Dishari Ghosh

Determination of Bone Mass Using Multisite Quantitative Ultrasound and Biochemical Markers of Bone Turnover During Residency at Extreme Altitude: A Longitudinal Study

A group of 221 male healthy volunteers of Indian Army were the subjects of the study. The baseline parameters of skeletal health were measured during their residency at an altitude of 3542 m. These subjects were then taken to an extreme altitude (EA, 5400-6700 m) where they stayed for about 4 months. The study parameters were repeated following their de-induction (DI) to 3542 m. On random selection, a subgroup was constituted from the above mentioned volunteers for detailed investigations on various bone turnover markers. Results of this study indicate a loss of body weight after DI from EA. The bone impairment was detected at the proximal phalanx, which is known to undergo early morpho-structural changes associated with bone resorption. The intact parathyroid hormone (i-PTH) levels showed a significant increase, while alkaline phosphatase (ALP) and bone specific alkaline phosphatase (BAP) activities declined significantly after DI from EA. This elevation in i-PTH might be required for maintenance of blood Ca level. 25 (OH) Vitamin D3 (25VitD) and calcitonin (CT) also showed a significant decline, which may suggest a negative impact on bone formation during sojourn at EA. The causes of deterioration of skeletal health at EA although are poorly understood but may be due to acute hypoxemia arising from extreme hypobaric hypoxia prevalent at extreme altitude.

Elevated pulmonary artery pressure and brain natriuretic peptide in high altitude pulmonary edema susceptible non-mountaineers.

Exaggerated pulmonary pressor response to hypoxia is a pathgonomic feature observed in high altitude pulmonary edema (HAPE) susceptible mountaineers. It was investigated whether measurement of basal pulmonary artery pressure (Ppa) and brain natriuretic peptide (BNP) could improve identification of HAPE susceptible subjects in a non-mountaineer population. We studied BNP levels, baseline hemodynamics and the response to hypoxia (FIo2 = 0.12 for 30 min duration at sea level) in 11 HAPE resistant (no past history of HAPE, Control) and 11 HAPE susceptible (past history of HAPE, HAPE-S) subjects. Baseline Ppa (19.31 ± 3.63 vs 15.68 ± 2.79 mm Hg, p < 0.05) and plasma BNP levels (52.39 ± 32.9 vs 15.05 ± 9.6 pg/ml, p < 0.05) were high and stroke volume was less (p < 0.05) in HAPE-S subjects compared to control. Acute hypoxia produced an exaggerated increase in heart rate (p < 0.05), mean arterial pressure (p < 0.05) and Ppa (28.2 ± 5.8 vs 19.33 ± 3.74 mm Hg, p < 0.05) and fall in peripheral oxygen saturation (p < 0.05) in HAPE-S compared to control. Receiver operating characteristic (ROC) curves showed that Ppa response to acute hypoxia was the best variable to identify HAPE susceptibility (AUC 0.92) but BNP levels provided comparable information (AUC 0.85). BNP levels are easy to determine and may represent an important marker for the determination of HAPE susceptibility.

Post-translational modifications of eNOS augment nitric oxide availability and facilitates hypoxia adaptation in Ladakhi women

The lower inhaled oxygen per volume at high altitude poses an intimidating challenge for humans to survive and reproduce. Indigenous populations of the Himalayas reportedly exhibit higher microcirculatory blood flow accompanied by higher orders of magnitude of nitric oxide (NO) products in lung, plasma and red blood cells as a vascular adaptation strategy for hypobaric hypoxia. The precise mechanism of such observed higher NO metabolites for hypoxia adaptation remains elusive. Studying high altitude native Ladakhi women, we observed significant higher eNOS mRNA and protein in blood/plasma as compared to lowland women. We also observed higher level of plasma l-citrulline and NOx (nitrates and nitrites) with concomitant lower levels of arginase mRNA and protein further suggesting higher eNOS activity and NO bioavailability. Interestingly, middle aged postmenopausal Ladakhi women exhibited significantly higher level of eNOS activity, NOx and cGMP as compared to age matched lowland women. Preferential phosphorylation of eNOS on stimulatory Ser1177 and Ser615 as well as dephosphorylation of inhibitory Thr495 site contributed to higher NO availability in Ladakhi women irrespective of age. We also observed higher levels of eNOS activating humoral factors like bradykinin and estrogen in both young and middle-aged Ladakhi women. These results suggest that an altered phosphorylation status, together with an enhanced expression of eNOS and potential humoral endothelial activators, are involved in enhanced activation of the eNOS-NO-cGMP pathway in Ladakhi women irrespective of age, reinforcing the hypothesis that NO metabolites play a major role in Himalayan pattern of hypoxia adaptation.

Impact of high altitude on key determinants of female reproductive health: a review

Imperishable research work was done on females visiting high-altitude (HA) areas for recreational activities or job purposes as well as on female HA natives. Hypoxia at HA is an unavoidable condition that affects the determinants of female reproductive functions like, the age of menarche and menopause, whole reproductive span, hormone synthesis, and fertility. This review will emphasize whether HA hypoxia is a threat to women: residents or visitors by analyzing these proximate determinants. Delayed menarcheal and advanced menopausal age was found to shorten the reproductive span in some HA populations, whereas in some cases, menstrual cycle was also reported to be irregular. In addition, the completed fertility rate (CFR) was increased when people migrated to lower altitude. Altered stress hormones and reproductive hormones were observed in sea-level females exposed to HA. Oxidative stress (OS) at HA was also reviewed to explain the probable reasons for the observed changes in these determinants because disturbed redox homeostasis may be a connecting link, affecting the reproductive functions. In conclusion, HA hypoxia plays a crucial role on various determinants of female reproductive health and this review will be helpful for more precise study along with the probable underlying mechanisms responsible for the changes in female reproductive functions at HA.

Rapid Acclimatization Strategies for High-Altitude Induction

High altitude (HA) is defined as elevation above 9,000 ft. At this altitude, most people develop acute mountain sickness (AMS). If untreated, this may lead to high-altitude pulmonary oedema (HAPE) or high-altitude cerebral oedema (HACE), both of which are potentially life-threatening. In emergencies/warlike conditions, rapid deployment of military personnel to high altitude frequently occurs without giving the adequate degree of altitude acclimatization, resulting in acute mountain sickness (AMS). Acclimatization to high altitude is the best strategy to prevent AMS, and this can be achieved by hypoxia preconditioning by the use of interventions like hypoxia mimetics. Efficacy of hypoxia mimetics, viz. cobalt chloride (CoCl2), ethyl 3, 4-dihydroxybenzoate (EDHB), sphingosine-1-phosphate (S1P) and other pharmacological agent nanocurmin in facilitating acclimatization to high altitude in animal model, has been discussed. An alternative approach to induce acclimatization and reduce incidence of AMS is the use of intermittent hypoxic exposure (IHE). This study was conducted to evaluate the effect of IHE exposure at sea level on incidence of AMS during acute ascent to 3,500 m altitude in Indian military personnel. The army volunteers were divided into two groups, viz. control and experimental. Experimental group of subjects were exposed to intermittent normobaric hypoxia consisting of 12 % FIO2 (altitude – air equivalent 4,350 m) for 4 h per day for 4 consecutive days. After giving IHT, the subjects were inducted to 3,500 m altitude (Leh) by air and different physiological parameters like AMS score (LLS), pulse arterial oxygen saturation (SaO2) and ventilatory parameters (V E, VO2, V T/Ti) were recorded daily. IHE-treated group showed a significant reduction in AMS at HA in comparison to control. IHE may be considered as an alternative approach to induce the altitude acclimatization at low altitude-based soldiers before their deployment to high-altitude operations in emergency-like conditions.

Alterations in Different Indices of Skeletal Health after Prolonged Residency at High Altitude

AIMS The aim of this study was to evaluate the effect of prolonged residency at high altitude (HA) on different indices of bone health in sea level (SL) residents staying at an altitude of 3450 m for 4 months to 1 year. The assessment of bone health parameters included multisite quantitative bone speed of sound (SOS), and markers of bone metabolism such as serum alkaline phosphatase (ALP), bone specific alkaline phosphatase (BAP), urinary deoxypyridinoline (DPD), C-terminal propeptide of type I collagen (CICP), N-telopeptide of type I collagen (NTX), and hormonal regulators such as 25-hydroxy vitamin D3 (25Vit D), intact parathyroid hormone (i-PTH), and cortisol. RESULTS The body weight in all the age groups was significantly lower at HA as compared to SL values. Prolonged residency at HA led to a significant decline in bone strength in terms of SOS, both at radius and phalanx. There was a significant increase in circulating Ca and ALP levels. Serum i-PTH and 25VitD levels decreased significantly. Significant decreases were also observed in CICP and BAP, bone formation markers, and serum NTX, DPD/Cr ratio, markers of bone resorption. CONCLUSION These observations suggest that prolonged residency under hypoxic environment is associated with a decline in both bone formation and bone resorption markers, reflecting a lower bone turnover at HA.