Burden of Severe Pneumonia,Pneumococcal Pneumonia and Pneumonia Deaths in Indian States: Modelling Based Estimates

The burden of severe pneumonia in terms of morbidity and mortality is unknown in India especially at sub-national level. In this context, we aimed to estimate the number of severe pneumonia episodes, pneumococcal pneumonia episodes and pneumonia deaths in children younger than 5 years in 2010. We adapted and parameterized a mathematical model based on the epidemiological concept of potential impact fraction developed CHERG for this analysis. The key parameters that determine the distribution of severe pneumonia episode across Indian states were state-specific under-5 population, state-specific prevalence of selected definite pneumonia risk factors and meta-estimates of relative risks for each of these risk factors. We applied the incidence estimates and attributable fraction of risk factors to population estimates for 2010 of each Indian state. We then estimated the number of pneumococcal pneumonia cases by applying the vaccine probe methodology to an existing trial. We estimated mortality due to severe pneumonia and pneumococcal pneumonia by combining incidence estimates with case fatality ratios from multi-centric hospital-based studies. Our results suggest that in 2010, 3.6 million (3.3–3.9 million) episodes of severe pneumonia and 0.35 million (0.31–0.40 million) all cause pneumonia deaths occurred in children younger than 5 years in India. The states that merit special mention include Uttar Pradesh where 18.1% children reside but contribute 24% of pneumonia cases and 26% pneumonia deaths, Bihar (11.3% children, 16% cases, 22% deaths) Madhya Pradesh (6.6% children, 9% cases, 12% deaths), and Rajasthan (6.6% children, 8% cases, 11% deaths). Further, we estimated that 0.56 million (0.49–0.64 million) severe episodes of pneumococcal pneumonia and 105 thousand (92–119 thousand) pneumococcal deaths occurred in India. The top contributors to India’s pneumococcal pneumonia burden were Uttar Pradesh, Bihar, Madhya Pradesh and Rajasthan in that order. Our results highlight the need to improve access to care and increase coverage and equity of pneumonia preventing vaccines in states with high pneumonia burden.     

Structural-Thermodynamic Relationships of Interactions in the N-Terminal ATP-Binding Domain of Hsp90

Despite its importance as a target in anti-cancer therapeutics and the numerous rational-based inhibitor design efforts aimed at it, there are only limited data available on structural-thermodynamic relationships of interactions of the N-terminal ATP-binding domain of Hsp90 (N-Hsp90). Here, we redress this by presenting an investigation of binding of nucleotides and ansamycin compounds to this domain. Interactions of nucleotides with N-Hsp90 are relatively weak (> 10 μM) and are strongly enthalpy driven over the temperature range 10-25 °C. Geldanamycin (GA) and its analogues 17-AAG [17-(allylamino)-17-demethoxy-GA] and 17-DMAG (17-N,N-dimethylaminoethylamino-17-demethoxy-GA) bind more strongly and have a dominant favourable enthalpic contribution over the temperature range investigated. We investigated the temperature dependence of the enthalpic contribution to binding. We found that while the ansamycin compounds have the commonly observed negative value, the nucleotides show a negligible or even a positive ΔC_p of binding. These data represent the first observation of a single binding site for which interactions with different ligands result in both negative and positive ΔC_p values. By addressing the likely impact of the potential contributions from protein-ligand interactions, we are able to attribute the anomalous ΔC_p for the nucleotides largely to a change in the conformation of the domain structure and local motion in the lid region of N-Hsp90 with the concomitant exposure of hydrophobic amino acid side chains.     

Exploiting the antivirulence efficacy of an ajoene-ciprofloxacin combination against Pseudomonas aeruginosa biofilm associated murine acute pyelonephritis

The study investigated the in vitro, ex vivo and in vivo efficacy of ajoene and ciprofloxacin (CIP) alone and in combination against Pseudomonas aeruginosa biofilms and biofilm-associated murine acute pyelonephritis. The ajoene–CIP combination exhibited significant greater (p < 0.05) antimotility and biofilm inhibitory effects than those obtained when they were applied individually. The combined action of the agents resulted in a significant increase in serum sensitivity and phagocytic uptake and killing of P. aeruginosa (p < 0.001) compared to the untreated control. Mice groups treated with an ajoene (25 mg kg^?1) and CIP (30 mg kg^?1 or 15 mg kg^?1) combination showed a significantly (p < 0.001) reduced bacterial load in the kidney and bladder as compared to that of infected controls and mice treated with solo agents on the fifth day post-infection. The decreased levels of biomarkers and photomicrographs of the kidney tissue of the treated mice showed a reduced severity of damage. Hence, the study highlights the antivirulent and therapeutic efficacy of the ajoene-CIP combination at the minimal dosage of CIP.     

Clinical and Treatment Aspects of Brown–Black Fungi

Brown–black (or dematiaceous) fungi are responsible for a wide variety of infectious syndromes in both immunocompetent and immunocompromised patients, including local infections, allergic disease, pneumonia, brain abscess, and disseminated infection. They are distinct from the more common hyaline molds, Aspergillus and Fusarium, that cause human disease. They are often found in soil and generally distributed worldwide. In recent years, these fungi have been increasingly recognized as important pathogens. Dematiaceous fungi may have unique pathogenic mechanisms owing to the presence of melanin in their cell walls, which imparts the characteristic dark color to their spores and hyphae. Diagnosis rests on careful microscopic and pathologic examination, as there are no specific laboratory tests to reliably identify these fungi. Therapy depends upon the clinical syndrome, although disseminated infection often has high mortality. Triazoles such as voriconazole, posaconazole, and itraconazole are the most active antifungal agents available. Further studies are needed to better understand the pathogenesis and optimal treatment of these uncommon infections.     

Pattern of Shoot Growth in Zizyphus mauritiana and Z. oenoplia

Shoot polymorphism and patterns of sylleptic branching and shoottip abscission in two Zizyphus species are reported. Z. mauritiana(ber) produced three types of proleptic shoots: vigorous, normaland spur-type, by reiteration or following pruning;Z. oenopliahad only one type of shoot. Both species revealed up to thirdorder sylleptic branching on the vigorous proleptic shoots witha characteristic pattern and rhythm. Bud dormancy breaking chemicalsgiven as pre-pruning foliar sprays in ber, did not alter thepattern of sylleptic branching. Zizyphus oenoplia produced morefirst and second order sylleptic branches compared to Z. mauritiana.All main axes and 97% of first order sylleptic branches ofZ.mauritiana abscised their apical buds during summer, but inZ. oenoplia all main axes and 54% of first order sylleptic branchesremained active. Shoot tip abscission was almost complete onthe higher order sylleptic branches of both species. Activefirst order branches in Z. oenoplia were confined to the tophalf of the shoot. Both species had a few dormant apical budsduring the summer on their sylleptic branches, emerging mostlyfrom the middle portion of the shoot. Some of the most vigorousfirst order branches of Z. oenoplia, which had dormant apicalbuds during summer, showed a change in the frequency of syllepticbranching when they resumed growth following monsoon showers.These characteristic growth and branching patterns may haveadaptive value for canopy development under arid and semi-aridconditions. Copyright 1999 Annals of Botany Company Ber, branching pattern, shoot polymorphism, shoot tip abscission, sylleptic branching, Zizyphus mauritiana, Zizyphus oenoplia.     

Modeling HIV-1 Induced Neuroinflammation in Mice: Role of Platelets in Mediating Blood-Brain Barrier Dysfunction

The number of HIV-1 positive individuals developing some form of HIV-associated neurocognitive disorder (HAND) is increasing. In these individuals, the integrity of the blood-brain barrier (BBB) is compromised due to an increase in exposure to pro-inflammatory mediators, viral proteins, and virus released from infected cells. It has been shown that soluble CD40L (sCD40L) is released upon platelet activation and is an important mediator of the pathogenesis of HAND but the underlying mechanisms are unclear, emphasizing the need of an effective animal model. Here, we have utilized a novel animal model in which wild-type (WT) mice were infected with EcoHIV; a derivative of HIV-1 that contains a substitution of envelope protein gp120 with that of gp80 derived from murine leukemia virus-1 (MuLV-1). As early as two-weeks post-infection, EcoHIV led to increased permeability of the BBB associated with decreased expression of tight junction protein claudin-5, in CD40L and platelet activation-dependent manner. Treatment with an antiplatelet drug, eptifibatide, in EcoHIV-infected mice normalized BBB function, sCD40L release and platelet activity, thus implicating platelet activation and platelet-derived CD40L in virally induced BBB dysfunction. Our results also validate and underscore the importance of EcoHIV infection mouse model as a tool to explore therapeutic targets for HAND.