TRC120038, a Novel Dual AT1/ETA Receptor Blocker for Control of Hypertension, Diabetic Nephropathy, and Cardiomyopathy in ob-ZSF1 Rats

In hypertensive subjects, angiotensin II and endothelin participate in a manner involving closely interwoven pathways in increasing blood pressure (BP) and inducing end organ damage. The primary objective of this study was to determine the effect of TRC120038, a novel dual AT1/ETA receptor blocker on BP, in obese Zucker spontaneously hypertensive fatty rats (ob-ZSF1), an animal model of moderate hypertension, diabetes with progressive renal and cardiac dysfunction. Ob-ZSF1 rats loaded with 0.5% salt were treated with TRC120038 (11.8 mg/kg bid.) or candesartan cilexetil (0.3 mg/kg od.) or vehicle control. Blood pressure (by radio-telemetry) and renal functional markers were monitored throughout the study. Cardiac function was assessed terminally by pressure volume catheter. Markers for renal dysfunction were measured and changes were evaluated histopathologically. TRC120038 showed greater fall in both systolic and diastolic BP in comparison to candesartan at its maximum antihypertensive dose. TRC120038 also reduced the severity of renal dysfunction and preserved cardiac function in ob-ZSF1 rat

Age-specifi c and sex-specifi c adult mortality risk in India in 2014: analysis of 0·27 million nationally surveyed deaths and demographic estimates from 597 districts

Background As child mortality decreases rapidly worldwide, premature adult mortality is becoming an increasingly important contributor to global mortality. Any possible worldwide reduction of premature adult mortality before the age of 70 years will depend on progress in India. Indian districts increasingly have responsibility for implementing public health programmes. We aimed to assess age-specifi c and sex-specifi c adult mortality risks in India at the district level. Methods We analysed data from fi ve national surveys of 0∙27 million adult deaths at an age of 15–69 years together with 2014 demographic data to estimate age-specifi c and sex-specifi c adult mortality risks for 597 districts. Cause of death data were drawn from the verbal autopsies in the Registrar General of India’s ongoing Million Death Study. Findings In 2014, about two-fi fths of India’s men aged 15–69 years lived in the 253 districts where the conditional probability of a man dying at these ages exceeded 50%, and more than a third of India’s women aged 15–69 years lived in the 222 districts where the conditional probability of a woman dying exceeded 40%. The probabilities of a man or woman dying by the age of 70 years in high-mortality districts was 62% and 54%, respectively, whereas the probability of a man or woman dying by the age of 70 years in low-mortality districts was 40% and 30%, respectively. The roughly 10-year survival gap between high-mortality and low-mortality districts was nearly as extreme as the survival gap between the entire Indian population and people living in high-income countries. Adult mortality risks at ages 15–69 years was highest in east India and lowest in west India, by contrast with the north–south divide for child mortality. Vascular disease, tuberculosis, malaria and other infections, and respiratory diseases accounted for about 60% of the absolute gap in adult mortality risk at ages 15–69 years between high-mortality and low-mortality districts. Most of the variation in adult mortality could not be explained by known determinants or risk factors for premature mortality. Interpretation India’s large variation in adult mortality by district, notably the higher death rates in eastern India, requires further aetiological research, particularly to explore whether high levels of adult mortality risks from infections and non-communicable diseases are a result of historical childhood malnutrition and infection. Such research can be complemented by an expanded coverage of known eff ective interventions to reduce adult mortality, especially in high-mortality district

Automated Knowledge Modeling for Cancer Clinical Practice Guidelines

Clinical Practice Guidelines (CPGs) for cancer diseases evolve rapidly due to new evidence generated by active research. Currently, CPGs are primarily published in a document format that is ill-suited for managing this developing knowledge. A knowledge model of the guidelines document suitable for programmatic interaction is required. This work proposes an automated method for extraction of knowledge from National Comprehensive Cancer Network (NCCN) CPGs in Oncology and generating a structured model containing the retrieved knowledge. The proposed method was tested using two versions of NCCN Non-Small Cell Lung Cancer (NSCLC) CPG to demonstrate the effectiveness in faithful extraction and modeling of knowledge. Three enrichment strategies using Cancer staging information, Unified Medical Language System (UMLS) Metathesaurus & National Cancer Institute thesaurus (NCIt) concepts, and Node classification are also presented to enhance the model towards enabling programmatic traversal and querying of cancer care guidelines. The Node classification was performed using a Support Vector Machine (SVM) model, achieving a classification accuracy of 0.81 with 10-fold cross-validation

Molecular Study of Glycoprotein (G) Gene Region of Rabies Virus from Spotted Deer, Delhi, India

Rabies is a viral zoonotic disease of public health importance in India. The disease is usually transmitted by a rabid animal bite, scratches and licks on broken skin and mucous membrane. Rabies is reported from all continents except Antarctica although prevalence is more in Asia and Africa. India is endemic for rabies virus (RABV) throughout the country except for islands of Lakshadweep, Andaman & Nicobar. In the present study, brain samples of clinically suspected animals obtained during the RABV outbreak at National Zoological Park, New Delhi, India, in 2016 were initially tested for rabies antigen by DFAT. All the 32 DFAT positive brain samples were then processed for RNA isolation. The extracted RNA was amplified for glycoprotein (G) gene of 590 bp by RT-PCR followed by nucleotide sequencing. Nucleotide alignment revealed only substitutions without any insertion or deletion. Amino acid alignment revealed replacement at four positions namely L244I, T264A, M310I and N375K. The amino acid change at position where Leucine is replaced by Isoleucine has not been observed in available RABV references of the G gene region either from India or other countries. This mutation was observed in all the samples included in the present study. A phylogenetic tree showed that all the study sequences belonged to Arctic like 1a lineage, in RABV genotype 1. In conclusion, RABV in the study region is acquiring genetic variation; which may have effect on the pathogenicity. This indicates that continued molecular surveillance of the circulating rabies virus strains should be carried out

TRC150094 attenuates progression of nontraditional cardiovascular risk factors associated with obesity and type 2 diabetes in obese ZSF1 rats

Chronic overnutrition and consequential visceral obesity is associated with a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus. Moreover, individuals who have a triad of hypertension, dysglycemia, and elevated triglycerides along with reduced high-density lipoprotein cholesterol have a greater residual cardiovascular risk even after factoring for the traditional risk factors such as age, smoking, diabetes, and elevated low-density lipoprotein cholesterol. In our previous study we demonstrated that TRC150094, when administered to rats receiving a high-fat diet, stimulated mitochondrial fatty acid oxidation (FAO) and reduced visceral adiposity, opening an interesting perspective for a possible clinical application. In the present study, oral administration of TRC150094 to obese Zucker spontaneously hypertensive fatty rats (obese ZSF1) improved glucose tolerance and glycemic profile as well as attenuated a rise in blood pressure. Obese ZSF1 rats treated with TRC150094 also showed reduced hepatic steatosis, reduced progression of nephropathy, and improved skeletal muscle function. At the cellular level, TRC150094 induced a significant increase in mitochondrial respiration as well as an increased FAO in liver and skeletal muscle, ultimately resulting in reduced hepatic as well as total body fat accumulation, as evaluated by magnetic resonance spectroscopy and magnetic resonance imaging, respectively. If reproduced in humans, these results could confirm that TRC150094 may represent an attractive therapeutic agent to counteract multiple residual cardiovascular risk components

Stabilization of high Tc phase in bismuth cuprate superconductor by lead doping

It has been widely ascertained that doping of lead in Bi-Sr-Ca-Cu-O systems promotes the growth of high T sub c (110 K) phase, improves critical current density, and lowers processing temperature. A systematic study was undertaken to determine optimum lead content and processing conditions to achieve these properties. A large number of samples with cationic compositions of Bi(2-x)Pb(x)Sr2Ca2Cu3 (x = 0.2 to 2.0) were prepared by conventional solid state reaction technique. Samples of all compositions were annealed together at a temperature and characterized through resistance temperature (R-T) measurements and x ray diffraction to determine the zero resistance temperature, T sub c(0) and to identify presence of phases, respectively. The annealing temperature was varied between 790 and 880 C to optimize processing parameters. Results are given. In brief, an optimum process is reported along with composition of leaded bismuth cuprate superconductor which yields nearly a high T sub c single phase with highly stable superconducting properties

Stabilization of high T(sub c) phase in bismuth cuprate superconductor by lead doping

It has widely been ascertained that doping of lead in Bi:Sr:Ca:Cu:O systems promotes the growth of high T(sub c) (110 K) phase, improves critical current density, and lowers processing temperature. A systematic investigation is undertaken to determine optimum lead content and processing conditions to achieve these. A large number of samples with cationic compositions of Bi(2-x)Pb(x)Sr2Ca2Cu3 (x = 0.2 to 2.0) were prepared by conventional solid state reaction technique. Samples of all compositions were annealed together at a temperature and characterized through resistance-temperature (R-T) measurements and x ray diffraction (XRD) to determine the zero resistance temperature, T(sub c)(0) and to identify presence of phases, respectively. The annealing temperature was varied between 790 C to optimize processing parameters. Results are given. In brief, an optimum process is reported along with composition of leaded bismuth cuprate superconductor which yields nearly a high T(sub c) single phase with highly stable superconducting properties

Approximation Algorithm for Line Segment Coverage for Wireless Sensor Network

The coverage problem in wireless sensor networks deals with the problem of covering a region or parts of it with sensors. In this paper, we address the problem of covering a set of line segments in sensor networks. A line segment ` is said to be covered if it intersects the sensing regions of at least one sensor distributed in that region. We show that the problem of finding the minimum number of sensors needed to cover each member in a given set of line segments in a rectangular area is NP-hard. Next, we propose a constant factor approximation algorithm for the problem of covering a set of axis-parallel line segments. We also show that a PTAS exists for this problem.Comment: 16 pages, 5 figures