Preclinical Development of an In Vivo BCG Challenge Model for Testing Candidate TB Vaccine Efficacy

There is an urgent need for an immunological correlate of protection against tuberculosis (TB) with which to evaluate candidate TB vaccines in clinical trials. Development of a human challenge model of Mycobacterium tuberculosis (M.tb) could facilitate the detection of such correlate(s). Here we propose a novel in vivo Bacille Calmette-Guérin (BCG) challenge model using BCG immunization as a surrogate for M.tb infection. Culture and quantitative PCR methods have been developed to quantify BCG in the skin, using the mouse ear as a surrogate for human skin. Candidate TB vaccines have been evaluated for their ability to protect against a BCG skin challenge, using this model, and the results indicate that protection against a BCG skin challenge is predictive of BCG vaccine efficacy against aerosol M.tb challenge. Translation of these findings to a human BCG challenge model could enable more rapid assessment and down selection of candidate TB vaccines and ultimately the identification of an immune correlate of protection

Spiral-Wave Turbulence and Its Control in the Presence of Inhomogeneities in Four Mathematical Models of Cardiac Tissue

Regular electrical activation waves in cardiac tissue lead to the rhythmic contraction and expansion of the heart that ensures blood supply to the whole body. Irregularities in the propagation of these activation waves can result in cardiac arrhythmias, like ventricular tachycardia (VT) and ventricular fibrillation (VF), which are major causes of death in the industrialised world. Indeed there is growing consensus that spiral or scroll waves of electrical activation in cardiac tissue are associated with VT, whereas, when these waves break to yield spiral- or scroll-wave turbulence, VT develops into life-threatening VF: in the absence of medical intervention, this makes the heart incapable of pumping blood and a patient dies in roughly two-and-a-half minutes after the initiation of VF. Thus studies of spiral- and scroll-wave dynamics in cardiac tissue pose important challenges for in vivo and in vitro experimental studies and for in silico numerical studies of mathematical models for cardiac tissue. A major goal here is to develop low-amplitude defibrillation schemes for the elimination of VT and VF, especially in the presence of inhomogeneities that occur commonly in cardiac tissue. We present a detailed and systematic study of spiral- and scroll-wave turbulence and spatiotemporal chaos in four mathematical models for cardiac tissue, namely, the Panfilov, Luo-Rudy phase 1 (LRI), reduced Priebe-Beuckelmann (RPB) models, and the model of ten Tusscher, Noble, Noble, and Panfilov (TNNP). In particular, we use extensive numerical simulations to elucidate the interaction of spiral and scroll waves in these models with conduction and ionic inhomogeneities; we also examine the suppression of spiral- and scroll-wave turbulence by low-amplitude control pulses. Our central qualitative result is that, in all these models, the dynamics of such spiral waves depends very sensitively on such inhomogeneities. We also study two types of control schemes that have been suggested for the control of spiral turbulence, via low amplitude current pulses, in such mathematical models for cardiac tissue; our investigations here are designed to examine the efficacy of such control schemes in the presence of inhomogeneities. We find that a local pulsing scheme does not suppress spiral turbulence in the presence of inhomogeneities; but a scheme that uses control pulses on a spatially extended mesh is more successful in the elimination of spiral turbulence. We discuss the theoretical and experimental implications of our study that have a direct bearing on defibrillation, the control of life-threatening cardiac arrhythmias such as ventricular fibrillation

Pancreatic tuberculosis mimicking malignancy in an immunocompetent Individual

Tuberculosis of pancreas in an immunocompetent individual is rare even in endemic regions. We report here one such case where in a 53-year-old man presented with jaundice, weight loss and cervical lymphadenopathy. Base line liver functions were deranged. Imaging studies of abdomen and chest revealed a pancreatic mass and miliary filtrates. Fine needle aspiration cytology of cervical lymph nodes was suggestive of tuberculosis. In view of deranged baseline liver functions the patient was started on a modified daily self-supervised antituberculosis treatment and oral corticosteroid treatment made an uneventful recovery with complete resolution of mass lesion

Carbonate xenoliths hosted by the Mesoproterozoic Siddanpalli Kimberlite Cluster (Eastern Dharwar craton): Implications for the geodynamic evolution of southern India and its diamond and uranium metallogenesis

A number of limestone and metasomatised carbonate xenoliths occur in the 1,090 Ma Siddanpalli kimberlite cluster, Raichur kimberlite Field, Eastern Dharwar craton, southern India. These xenoliths are inferred to have been derived from the carbonate horizons of the Kurnool (Palnad) and Bhima Proterozoic basins and provide evidence for a connection between these basins in the geological past. A revised Mesoproterozoic age is proposed for the Bhima and Kurnool (Palnad) basins based on this kimberlite association and is in agreement with similar proposals made recently for the Chattisgarh and Upper Vindhyan sediments in Central India. The observed Bhima–Kurnool interbasinal uplift may have been caused by: (1) extension- or plume-related mafic alkaline magmatism that included the emplacement of the southern Indian kimberlites at *1.1 Ga, (2) mantle plume-related doming of the peninsular India during the Cretaceous, or (3) Quaternary differential uplift in this region. It is not possible, with the currently available geological information to constrain the exact timing of this uplift. The deep erosion of primary diamond sources in the Raichur kimberlite Field in the upper reaches of the Krishna River caused by this uplift could be the elusive source of the alluvial diamonds of the Krishna valley. Mesoproterozoic sedimentary basins can host world class unconformity-type uranium deposits. In light of its inferred Mesoproterozoic age, a more detailed stratigraphic and metallogenic analysis of the Kurnool basin is suggested for uranium exploration