blood samples collected from P. falciparum infected mild and severe malaria patients of Chhattisgarh and West Bengal were used to sequence regions encoding block 2 and MSP1-19 of msp1. Sequences were analysed using MEGA7, DnaSPv5, Arlequin3.5 and BepiPred.ResultsAll three major MSP1 block 2 allele families namely K1, MAD20 and RO33 were detected in the samples and they together resulted in 41 indel variants. Chhattisgarh samples displayed an average MOI of 2.07 ± 1.59 which was higher in mild malaria and in age group < 18 years. Ultra-structure of block 2 alleles revealed that mutation and repeat expansion were two major mechanisms responsible for allelic variability of K1 and MAD20. Regions flanking block 2 were highly variable in Chhattisgarh with average mismatch differences (k) ranging from 1.198 to 5.156 for three families. In contrast, region encompassing MSP1-19 exhibited limited heterogeneity (kChhattisgarh = 1.45, kWest Bengal = 1.363). Of the 50 possible B cell linear epitopes predicted from block 2 variants, 94.9% (131 of 138) of the parasites could be represented by three conserved antigens.ConclusionsPresent data indicates that natural selection and transmission intensity jointly play a role in controlling allelic diversity of MSP1 in Indian parasite isolates. Despite remarkable genetic variability, a limited number of predominant and conserved epitopes are present in Indian parasite isolates reinstating the importance of MSP1 as a promising malaria vaccine candidate.Electronic supplementary materialThe online version of this article (10.1186/s12936-018-2592-y) contains supplementary material, which is available to authorized users.

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Diazepam used in the treatment of eclampsia crosses the placental barrier readily, and may cause various clinical effects in the neonates. Twenty-five (25) live born babies of eclamptic mothers receiving diazepam were studied and cord blood diazepam concentration was estimated. Effect of low dose of diazepam is minimal apart from lowering of rectal temperature and the effects lasted for a period of 12 hours. But high dose (> 30 mg) of diazepam and prolonged duration of diazepam therapy in mothers causes significant depression of the newborn and the effects lasted for a period of 36-48 hours. As the clinical condition of the newborn is not related to the diazepam concentration in cord blood, the cord blood estimation is not helpful in the assessment of clinical effects of the drug in newborn. The tissue storage of the drug in newborn appears to be responsible for the clinical effects.

Introduction: Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, eczema, and recurrent infections. The disease is usually associated with small defective platelets. Case Presentation: We described an 18-month-old boy who presented with lower gastrointestinal bleeding, eczema, and recurrent infections. There was pancytopenia with normal-sized platelets. In addition, the CD4 count was significantly low and serum IgA and IgE levels were increased. The diagnosis of WAS was confirmed by detecting a mutation of WAS gene, which was due to a deletion mutation resulting in frameshift (c.177DelT). Conclusions: Usually microplatelets with mean platelet volume of 4-5 fL are seen in WAS, but in this case, the patient had normal-sized platelets with a rare mutation of WAS gene. Therefore, high index of clinical suspicion is needed to diagnose WAS.

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