A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.

The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

Genetic variation in the HLA region is associated with susceptibility to herpes zoster.

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.

Plastid transformation in eggplant (Solanum melongena L.).

We have developed a method for plastid transformation in eggplant (Solanum melongena L.), a solanaceous plant species. Plastid transformation in eggplant was achieved by bombardment of green stem segments with pPRV111A plastid expression vector carrying the aadA gene encoding aminoglycoside 3''-adenylyltransferase. Biolistic delivery of the pPRV111A plasmid yielded transplastomic plants at a frequency of two per 21 bombarded plates containing 25 stem explants each. Integration of the aadA gene in the plastome was verified by PCR analysis and also by Southern blotting using 16S rDNA (targeting sequence) and the aadA gene as a probe. Transplastomic expression of the aadA gene was verified by RT-PCR. The development of transplastomic technology in eggplant may open up exciting possibilities for novel gene introduction and expression in the engineered plastome for agronomic or pharmaceutical traits.

Synthesis and antitubercular activity of substituted phenylmethyl- and pyridylmethyl amines.

A total of 42 benzyl- and pyridylmethyl amines were synthesized either by reductive amination of aromatic/heteroaromatic aldehydes with amines or by conjugate addition of amines to the cinnamates followed by reduction of the ester group with lithium aluminium hydride to the respective propanolamines. All the synthesized compounds were evaluated against both avirulent and virulent strains of Mycobacterium tuberculosis. Many of the compounds exhibited MIC as low as 1.56microg/mL. Few of potent compounds were also evaluated against clinical isolates of MDR TB and found to be active at one or other concentrations with MIC as low as 3.12microg/mL.

Search of antitubercular activities in tetrahydroacridines: synthesis and biological evaluation.

A series of 9-substituted tetrahydroacridines were synthesized by nucleophilic substitution of chloro group with different nucleophiles in 9-chlorotetrahydroacridine (2). The latter could be obtained by POCl(3) mediated cyclization of the intermediate enamine, which in turn, was prepared by acid catalyzed condensation of anthranilic acid and cyclohexanone. Most of the compounds on antitubercular evaluation against M. tuberculosis H37 Rv and H37 Ra strains exhibited potent activities with MIC 6.125-0.78 microg/mL comparable to the standard drugs.

Current status of malaria control.

Malaria caused by Plasmodium parasites kills approximately 1-3 million people and causes disease in 300-500 million people annually throughout the world. The current approaches to curtail this disease include vector control, vaccination, immunotherapy and chemotherapy. The vector control is achieved by reducing vector density, interrupting their life cycle, and creating a barrier between the human host and mosquitoes. A number of vaccine candidates are being clinically tried and R&D effort in this direction is coming in a big way. Currently there are only limited safe drugs for the treatment of this disease, however, reports of emerging resistance against existing drugs warrant the introduction of new drugs, which are unlikely to come from pharmaceutical industries because of limited commercial opportunities. One of the most important current approaches to develop new drugs involves the synthesis of chemical libraries and evaluate them against most validated biochemical targets of malarial parasite. Although a number of such targets in antimalarial drug development are known today, yet only validated and selective biochemical targets including mitochondrial transport, glycolic pathway, folate pathway, proteases and heme metabolism, apicoplast metabolism, glycophospatidyl inositol, lipid metabolism (glycerophospholipids), peptidyl deformylase and oxidative stress in parasite-infected erythrocytes have been discussed here. The well known antimalarial drugs and different drug combinations for the treatment of malaria are also briefly reviewed. A survey of the recently discovered new molecules active against malaria has also been narrated. Lastly, the future of malaria chemotherapy and new directions emerging from literature has been elucidated.

A multivariate study of three body measurements of different states of India.

Considerable attempts have been made to study the changes in three important body measurements (viz. body height, body weight and chest circumference) in young healthy males between different states of India using univariate statistical analysis in which body measurements are assumed to be independent of each other. Actually these body measurements are correlated with each other and thus the assumption of independence is violated in univariate statistical analysis. Hence the results obtained by univariate statistical analysis may be misleading. An attempt has, therefore, been made in the present study to apply multivariate statistical analysis in order to have an idea about the simultaneous changes in these three correlated measurements between different states of India in healthy Indian males of age ranging from 16-21 years. It has been concluded that significant changes take place in these three body measurements simultaneously of young healthy males of 16-21 years of age between different states of India.

Synthesis and antimycobacterial activities of glycosylated amino alcohols and amines.

Reduction of glycosyl beta-amino esters (6-14 and 25-30) with lithium aluminum hydride resulted in glycosyl amino alcohols (15-23 and 31-36) in good yields. However, reductive amination of glycosyl aldehydes (1-3) with different amines in presence of sodium borohydride resulted in good to moderate yields of glycosyl amines (37-41). All the compounds were evaluated for antitubercular activity against Mycobacterium tuberculosis H37Ra and H37Rv. Compounds 18, 21, 35 and 36 exhibited antitubercular activities with MIC ranging from 6.25 to 3.12 microg ml(-1).

Estimation of human endurance time.

A prediction formula has been evolved for estimation of human endurance time from aerobic and anaerobic fraction of the total oxygen utilization. The derivation of the formula is based on the assumption that fractional change in endurance time varies directly as the fractional change in aerobic fraction in the same direction and varies as the fractional change in anaerobic fraction in the opposite direction. The validity of the prediction formula has been tested on two sets of data. The first set is consisting of 31 observations on 13 Indian subjects and a second set of data is consisting of 7 observations on one subject collected from literature. The multiple correlations for these sets of data were 0.9650 and 0.9996, respectively. These multiple correlations were highly significant (p < 0.001). It has been concluded that aerobic and anaerobic fractions of total oxygen utilization are significant predictors of human endurance time.

Blood gases, hematology, and renal blood flow during prolonged mountain sojourns at 3500 and 5800 m.

BACKGROUND: This study mainly focused on renal blood flow, hematological parameters, blood gases, and blood pH, which are affected on exposure to moderate (3500 m) and extreme altitudes (5800 m) in sea level residents. HYPOTHESIS: Acute and prolonged exposure to high or extreme altitude may cause pathophysiological changes in kidney and renal plasma/blood flow, leading to retention of fluids in the tissues. Combined with the decreased availability of oxygen to the tissues, these may be responsible for high altitude maladies. METHOD: Fifteen male sea level (SL) volunteers, 22-25 yr old, were studied for blood gases, blood viscosity, hematocrit, hemoglobin concentration, and effective renal blood/plasma flow at Delhi (260 m), 3500 m (60 d stay), 5800 m (70 d stay), and 7 d after return to SL. RESULTS: Compared with SL, a significant increase from 7.34 to 7.43 (p < 0.01) in blood pH was observed at 3500 m that remained significantly increased at 5800 m. PO2 was about 39% less at 5800 m than at SL. PCO2 reduced significantly from 42.07 to 28.05 mm Hg on return from 5800 m to SL. The blood viscosity increased significantly (38%) at 5800 m and decreased significantly by 38% (p < 0.01) after return to SL. The effective renal plasma flow reduced significantly (p < 0.01) from 615.6 at SL to 381.5 ml x min(-1) x 1.73 m(-2) at 5800 m. CONCLUSION: The study suggests a crucial role of renal function in the acclimatization process; renal function also appears to be one factor by which the body protects itself against severe hypoxia.

Dimensional statistics for estimation of lung volumes.

The theory of dimension has been widely used in physics to check the validity of formulae. This theory has not been used more frequently in statistics as compared to physics for development of various prediction formulae/equations in applied physiology. An attempt has, therefore, been made in the present investigation to evolve formulae for estimation of lung volumes from cubic function of height based on dimensional considerations in boys and girls 8-13 and 16-21 years of age.

A multivariate study of some lung function tests at different age groups in healthy Indian males.

Considerable attempts have been made to study the changes in lung function in man in different age groups using univariate statistical techniques in which the lung function tests were assumed to be independent of each other. Actually the lung function tests are well correlated with each other and, thus, the inferences drawn on the basis of univariate statistical analysis may be misleading due to the violation of the assumption of independence. On the other hand, simultaneous changes in lung function in man in different age groups cannot be tested using univariate statistical techniques. Keeping in view such shortcomings of the univariate statistical techniques, an attempt has been made in the present investigation to study simultaneous changes in some lung function tests [viz. vital capacity (VC), forced vital capacity (FVC), forced expiratory volume for one second (FEV1), expiratory reserve volume (ERV), inspiratory capacity (IC) and maximum voluntary ventilation (MVV)] at different age groups (viz. 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60 and 61-70 years) in healthy Indian males using multivariate statistical techniques (viz. Wilks' statistic (A) and Mahalanobis' D2 statistic) for drawing valid statistical inferences. It is concluded that remarkable significant changes take place in lung function after the age of forty years.

Regression models in physiological research.

Regression models play a significant role for appropriate interpretations of complex phenomena of biomedical sciences. In the present paper an attempt has been made to critically review the applications of regression models in physiological research pertaining to the solutions of various defence oriented problems of indirect estimation of human endurances, fitness, physical work capacity, energy expenditure at different work rates, body density and lean body mass from body measurements at high altitude, ventilatory 'norms' for wider age groups from physical characteristics, heat output and index finger temperature from ambient temperature, leg muscle volume and fat free mass from X-ray radiographs and stature, total body volume from anthropometric measurements, thermoregulatory efficiency at different environmental situations etc. These regression models are of practical significance for screening personnel in defence services, mines, industrial work, sports and the like.

Prediction of birth weight from simple anthropometric measurements in Indian male and female new born babies.

An attempt has been made in this paper to select suitable combination of predictors of birth weight from three anthropometric measurements (viz. length, head and chest circumferences) taken at birth of Indian male and female new born babies. The best combination of predictors was selected by examining the separate effects of each of the three concomitant variables on birth weight using the technique of multivariate regression analysis. The combination of head and chest circumferences was found to be the most appropriate for estimation of birth weight in view of the simplicity and non-invasiveness of measuring these two body circumferences. Keeping in view of the high multiple correlations, nomograms have been constructed to predict birth weights from head and chest circumferences in male and female new born babies. These nomograms will serve well as a simple and quick methods for predicting birth weight from head and chest circumferences in Indian male and female new born babies whenever the Direct weighing at birth is not feasible.

Prediction of maximal aerobic power in healthy Indian males 21-58 years of age.

An attempt has been made in this paper to predict maximal aerobic power (VO2max) in healthy Indian males by three important physical characteristics (viz. age, height and body weight) using the technique of multivariate regression analysis for a wide age group ranging from 21 to 58 years. It has been observed that these characteristics can contribute significantly to the prediction of maximal aerobic power. Three combinations of predictors of two predictors at a time have also been tried to predict maximal aerobic power. Out of these three combinations, the combination of age and body weight has the maximum multiple correlation (R = 0.536, P < 0.001) for a group of 146 subjects of healthy Indian males. A nomogram has been constructed to predict VO2max from age and body weight in order to make the developed multiple linear regression equation of more practical utility to the biomedical scientists who may not be well acquainted with the statistical computational work.

Efficacy of pentoxifylline with aspirin in the treatment of frostbite in rats.

The efficacy of pentoxifylline--a haemorrheologic agent along with aspirin--an analgesic agent was evaluated in the amelioration of the tissue damage due to experimentally induced frostbite in 5 groups (20 each) of rats with body weights ranging between 175 and 200 g. Frostbite was produced experimentally in the hind limbs by exposing the animals to -15 +/- 1 degrees C for 1 h using the harness technique, with simultaneous recording of rectal and environmental temperatures. The degree of tissue damage was assessed on the basis of tissue necrosis after 15 days. Administration of pentoxifylline (40 mg/kg bw) 30 min before and 30 min after the cold exposure followed by two doses of the same daily for the next 5 days along with aspirin (5 mg/kg bw) twice daily for the same duration only after cold exposure, resulted in significant improvement in the degree of tissue preservation. The findings of this preliminary study have brought to light the potential usefulness of these drugs in the treatment of frostbite. The combined pharmacological properties of these two drugs might have altered the haemorrheologic status of blood and produced the curative beneficial effect in improving tissue survival following experimentally induced frostbite in rats.

Fit of Ehrenberg's equation to height & weight of young healthy Indian males.

Height-weight relationship in young healthy Indian males (16-21 yr) has been established for different states of India as well as for the combined data of all the states. It was observed that these relationships have large deviations of the intercepts and slopes from the intercept (a = 0.4) and slope (b = 0.8) of the Ehrenberg's equation. The results of the present study show that Ehrenberg's equation may not be applicable for young healthy Indian males aged 16-21 yr.

High altitude effects on human taste intensity and hedonics.

BACKGROUND: The study was conducted on human volunteers taken to 3500 m altitude for a period of 3 wk. METHODS: Subjects rated four compounds representing sweet, salty, sour and bitter taste, and the hedonic matrix in terms of taste threshold, taste intensity, and taste hedonicity were recorded using category scale. Blood sugar levels were estimated weekly. RESULTS: An increase in the taste thresholds for glucose and sodium chloride was shown while quinine sulphate and citric acid thresholds recorded a decrease. The taste intensity ratings showed a linear relationship with increasing logarithmic molar concentrations of each solution, as compared with taste hedonicity which showed an inverted 'U' type function. The blood picture did not reveal any change in the blood sugar level. All the parameters recorded at high altitude (HA) showed a tendency to return to basal values after reinduction to sea level. CONCLUSION: The study suggests that HA hypoxic stress brings about changes in the hedonic responses, primarily an increased palatibility for sweetness; we speculate that the mechanism may be anorexia-linked nutritional stress.

Height-weight relationship in young healthy males of some hilly areas of India.

The relationships between height and weight in young healthy males (16-21 years) of hilly areas of Uttar Pradesh, Jammu and Kashmir and West Bengal were established. It has been observed that the intercepts and slopes of the height-weight relationships of this group of subjects deviate to a high degree from those of Ehrenberg's law-like relationship. It is therefore concluded that Ehrenberg's law-like relationship of the form: log w = 0.8 h + 0.4 may not hold good for the data on height (h) in metres and weight (w) in kilograms for young healthy males of hilly areas of India. The results of the present study are in agreement with our earlier studies.