Ladakh, India
Ladakh, India

Time filter

Source Type

Vibhuti A.,Institute of Genomics and Integrative Biology | Arif E.,Institute of Genomics and Integrative Biology | Mishra A.,Institute of Genomics and Integrative Biology | Deepak D.,Dr Ram Manohar Lohia Hospital | And 4 more authors.
Clinica Chimica Acta | Year: 2010

Background: The genetic susceptibility to chronic obstructive pulmonary disease (COPD) depends on detoxification and antioxidant enzymes, which detoxify cigarette smoke reactive components that, otherwise, generate oxidative stress. Methods: In a case-control study of 346 subjects with and without COPD, we examined the polymorphisms 462Ile/Val, 3801T/C of CYP1A1, -3860G/A of CYP1A2 and -930A/G, 242C/T of CYBA individually or in combination and their contribution to oxidative stress markers by measuring malondialdehyde (MDA), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GPx). Results: COPD patients had significantly increased MDA concentration (p<0.001) and decreased CAT activity, GSH concentration, GPx activity (p≤0.01). The patients were over-represented by the alleles 462Val, 3801C of CYP1A1 and -930G, 242C of CYBA (p<0.001, p=0.003, p=0.030 and p=0.031, respectively) and consequently the haplotypes of same alleles i.e. 462Val:3801C, 462Val:3801T and -930G:242C (p=0.048, p=0.016 and p=0.039, respectively). Similarly, CYP1A1 and CYP1A2 haplotypes, 462Val:3860G and 462Val:3801T:3860G were significantly over-represented (p=0.001 and p=0.003), respectively in patients. The same alleles-associated genotype-combinations between genes were more prevalent in patients. Of note, the genotypes, 462Ile/Val+Val/Val, 3801TC+CC of CYP1A1 and -930AG+GG of CYBA associated with increased MDA concentration (p=0.018, p=0.045 and p=0.017, respectively), decreased CAT activity (p<0.0001, p=0.080 and p<0.0001, respectively) and GSH concentration (p<0.0001, p=0.0002 and p=0.011, respectively) in patients. Conclusion: The identified alleles, its haplotypes and the genotype-combination along with increased oxidative stress, signify the importance in susceptibility to COPD. © 2010 Elsevier B.V.


Ali Z.,Institute of Genomics and Integrative Biology | Ali Z.,University of Pune | Mishra A.,Institute of Genomics and Integrative Biology | Mishra A.,University of Pune | And 10 more authors.
PLoS ONE | Year: 2012

Background: The interactions among various biomarkers remained unexplored under the stressful environment of high-altitude. Present study evaluated interactions among biomarkers to study susceptibility for high altitude pulmonary edema (HAPE) in HAPE-patients (HAPE-p) and adaptation in highland natives (HLs); both in comparison to HAPE-free sojourners (HAPE-f). Methodology/Principal Findings: All the subjects were recruited at 3500 m. We measured clinical parameters, biochemical levels in plasma and gene expression using RNA from blood; analyzed various correlations between and among the clinical parameters, especially arterial oxygen saturation (SaO2) and mean arterial pressure (MAP) and biochemical parameters like, asymmetric dimethylarginine (ADMA), serotonin (5-HT), 8-iso-prostaglandin F2α (8-isoPGF2α), endothelin-1 (ET-1), plasma renin activity (PRA), plasma aldosterone concentration (PAC), superoxide dismutase (SOD) and nitric oxide (NO) in HAPE-p, HAPE-f and HLs. ADMA, 5-HT, 8-isoPGF2α, ET-1 levels, and PAC were significantly higher (p<0.0001, each), whereas SOD activity and NO level were significantly lower in HAPE-p than HAPE-f (p≤0.001). Furthermore, ADMA, 5-HT, 8-isoPGF2α, NO levels and PAC were significantly higher (p<0.0001), whereas ET-1 level significantly (p<0.0001) and SOD activity non-significantly (p>0.05) lower in HLs than HAPE-f. The expression of respective genes differed in the three groups. In the correlations, SaO2 inversely correlated with ADMA, 5-HT and 8-isoPGF2α and positively with SOD in HAPE-p (p≤0.009). MAP correlated positively with 5-HT and 8-isoPGF2α in HAPE-p and HLs (p≤0.004). A strong positive correlation was observed between ADMA and 5-HT, 5-HT and 8-isoPGF2α (p≤0.001), whereas inverse correlation of SOD with ET-1 in HAPE-p and HLs (p≤0.004), with 5-HT and 8-isoPGF2α in HAPE-p (p = 0.01) and with 5-HT in HLs (p = 0.05). Conclusions/Significance: The interactions among these markers confer enhanced vascular activity in HLs and HAPE in sojourners. © 2012 Ali et al.


Ali Z.,CSIR - Central Electrochemical Research Institute | Ali Z.,University of Pune | Waseem M.,CSIR - Central Electrochemical Research Institute | Kumar R.,CSIR - Central Electrochemical Research Institute | And 4 more authors.
Gene | Year: 2016

Context: Few potential candidate genes coding for type I and II receptors of transforming growth factor beta signaling pathway and the serotonin transporter have been associated with pulmonary hypertension (PH). The latter being a phenotype for high altitude pulmonary edema (HAPE), these genes are hypothesized to be crucial markers to investigate under the hypobaric hypoxic environment of high altitude. Aims: We hence aimed to investigate bone-morphogenetic protein-2 (BMP2), bone morphogenetic protein receptor type-II (BMPR-2), activin receptor-like kinase-1 (ALK-1), serotonin transporter (5-HTT) and serotonin (5-HT) for their contribution, individually/epistatically, to clinical endpoints by altering downstream signaling molecules. Methods and materials: In a case-control design, interactions between/among polymorphisms of BMPR-2, ALK-1 and 5-HTT were screened in 200 HAPE-patients (HAPE-p) and 200 HAPE-free sojourners (HAPE-f). Plasma biomarker BMP-2 and 5-HT were estimated. The relative gene expression was also witnessed in 20 humans/10 rats followed by correlation analyses. Results: The genotype/allele models revealed the prevalence of BMPR-2 rs6717924A-rs4303700A-rs1048829A; ALK-1 rs11169953T-rs3759178C-rs706816C and 5-HTT rs6354C in HAPE (P ≤ 0.05). Multifactor dimensionality reduction for interactions among genes revealed a 4-locus model of BMPR-2 rs6717924G/A; ALK-1 rs11169953C/T-rs706816T/C and 5-HTT rs6354A/C as the best disease predicting (P ≤ 0.001); whereas HapEvolution analysis confirmed the alleles rs6717924A, rs4303700A and rs6354C as the best interacting (P ≤ 0.01). Plasma levels of BMP-2 and 5-HT were elevated in HAPE (P ≤ 0.0001). The expression of BMP-2, ALK-1, 5-HT, 5-HTT was elevated and of BMPR-2 decreased in humans and rats (P ≤ 0.05).The risk alleles BMPR-2 rs6717924A-rs4303700G-rs1048829A; ALK-1 rs11169953T-rs706816C and 5-HTT rs6354C correlated inversely with arterial oxygen saturation (SaO2) and positively with mean arterial pressure (MAP), BMP-2 and 5-HT in HAPE. Likewise, haplotypes BMPR-2 GGGCGAAAA, AAATAGGGA and ALK-1 CCTCAAAG, CCTTAAAG correlated with clinical markers and biomarkers (P ≤ 0.01). BMP-2 and 5-HT correlated positively with MAP and negatively with SaO2 (P ≤ 0.01). Conclusions: The genetic-interactions among BMPR-2, ALK-1, and 5-HTT polymorphisms, elevated BMP-2 and 5-HT levels and differential gene expression substantiated the strong genetic contribution in HAPE pathophysiology. © 2016 Elsevier B.V.


Mishra A.,CSIR - Central Electrochemical Research Institute | Mishra A.,University of Pune | Mohammad G.,SNM Hospital | Norboo T.,Ladakh Institute of Prevention | And 2 more authors.
Journal of Applied Physiology | Year: 2015

Hypobaric hypoxia at high altitude (HA) results in reduced blood arterial oxygen saturation, perfusion of organs with hypoxemic blood, and direct hypoxia of lung tissues. The pulmonary complications in the cells of the pulmonary arterioles due to hypobaric hypoxia are the basis of the pathophysiological mechanisms of high-altitude pulmonary edema (HAPE). Some populations that have dwelled at HA for thousands of years have evolutionarily adapted to this environmental stress; unadapted populations may react with excessive physiological responses that impair health. Individual variations in response to hypoxia and the mechanisms of HA adaptation provide insight into physiological responses. Adaptive and maladaptive responses include alterations in pathways such as oxygen sensing, hypoxia signaling, K+- and Ca2+-gated channels, redox balance, and the renin-angiotensin-aldosterone system. Physiological imbalances are linked with genetic susceptibilities, and nonhomeostatic responses in gene regulation that occur by small RNAs, histone modification, and DNA methylation predispose susceptible humans to these HA illnesses. Elucidation of the interaction of these factors will lead to a more comprehensive understanding of HA adaptations and maladaptations and will lead to new therapeutics for HA disorders related to hypoxic lungs. Copyright © 2015 the American Physiological Society.


Puri G.D.,Post Graduate Institute of Medical Education and Research | Jayant A.,Post Graduate Institute of Medical Education and Research | Tsering M.,SNM Hospital | Dorje M.,SNM Hospital | Tashi M.,SNM Hospital
Indian Journal of Anaesthesia | Year: 2012

Background: Closed loop anaesthesia delivery systems (CLADSs) are a recent advancement in accurate titration of anaesthetic drugs. They have been shown to be superior in maintaining adequate depth of anaesthesia with few fluctuations as compared with target-controlled infusion or manual titration of drug delivery. Methods: Twenty patients scheduled to undergo general abdominal or orthopaedic procedures under general anaesthesia at Leh (3505 m above sea level) were recruited as subjects. Anaesthesia was delivered by a patented closed loop system that uses the Bispectral Index (BISTM) as a feedback parameter to titrate the rate of propofol infusion. All vital parameters, drug infusion rate and the BISTM values were continuously recorded and stored online by the system. The data generated was analysed for the adequacy of anaesthetic depth, haemodynamic stability and post-operative recovery parameters. Results: The CLADS was able to maintain a BISTM within ±10 of the target of 50 for 85.0±7.8% of the time. Haemodynamics were appropriately maintained (heart rate and mean arterial blood pressure were within 25% of baseline values for 91.2±2.2% and 94.1±3% of the total anaesthesia time, respectively). Subjects were awake within a median of 3 min from cessation of drug infusion and achieved fitness to recovery room discharge within a median of 15 min. There were no adverse events or report of awareness under anaesthesia. Conclusions: The study demonstrates the safety of our CLADS at high altitude. It seeks to extend the use of our system in challenging anaesthesia environments. The system performance was also adequate and no adverse events were recorded.


Pandey P.,CSIR - Central Electrochemical Research Institute | Pandey P.,University of Pune | Mohammad G.,SNM Hospital | Singh Y.,CSIR - Central Electrochemical Research Institute | And 3 more authors.
Clinical and Experimental Hypertension | Year: 2016

Background and objectives: High-altitude essential hypertension (HAEH) is a disease occurring in permanent residents of high-altitude regions. The disease is characterized with SBP ≥140 mmHg and DBP ≥90 mmHg. HAEH is known to run in families, i.e. the disease has genetic component. Rho-associated coiled-coil containing protein kinase 2 (ROCK2) is a stress-activated serine-threonine kinase known to disturb vascular-homeostasis leading to an increase in systemic vascular resistance, hallmark of HAEH. ROCK2 is implicated in sea-level essential hypertension but its role in HAEH is yet to be elucidated. Methods: The present study deals with genotyping 13 polymorphisms of ROCK2 gene in demographicaly matched human cases (n = 65) and controls (n = 38) by Sequenom MS (TOF)-based MassARRAY platform using iPLEX Gold technology. Results: A significant association was observed for GG genotype (SNP, rs978906), AA genotype (SNP, rs6753921), GG genotype (SNP, rs10495582) and AA genotype (SNP, rs2230774) with HAEH (p < 0.05). The 4 SNPs were tagged to each other and formed a 35 kb LD block (r2 > 0.90). Haplotype AGCC, composed of wild-type alleles of the SNPs was over represented in controls. In contrast, haplotype GAGA, composed of variant-alleles was observed to be in higher proportion in cases. Moreover, SBP levels (mmHg) were higher in cases with risk genotype against the ones having protective genotype (p = 0.05). Bioinformatic analysis revealed binding of a critical transcription factor, SRF to variant-allele G of SNP rs10495582. SRF has been reported in previous studies to promote ROCK2 transcriptional expression. Interpretation and conclusions: The data clearly suggests association of ROCK2 polymorphisms and haplotypes with HAEH. © 2016 Taylor & Francis Group, LLC.


PubMed | CSIR - Central Electrochemical Research Institute and SNM Hospital
Type: Journal Article | Journal: Clinical and experimental hypertension (New York, N.Y. : 1993) | Year: 2016

High-altitude essential hypertension (HAEH) is a disease occurring in permanent residents of high-altitude regions. The disease is characterized with SBP 140mmHg and DBP 90mmHg. HAEH is known to run in families, i.e. the disease has genetic component. Rho-associated coiled-coil containing protein kinase 2 (ROCK2) is a stress-activated serine-threonine kinase known to disturb vascular-homeostasis leading to an increase in systemic vascular resistance, hallmark of HAEH. ROCK2 is implicated in sea-level essential hypertension but its role in HAEH is yet to be elucidated.The present study deals with genotyping 13 polymorphisms of ROCK2 gene in demographicaly matched human cases (n=65) and controls (n=38) by Sequenom MS (TOF)-based MassARRAY platform using iPLEX Gold technology.A significant association was observed for GG genotype (SNP, rs978906), AA genotype (SNP, rs6753921), GG genotype (SNP, rs10495582) and AA genotype (SNP, rs2230774) with HAEH (p<0.05). The 4 SNPs were tagged to each other and formed a 35kb LD block (r(2)>0.90). Haplotype AGCC, composed of wild-type alleles of the SNPs was over represented in controls. In contrast, haplotype GAGA, composed of variant-alleles was observed to be in higher proportion in cases. Moreover, SBP levels (mmHg) were higher in cases with risk genotype against the ones having protective genotype (p=0.05). Bioinformatic analysis revealed binding of a critical transcription factor, SRF to variant-allele G of SNP rs10495582. SRF has been reported in previous studies to promote ROCK2 transcriptional expression.The data clearly suggests association of ROCK2 polymorphisms and haplotypes with HAEH.


PubMed | Gb Pant Hospital, CSIR - Central Electrochemical Research Institute and Snm Hospital
Type: Journal Article | Journal: Hypertension research : official journal of the Japanese Society of Hypertension | Year: 2015

CYBA (p22(phox)) is an integral constituent of the NADPH oxidases and is consequently a main component of oxidative stress, which is strongly associated with hypertension. This study investigates the contribution of CYBA polymorphisms toward the complex etiology of hypertension in two ethnically different populations, one located at a high altitude and the other at a low altitude. The significance of CYBA single nucleotide polymorphisms and their correlation with clinical and biochemical phenotypes were investigated in age- and ethnicity-matched unrelated permanent high-altitude residents (>3500m) comprising 245 controls and 241 patients. The results were replicated in a second population comprising 935 controls and 545 patients who lived at a low altitude (<200m). The analysis of covariance revealed that CYBA risk alleles and their haplotypes, rs8854A/rs9932581G/rs4873C and rs8854G/rs9932581G/rs4873C, were positively correlated with clinical parameters, for example, systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP), and biochemical parameters, for example, 8-isoPGF2 level, and inversely correlated with catalase activity in patients compared with controls (P0.01, each). Conversely, the protective alleles and their haplotype, rs8854G/rs9932581A/rs4873T, were inversely correlated with SBP, DBP, MAP and 8-isoPGF2 level, and positively correlated with catalase activity (P0.001, each). Furthermore, correlation analysis between the clinical and biochemical parameters revealed a positive correlation of SBP, DBP and MAP with 8-isoPGF2 levels and a negative correlation with catalase activity in both populations (P<0.0001, each). CYBA (p22(phox)) variants influence the markers of oxidative stress and are associated with hypertension.


PubMed | University of Pune, CSIR - Central Electrochemical Research Institute and SNM Hospital
Type: Journal Article | Journal: Gene | Year: 2016

Few potential candidate genes coding for type I and II receptors of transforming growth factor beta signaling pathway and the serotonin transporter have been associated with pulmonary hypertension (PH). The latter being a phenotype for high altitude pulmonary edema (HAPE), these genes are hypothesized to be crucial markers to investigate under the hypobaric hypoxic environment of high altitude.We hence aimed to investigate bone-morphogenetic protein-2 (BMP2), bone morphogenetic protein receptor type-II (BMPR-2), activin receptor-like kinase-1 (ALK-1), serotonin transporter (5-HTT) and serotonin (5-HT) for their contribution, individually/epistatically, to clinical endpoints by altering downstream signaling molecules.In a case-control design, interactions between/among polymorphisms of BMPR-2, ALK-1 and 5-HTT were screened in 200 HAPE-patients (HAPE-p) and 200 HAPE-free sojourners (HAPE-f). Plasma biomarker BMP-2 and 5-HT were estimated. The relative gene expression was also witnessed in 20 humans/10 rats followed by correlation analyses.The genotype/allele models revealed the prevalence of BMPR-2 rs6717924A-rs4303700A-rs1048829A; ALK-1 rs11169953T-rs3759178C-rs706816C and 5-HTT rs6354C in HAPE (P0.05). Multifactor dimensionality reduction for interactions among genes revealed a 4-locus model of BMPR-2 rs6717924G/A; ALK-1 rs11169953C/T-rs706816T/C and 5-HTT rs6354A/C as the best disease predicting (P0.001); whereas HapEvolution analysis confirmed the alleles rs6717924A, rs4303700A and rs6354C as the best interacting (P0.01). Plasma levels of BMP-2 and 5-HT were elevated in HAPE (P0.0001). The expression of BMP-2, ALK-1, 5-HT, 5-HTT was elevated and of BMPR-2 decreased in humans and rats (P0.05). The risk alleles BMPR-2 rs6717924A-rs4303700G-rs1048829A; ALK-1 rs11169953T-rs706816C and 5-HTT rs6354C correlated inversely with arterial oxygen saturation (SaO2) and positively with mean arterial pressure (MAP), BMP-2 and 5-HT in HAPE. Likewise, haplotypes BMPR-2 GGGCGAAAA, AAATAGGGA and ALK-1 CCTCAAAG, CCTTAAAG correlated with clinical markers and biomarkers (P0.01). BMP-2 and 5-HT correlated positively with MAP and negatively with SaO2 (P0.01).The genetic-interactions among BMPR-2, ALK-1, and 5-HTT polymorphisms, elevated BMP-2 and 5-HT levels and differential gene expression substantiated the strong genetic contribution in HAPE pathophysiology.


PubMed | CSIR Institute of Genomics and Integrative Biology, University of Pune, Vanderbilt University, SNM Hospital and Ladakh Institute of Prevention
Type: Journal Article | Journal: Journal of applied physiology (Bethesda, Md. : 1985) | Year: 2015

Hypobaric hypoxia at high altitude (HA) results in reduced blood arterial oxygen saturation, perfusion of organs with hypoxemic blood, and direct hypoxia of lung tissues. The pulmonary complications in the cells of the pulmonary arterioles due to hypobaric hypoxia are the basis of the pathophysiological mechanisms of high-altitude pulmonary edema (HAPE). Some populations that have dwelled at HA for thousands of years have evolutionarily adapted to this environmental stress; unadapted populations may react with excessive physiological responses that impair health. Individual variations in response to hypoxia and the mechanisms of HA adaptation provide insight into physiological responses. Adaptive and maladaptive responses include alterations in pathways such as oxygen sensing, hypoxia signaling, K(+)- and Ca(2+)-gated channels, redox balance, and the renin-angiotensin-aldosterone system. Physiological imbalances are linked with genetic susceptibilities, and nonhomeostatic responses in gene regulation that occur by small RNAs, histone modification, and DNA methylation predispose susceptible humans to these HA illnesses. Elucidation of the interaction of these factors will lead to a more comprehensive understanding of HA adaptations and maladaptations and will lead to new therapeutics for HA disorders related to hypoxic lungs.

Loading SNM Hospital collaborators
Loading SNM Hospital collaborators