Modulation of the immune response and infection pattern to Leishmania donovani in visceral leishmaniasis due to arsenic exposure: An in vitro study.

The arsenic contamination of ground water in visceral leishmaniasis (VL) endemic areas in Bihar, India leads to human exposure through drinking water. Possibly, the consumed arsenic (As) accumulates in the tissues of VL patients, who subsequently internalize intracellular amastigotes to confer resistance against chemotherapy to the parasite, leading to modulation in the host's immune response. This hypothesis appears to be consistent with the in vitro findings that in arsenic-exposed parasites, the mitochondrial membrane potential became depolarized, whereas the reduced thiol and lactate production was overexpressed with enhanced glucose consumption; therefore, the reduced thiol possibly supports an immunosuppressive state in the host cells. This observation was well supported by the down-regulated expression of pro-inflammatory cytokines (IL-2, IL-12, IFN-γ, and TNF-α) with a suppressed anti-leishmanial function of macrophage (NO, ROS). In contrast, the pathophysiological mechanism of VL has received ample support by the promotion of Th2 cytokines (IL-4 and IL-10) in the presence of arsenic-exposed Leishmania parasites (LdAS). Dysfunction of mitochondria and the overexpression of lactate production raise the possibility of the Warburg effect being operative through the up-regulation of glucose consumption by parasites to enhance the energy production, possibly augmenting virulence. Therefore, we surmise from our data that arsenic exposure to Leishmania donovani modulates the immune response and infection pattern by impairing parasite function, which may affect the anti-leishmanial effect in VL.

Chemical analysis of groundwater of Nathnagar Block under Bhagalpur District, Bihar (India).

The chemical analysis of groundwater samples from hundred handpumps in five villages of the Nathnagar Block under Bhagalpur District, Bihar, India indicates that the water samples in the area were slightly alkaline and the concentration of total hardness and heavy metal like arsenic were above the drinking water specifications as prescribed by World Health Organization (1999) and ISI (2003); whereas other chemical parameters were well within the permissible limit. The results of the present study suggest that the groundwater sources under investigation were suitable for domestic purposes including drinking except for arsenic. The concentration of arsenic in most of the handpumps analyzed was high, and that might be attributed to the excessive withdrawal of the groundwater and changes in the geo-chemical environment of the Ganga river. Moreover, the Ganga River System itself carries high sediment bed loads which contain several trace elements, including arsenic. Some effective measures like rainwater harvesting and artificial recharge techniques are urgently required and suggested for water quality management in this region.

Efficacy of tadalafil in secondary Raynaud's phenomenon resistant to vasodilator therapy: a double-blind randomized cross-over trial.

OBJECTIVE: To evaluate the efficacy of tadalafil as add-on therapy in secondary RP resistant to vasodilators. METHODS: Patients with scleroderma and MCTD having four or more RP attacks per week despite being on vasodilators were randomized to receive either placebo or tadalafil (20 mg) on alternate days as add-on therapy to their current vasodilators for 6 weeks. After a 7-day washout, patients were crossed over to the other arm. Primary endpoints were improvement in the daily frequency and duration of RP episodes and RP condition score (RCS). Secondary outcome measures were healing of existing and appearance of new digital ulcers (DUs) and improvement in scleroderma-specific HAQ (SHAQ), quality of life (QoL), flow-mediated dilatation (FMD), patient and physician global assessment. RESULTS: Twenty-four of 25 recruited patients completed the study. All the patients were receiving calcium channel blockers and in addition 18 were receiving other vasodilators. During tadalafil therapy significant improvement in mean daily frequency, mean daily duration of RP and mean daily RCS were observed as compared with baseline and placebo. All the 24 digital lesions healed during tadalafil therapy as compared with 3/13 during the placebo treatment (P<0.0001). One new DU was reported during tadalafil therapy vs 13 during placebo therapy (P=0.0005). QoL, SHAQ, FMD, patient and physician global assessment significantly improved while on tadalafil. No serious adverse event was observed. CONCLUSION: Tadalafil as add-on therapy improves symptoms of RP, heals and prevents new DUs and improves QoL in patients with resistant secondary RP. TRIAL REGISTRATION: Clinicaltrials.gov, http://clinicaltrials.gov/, identifier: NCT00626665.