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Li, Xiaoxu, Zhijun Pu, Gang Xu, Yidong Yang, Yu Cui, Xiaoying Zhou, Chenyuan Wang, Zhifeng Zhong, Simin Zhou, Jun Yin, Fabo Shan, Chengzhong Yang, Li Jiao, Dewei Chen, and Jian Huang. Hypoxia-induced myocardial hypertrophy companies with apoptosis enhancement and p38-MAPK pathway activation. High Alt Med Biol. 25:186-196, 2024. Background: Right ventricular function and remodeling are closely associated with symptom severity and patient survival in hypoxic pulmonary hypertension. However, the detailed molecular mechanisms underlying hypoxia-induced myocardial hypertrophy remain unclear. Methods: In Sprague-Dawley rats, hemodynamics were assessed under both normoxia and hypobaric hypoxia at intervals of 7 (H7), 14 (H14), and 28 (H28) days. Morphological changes in myocardial tissue were examined using hematoxylin and eosin (HE) staining, while myocardial hypertrophy was evaluated with wheat germ agglutinin (WGA) staining. Apoptosis was determined through TUNEL assays. To further understand the mechanism of myocardial hypertrophy, RNA sequencing was conducted, with findings validated via Western blot analysis. Results: The study demonstrated increased hypoxic pulmonary hypertension and improved right ventricular diastolic and systolic function in the rat models. Significant elevations in pulmonary arterial systolic pressure (PASP), mean pulmonary arterial pressure (mPAP), right ventricular mean pressure (RVMP), and the absolute value of +dp/dt max were observed in the H14 and H28 groups compared with controls. In addition, right ventricular systolic pressure (RVSP), -dp/dt max , and the mean dp/dt during isovolumetric relaxation period were notably higher in the H28 group. Heart rate increased in the H14 group, whereas the time constant of right ventricular isovolumic relaxation (tau) was reduced in both H14 and H28 groups. Both the right heart hypertrophy index and the heart weight/body weight ratio (HW/BW) were elevated in the H14 and H28 groups. Myocardial cell cross-sectional area also increased, as shown by HE and WGA staining. Western blot results revealed upregulated HIF-1α levels and enhanced HIF-2α expression in the H7 group. In addition, phosphorylation of p38 and c-fos was augmented in the H28 group. The H28 group showed elevated levels of Cytochrome C (Cyto C), whereas the H14 and H28 groups exhibited increased levels of Cleaved Caspase-3 and the Bax/Bcl-2 ratio. TUNEL analysis revealed a rise in apoptosis with the extension of hypoxia duration in the right ventricle. Conclusions: The study established a link between apoptosis and p38-MAPK pathway activation in hypoxia-induced myocardial hypertrophy, suggesting their significant roles in this pathological process.

Horakova, Lenka , Susi Kriemler, Vladimír Študent, Jacqueline Pichler Hefti, David Hillebrandt, Dominique Jean, Kastė Mateikaitė-Pipirienė, Peter Paal, Alison Rosier, Marija Andjelkovic, Beth Beidlemann, Mia Derstine, and Linda E. Keyes. Hormonal contraception and menstrual cycle control at high altitude: a scoping review-UIAA Medical Commission recommendations. High Alt Med Biol. 00:00-00, 2024. Background: Women who use hormonal contraception (HC) may have questions about their use during travel to high altitude. This scoping review summarizes current evidence on the efficacy and safety of HC and cycle control during high-altitude travel. Methods: We performed a scoping review for the International Climbing and Mountaineering Federation (UIAA) Medical Commission series on Women's Health in the Mountains. Pertinent literature from PubMed and Cochrane was identified by keyword search combinations (including contraception) with additional publications found by hand search. Results: We identified 17 studies from 7,165 potentially eligible articles. No articles assessed the efficacy of contraception during a short-term high-altitude sojourn. Current data show no advantage or disadvantage in HC users for acclimatization or acute mountain sickness (AMS). Use of HC during high-altitude travel is common and safe for menses suppression. A potential concern of estrogen-containing HC is the increased thrombotic risk, which theoretically could be compounded in hypobaric hypoxia. Conclusions: Evidence is limited for the interaction of HC and high altitude on performance, thrombosis, and contraceptive efficacy. HC does not affect the risk of AMS. The most efficacious and safest method at high altitude is generally the one women are most familiar with and already using.

Jatwani, Arti, and Rajkumar Tulsawani. Ganoderma lucidum induces myogenesis markers to avert damage to skeletal muscles in rats exposed to hypobaric hypoxia. High Alt Med Biol . 24:287-295, 2023. Background: Hypobaric hypoxia (HH) has been reported to induce skeletal muscle loss and impair myogenesis. Aqueous extract of G. lucidum (AqGL) contains bioactive metabolites attributed to various pharmacological effects. In this study, protective effect of AqGL in ameliorating muscle mass loss following acute HH has been reported. Materials and Methods: Male Sprague-Dawley rats were divided into following five groups of six rats in each group: unexposed control (Group 1), 6 hours of HH exposure (Group 2), 6 hours of HH exposure+AqGL extract 50 mg/kg body weight (BW) (Group 3), 6 hours of HH exposure+AqGL extract 100 mg/kg BW (Group 4), and 6 hours of HH exposure+AqGL extract 200 mg/kg BW (Group 5). Experimental animals from all groups, except Group, 1 were exposed to HH, simulated altitude of 25,000 ft for 6 hours. After exposure period, gastrocnemius muscle was collected, weighed, and morphological, biochemical, and molecular markers were analyzed. Results: HH-exposed rat muscle showed significant ( p  < 0.05) increase in oxidative stress markers (reactive oxygen species & malondialdehyde), which was concomitant with decrease in its mass compared to controls. AqGL treatment significantly ( p  < 0.05) prevented muscle oxidative stress, restored reduced glutathione content, reduced protein carbonyl content and advanced oxidation protein product, and restored muscle mass loss at effective dose of 100 mg/kg BW. Furthermore, AqGL supplementation enhanced Myf5 ( p  < 0.01), MyoD ( p  < 0.01), MyoG ( p  < 0.05), and Mrf4 (nonsignificantly), brain-derived neurotrophic factor ( p  < 0.01), and interleukin 6 ( p  < 0.01) expression along with restoration of tumor necrosis factor alpha ( p  < 0.001) and myostatin ( p  < 0.05) in hypoxia-exposed muscle, evidencing induction of myogenesis markers. Moreover, histological analysis showed increased myocyte number; nuclei shifted toward the periphery in the treatment group supporting muscle regeneration. Conclusion: AqGL supplementation attenuates muscle mass loss by preventing oxidative stress and inducing modulation in myogenesis markers under HH environment.

Apte, Chandrashekhar V. Barometric pressure at high altitude: revisiting West's prediction equation, and more. High Alt Med Biol. 24:85-93, 2023. Introduction: Since an earlier prediction equation to calculate barometric pressure at a given altitude had been tested against limited barometric pressure observations, its accuracy needed to be re-validated against additional pressure observations. Methods: Five-year (2016-2020) barometric pressure and altitude data were downloaded from an open-source website for 25 select locations. The calculated predicted pressure was compared with mean 5-year, mean monthly, and mean daily pressures. Percent prediction error and root mean square errors were used to assess accuracy of the prediction equation. Results: The original prediction equation was accurate to within 1% for locations only within 22° latitude. It was increasingly inaccurate at higher latitudes and also for means based on shorter time spans (e.g., mean monthly and daily pressures). A new prediction equation was proposed by developing a model using downloaded data. The new equation resulted in more accurate predictions for all latitudes and all time spans. The new equation also performed well when tested at seven new locations. Conclusions: Ideally, medical professionals at high altitude should rely on actual barometric pressure observations to assess hypoxic risk. In the absence of actual measurements, the suggested new prediction equation may be used to estimate, with some limitations, the ambient barometric pressure at latitudes below 47° and altitudes up to about 4,700 m.

Kammerer, Tobias, Anna Walzl, Thomas Müller, Philipp Groene, Giulia Roveri, Rachel Turner, Johanna Roche, Hannes Gatterer, Christoph Siebenmann, and Simon T. Schäfer. Effects of hypobaric hypoxia on coagulation in healthy subjects exposed to 3,500 m altitude. High Alt Med Biol . 24:94-103, 2023. Background: Hypoxia is discussed as a trigger for prothrombotic changes both in intensive care and high altitude medicine. This research study aimed to evaluate the effect of isolated hypobaric hypoxia (HH) on coagulation in females in a highly standardized setting. Methods: Twelve healthy female subjects were studied under HH (equivalent to 3,500 m) and normoxia (NX) during two 4-day sojourns, in a strictly controlled crossover design. Nutrition, fluid intake, hormonal status (i.e., menstrual cycle variation), and physical stress were standardized. Functional coagulation and blood lysis were measured by viscoelastometry and compared between HH and NX. In addition, plasma-based coagulation tests (PBCTs), namely prothrombin time, activated partial thromboplastin time, fibrinogen, factor VIII coagulation activity (FVIII:C), von Willebrand factor antigen (vWF:Ag), and von Willebrand factor ristocetin cofactor activity (vWF:RCo) were measured. Results: Neither for Viscoelastic Haemostatic Assays nor for PBCTs significant changes were found for HH compared with NX (all p  > 0.05). Specifically, the lysis ability, as well as clotting time, clot formation, clot amplitude, and maximum clot firmness unchanged were similar between HH and NX. This also applied to all other variables. Conclusion: We demonstrate that moderate HH per se has no influence on blood coagulation in healthy females.

Bellovary, Bryanne N., Andrew D. Wells, Zachary J. Fennel, Jeremy B. Ducharme, Jonathan M. Houck, Trevor J. Mayschak, Ann L. Gibson, Scott N. Drum, and Christine M. Mermier. Could orthostatic stress responses predict acute mountain sickness susceptibility before high altitude travel? A pilot study. High Alt Med Biol . 24:19-26, 2023. Purpose: This study assessed head-up tilt (HUT) responses in relation to acute mountain sickness (AMS)-susceptibility during hypoxic exposure. Materials and Methods: Fifteen participants completed three lab visits: (1) protocol familiarization and cycle maximal oxygen consumption (VO 2 max) test; (2) HUT test consisting of supine rest for 20 minutes followed by 70° tilting for ≤40 minutes; and (3) 6 hours of hypobaric hypoxic exposure (4,572 m) where participants performed two 30-minute cycling bouts separated by 1 hour at a 50% VO 2 max workload within the first 3 hours and rested when not exercising. During HUT, systolic blood pressure (SBP), diastolic blood pressure, heart rate (HR), and variability (blood pressure variability [BPV] and HR variability [HRV]) were measured continuously. The AMS scores were determined after 6 hours of exposure. Correlations determined relationships between HUT cardiovascular responses and AMS scores. Repeated-measures analysis of variance (ANOVA) assessed differences between those with and without AMS symptoms during HUT. Results: Higher AMS scores correlated with greater change in SBP variability ( r  = 0.52, p  = 0.048) and blunted changes in HRV (root mean square of successive differences between normal heartbeats r  = 0.81, p  = 0.001, percentage of adjacent normal sinus intervals that differ by more than 50 milliseconds [pNN50] r  = 0.87, p  < 0.001) during HUT. A pNN50 interaction ( p  = 0.02) suggested elevated cardiac sympathetic activity at baseline and a blunted increase in cardiac sympathetic influence throughout HUT in those with AMS (pNN50 baseline: AMS = 26.2% ± 15.3%, no AMS = 51.0% ± 13.5%; first 3 minutes into HUT: AMS = 17.2% ± 19.1%, no AMS = 17.1% ± 10.9%; end of HUT: AMS = 6.2% ± 9.1%, no AMS 11.0% ± 10.0%). Conclusions: The results suggest autonomic responses via HUT differ in AMS-susceptible individuals. Changes in HRV and BPV during HUT may be a promising predictive measurement for AMS-susceptibility, but further research is needed for confirmation.

Sharma, Vandana, Rajeev Varshney, and Niroj Kumar Sethy. Identification of suitable reference genes for lowlanders exposed to high altitude and Ladakhi highlanders. High Alt Med Biol . 23:319-329, 2022. Background: Identifying a stable and reliable reference gene (RG) is a prerequisite for the unbiased and unambiguous analysis of gene expression data. It has become evident that conventionally used housekeeping genes such as beta-actin ( ACTB ), glyceraldehyde-3-phosphate dehydrogenase ( GAPDH ), and peptidylprolyl Isomerase A ( PPIA ) exhibit varied expression patterns under hypoxia. Hence, the identification of stable RGs for humans exposed to hypobaric hypoxia can enhance the accuracy of gene expression studies by limiting the negligent use of random housekeeping genes. Methods: Using TaqMan™ array-based quantitative real-time quantitative polymerase chain reaction, we evaluated the expression of 32 commonly used human RGs among lowlanders at Delhi (altitude 216 m, SL), lowlanders at Leh (altitude 3,524 m) after 1 day (HA-D1) and 7 days (HA-D7), as well as indigenous Ladakhi highlanders at the same altitude. The expression stability of the RGs was evaluated using geNorm, NormFinder, BestKeeper, Delta CT method, and RefFinder algorithms. Results: Our studies identify TATA-box binding protein ( TBP ), proteasome 26S subunit, ATPase 4 ( PSMC4 ), and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta ( YWHAZ ) as the most stable human RGs for normalizing human gene expression under hypobaric hypoxia. In addition, we report the combination of TBP and cyclin-dependent kinase inhibitor 1B ( CDKN1B ) as the most stable RG for studying lowlander gene expression during high-altitude exposure. In contrast, RPL30 and 18S exhibited maximum variation across study groups and were identified as the least stable RGs.

Cao, Yinhang, Naoto Fujii, Tomomi Fujimoto, Yin-Feng Lai, Takeshi Ogawa, Tsutomu Hiroyama, Yasushi Enomoto, and Takeshi Nishiyasu. CO 2 -enriched air inhalation modulates the ventilatory and metabolic responses of endurance runners during incremental running in hypobaric hypoxia. High Alt Med Biol . 23:125-134, 2022. Aim: We measured the effects of breathing CO 2 -enriched air on ventilatory and metabolic responses during incremental running exercise under moderately hypobairc hypoxic (HH) conditions. Materials and Methods: Ten young male endurance runners [61.4 ± 6.0 ml/(min·kg)] performed incremental running tests under three conditions: (1) normobaric normoxia (NN), (2) HH (2,500 m), and (3) HH with 5% CO 2 inhalation (HH+CO 2 ). The test under NN was always performed first, and then, the two remaining tests were completed in random and counterbalanced order. Results: End-tidal CO 2 partial pressure (55 ± 3 vs. 35 ± 1 mmHg), peak ventilation (163 ± 14 vs. 152 ± 12 l/min), and peak oxygen uptake [52.3 ± 5.5 vs. 50.5 ± 4.9 ml/(min·kg)] were all higher in the HH+CO 2 than HH trial (all p  < 0.01), respectively. However, the duration of the incremental test did not differ between HH+CO 2 and HH trials. Conclusion: These data suggest that chemoreflex activation by breathing CO 2 -enriched air stimulates breathing and aerobic metabolism during maximal intensity exercise without affecting exercise performance in male endurance runners under a moderately hypobaric hypoxic environment.

Committeri Giorgia, Danilo Bondi, Carlo Sestieri, Ginevra Di Matteo, Claudia Piervincenzi, Christian Doria, Roberto Ruffini, Antonello Baldassarre, Tiziana Pietrangelo, Rosamaria Sepe, Riccardo Navarra, Piero Chiacchiaretta, Antonio Ferretti, and Vittore Verratti. Neuropsychological and neuroimaging correlates of high-altitude hypoxia trekking during the "Gokyo Khumbu/Ama Dablam" expedition. High Alt Med Biol . 23:57-68, 2022. Background: Altitude hypoxia exposure may produce cognitive detrimental adaptations and damage to the brain. We aimed at investigating the effects of trekking and hypoxia on neuropsychological and neuroimaging measures. Methods: We recruited two balanced groups of healthy adults, trekkers ( n  = 12, 6 F and 6 M, trekking in altitude hypoxia) and controls (gender- and age-matched), who were tested before (baseline), during (5,000 m, after 9 days of trekking), and after the expedition for state anxiety, depression, verbal fluency, verbal short-term memory, and working memory. Personality and trait anxiety were also assessed at a baseline level. Neuroimaging measures of cerebral perfusion (arterial spin labeling), white-matter microstructural integrity (diffusion tensor imaging), and resting-state functional connectivity (functional magnetic resonance imaging) were assessed before and after the expedition in the group of trekkers. Results: At baseline, the trekkers showed lower trait anxiety ( p  = 0.003) and conscientiousness ( p  = 0.03) than the control group. State anxiety was lower in the trekkers throughout the study ( p  < 0.001), and state anxiety and depression decreased at the end of the study in both groups ( p  = 0.043 and p  = 0.007, respectively). Verbal fluency increased at the end of the study in both groups ( p  < 0.001), whereas verbal short-term memory and working memory performance did not change. No significant differences between before and after the expedition were found for neuroimaging measures. Conclusions: We argue that the observed differences in the neuropsychological measures mainly reflect aspecific familiarity and learning effects due to the repeated execution of the same questionnaires and task. The present results thus suggest that detrimental effects on neuropsychological and neuroimaging measures do not necessarily occur as a consequence of short-term exposure to altitude hypoxia up to 5,000 m, especially in the absence of altitude sickness.

Diaz, Gabriel F., Alicia Marquez, Ariel Ruiz-Parra, Maurice Beghetti, and Dunbar Ivy. An acute hyperoxia test predicts survival in children with pulmonary hypertension living at high altitude. High Alt Med Biol . 22:395-405, 2021. Background: Pulmonary hypertension (PH) causes significant morbidity and mortality in children at altitude. Materials and Methods: Fifty-two children living at 2,640 m were included. During hyperoxia test (O 2 Test), patients received high oxygen concentrations (FiO 2 >80, through Mask, using Venturi or nonrebreathing mask); echocardiography was used to evaluate pulmonary vasculature reactivity. A decrease >20% from the basal pulmonary artery systolic pressure was considered a positive response. Results: Most of the patients had severe PH. The median age at diagnosis was 4.5 years; 34 were female (65.4%). Idiopathic PH was present in 44 patients (84.6%). Six developed severe PH after ductus closure. They were classified in responders ( n  = 25), and nonresponders ( n  = 26). Responders were younger (3 years vs. 7 years, p  = 0.02), and 22 (88%), had better functional class (FC) 1-2, than nonresponders: 18 (69.23%) of them had worse FC: 3-4 ( p  = 0.000). In responders, 10/12 who went to live at low altitude became asymptomatic, compared with 7/13 who remained at high altitude. FC 1-2 was achieved by 70% of the patients with idiopathic PH who went to a low altitude, compared with 30% who continued at high altitude ( p  = 0.03). In nonresponders, 10/26 patients moved to a low altitude: four improved, one worsened, and five died; of the 16/26 patients living at high altitude, four are stable, eight worsened, and four died. Four patients (30.76%) in responder group and nine (69.24%) in the nonresponder group died ( p  = 0.03). There were differences between both groups in systolic (88 mm Hg vs. 110 mm Hg; p  = 0.037), diastolic (37 mm Hg vs. 56 mm Hg; p  = 0.035), and mean pulmonary artery pressures (57 mm Hg vs. 88 mm Hg; p  = 0.038). Conclusions: This specific hyperoxia test applied until 24 hours (not published before) helps to predict survival and prognosis of children with PH. Children with PH at a high altitude improve at low altitude.

Bondi, Danilo, Vittore Verratti, Raffaella Nori, Laura Piccardi, Giulia Prete, Tiziana Pietrangelo, and Luca Tommasi. Spatial abilities at high altitude: Exploring the role of cultural strategies and hypoxia. High Alt Med Biol . 22: 157-165, 2021. Background: Over the past couple of decades, the number of people of different cultures traveling to places of high altitude (HA) increased. At HA, a decline in cognitive abilities has been described, including spatial skills. However, it is still unknown whether people accustomed to hypobaric hypoxia are less susceptible to cognitive decline. Method: We aimed to determine if three ethnic groups would show any difference in the performance of spatial abilities. Italian trekkers (46.20 ± 15.83 years), Nepalese porters (30.33 ± 8.55 years), and lowlander and highlander Sherpas (30.33 ± 8.55 and 37.00 ± 16.51 years) were tested with a building photograph recognition, a map orienting, and a mental rotation task during a Himalayan expedition. Accuracy and response times were collected at low altitude (LA) and HA. Results: Nepalese performed the worst (photograph task: p  = 0.015, η 2 p  = 0.36; map task: p  = 0.016, η 2 p  = 0.36), but the difference was mitigated after correcting for length of schooling. Participants took more time to respond at LA than in HA condition (photograph task: 24.0 ± 15.3 seconds vs. 12.7 ± 6.3 seconds, p  = 0.008, η 2 p  = 0.57; map task: 12.5 ± 1.8 seconds vs. 7.8 ± 0.6 seconds, p  = 0.038, η 2 p  = 0.40). In the map task, participants performed with greater accuracy at LA (5.1 ± 0.4 vs. 4.4 ± 0.4 number of correct responses, p  = 0.006, η 2 p  = 0.59). Conclusions: Altitude hypoxia elicited impairments in cognitive spatial tasks. This may be due to the inability to acquire new unfamiliar patterns, and to the difficulty in managing a high cognitive workload. The ethnic differences were ascribed to schooling, even we consider the different system of reference usually exploited in each culture (egocentric: dependent, or allocentric: independent from the personal viewpoint), and that Westerners are more likely to focus on specific details of the scene. Further studies should investigate the diverse strategies to complete spatial tasks.

Betge, Stefan, Stefan Drinda, Thomas Neumann, Laura Bäz, Alexander Pfeil, Christian Schulze, Ralf Mrowka, Christian Jung, and Marcus Franz. Influence of macitentan on the vascular tone and recruitment of finger capillaries under hypobaric hypoxia in high altitude. High Alt Med Biol . 21:336-345, 2020. Introduction: Acute normobaric (NH) and hypobaric hypoxia (HH) has effects on the vascular tone of larger arteries and may have effects on the microcirculation. These effects may be noninvasively detectable by automated devices. A part of these effects may be mediated by endothelin (ET) and should be influenced by macitentan (MAC), a dual endothelin receptor antagonist (ERA). Methods: We used photoplethysmographic sensors, fingertip volume sensors, nailfold capillaroscopy, and laser Doppler probes at rest and after a 5-minute forearm ischemia in healthy study subjects under NH, under HH, and under HH plus a single dose of MAC. Results: NH at simulated 4000 m led to increased heart rates (HR) and pulse wave velocities (PWV) and reduced augmentation index (AIX). The values for the AIX showed a high SD and differed between the used devices. At simulated 5500 m, only baseline mean value (BMV; EndoPAT) showed a further change, indicating less filled capillaries of the fingertips. HH (2978 m) increased HR, blood pressure values, and PWV. Focusing on the microcirculation of the fingertips, HH reduced the BMV and the nailfold capillary density and the postischemic capillary recruitment. MAC had no effect on the BMV, but antagonized the effects of HH on the nailfold capillaries and led to a strongly increased postischemic diameter of the arterial limbs. Concordantly, the postischemic blood flow velocity increment, measured through ultrasound Doppler, was increased at ALT+MAC. Conclusions: The BMV may be a parameter for changes of the microcirculation of the finger tips. A single dose of MAC blocked hypoxia-induced capillary rarefaction and enhanced postischemic hyperemia of the fingertips. These results indicate the importance of ET-1 for the regulation of the microcirculation under hypoxia. The German Registry of Clinical Studies (DRKS) ID: 00005459.

Background: Both dynamic and static visual performances are essential for safety and motoric performance at altitude. There is a lack of information regarding alterations in dynamic visual performance (DVP) in oxygen-reduced environments. The purpose of this study was to analyze DVP in natural hypoxic conditions in a group of young, healthy hikers. Methods: DVP in four parafoveal subfields was analyzed using the computer-assisted Düsseldorf Test for Dynamic Vision . Measurements were performed twice at altitudes above 3500 m during an 8-day alpine hike. Results: On day 5 (3647 m), no changes in DVP were detected. On day 6 (4554 m), however, we found a significant reduction in DVP in the superior parafoveal retinal subfield, partly representing the lower visual field. The observed changes did not correlate with oxygen saturation, hematocrit, or cardiovascular parameters. We found no interrelation between symptoms of acute mountain sickness and DVP at altitude. Conclusions: Our data suggest that hiking at altitudes above 4500 m results in lower DVP in the visual field of healthy young people. The alteration might affect motor performance and coordination, increasing the risk of accidents.

Background: This study aimed to explore the effects of netrin-1 on hypobaric hypoxia-induced lung injury in mice. Methods: We exposed 6-8-week-old C57BL/6 mice to hypobaric stress at 340 mmHg for 30 minutes followed by 260 mmHg for different periods (6, 12, 18, and 24 hours) to observe the severity of lung injury (O 2 concentration, 21%; 54.6 mmHg). The wet/dry weight ratio and protein leakage from the mouse lung were used to determine the suitable exposure time. Netrin-1 was injected into the tail vein of mice before 18-hour decompression. Inflammatory cytokines, lung injury scores, and activity of nuclear factor κB were evaluated. The expression of apoptosis-related proteins was also examined. Results: Protein concentration in the bronchoalveolar lavage fluid was significantly higher in the 18-hour group ( p  < 0.05). Pulmonary pathology revealed neutrophil infiltration, alveolar septum thickening, and tissue edema. Injury score and macrophage inflammatory protein 2 levels were also increased. Intrinsic apoptosis pathway was activated. Hypoxia decreased the expression of Bcl2 protein, the number of active caspase-3-stained cells, and UNC5HB receptors. Pretreatment with netrin-1 reduced protein leakage, inhibited neutrophil migration, lowered the injury score, attenuated apoptosis, and increased UNC5HB receptor expression. Conclusion: Netrin-1 dampens hypobaric hypoxia-induced lung injury by inhibiting neutrophil migration and attenuating apoptosis.

Background: Exposure to hypobaric hypoxia (HH) has been reported to cause neurodegeneration and memory impairment. Hippophae rhamnoides , Prunus armeniaca , and Rhodiola imbricata , the indigenous plants of Indian Trans-Himalaya are widely used in traditional Tibetan and Amchi system of medicine. These are rich sources of diverse bioactive metabolites having prophylactic and therapeutic uses against a wide array of neurodegenerative diseases. The objective of this study was to elucidate the prophylactic and neuroprotective efficacy of formulated phytococktail (PC) against simulated HH-induced neurodegeneration in male Sprague Dawley (SD) rats. Materials and Methods: A PC containing H. rhamnoides fruit pulp, P. armeniaca fruit pulp, and R. imbricata dry root extract (100:50:1) was formulated. The neuroprotective efficacy of PC was evaluated in male SD rats following exposure to 7 day HH at simulated altitude (25,000 ft, 282 mm Hg). Rats were divided into four groups viz., normoxia group (NOR), normoxic group treated with PC (NORPC), 7 day hypoxic group treated with vehicle (7DH), and 7 day hypoxic group treated with PC (7DHPC). Memory impairment and neuromorphological alterations were measured. Targeted protein expression was analyzed by immunoblotting study. Results: PC supplementation significantly reduced the oxidative stress markers during exposure to HH. Spatial memory impairment by HH was significantly ameliorated by PC. HH-induced augmented pyknosis, decreased dendritic arborization, and increased Hoechst-positive neurons in hippocampal CA3 region were significantly ameliorated by PC. Immunoblotting study showed upregulation of BDNF and TrkB expression by PC. PC also prevented the hippocampal neurodegeneration by activating the PI3K/AKT signaling pathway, which leads to GSK-3β inactivation by its phosphorylation and alleviation of hippocampal Caspase3 expression leading to inhibition of apoptotic neuronal cell death. Conclusion: The present study advocates the potential role of PC as an effective neuroprotective supplement in preventing HH-induced neurodegeneration. Activation of the PI3K/Akt pathway through BDNF/TrkB interaction following PC supplementation after exposure to HH inhibits hippocampal neuronal apoptosis and memory impairment.

Introduction: Cognitive function has been compromised during high-altitude (HA) exposure due to slowing of mental processing. Materials and Methods: A total of 20 Indian and 20 Kyrgyz soldiers were studied at 4111 m to assess cognitive function in two different ethnic groups. Paired associate learning, pattern recognition memory, spatial span (SSP), spatial working memory (SWM), choice reaction time (CRT), and simple reaction time (SRT) were evaluated at sea level and on days 3, 7, 14, and 21 of HA stay and on day 3 of deinduction. Results: All the parameters were significantly affected at HA. Indian soldiers were acclimatized by 7 days but Kyrgyz soldiers required 21 days for acclimatization. A slow impairment in SWM, CRT, and SRT was observed in Kyrgyz soldiers than in Indian soldiers and it continues throughout 21 days of HA stay, but for Indian soldiers the deterioration was maximum on day 7 and improvement in SWM, CRT, and SRT was observed on day 14 and close to baseline value on day 21. After deinduction, although Indian soldiers attained the normal value, Kyrgyz soldiers had higher value than baseline in SSP, SWM, CRT, and SRT. Conclusion: Difference in the cognitive performances of Indian and Kyrgyz soldiers may be due to the ethnogenetic diversity of these two groups.

Background/Aims: High-altitude polycythemia is defined by the increase of hematocrit and hemoglobin at high altitudes caused by production of excessive erythrocytes. Eryptosis is a process by which mature erythrocytes undergo self-destruction sharing several features with apoptosis. However, the eryptosis in high-altitude hypobaric hypoxia is unknown. Thus, the main purpose of this study was to investigate whether chronic hypoxia affected eryptosis and, if so, by what mechanisms. Methods: Biotin labeling technology was utilized to study the survival of red blood cells in chronic hypoxia. Flow cytometry was used to determine the volume of mature erythrocytes from forward scatter, phosphatidylserine scrambling from annexin-V-binding, intracellular Ca 2+ from Fluo-3-AM, reactive oxygen species (ROS) abundance from ROS-probe, and ceramide and CD47 abundance utilizing specific antibodies. Results: The volume of mature erythrocytes was significantly changed, and the percentage of annexin-V-binding cells was significantly decreased under chronic hypobaric hypoxia. Erythrocyte survival was improved under chronic hypoxia, and chronic hypoxia resulted in a decrease in intracellular Ca 2+ in vivo and influenced eryptosis which was induced by the Ca 2+ -ionophore ionomycin (1 μM, 60 minutes) in vitro Chronic hypobaric hypoxia can inhibit eryptosis by decreasing intracellular Ca Conclusions: Chronic hypobaric hypoxia can inhibit eryptosis by decreasing intracellular Ca 2+ and increasing integrin-associated protein CD47.

Background: Hypobaric hypoxia (HH) increases the risk of high altitude-related illnesses (HARI). The pathophysiological mechanism(s) involved are still partially unknown. Altered vascular reactivity as consequence of endothelial dysfunction during HH might play a role in this phenomenon. Adiponectin exerts protective effect on cardiovascular system since it modulates NO release, antagonizing endothelial dysfunction. Aims of this study, performed in a selected population of airforce aviators, were (1) to investigate whether exposure to acute HH might be associated with endothelial dysfunction and (2) to evaluate whether adiponectin might be involved in modulating this phenomenon. Methods: Twenty aviators were exposed to acute HH in a hypobaric chamber by simulating altitude of 8000 and then 6000 m for 2 hours. Vascular reactivity was evaluated by the EndoPAT test immediately before and after the HH; salivary and blood adiponectin levels were measured. Results: EndoPAT performed immediately after HH divided pilots in two groups: 12 pilots with preserved vascular reactivity and 8 pilots with reduction of vascular reactivity, indicating that HH exposure might cause endothelial dysfunction. Salivary and blood adiponectin levels increased post-HH in a time-dependent manner in all aviators, but the significant increase was observed only in those with preserved vascular reactivity suggesting that HH stimulated release of adiponectin that, in turn, by exerting a protective effect, might reduce endothelial dysfunction. Conclusions: Acute HH may cause endothelial dysfunction due, at least in part, to reduced release of adiponectin. This phenomenon might be involved in pathophysiology of HARI.

In hypobaric hypoxia (HH) at high altitude, the immune responses are changed probably due to oxidative stress-induced production of free radicals and nonradicals. Vitamin E is an antioxidant and protects the cells from oxidative damage. The present study was carried out to study the antioxidant role of vitamin E on the immune changes induced by oxidative stress in HH at high altitude. Select immune responses (phagocytic activity of white blood cell [WBC], cytotoxic activity of splenic mononuclear cells [MNCs], and delayed type of hypersensitivity [DTH]) and hematological changes (total count and differential count [DC] of WBC) were measured in male rats exposed to intermittent HH (at 5486.4 m in a simulated chamber for 8 hours/d for 6 consecutive days) and in normobaric condition with and without p.o. administration of vitamin E in three different doses (20, 40, and 60 mg/kg body weight). The increase of phagocytic activity of blood WBC, and reduction of cytotoxic activity of splenic MNC and DTH response were observed in rats exposed to HH. After the administration of vitamin E at different doses, the immune changes were blocked in a dose-dependent manner. Exposure to HH also led to the elevation of serum corticosterone (CORT), which was arrested after administration of vitamin E. The results indicate that the immune changes in HH at high altitude are probably mediated by the production of free radicals and nonradicals, and vitamin E can block these immune changes by its reactive oxygen species quenching effects.

Aim: High altitude exposure alters biochemical, metabolic, and physiological features of heart and skeletal muscles, and hence has pathological consequences in these tissues. Central to these hypoxia-associated biochemical/metabolic shuffling are energy deficit accumulation of free radicals and ensuing oxidative damage in the tissue. Recent preclinical/clinical studies indicate sphingosine-1-phosphate (S1P) axis, comprising S1P G protein coupled receptors (S1PR 1-5 ) and its synthesizing enzyme-sphingosine kinase (SphK) to have key regulatory roles in homeostatic cardiac and skeletal muscle biology. In view of this, the aim of the present study was to chart the initiation and progression of biochemical/metabolic shuffling and assess the coincident differential modulation of S1PR (1-5) expression and total SphK activity in cardiac and skeletal muscles from rats exposed to progressive hypobaric hypoxia (HH; 21,000 feet for 12, 24, and 48 hours)., Results: HH-associated responses were evident as raised damage markers in plasma, oxidative stress, decreased total tissue protein, imbalance of intermediate metabolites, and aerobic/anaerobic enzyme activities in cardiac and skeletal muscles (gastrocnemius and soleus) culminating as energy deficit., Conclusion: Cardiac and gastrocnemius muscles were more susceptible to hypoxic environment than soleus muscle. These differential responses were directly and indirectly coincident with temporal expression of S1PR (1-5) and SphK activity.

Objective: To determine whether 2 days of staging at 2500-3500 m, combined with either high or low physical activity, reduces acute mountain sickness (AMS) during subsequent ascent to 4300 m., Methods: Three independent groups of unacclimatized men and women were staged for 2 days at either 2500 m (n = 18), 3000 m (n = 16), or 3500 m (n = 15) before ascending and living for 2 days at 4300 m and compared with a control group that directly ascended to 4300 m (n = 12). All individuals departed to the staging altitudes or 4300 m after spending one night at 2000 m during which they breathed supplemental oxygen to simulate sea level conditions. Half in each group participated in ∼3 hours of daily physical activity while half were sedentary. Women accounted for ∼25% of each group. AMS incidence was assessed using the Environmental Symptoms Questionnaire. AMS was classified as mild (≥0.7 and <1.5), moderate (≥1.5 and <2.6), and severe (≥2.6)., Results: While staging, the incidence of AMS was lower (p < 0.001) in the 2500 m (0%), 3000 m (13%), and 3500 m (40%) staged groups than the direct ascent control group (83%). After ascent to 4300 m, the incidence of AMS was lower in the 3000 m (43%) and 3500 m (40%) groups than the 2500 m group (67%) and direct ascent control (83%). Neither activity level nor sex influenced the incidence of AMS during further ascent to 4300 m., Conclusions: Two days of staging at either 3000 or 3500 m, with or without physical activity, reduced AMS during subsequent ascent to 4300 m but staging at 3000 m may be recommended because of less incidence of AMS.

Patrician, Alexander, Harald Engan, David Lundsten, Ludger Grote, Helena Vigetun-Haughey, and Erika Schagatay. The effect of dietary nitrate on nocturnal sleep-disordered breathing and arterial oxygen desaturation at high altitude. High Alt Med Biol 19:21-27, 2018.-Sleep-disordered breathing and fluctuations in arterial oxygen saturation (SaO 2 ) are common during sleep among lowlanders ascending to high altitude. Dietary nitrate (NO 3 - ) supplementation has been shown to lower the O 2 consumption in various conditions. Our objective was to investigate whether dietary NO 3 - could reduce sleep-disordered breathing and SaO 2 desaturation during sleep at altitude. Cardiorespiratory responses during sleep were measured in 10 healthy lowlanders at 330 m and then again in the Himalayas at 3700-4900 m. Each subject received two 70 mL shots of either beetroot juice (BR; ∼5.0 mmol NO 3 - per shot) or placebo (PL: ∼0.003 mmol NO 3 - per shot) in a single-blinded, weighted order over two consecutive nights at altitude. At 2.5-4.5 hours into sleep at altitude, BR increased the SaO 2 desaturation drop (4.2 [0.1]% with PL vs. 5.3 [0.4]% with BR; p = 0.024) and decreased the SaO 2 desaturation duration (14.1 [0.9] seconds with PL to 11.1 [0.9] seconds with BR; p = 0.0.041). There was a reduction in breaths with flow limitation (p = 0.025), but no changes in Apnea-Hypopnea Index (AHI), mean and minimum SaO 2 . The study suggests BR supplementation does not improve AHI or oxygenation, but may increase fluctuations in arterial O 2 saturation during sleep at altitude in native lowlanders.

Sheth, Chandni, Hendrik Ombach, Paul Olson, Perry F. Renshaw, and Shami Kanekar. Increased anxiety and anhedonia in female rats following exposure to altitude. High Alt Med Biol. 19:81-90, 2018.-Anxiety disorders are chronic, highly prevalent conditions, often comorbid with depression. Both anxiety and depression form major risk factors for suicide. Living at altitude is associated with higher rates of depression and suicide, leading us to address whether anxiety disorders may also be amplified at altitude. Using a novel translational animal model, we previously showed that depression-like behavior increases with altitude of housing in female, but not male rats. We now use this model to examine the effects of altitude on both anxiety-like behavior and anhedonia, a core symptom of depression. After housing for a week at sea level, 4500 or 10,000 ft, rats were evaluated for anxiety in the open-field test or the elevated plus maze, and anhedonia in the sucrose preference test. Another group was tested at baseline. Anxiety-like behavior increased in females housed at altitude. In females, lower sucrose preference was seen in those housed at 10,000 ft versus those at sea level. Males showed no change in anxiety or anhedonia across groups. These data suggest that living at moderate-high altitude may pose a risk factor for those vulnerable to anxiety disorders, with the potential to be particularly detrimental to females at altitude.

Irarrázaval, Sebastián, Claudio Allard, Juan Campodónico, Druso Pérez, Pablo Strobel, Luis Vásquez, Inés Urquiaga, Guadalupe Echeverría, and Federico Leighton. Oxidative stress in acute hypobaric hypoxia. High Alt Med Biol. 18:128-134, 2017.-The effects of acute hypobaric hypoxia endured by mountaineers were studied, specifically as evidenced by acute mountain sickness (AMS) and oxidative stress damage. Ten male volunteers were exposed to acute hypobaric hypoxia, and AMS was evaluated through arterial oxygen saturation (SaO 2 ), cardiac rate, and the Lake Louise Score (LLS). Oxidative stress was determined through blood profile tests performed 24 hours before and after high-altitude exposure, assessing the oxidative damage and antioxidant profiles. Dietary habits were assessed using the Chilean Mediterranean Diet Index. During ascent (i.e., first 8 hours), all volunteers presented AMS (LLS ≥3 points), as manifested by a median LLS increment of four points, a 15 bpm cardiac rate, and 17% decrease in SaO 2 . Additionally, plasma lipid oxidative damage increased after the expedition, as evaluated through malondialdehyde, which was directly correlated with the LLS (R 2  = 0.720, p = 0.003) and inversely correlated with SaO 2 (R 2  = 0.436; p = 0.035) at a high altitude. Preascent carbonyl levels were inversely correlated to SaO 2 (R 2  = 0.490; p = 0.008) and directly correlated to cardiac rate (R 2  = 0.225, p = 0.016) at a high altitude. Moreover, dietary habits were inversely correlated with increased carbonyls during the expedition (R 2  = 0.436; p = 0.047). In conclusion, acute hypobaric hypoxia induced AMS and an increment in oxidative stress markers 24 hours after altitude exposure in the volunteers. Furthermore, oxidative stress damage was related to AMS severity. Finally, volunteers with closer adherence to a Mediterranean diet presented a lower increase in oxidative damage during ascent, reflecting the potential preventive role of diet against AMS.

Van Iterson, Erik H., Eric M. Snyder, and Bruce D. Johnson. The influence of 17 hours of normobaric hypoxia on parallel adjustments in exhaled nitric oxide and airway function in lowland healthy adults. High Alt Med Biol. 18:1-10, 2017.-Currently, there is a disparate understanding of the role that normobaric hypoxia plays in affecting nitric oxide (NO) measured in exhaled air (eNO) and airway function in lowland healthy adults. Compared to normobaric normoxia, this study aimed to test the effect of 17 hours of normobaric hypoxia on relationships between eNO and airway function in healthy adults. In a crossover study including 2 separate visits, 26 lowland healthy Caucasian adults performed eNO and pulmonary function tests on visit 1 in normobaric normoxia, while repeating all tests on visit 2 following 17 hours of normobaric hypoxia (12.5% O 2 ). Compared to normobaric normoxia, eNO (29 ± 24 vs. 36 ± 28 ppb), forced expiratory volume in one second (FEV 1 ) (4.1 ± 0.7 vs. 4.3 ± 0.8 L), mean forced expiratory flow between 25% and 75% FVC (FEF 25-75 ) (3.9 ± 1.0 vs. 4.2 ± 1.2 L/s), and forced expiratory flow at 75% FVC (FEF 75 ) (2.0 ± 0.7 vs. 2.3 ± 0.8 L/s) increased in normobaric hypoxia, respectively (all p < 0.05). Correlations at normoxia between eNO and FEV 1 (r = 0.39 vs. 0.44), FEF 25-75 (r = 0.51 vs. 0.51), and FEF 75 (r = 0.53 vs. 0.55) persisted as both parameters increased in hypoxia, respectively. For the first time, these data suggest that 17 hours of hypoxic breathing in the absence of low ambient pressure contribute to increased eNO and airway function in lowland healthy adults.

Latshang, Tsogyal Daniela, Daniela Juliana Mueller, Christian Maurizio Lo Cascio, Anne-Christin Stöwhas, Katrin Stadelmann, Noemi Tesler, Peter Achermann, Reto Huber, Malcolm Kohler, and Konrad Ernst Bloch. Actigraphy of wrist and ankle for measuring sleep duration in altitude travelers. High Alt Med Biol. 17:194-202, 2016-Aims: Actigraphy might be convenient to assess sleep disturbances in altitude field studies. Therefore, we evaluated whether actigraphy accurately measures sleep duration in healthy subjects traveling to altitude., Methods: Fifty-one healthy men, aged mean ± standard deviation (SD) 27 ± 9 years, were studied during one night at Zurich (490 m), two nights at Davos Wolfgang (1630 m), and two nights at Jakobshorn (2590 m), in randomized order. Sleep duration measured by actigraphy, using a one-axis device at the wrist (n = 51), a three-axis device at the other wrist, and a three-axis device at the ankle (n = 22), was compared with corresponding total sleep time (TST) measured by polysomnography., Results: During 255 polysomnographic overnight studies, 449 paired actigraphic recordings were obtained. The median polysomnographic-derived TST ranged from 397 to 408 minutes. Actigraphic mean TST from wrists with one-axis and three-axis devices, and from ankle agreed well with polysomnographic values with a bias of +1, -7, +6 minutes, respectively. Corresponding limits of agreement (±2 SD of bias) were ±51, ±60, and ±59 minutes. Limits of agreement of mean TST over five nights by actigraphy and polysomnography were similar to the coefficient of repeatability (2 SD of mean) of polysomnographic TST, that is, ±31, ±38, and ±36 minutes versus ±34 minutes., Conclusions: Actigraphy of the wrist or ankle by a one-axis or a three-axis device accurately estimates mean TST in groups of subjects and mean TST over several nights in individuals traveling to altitude. Therefore, actigraphy is valuable for assessing effects of altitude and other environmental influences on sleep duration during field studies over extended periods.

Saugy, Jonas J., Laurent Schmitt, Sibylle Fallet, Raphael Faiss, Jean-Marc Vesin, Mattia Bertschi, Raphaël Heinzer, and Grégoire P. Millet. Sleep disordered breathing during live high-train low in normobaric versus hypobaric hypoxia. High Alt Med Biol. 17:233-238, 2016.-The present study aimed to compare sleep disordered breathing during live high-train low (LHTL) altitude camp using normobaric hypoxia (NH) and hypobaric hypoxia (HH). Sixteen highly trained triathletes completed two 18-day LHTL camps in a crossover designed study. They trained at 1100-1200 m while they slept either in NH at a simulated altitude of 2250 m or in HH. Breathing frequency and oxygen saturation (SpO 2 ) were recorded continuously during all nights and oxygen desaturation index (ODI 3%) calculated. Breathing frequency was lower for NH than HH during the camps (14.6 ± 3.1 breath × min -1 vs. 17.2 ± 3.4 breath × min -1 , p < 0.001). SpO 2 was lower for HH than NH (90.8 ± 0.3 vs. 91.9 ± 0.2, p < 0.001) and ODI 3% was higher for HH than NH (15.1 ± 3.5 vs. 9.9 ± 1.6, p < 0.001). Sleep in moderate HH is more altered than in NH during a LHTL camp.

Goswami, Ananda Raj, Goutam Dutta, and Tusharkanti Ghosh. Naproxen, a nonsteroidal anti-inflammatory drug can affect daily hypobaric hypoxia-induced alterations of monoamine levels in different areas of the brain in male rats. High Alt Med Biol. 17:133-140, 2016.-The oxidative stress (OS)-induced prostaglandin (PG) release, in hypobaric hypoxic (HHc) condition, may be linked with the changes of brain monoamines. The present study intends to explore the changes of monoamines in hypothalamus (H), cerebral cortex (CC), and cerebellum (CB) along with the motor activity in rats after exposing them to simulated hypobaric condition and the role of PGs on the daily hypobaric hypoxia (DHH)-induced alteration of brain monoamines by administering, an inhibitor of PG synthesis, naproxen. The rats were exposed to a decompression chamber at 18,000 ft for 8 hours per day for 6 days after administration of vehicle or naproxen (18 mg/kg body wt.). The monoamine levels (epinephrine, E; norepinephrine, NE; dopamine, DA; and 5-hydroxytryptamine, 5-HT) in CC, CB, and H were assayed by high-performance liquid chromatography (HPLC) with electrochemical detection, and the locomotor behavior was measured by open field test. The NE and DA levels were decreased in CC, CB, and H of the rat brain in HHc condition. The E and 5-HT levels were decreased in CC, but in H and CB, they remained unaltered in HHc condition. These DHH-induced changes of monoamines in brain areas were prevented after administration of naproxen in HHc condition. The locomotor behavior remained unaltered in HHc condition and after administration of naproxen in HHc condition. The DHH-induced changes of monoamines in the brain in HHc condition are probably linked with PGs that may be induced by OS.

The growth of the body and bone mass and the mechanical properties of appendicular bone are impaired in immature rats exposed to different simulated high altitudes (SHA) (1850-5450 m) between the 32nd and the 74th days of postnatal life. Now, we report the effects of exposure to 4100 m on the above cited variables in female rats from infancy (age: 1 month) to adulthood (age: 8 months) to define the occurrence of catch up and to establish whether the effects of altitude are transient or permanent. The ex vivo right femur was mechanically tested in three-point bending. Body weight and length, and structural (loads at yielding and fracture, and stiffness) and architectural (diaphyseal cross-sectional area, cortical area, and cross-sectional moment of inertia) properties were measured at 2, 4, 6, and 8 months of exposure to SHA. The negative influence of hypoxia on all variables was similar at different ages or, in other words, the difference among ages was maintained at any extent of hypoxia. Hypoxia did not affect the elastic modulus, thus suggesting that the mechanical properties of the bone tissue were maintained. Catch up did not occur. The resulting osteopenic bone remained appropriate to its mechanical function during the entire exposure to SHA.

Under hypoxia, alterations in muscle contractile properties and faster fatigue development have been reported. This study investigated the efficacy of tensiomyography (TMG) in assessing muscle contractile function at acute moderate altitude. Biceps femoris (BF) and vastus lateralis (VL) muscles of 18 athletes (age 20.1 ± 6.1 years; body mass 65.4 ± 13.9 kg; height 174.6 ± 9.5 cm) were assessed at sea level and moderate altitude using electrically evoked contractions on two consecutive days. Maximum radial displacement (Dm), time of contraction (Tc), reaction time (Td), sustained contraction time (Ts), and relaxation time (Tr) were recorded at 40, 60, 80, and 100 mA. At altitude, VL showed lower Dm values at 40 mA (p = 0.008; ES = -0.237). Biceps femoris showed Dm decrements in all electrical stimulations (p < 0.001, ES > 0.61). In VL, Tc was longer at altitude at 40 (p = 0.031, ES = 0.56), and 100 mA (p = 0.03, ES = 0.51). Regarding Td, VL showed significant increases in all electrical intensities under hypoxia (p ≤ 0.03, ES ≥ 0.33). TMG appears effective at detecting slight changes in the muscle contractile properties at moderate altitude. Further research involving TMG along with other muscle function assessment methods is needed to provide additional insight into peripheral neuromuscular alterations at moderate altitude.

Lipman, Grant S., Nicholas C. Kanaan, Caleb Phillips, Dave Pomeranz, Patrick Cain, Kristin Fontes, Becky Higbee, Carolyn Meyer, Michael Shaheen, Sean Wentworth, and Diane Walsh. Study Looking at End Expiratory Pressure for Altitude Illness Decrease (SLEEP-AID). High Alt Med Biol 16:154-161, 2015.--Acute mountain sickness (AMS) affects 25%-70% of the tens of millions of high altitude travelers annually, with hypoxia and nocturnal desaturations as major contributing factors. This is the first double blind randomized placebo controlled trial to assess expiratory positive airway pressure (EPAP) for AMS prevention and nocturnal hypoxic events. Healthy adult participants trekking in the Khumbu region of the Himalayas were randomized to a single-use EPAP nasal strip, or a visually identical sham device (placebo) prior to first night sleeping between 4371-4530 m (14,340-14,800 ft). The primary outcome was AMS incidence, measured by Lake Louise Questionnaire (LLQ), with secondary outcomes of AMS severity (by LLQ) and physiologic sleep indices measured by continuous sleep monitor. Intent-to-treat analysis included 219 participants with comparable demographic characteristics, of which 115 received EPAP and 104 placebo. There was no decrease in AMS with EPAP intervention (14% EPAP vs. 17% placebo; p=0.65; risk difference (-)3.15%, 95% CI (-)12.85%-6.56%). While overall AMS severity was not different between groups, EPAP reported decreased incidence of headache (64% vs. 76%; p<0.05, OR 0.51, 95% CI 0.27-0.95) and dizziness (81% vs. 98%; p<0.03, OR 0.29, 95% CI 0.09-0.78). During sleep, EPAP resulted in significant improvements in average peripheral oxygenation (Spo(2)) (80% versus 78%; p<0.01, mean difference=2, 95% CI 0.58-3.63) and a reduced percentage of time below 80% Spo(2) (31% vs. 46%; p<0.03, median difference=16, 95% CI 2.22-28.18). This lightweight and inexpensive EPAP device did not prevent acute mountain sickness, but did reduce the subgroup incidence of headache and dizziness while improving average nighttime peripheral oxygenation.

Rates of depression and suicide are higher in people living at altitude, and in those with chronic hypoxic disorders like asthma, chronic obstructive pulmonary disorder (COPD), and smoking. Living at altitude exposes people to hypobaric hypoxia, which can lower rat brain serotonin levels, and impair brain bioenergetics in both humans and rats. We therefore examined the effect of hypobaric hypoxia on depression-like behavior in rats. After a week of housing at simulated altitudes of 20,000 ft, 10,000 ft, or sea level, or at local conditions of 4500 ft (Salt Lake City, UT), Sprague Dawley rats were tested for depression-like behavior in the forced swim test (FST). Time spent swimming, climbing, or immobile, and latency to immobility were measured. Female rats housed at altitude display more depression-like behavior in the FST, with significantly more immobility, less swimming, and lower latency to immobility than those at sea level. In contrast, males in all four altitude groups were similar in their FST behavior. Locomotor behavior in the open field test did not change with altitude, thus validating immobility in the FST as depression-like behavior. Hypobaric hypoxia exposure therefore induces depression-like behavior in female rats, but not in males.

Background: Classically, biomarkers such as the natriuretic peptides (NPs) BNP/NT-proBNP are associated with the diagnosis of heart failure and hs-cTnT with acute coronary syndromes. NPs are also elevated in pulmonary hypertension. High pulmonary artery systolic pressure (PASP) is a key feature of high altitude pulmonary edema (HAPE), which may be difficult to diagnose in the field. We have previously demonstrated that NPs are associated with high PASP and the presence of acute mountain sickness (AMS) in a small cohort at HA. We aimed to investigate the utility of several common cardiac biomarkers in diagnosing high PASP and AMS., Methods: 48 participants were assessed post-trekking and at rest at three altitudes: 3833 m, 4450 m, and 5129 m. NPs, hs-cTnT and hsCRP, were quantified using immunoassays, PASP was measured by echocardiography, and AMS scores were recorded., Results: Significant changes occurred with ascent in NPs, hs-cTnT, hsCRP (all p<0.001) and PASP (p=0.006). A high PASP (≥40 mm Hg) was associated with higher NPs, NT-proBNP: 137±195 vs. 71.8±68 (p=0.001); BNP 15.3±18.1 vs. 8.7±6.6 (p=0.001). NPs were significantly higher in those with AMS or severe AMS vs. those without (severe AMS: NT-proBNP: 161.2±264 vs. 76.4±82.5 (p=0.008)). The NPs correlated with hsCRP. cTnT increased with exercise at HA and was also higher in those with a high PASP (13.8±21 vs. 7.8±6.5, p=0.018)., Conclusion: The NPs and hs-cTnT are associated with high PASP at HA and the NPs with AMS.

Unlabelled: Abstract Feuerecker, Matthias, Brian Crucian, Alex P. Salam, Ales Rybka, Ines Kaufmann, Marjan Moreels, Roel Quintens, Gustav Schelling, Manfred Thiel, Sarah Baatout, Clarence Sams, and Alexander Choukèr. Early adaption in the Antarctic environment at Dome C: Consequences on stress-sensitive innate immune functions. High Alt Med Biol 15:341-348, 2014.-Purpose/Aims: Medical reports of Antarctic expeditions indicate that health is affected under these extreme conditions. The present study at CONCORDIA-Station (Dome C, 3233 m) seeks to investigate the early consequences of confinement and hypobaric hypoxia on the human organism., Methods: Nine healthy male participants were included in this study. Data collection occurred before traveling to Antarctica (baseline), and at 1 week and 1 month upon arrival. Investigated parameters included basic physiological variables, psychological stress tests, cell blood count, stress hormones, and markers of innate immune functions in resting and stimulated immune cells. By testing for the hydrogen peroxide (H2O2) production of stimulated polymorphonuclear leukocytes (PMNs), the effects of the hypoxia-adenosine-sensitive immune modulatory pathways were examined., Results: As compared to baseline data, reduced oxygen saturation, hemoconcentration, and an increase of secreted catecholamines was observed, whereas no psychological stress was seen. Upon stimulation, the activity of PMNs and L-selectin shedding was mitigated after 1 week. Endogenous adenosine concentration was elevated during the early phase. In summary, living conditions at high altitude influence the innate immune system's response. After 1 month, some of the early effects on the human organism were restored., Conclusion: As this early adaptation is not related to psychological stress, the changes observed are likely to be induced by environmental stressors, especially hypoxia. As hypoxia is triggering ATP-catabolism, leading to elevated endogenous adenosine concentrations, this and the increased catecholamine concentration might contribute to the early, but reversible downregulation of innate immune functions. This indicates the slope of innate immune adaptation to hypoxia.

Cardiovascular disease risk is heightened during exposure to altered gravity and/or altered barometric conditions. Previous work has suggested that this heightened cardiovascular risk is due to enhancements of endothelial cell inflammatory and/or thrombogenic responses. In recent work, the role of platelets on instigating or inhibiting endothelial cell responses associated with cardiovascular disease has been found to be dependent on both biochemical and biophysical factors. In this work, we aimed to determine how two biophysical forces, gravity and atmospheric pressure, alter endothelial cell and platelet functions and their interactions to instigate or inhibit cardiovascular disease responses. To address this aim, endothelial cells and platelets were subjected to a force 8 times greater than the normal gravitational force, for up to 30 minutes. In separate experiments, endothelial cells and platelets were subjected to 50% of normal atmospheric pressure. Endothelial cell and platelet responses, associated with cardiovascular diseases, were measured as a time course during exposure. In general, the exposure of endothelial cells to either hypergravity or hypobaric conditions enhanced cardiovascular disease responses. However, the presence of platelets generally inhibited endothelial cell responses. Platelet activation was, however, somewhat enhanced under both hypergravity and hypobaric conditions. Our data suggest that altered biophysical forces can modulate endothelial cell and platelet responses that are salient for cardiovascular disease progression. However, the interaction of these two cells tends to restrain the progression of the pro-cardiovascular disease responses.

High altitude training is a widely used strategy for improving aerobic exercise performance. Both Rhodiola crenulata (R) and Cordyceps sinensis (C) supplements have been reported to improve exercise performance. However, it is not clear whether the provision of R and C during high altitude training could further enhance aerobic endurance capacity. In this study, we examined the effect of R and C based supplementation on aerobic exercise capacity following 2-week high altitude training. Alterations to autonomic nervous system activity, circulatory hormonal, and hematological profiles were investigated. Eighteen male subjects were divided into two groups: Placebo (n=9) and R/C supplementation (RC, n=9). Both groups received either RC (R: 1400 mg+C: 600 mg per day) or the placebo during a 2-week training period at an altitude of 2200 m. After 2 weeks of altitude training, compared with Placebo group, the exhaustive run time was markedly longer (Placebo: +2.2% vs. RC: +5.7%; p<0.05) and the decline of parasympathetic (PNS) activity was significantly prevented in RC group (Placebo: -51% vs. RC: -41%; p<0.05). Red blood cell, hematocrit, and hemoglobin levels were elevated in both groups to a comparable extent after high altitude training (p<0.05), whereas the erythropoietin (EPO) level remained higher in the Placebo group (∼48% above RC values; p<0.05). The provision of an RC supplement during altitude training provides greater training benefits in improving aerobic performance. This beneficial effect of RC treatment may result from better maintenance of PNS activity and accelerated physiological adaptations during high altitude training.