Malaria during pregnancy and infancy, in an area of intense malaria transmission in central India

The clinico-epidemiological pattern of malarial infection in a cohort of pregnant women and infants was analysed during a malaria epidemic (1997-1998). The subjects were all members of tribal communities in an isolated and almost inaccessible area of central India. Overall, 151 (55%) of the 274 pregnant women investigated were found to have malarial infections at some time during the study, with Plasmodium falciparum predominating (88% of infections). All of the women investigated, whether primigravidae (42% found infected), secundigravidae (68%) or multigravidae (54%), were at great risk of developing severe malaria. When trimesters were compared, the highest prevalence of P. falciparum infection was recorded in the second (59% infected), irrespective of parity. Of the women found infected with P. falciparum, 3% had abortions, 4% stillbirths and 2% had babies who died while neonates. The small number of P. vivax infections observed prevented similar analyses for this species of parasite. Malarial infection was also seen in 218 (41%) of the 535 infants investigated. The values of age-specific prevalences revealed that > 30% of the infants examined at 2 months of age were then found to have P. vivax and/or P. falciparum parasitaemias. At 1 year of age, overall malaria prevalence was 50%, with P. vivax representing 25% of the infections and P. falciparum the rest. Subsequent follow-up revealed that three of the infants investigated, each of whom had had P. falciparum infections previously, died before their first birthdays. Re-infections (or treatment failures) were found to be common, both in the infants and the pregnant women. Pregnant women and infants from the study area clearly require systematic intervention to reduce their malaria-attributable morbidity.     

A novel predictor of clinical response to methotrexate in patients with rheumatoid arthritis: a pilot study of in vitro T cell cytokine suppression

OBJECTIVE: Methotrexate (MTX) is an important drug for treatment of rheumatoid arthritis; however, there is variation in the clinical response. MTX inhibits T cell cytokine production, with significant interindividual variability in the dose required. We investigated if the variability in clinical response was related to variability in the in vitro assay. METHODS:Patients with disease modifying antirheumatic drug-naive, active RA [1982 American College of Rheumatology (ACR) criteria] seen from September 2005 through January 2006 were enrolled. MTX was started at 10 mg/week and increased monthly by 2.5 mg/week. Baseline whole-blood cultures were set up with anti-CD3, anti-CD28, and increasing doses of MTX. Supernatants were harvested at 96 hours and tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin 10 (IL-10) concentrations were estimated by ELISA. The dose of MTX (ID50) required for 50% suppression of production of cytokines and the change in Disease Activity Score-28 (DeltaDAS) at 4 months were noted. RESULTS: T cell stimulation resulted in significant increase in cytokine release, and addition of MTX led to a dose-dependent suppression of all 3 cytokines. There was significant negative correlation of DeltaDAS with ID50 values for TNF-alpha (R = -0.62, p < 0.01) and IFN-gamma (R = -0.43, p = 0.04). At 4 months, EULAR moderate and ACR 20% responses were achieved by 13 and 16 patients, respectively. EULAR moderate response could be predicted using ROC curves for TNF-alpha (sensitivity 93%, specificity 86%) and IFN-gamma (60% specificity, 71% sensitivity). ACR response was correctly predicted in 14 of 16 ACR 20% responders and in all ACR 50% and ACR 70% responders. CONCLUSION: An in vitro TNF-alpha suppression assay may help predict clinical response to MTX in RA.     

Secretory factors in the retrocerebral endocrine-aortal complex of the water-bug, Sphaerodema annulatum (Heteroptera: Belostomatidae)

A histological study of the retrocerebral endocrine-aortal complex of Sphaerodema annulatum, employing conventional neurosecretory stains, reveals the presence of three qualitatively different secretory factors—one present in the corpora cardiaca (CC) and the other two distributed in the corpora allata (CA), aorta wall and nerves going to the pericardial cells. For reasons discussed in the paper, the factor present in the CC is regarded as an indigenous secretion produced by their own intrinsic secretory cells, and the remaining two as cerebral in origin, produced by two tinctorially different neurosecretory cell types.     

Factors influencing the basal and recombinant human thyrotropin-stimulated serum thyroglobulin in patients with metastatic thyroid carcinoma

The serum thyroglobulin (Tg) level is the most sensitive marker for detecting residual thyroid carcinoma. We hypothesized that the basal and TSH-stimulated Tg levels in patients with metastatic thyroid carcinoma would reflect tumor volume, histological subtype, and location of metastatic lesions. A retrospective review of 417 thyroid cancer survivors undergoing evaluation for residual disease with the assistance of recombinant human TSH (rhTSH) was performed. In 169 patients with metastatic disease, we found that the basal Tg level directly correlated with the number of lesions, and that it was highest in patients with follicular and lowest in those with papillary thyroid carcinoma. The basal Tg level was highest in patients with bone metastases and lowest in those with cervical metastases. The fold increase in the serum Tg after rhTSH treatment was highest in papillary thyroid carcinoma and lowest in Hurthle cell carcinoma. The fold increase in Tg was not influenced by tumor volume or by the site of metastatic lesions. Multivariate analysis showed multiple interactions between factors, but did not identify one factor that significantly influenced basal Tg or fold increase. We conclude that the location and volume of metastases influence basal Tg, but not its responsiveness to rhTSH, whereas the histological type of carcinoma influences both basal Tg and responsiveness to rhTSH.     

Identification of BRaf-Sparing Amino-Thienopyrimidines with Potent IRE1α Inhibitory Activity

Amino-quinazoline BRaf kinase inhibitor 2 was identified from a library screen as a modest inhibitor of the unfolded protein response (UPR) regulating potential anticancer target IRE1α. A combination of crystallographic and conformational considerations were used to guide structure-based attenuation of BRaf activity and optimization of IRE1α potency. Quinazoline 6-position modifications were found to provide up to 100-fold improvement in IRE1α cellular potency but were ineffective at reducing BRaf activity. A salt bridge contact with Glu651 in IRE1α was then targeted to build in selectivity over BRaf which instead possesses a histidine in this position (His539). Torsional angle analysis revealed that the quinazoline hinge binder core was ill-suited to accommodate the required conformation to effectively reach Glu651, prompting a change to the thienopyrimidine hinge binder. Resulting analogues such as 25 demonstrated good IRE1α cellular potency and imparted more than 1000-fold decrease in BRaf activity.     

Averting transmission: A pivotal target to manage amoebiasis

Amoebiasis is a parasitic infectious disease caused by the enteric protozoan Entamoeba histolytica, a leading basis of deaths accounted to parasites, succeeding malaria and schistosomiasis. Conventional treatment methodologies used to deal with amoebiasis mainly rely on the administration of anti‐amoebic compounds and vaccines but are often linked with substantial side‐effects on the patient. Besides, cases of development of drug resistance in protozoans have been recorded, contributing further to the reduction in the efficiency of the treatment. Loopholes in the efficacious management of the disease call for the development of novel methodologies to manage amoebiasis. A way to achieve this is by targeting the essential metabolic processes of ‘encystation’ and ‘excystation’, and the associated biomolecules, thus interrupting the biphasic life cycle of the parasite. Technologies like the CRISPR‐Cas9 system can efficiently be exploited to discover novel and essential molecules that regulate the protozoan's metabolism, while efficiently manipulating and managing the known drug targets, leading to an effective halt and forestall to the enteric infection. This review presents a perspective on these essential metabolic processes and the associated molecules that can be targeted efficaciously to prevent the transmission of amoebiasis, thus managing the disease and proving to be a fruitful endeavour.     

Putative roles of a proline–glutamic acid-rich protein (PE3) in intracellular survival and as a candidate for subunit vaccine against Mycobacterium tuberculosis

The proline–glutamic acid (PE) protein family of Mycobacterium tuberculosis (Mtb) plays diverse roles in the pathogenesis and modulation of host immune responses. The uniqueness of conserved regions of PE proteins may be useful to test and validate their corresponding functions. Hence, the present study has been undertaken to demonstrate the role of PE3 (Rv0159c) for persistence, host immune response and immunoprophylaxis. We have expressed Mtb-specific PE3 gene in M. smegmatis (MS) and used the strain to infect J774A.1 macrophage cells and BALB/c mice. It was observed that during the infection, the MS expressing PE3 showed higher bacterial load when compared to infection with wild-type MS. In hypoxic condition, the expression level of PE3 gene was induced in Mtb, which further showed its relevance in the cell survival during hypoxia-induced persistence. The expression level of PE3 in Mtb was markedly induced during chronic stage of murine infection, which reiterated its importance in mycobacterial persistence in the host. The immunization of mice with recombinant PE3 protein stimulated the secretion of TNF, IL-6 and IL-2 cytokines and generated strong protective immunity against challenge with live mycobacteria, which was evidenced by decreased viable bacilli in the lungs, histopathological changes and increased survival of PE3 immunized mice. Conclusively, the results indicated that PE3 plays significant roles in mycobacterial persistence during infection, modulate host immune response and hence could be a prospective candidate for the development of subunit vaccine against tuberculosis.     

Molecular identification of enteroviruses associated with aseptic meningitis in children from India

We identified and characterized enteroviruses associated with aseptic meningitis in children between April 2009 and March 2010. Enterovirus RNA was detected in 51 (45.5 %) of 112 CSF samples. Molecular typing by RT-PCR and sequencing of a partial VP1 region revealed the predominance of echovirus (ECV) 32 (n = 20), followed by ECV 11 (n = 10), ECV 13 and ECV 14 (n = 5 each), coxsackievirus (CV) B3 and CV B6 (n = 3 each), CV A2, CV A10 and ECV 30 (n = 1 each). Phylogenetic analysis of ECV 32 showed 0 to 4 % sequence divergence among strains of the present study and 20-23 % from the prototype Puerto Rico strain at the nucleotide level. This is the first report of ECV 32 associated with an aseptic meningitis epidemic and identification of seven different enterovirus serotypes (CV A2, CV A10, CV B3, CV B6, ECV 13, ECV 14 and ECV 32) in meningitis cases from India.     

Tissue specific expression of sialic acid metabolic pathway: role in GNE myopathy

Journal of Muscle Research and Cell Motility - GNE myopathy is an adult-onset degenerative muscle disease that leads to extreme disability in patients. Biallelic mutations in the rate-limiting...     

Evolution of β-catenin-independent Wnt–GSK3–mTOR signalling in regulation of energy metabolism in isoproterenol-induced cardiotoxicity model

Inflammation Research - Isoproterenol (ISO) is widely used agent to study the effects of interventions which could prevent or attenuate the development of myocardial infarction. The sequence of...