Abstract. India is one of three countries that account for an estimated 300,000 of 500,000 cases of visceral leishmaniasis (VL) occurring annually. Bihar State is the most affected area of India, with more than 90% of the cases. Surveys were conducted in two villages within the Saran district of Bihar, India, from 2009 to July of 2011 to assess risk factors associated with VL. Forty-five cases were identified, and individuals were given an oral survey. The results indicated that men contracted the disease more than women (58%), and cases over the age of 21 years accounted for 42% of the total VL cases. April to June showed the highest number of new cases. Of 135 households surveyed for sleeping conditions, 95% reported sleeping outside, and 98% slept in beds. Proximity to VL cases was the greatest risk factor (cluster 1 relative risk = 11.89 and cluster 2 relative risk = 138.34). The VL case clustering observed in this study can be incorporated in disease prevention strategies to more efficiently and effectively target VL control efforts.

Optimal right ventricular (RV) function in pulmonary hypertension (PH) requires structural and functional coupling between the RV cardiomyocyte and its adjacent capillary network. Prior investigations have indicated that RV vascular rarefaction occurs in PH, which could contribute to RV failure by reduced delivery of oxygen or other metabolic substrates. However, it has not been determined if rarefaction results from relative underproliferation in the setting of tissue hypertrophy or from actual loss of vessels. It is also unknown if rarefaction results in inadequate substrate delivery to the RV tissue. In the present study, PH was induced in rats by SU5416-hypoxia-normoxia exposure. The vasculature in the RV free wall was assessed using stereology. Steady-state metabolomics of the RV tissue was performed by mass spectrometry. Complementary studies were performed in hypoxia-exposed mice and rats. Rats with severe PH had evidence of RV failure by decreased cardiac output and systemic hypotension. By stereology, there was significant RV hypertrophy and increased total vascular length in the RV free wall in close proportion, with evidence of vessel proliferation but no evidence of endothelial cell apoptosis. There was a modest increase in the radius of tissue served per vessel, with decreased arterial delivery of metabolic substrates. Metabolomics revealed major metabolic alterations and metabolic reprogramming; however, metabolic substrate delivery was functionally preserved, without evidence of either tissue hypoxia or depletion of key metabolic substrates. Hypoxia-treated rats and mice had similar but milder alterations. There is significant homeostatic vascular adaptation in the right ventricle of rodents with PH.

Hypoxic pulmonary vasoconstriction (HPV) results in robust increases in pulmonary artery pressures (PAP), which underlie the development of pulmonary hypertension (PH), and potentially edema, in those that travel to or work at altitude. Endothelin‐1 receptor (ET‐1) antagonists are currently given orally to treat PH, however intrapulmonary delivery of this therapeutic may provide acute relief of the HPV response at a lower dose and thus could ameliorate the functional impairments caused by PH whilst minimizing the amount of drug required. Despite this potential, the efficacy of intrapulmonary ET‐1 antagonist therapy to treat hypoxia induced PH has yet to be determined. We tested the hypothesis that intrapulmonary delivery of the ET‐1 receptor antagonist Ambrisentan would attenuate an HPV mediated increase in PAP when compared to a saline control. Adult male Sprague‐Dawley rats were randomized into three groups to receive aerosolized saline (Saline, n=8), a low dose (ALD, 1 mg/kg, n=8) or high dose (AHD, 5 mg/kg, n=8) of Ambrisentan (administered via a microinhaler) following the induction of HPV (via 13% inspired O2, simulating ~4000m). PAP were monitored continuously throughout the procedure via indwelling catheters. Pre‐hypoxia PAP values were not different between groups (Saline: 18 ± 1, ALD 19 ± 1, AHD: 17 ± 1 mmHg, P>0.05). Following an initial hypoxia induced increase in PAP (Saline: 37 ± 1, ALD: 30 ± 2, AHD: 33 ± 2 mmHg, P<0.05 vs. pre‐hypoxia for all) intrapulmonary Ambrisentan reduced significantly PAP when compared to Saline (Saline: 34 ± 1, ALD: 23 ± 1, AHD, 23 ±1 mmHg, P<0.05) with no significant differences between ALD and AHD (P>0.05). Intrapulmonary delivery of the ET‐1 receptor antagonist Ambrisentan reduced significantly the increase in PAP following exposure to hypoxia with no significant differences between low and high doses. These results suggest that intrapulmonary delivery of Ambrisentan, at a dose approximating 1/5th of that given orally, may be an effective therapeutic for the treatment of hypoxia induced PH. Given the life threatening complications and impaired work capacity associated with PH and high altitude pulmonary edema (HAPE), individuals traveling to or working at altitude (i.e. military and mining personnel, mountain athletes) as well as those suffering from pathologically induced PH may benefit from acute intrapulmonary delivery of Ambrisentan.Support or Funding InformationONR# N00014‐14‐1‐0699DARPA # N66001‐10‐C‐2134