Impact of Direct Acting Antiviral Therapy for Treatment of Hepatitis C Genotypes 1, 3 and 4: A Real Life Experience from India.

OBJECTIVE: To assess impact of Direct Acting Antiviral (DAA) therapies for treatment of Hepatitis C Virus (HCV) genotypes 1, 3 and 4 in a real-world cohort from India. METHODS: Adults with chronic HCV infection treated with Sofosbuvir (SOF) and Ledipasvir (LDV) (genotypes 1 and 4) or SOF and Daclatasvir (DCV) (genotype 3), with or without Ribavirin (RBV) between December 2015 and December 2016 were included. The primary endpoint was Sustained Virological Response at Post-treatment Week 12 (SVR12). RESULTS: Of the 648 patients, 181 received SOF/LDV (65 with RBV) and 467 received SOF/DCV (135 with RBV). Most patients were males (65.4%), aged 41-60 years (49.4%) and treatment-naïve (92.6%). Genotype 3 (72.1%) was most common, followed by genotypes 1 (22.4%) and 4 (5.6%). Forty two percent patients (n = 271) had cirrhosis (112 patients were decompensated). SVR12 (modified intention-to-treat) was achieved by 98.1% of patients (512/522) (100% in genotypes 1 and 4, and 97.3% (362/372) in genotype 3). On intention to treat analysis, SVR12 was 88.1% (512/581) [genotype 1-96.8% (121/125), genotype 3-85.2%, genotype 4-93.5% (29/31)]. Seventy patients had treatment failure (non response in 6, virological breakthrough in 2, 10 patients relapsed, 2 died and 50 were lost to follow up). High SVR was observed regardless of HCV genotype, presence of cirrhosis or past history of treatment. No major adverse events warranting discontinuation of treatment were noted. CONCLUSIONS: DAA therapy for HCV genotypes 1, 3 and 4 achieves high SVR rates in all patients, including those with cirrhosis and previous non-responders.

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.

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.

Sleep architecture at 4300 m altitude in a sample of Indian lowlanders.

The present study aimed to evaluate sleep architecture at 4300 m in a sample of 10 healthy Indian lowlanders, mean age 25.7 +/- 5.1 yrs. Polysomnography on two consecutive nights each was performed at sea level and 4300 m, the first night for adaptation and the second one for actual recording. Total sleep time reduced from 433.33 +/- 8.95 to 412.06 +/- 13.13 minutes (P < 0.0005), sleep latency increased from 11.56 +/- 6.85 to 22.22 +/- 7.95 minutes (P < 0.0025), deep NREM sleep (S3 + S4) reduced from 79.56 +/- 28.45 to 45.39 +/- 25.32 minutes (P < 0.01), light NREM sleep (S1 + S2) increased from 272.94 +/- 20.63 to 296.72 +/-23.24 minutes (P < 0.05), REM decreased from 80.89 +/- 7.65 to 69.94 +/- 11.30 minutes (P < 0.02) and periodic breathing was present in 4 of 10 participants on the second night at 4300 m. Decreased sleep quality (P < 0.0005) and increased sleep disturbances (P < 0.0005) were reported in subjective ratings at high altitude. Changes in sleep architecture similar to but of a greater magnitude are present on the second night of staged induction to 4300 m, than reported at 3500 m in our earlier study.

Corticosterone synthesis inhibitor metyrapone ameliorates chronic hypobaric hypoxia induced memory impairment in rat.

Chronic exposure to hypobaric hypoxia causes oxidative stress and neurodegeneration leading to memory impairment. The present study aimed at investigating the role of corticosterone in hypoxia induced neurodegeneration and effect of metyrapone, a corticosterone synthesis inhibitor that reduces the stress induced elevation of corticosterone without affecting the basal level, in ameliorating chronic hypobaric hypoxia induced cognitive decline. Rats were exposed to simulated altitude of 25,000 ft for 0, 3, 7, 14 and 21 days to determine the temporal alterations in corticosterone and its receptors following exposure to hypobaric hypoxia. Our results showed an elevation of corticosterone in plasma and hippocampal tissue following 7 days of exposure, which declined on prolonged hypoxic exposure for 21 days. A concomitant increase in ROS and lipid peroxidation was observed along with depletion of intracellular antioxidants. Glucocorticoid and mineralocorticoid receptors were upregulated on 3 and 7 days of hypoxic exposure. Though expression of Glut1 and Glut3 were upregulated on 3 days of hypoxic exposure, sharp decline in Glut1 expression following 7 days of hypoxic exposure leads to reduced neuronal glucose uptake. Administration of metyrapone from 3rd to 7th day of hypoxic exposure to suppress hypoxia induced increase in corticosterone levels resulted in reduced oxidative damage, neurodegeneration and improvement of intracellular energy status. The metyrapone treated hypoxic animals performed better in the Morris Water Maze. Further, administration of exogenous corticosterone along with metyrapone during hypoxic exposure blunted the neuroprotective effect of metyrapone indicating a role for corticosterone in mediating hypobaric hypoxia induced neurodegeneration and memory impairment.

Modulatory effects of seabuckthorn (Hippophae rhamnoides L.) in hypobaric hypoxia induced cerebral vascular injury.

Cerebral edema caused by vascular leakage is a major problem in various injuries of the CNS, such as stroke, head injury and high-altitude illness. A common feature of all these disorders is the fact that they are associated with tissue hypoxia. Hypoxia has been suggested to be a major pathogenic factor for the induction of vascular leakage in the brain. The objective of the present study was to evaluate potential of seabuckthorn (SBT) (Hippophae rhamnoides L.) seed oil in curtailing hypoxia induced transvascular fluid leakage in brain of hypoxia-exposed rats. Exposure of animals to hypobaric hypoxia (9144 m, 5h) caused a significant increase in the transvascular leakage studied by measuring water content and leakage of sodium fluorescein dye in the brain. Hypoxic stress also significantly enhanced the oxidative stress markers such as free radicals and malondialdehyde and it accompanied with decreased levels of antioxidants such as glutathione, glutathione peroxidase and superoxide dismutase. Pretreatment of animals with SBT seed oil significantly restricted the hypoxia induced increase in fluorescein dye leakage suggesting protection against hypoxia induced transvascular leakage in the brain. Hypoxia induced increase in the levels of free radicals and malondialdehyde were significantly lowered after SBT pretreatment. The SBT seed oil pretreatment also resulted in the significantly improved hypoxic tolerance as evidenced by increased hypoxic gasping time and survival time and decreased plasma catecholamine levels, as compared to hypoxic animals. These observations suggest that SBT seed oil possesses significant hypoxia protection activity and curtailed hypoxia induced enhanced vascular leakage in the brain.

Erythropoietin levels in lowlanders and high-altitude natives at 3450 m.

BACKGROUND: This study is aimed to determine whether short or prolonged residency at high altitude (HA) elicits erythropoietin (EPO) secretion effectively in subjects who were able to acclimatize and those who were not able to acclimatize and suffered from acute mountain sickness (AMS) and high altitude pulmonary edema (HAPE). METHODS: Plasma EPO was measured in 16 lowland residents (LLR) at sea level (SL) and during 11 d of their sojourn at an altitude of 3450 m. Identical studies were also conducted in LLR acclimatized to HA (LLR-accl), high altitude natives (HAN) and in patients of AMS and HAPE. RESULTS: In LLR at SL, the mean +/- SD EPO levels were 8.93 +/- 3.75 mU x ml(-1), increased significantly after 8 h (20.0 +/- 11.06) of arrival at HA, peaked by day 1 (27.91 +/- 10.74 mU x ml(-1)), and started declining thereafter. The hemoglobin and hematocrit also increased after 8 h of arrival at HA and the increased levels were maintained during sojourn at high altitude. The EPO levels in LLR-accl were found to be significantly higher than the LLR SL values, but were not significantly different in HAN. The EPO levels in patients of AMS were not significantly different than the LLR values during the initial 2 d after arrival at HA but were found to be increased in patients of HAPE. CONCLUSION: Short or prolonged residency at HA is associated with increased secretion of EPO. The EPO response to hypoxia is not significantly altered in AMS but is markedly enhanced in HAPE, which may be due to exaggerated hypoxemia in these patients.

Autonomic nervous system and adrenal response to cold in man at Antarctica.

OBJECTIVE: To evaluate the role of the autonomic nervous system and adrenal system in acclimatization to cold in tropical men during short or prolonged sojourns at Antarctica. METHODS: The study was carried out on volunteers of the 18th winter over team (WOT) and 19th summer team (ST) of an Indian Antarctic Expedition. The ST members were evaluated at Delhi; during voyage; and on days 7, 30, and 60 of their stay at Antarctica. Identical studies were performed in WOT members who had stayed at Antarctica for 14 months. The parameters examined included heart rate, blood pressure, oral temperature, index finger skin temperature, heart rate variability, urinary epinephrine and norepinephrine, and salivary cortisol. RESULTS: The resting heart rate and blood pressure in ST members significantly increased (P < .05) on days 7 and 30 of their stay at Antarctica and returned to baseline Delhi values by day 60. The index finger temperature declined (P < .05) on day 7 at Antarctica and remained at lower levels during the entire period of observations. Heart rate variability showed an imbalance of autonomic nervous system effects with predominance of low-frequency band on day 7 of stay and returned to Delhi values by day 60. The urinary excretion of epinephrine and norepinephrine and salivary cortisol were also increased on day 7 and declined to baseline Delhi values after 2 months of stay. Compared with the ST group, the WOT group showed a significantly higher (P < .05) resting heart rate, blood pressure, and low-frequency power and urinary excretion of norepinephrine. CONCLUSIONS: These observations suggest that Antarctic residency during austral summer results in gradual attenuation of sympathetic tone and a shift of autonomic balance toward the parasympathetic side. However, WOT members showed a predominance of sympathetic and adrenal activity compared with initial responses of ST members, suggesting deconditioning or possible resetting of the autonomic nervous system.

Effects of Hatha yoga and Omkar meditation on cardiorespiratory performance, psychologic profile, and melatonin secretion.

OBJECTIVES: To evaluate effects of Hatha yoga and Omkar meditation on cardiorespiratory performance, psychologic profile, and melatonin secretion. SUBJECTS AND METHODS: Thirty healthy men in the age group of 25-35 years volunteered for the study. They were randomly divided in two groups of 15 each. Group 1 subjects served as controls and performed body flexibility exercises for 40 minutes and slow running for 20 minutes during morning hours and played games for 60 minutes during evening hours daily for 3 months. Group 2 subjects practiced selected yogic asanas (postures) for 45 minutes and pranayama for 15 minutes during the morning, whereas during the evening hours these subjects performed preparatory yogic postures for 15 minutes, pranayama for 15 minutes, and meditation for 30 minutes daily, for 3 months. Orthostatic tolerance, heart rate, blood pressure, respiratory rate, dynamic lung function (such as forced vital capacity, forced expiratory volume in 1 second, forced expiratory volume percentage, peak expiratory flow rate, and maximum voluntary ventilation), and psychologic profile were measured before and after 3 months of yogic practices. Serial blood samples were drawn at various time intervals to study effects of these yogic practices and Omkar meditation on melatonin levels. RESULTS: Yogic practices for 3 months resulted in an improvement in cardiorespiratory performance and psychologic profile. The plasma melatonin also showed an increase after three months of yogic practices. The systolic blood pressure, diastolic blood pressure, mean arterial pressure, and orthostatic tolerance did not show any significant correlation with plasma melatonin. However, the maximum night time melatonin levels in yoga group showed a significant correlation (r = 0.71, p < 0.05) with well-being score. CONCLUSION: These observations suggest that yogic practices can be used as psychophysiologic stimuli to increase endogenous secretion of melatonin, which, in turn, might be responsible for improved sense of well-being.