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Effects of photoperiodicity caused by both the age and individual physiological reactivity estimated by resistance to hypobaric hypoxia on the levels of lipid peroxidation, protein oxidation (aldehydic and ketonic derivatives), total antioxidant capacity, activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase), and biochemical parameters of aerobic and anaerobic pathways in hepatic tissue depending on the blood melatonin level were studied. The study was carried out on 96 6- and 21-month-old male rats divided into hypoxia resistance groups (LR, low resistance, HR, high resistance). The analyses were conducted at four photoperiods: winter (January), spring (March), summer (July), and autumn (October). Our results indicate a significant effect of melatonin, i.e. over 80%, revealed by the complete statistical model of the studied biomarkers of oxidative stress and oxygen-dependent parameters of metabolism. The effects of melatonin vary with age and between photoperiods, which in turn was determined by individual physiological reactivity. In terms of the photoperiods, the melatonin content in the group of the adult animals with low resistance to hypoxia decreased from winter to summer. In a group of old animals in comparison with adults, the melatonin content in all the studied photoperiods was much lower as well, regardless of their hypoxia resistance. In the group of old animals with low resistance to hypoxia, the melatonin content decreased throughout the photoperiods as follows: winter, autumn, summer, and spring. As can be concluded, spring is a critical period for old animals, particularly those with low hypoxia resistance. The important role of melatonin in these processes was also confirmed by our correlation analysis between oxidative stress biomarkers, energy-related metabolites, and antioxidant enzymes in the hepatic tissue of rats of different ages, with different resistance to hypoxia, and in different photoperiods. The melatonin concentration in the blood of highly resistant rats was higher than in those with low resistance to hypoxia. Melatonin determines the individual constitutional level of resistance to hypoxia and is responsible for individual enzymatic antioxidative responses, depending on the four photoperiods. Our studies have shown that melatonin levels are related to the redox characteristics of antioxidant defenses against lipid peroxidation and oxidative modification of proteins in old rats with low resistance to hypoxia, compared to a group of highly resistant adults. Finally, the melatonin-related mechanisms of antioxidative protection depend on metabolic processes in hepatic tissue and exhibit photoperiodical variability in adult and old rats.

2021.—Many previous studies have examined hypoxia-induced physiological responses using various conditions, e.g., artificially reduced atmospheric oxygen concentration [normobaric hypoxia (NH) condition] or low barometric pressure at a mountain [hypobaric hypoxia (HH) condition]. However, when comparing the results from these previous studies conducted in artificial NH and HH including real high altitude, we must consider the possibility that environmental factors, such as temperature, humidity, and fraction of inspired carbon dioxide, might affect the physiological responses. Therefore, we examined cardiorespiratory responses and exercise performances during low- to high-intensity exercise at a fixed heart rate (HR) in both NH and HH using a specific chamber where atmospheric oxygen concentration and barometric pressure as well as the abovementioned environmental factors were precisely controlled. Ten well-trained university students (eight males and two females) performed the exercise test consisting of two 20-minute submaximal pedaling at the intensity corresponding to 50% (low) and 70% (high) of their HR reserve, under three conditions [NH (fraction of inspired oxygen, 0.135; barometric pressure, 754 mmHg), HH (fraction of inspired oxygen, 0.209; barometric pressure, 504 mmHg), and normobaric normoxia (NN; fraction of inspired oxygen, 0.209; barometric pressure, 754 mmHg)]. Peripheral oxygen saturation (SpO2) to estimate arterial oxygen saturation and partial pressure of end-tidal carbon dioxide (PETCO2) were monitored throughout the experiment. SpO2, PETCO2, and power output at fixed HRs (i.e., pedaling efficiency) in NH and HH were all significantly lower than those in NN. Moreover, high-intensity exercise in HH induced greater decreases in SpO2 and power output than did high-intensity exercise in NH (NH vs. HH; SpO2, 78.2% - 5.0% vs. 75.1% - 7.1%; power output, 120.7 - 24.9 W vs. 112.4 - 23.2 W, both p < 0.05). However, high-intensity exercise in HH induced greater increases in PETCO2 than did high-intensity exercise in NH (NH vs. HH; 54.2 - 5.9mmHg vs. 57.2 - 3.4 mmHg, p < 0.01). These results suggest that physiological responses and power output at a fixed HR during hypoxic exposure might depend on the method used to generate the hypoxic condition.

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, η2p = 0.36; map task p = 0.016, η2p = 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, η2p = 0.57; map task 12.5 ± 1.8 seconds vs. 7.8 ± 0.6 seconds, p = 0.038, η2p = 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, η2p = 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.

Globally, about 400 million people reside at terrestrial altitudes above 1500 m, and more than 100 million lowlanders visit mountainous areas above 2500 m annually. The interactions between the low barometric pressure and partial pressure of O2, climate, individual genetic, lifestyle and socio-economic factors, as well as adaptation and acclimatization processes at high elevations are extremely complex. It is challenging to decipher the effects of these myriad factors on the cardiovascular health in high altitude residents, and even more so in those ascending to high altitudes with or without preexisting diseases. This review aims to interpret epidemiological observations in high-altitude populations; present and discuss cardiovascular responses to acute and subacute high-altitude exposure in general and more specifically in people with preexisting cardiovascular diseases; the relations between cardiovascular pathologies and neurodegenerative diseases at altitude; the effects of high-altitude exercise; and the putative cardioprotective mechanisms of hypobaric hypoxia.

It is known that the altitude area causes hypoxic conditions due to the low oxygen partial pressure. This study was conducted to estimate oxidative stress indices in the heart tissue after Wister rats exposure to the acute intermittent hypobaric hypoxia. Hypobaric hypoxia exposure was simulated by keeping the rats in a hypobaric chamber for 1 min at 35,000 feet altitude. After that the altitude was gradually reduced to 30,000 and 25,000 feet and maitained for 5 min. 25 male Wistar rats were divided into control group and four treatment groups (I-IV), consisting of rats exposed 1, 2, 3 and 4 times to hypobaric hypoxia with a frequency once a week. The animals were removed from the experiment at the height of 18,000 feet and the heart tissue was obtained. The carbonyl groups and MDA levels and superoxide dismutase and catalase activity were exami­ned in the supernatant of the heart tissue homogenate. In the samples of group I, the decrease in catalase activity with a simultaneous notable increase in carbonyl groups level was observed compared to control. In the samples of groups III and IV, the carbonyl level normalized and the activity of both antioxidant enzymes increased significantly. It was concluded that the increase of antioxidant enzymes activity can contribute to cardiac tissue adaptive response to acute hypobaric hypoxia exposure.

The present study explored the impact of pre-altitude serum (s)-ferritin and iron supplementation on changes in hemoglobin mass (ΔHbmass) following altitude training. Measures of Hbmass and s-ferritin from 107 altitude sojourns (9-28 days at 1800-2500 m) with world-class endurance athletes (males n = 41, females n = 25) were analyzed together with iron supplementation and self-reported illness. Altitude sojourns with a hypoxic dose [median (range)] of 1169 (912) km·h increased Hbmass (mean ± SD) 36 ± 38 g (3.7 ± 3.7%, p 100 µg·L-1 , respectively, with no group difference (p = 0.400). Hbmass increased by 4.1 ± 3.9%, 3.0 ± 3.0% and 3.7 ± 4.7% without, ≤50 mg·day-1 or >50 mg·day-1 supplemental iron, respectively (p = 0.399). Linear mixed model analysis revealed no interaction between pre-altitude s-ferritin and iron supplementation on ΔHbmass (p = 0.906). However, each 100 km·h increase in hypoxic dose augmented ΔHbmass by an additional 0.4% (95% CI: 0.1-0.7%; p = 0.012), while each 1 g·kg-1 higher pre-altitude Hbmass reduced ΔHbmass by -1% (-1.6 to -0.5; p < 0.001), and illness lowered ΔHbmass by -5.7% (-8.3 to -3.1%; p < 0.001). In conclusion, pre-altitude s-ferritin or iron supplementation were not related to the altitude-induced increase in Hbmass (3.7%) in world-class endurance athletes with clinically normal iron stores.

ObjectiveThe aim was to determine the effects of chronic intermittent hypobaric hypoxia (CIHH) on prostate-specific antigen (PSA) levels in Chilean miners who work at different altitudes.MethodsA cross-sectional study was conducted between April and July 2019. Miners from five mines (N=338) at different altitudes were evaluated. We recorded sociodemographic, working and altitude information. Haemoglobin oxygen saturation (SaO2) and haemoglobin (Hb) were measured in situ, while PSA and testosterone were analysed at a low level. Linear mixed-effect models were used to evaluate the association between PSA level and two CIHH exposures: composite CIHH (with four descriptors) and ChileStd-CIHH (CIHH Chilean standard; based on the Chilean technical guide for occupational exposure to CIHH). All models were adjusted by age, body mass index and day of the work the samples were taken.ResultsHighest and lowest PSA levels were found in mines ≥3000 m above sea level (mine 3: median=0.75, IQR=−0.45; mine 4: median=0.46, IQR=−0.35). In the multilevel models, the wider altitude difference between mining operation and camp showed lower PSA levels (model D: βPSA=−0.93 ng/mL, βlogPSA=−0.07, p2, Hb and testosterone. The descriptors of composite CIHH explained better PSA variations than ChileStd-CIHH (model D: marginal R2=0.090 vs model A: marginal R2=0.016).ConclusionsOccupational health regulations and high altitude medicine should consider these results as initial evidence on the inclusion of new descriptors for CIHH and the possible effect of this exposure on PSA levels in this male-dominated occupational sector.

The Elevation Training Mask (ETM) has been assessed for its impact on exercise performance using acute and training protocols. Although the ETM is widely available to consumers, little research exists for validation of the ETM mask settings. Therefore, the purpose of this study was to compare physiological responses during exercise for the ETM mask settings against moderate hypobaric hypoxia. Nine participants living at moderate altitude (1600–1650 m) rested (10 min) and cycled in hypobaric hypoxia simulating 2743 m (ALT), in hypobaric hypoxia simulating 1829 m with the ETM set to 914 m (ALT + ETM), and with the ETM set to 2743 m (ETM) in a randomized order. Participants cycled for 20 min at 60% VO2max as determined by a maximal exertion test (VO2max) at baseline altitude. Oxygen consumption was measured throughout each test. There were no differences between conditions at rest. Repeated measures ANOVA showed the ALT condition elicited significantly greater VO2 compared to the ETM condition and 60% VO2max at baseline altitude (P

Background Studies have revealed the protective effect of DL-3-n-butylphthalide (NBP) against diseases associated with ischemic hypoxia. However, the role of NBP in animals with hypobaric hypoxia has not been elucidated. This study investigated the effects of NBP on rodents with acute and chronic hypobaric hypoxia. Methods Sprague-Dwaley rats and Kunming mice administered with NBP (0, 60, 120, and 240 mg/kg for rats and 0, 90, 180, and 360 mg/kg for mice) were placed in a hypobaric hypoxia chamber at 10,000 m and the survival percentages at 30 min were determined. Then, the time and distance to exhaustion of drug-treated rodents were evaluated during treadmill running and motor-driven wheel-track treadmill experiments, conducted at 5800 m for 3 days or 20 days, to evaluate changes in physical functions. The frequency of active escapes and duration of active escapes were also determined for rats in a shuttle-box experiment, conducted at 5800 m for 6 days or 27 days, to evaluate changes in learning and memory function. ATP levels were measured in the gastrocnemius muscle and malonaldehyde (MDA), superoxide dismutase (SOD), hydrogen peroxide (H2O2), glutathione peroxidase (GSH-Px), and lactate were detected in sera of rats, and routine blood tests were also performed. Results Survival analysis at 10,000 m indicated NBP could improve hypoxia tolerance ability. The time and distance to exhaustion for mice (NBP, 90 mg/kg) and time to exhaustion for rats (NBP, 120 and 240 mg/kg) significantly increased under conditions of acute hypoxia compared with control group. NBP treatment also significantly increased the time to exhaustion for rats when exposed to chronic hypoxia. Moreover, 240 mg/kg NBP significantly increased the frequency of active escapes under conditions of acute hypoxia. Furthermore, the levels of MDA and H2O2 decreased but those of SOD and GSH-Px in the sera of rats increased under conditions of acute and chronic hypoxia. Additionally, ATP levels in the gastrocnemius muscle significantly increased, while lactate levels in sera significantly decreased. Conclusion NBP improved physical and learning and memory functions in rodents exposed to acute or chronic hypobaric hypoxia by increasing their anti-oxidative capacity and energy supply.

Ji, Weizhong, Yaqing Zhang, Ri-li Ge, Yaqi Wan, and Jie Liu. NMDA receptor-mediated excitotoxicity is involved in neuronal apoptosis and cognitive impairment induced by chronic hypobaric hypoxia exposure at high altitude.

Context Previous studies indicate that compound Danshen Dripping Pill (CDDP) improves the adaptation to high-altitude exposure. However, its mechanism of action is not clear. Objective To explore the protective effect of CDDP on hypobaric hypoxia (HH) and its possible mechanism. Materials and methods A meta-analysis of 1051 human volunteers was performed to evaluate the effectiveness of CDDP at high altitudes. Male Sprague-Dawley rats were randomized into 5 groups (n = 6): control at normal pressure, model, CDDP-170 mg/kg, CDDP-340 mg/kg and acetazolamide groups. HH was simulated at an altitude of 5500 m for 24 h. Animal blood was collected for arterial blood-gas analysis and cytokines detection and their organs were harvested for pathological examination. Expression levels of AQP1, NF-κB and Nrf2 were determined by immunohistochemical staining. Results The meta-analysis data indicated that the ratio between the combined RR of the total effective rate and the 95% CI was 0.23 (0.06, 0.91), the SMD and 95% CI of SO2 was 0.37 (0.12, 0.62). Pre-treatment of CDDP protected rats from HH-induced pulmonary edoema and heart injury, left-shifted oxygen-dissociation curve and decreased P50 (30.25 ± 3.72 vs. 37.23 ± 4.30). Mechanistically, CDDP alleviated HH-reinforced ROS by improving SOD and GPX1 while inhibiting pro-inflammatory cytokines and NF-κB expression. CDDP also decreased HH-evoked D-dimer, erythrocyte aggregation and blood hemorheology, promoting AQP1 and Nrf2 expression. Discussion and conclusions Pre-treatment with CDDP could prevent HH-induced tissue damage, oxidative stress and inflammatory response. Suppressed NF-κB and up-regulated Nrf2 might play significant roles in the mechanism of CDDP.

High altitude (HA), with the main feature of hypobaric hypoxia, is an independent risk factor for thrombosis. However, little is known on the alterations of fibrinolytic system in adaptation to HA. In this study, we investigated changes of fibrinolytic system parameters between individuals permanently living at HA and low altitude (LA) regions, and provided data for further studies on HA-induced thrombotic disease. A total of 226 eligible participants, including 103 LA participants, 100 healthy HA subjects and 23 high altitude polycythemia (HAPC) patients, were recruited in this study. Six fibrinolytic parameters, i.e. fibrinogen (Fbg), D-dimer (DDi), antithrombin III (AT-III), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and plasminogen (PLG) were analyzed respectively. PAI-1 and tPA were performed by using bio-immuno-assays and an automated coagulation analyzer was used to conduct Fbg, DDi, AT-III and PLG tests. Plasma levels of Fbg, DDi, PAI-1 and PLG were significantly higher in healthy HA group than in LA group (all p < 0.05), whereas tPA was significantly lower in healthy HA group. No significant difference in AT-III was observed between healthy HA and LA groups (p > 0.05). All these fibrinolytic parameters showed no significant distinctions between healthy HA subjects and HAPC patients (all p > 0.05). HGB showed no relationship with fibrinolytic parameters in HA cohort. This study demonstrates that HA environment has a significant effect on fibrinolytic system and provides a foundation for further studies on HA hypobaric hypoxia-induced thrombotic disease.

The possibility of efficient use of the theory of hibernation ensembles to ensure vital activity in extreme conditions is considered. Hibernation ensembles are strictly selected sets of tools, among which are special combinations of pharmacological preparations and hypostabilizers, respiratory mixtures different in gas composition, controlled hypothermia, etc., which, when coordinated, cause the formation of a special state of the body, referred to as «hypobiosis and cryobiosis» or artificial hibernation. The data of experimental studies on changes in the body’s resistance to the extreme effects of gamma radiation, to acute hypobaric hypoxia and to flight overloads under conditions of artificially induced hibernation are generalized to determine the possibility of using the theory of hibernation ensembles while ensuring vital activity under extreme influences. It is shown that under the influence of vegetotropic agents against the background of hypothermia, the metabolic processes slow down significantly and the organism of warm-blooded animals begins to acquire ambient temperature. The condition that occurs in this case is accompanied by an increase in the body’s resistance to extreme factors, such as acute hypobaric hypoxia, deep hypothermia, exposure to ionizing radiation, toxic lesions, massive blood loss, pain shock, etc. This area of research is of particular relevance for the development of methods for long-term life support person in extreme conditions, with severe injuries and in the provision of medical care in conditions of mass admission victims, since it provides a reserve of time necessary for organizing the safe transportation of victims to the places of specialized and high-tech medical care, that is, actually providing medical care at a later date.

espanolEste articulo sirve para iniciarse en las bases docentes de la actual fisiologia de la aviacion, cuyo origen se remonta al comienzo de la Segunda Guerra Mundial. Bombarderos en picado (1941) de Michael Curtiz es un excelente material docente para ayudar en la comprension de las distintas causas del sincope de los pilotos en las alturas, permitiendo la reflexion y la busqueda de soluciones o alternativas a traves de experimentos que permiten la recuperacion de la homeostasis corporal. Su material audiovisual comparte escenas reales del ejercito americano que permiten acceder a estos descubrimientos y al avance del estado actual de la moderna fisiologia aeroespacial. EnglishThis article serves to begin in the teaching bases of the current aviation physiology, whose origin dates back to the beginning of World War II. Dive Bomber (1941) by Michael Curtiz is an excellent teaching material to help in the understanding of the different causes of the pilots’ syncope at heights, allowing thinking and the search for solutions or alternatives through experiments that allow the recovery of the body homeostasis. His audiovisual material shares real scenes of the United States Army that allow access to these discoveries and the progress of the current state of modern aerospace physiology.

—Venous blood samples were collected for biochemical analyses from 16 members of a year-long expedition to the Vostok research station in Antarctica. The physiologically important factors were hypobaric hypoxia (Р = 460 mm Hg) due to the station location (the ice dome of Central Antarctica), hypokinesia due to prolonged stay indoor because of the extremely low temperatures outside the station, physical and social isolation from the outer world. The participants were divided into two groups: the experimental one, who periodically received a vitamin-amino acid complex for the prevention and correction of asthenia, and the control one, who received a placebo. Biochemical analysis revealed undulating blood levels of protein and main protein fractions within the physiological norm. Starting from month 4 of the expedition, concentrations of γ- and β-globulins showed a statistically significant increase. This increase persisted for 2 months after the expedition, therefore, there are sufficient body reserves. There were no differences in concentrations of the studied parameters between the experimental and control groups. It is speculated that hypobaric hypoxia plays a positive role in maintaining non-specific body resistance in the year-long period of life in isolation and hypokinesia.

Hypoxia, particularly hypobaric hypoxia, is a multifaceted entity which includes certain molecular, patho-physiological and biochemical aspects. Any single aspect in itself cannot help us elucidate hypobaric hypoxia in its entirety. We observed three crucial lacunae within the existing literature. These include a lack of high-throughput investigations into redox PTMs, particularly NO-based PTMs; a prophylactic supplement with proven efficacy and safety which doesn’t involve medical supervision and is not contraindicated in hepatic, renal and cardiac insufficiencies; and a clinically validated rodent model of HAPE without any genetic/pharmacological manipulations. In the present study, we present an antagonistic interplay between nitrosylation and carbonylation which shows an additional NO-based network that is active in acclimatised individuals. Then we present a micronised aqueous suspension of silymarin which is efficacious at low doses in providing antioxidant, anti-inflammatory and hypoxia-adaptive vascular responses in addition to being a free radical quencher itself. Silymarin has an excellent safety and efficacy profile in humans. Finally, we create a SD rat model of HAPE which was used to reverse-translate a previously known HAPE marker in humans (SULT1A1) and elucidate the synergistic occurrence of HAPE and inflammation cascades. This is the first radiologically validated rodent HAPE model. In conclusion, we were able to elucidate the molecular, biochemical and patho-physiological aspects of hypobaric hypoxia which were left out by previous studies.

Hypoxia triggers complex inter- and intracellular signals that regulate tissue oxygen (O2) homeostasis, adjusting convective O2 delivery and utilization (i.e., metabolism). Human populations have been exposed to high-altitude hypoxia for thousands of years and, in doing so, have undergone natural selection of multiple gene regions supporting adaptive traits. Some of the strongest selection signals identified in highland populations emanate from hypoxia-inducible factor (HIF) pathway genes. The HIF pathway is a master regulator of the cellular hypoxic response, but it is not the only regulatory pathway under positive selection. For instance, regions linked to the highly conserved Notch signaling pathway are also top targets, and this pathway is likely to play essential roles that confer hypoxia tolerance. Here, we explored the importance of the Notch pathway in mediating the cellular hypoxic response. We assessed transcriptional regulation of the Notch pathway, including close cross-talk with HIF signaling, and its involvement in the mediation of angiogenesis, cellular metabolism, inflammation, and oxidative stress, relating these functions to generational hypoxia adaptation., KAO received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (No 890768). AJM was funded by the Research Councils UK (EP/E500552/1). TSS was funded by the National Institutes of Health (R01HL145470), National Geographic Explorer Award, and the John B. West Endowed Chair in Respiratory Physiology.

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.