Lateral Preferences as Possible Phenotypic Predictors of the Reserves of the Cardiovascular System and the Features of Sensorimotor Integration in Climbers

The lateral preferences of the hands, the reserves of the cardiovascular system and the features of sensorimotor integration in mountain climbers as possible predictors of adaptation to extreme factors of the external environment have been investigated. The subjects were 15 climbers of high class (men aged 25.5–62.8 years). We used the following methods: reflexometric technique ReBFB (complex sensorimotor reaction in the model of go/no-go, computer simulation according to Chernikov); the assessment of lateral preferences using the standard samples; the orthostatic test (with the recording of the heart rate and evaluation of adaptive reserves based on the indices of mathematical analysis of the cardiac rhythm in the transition period according to a technique by Riftin). Sensorimotor integration was performed under normal conditions and under normobaric hypoxia. All indicators were correlated with the age and proficiency of the climbers. We observed no statistically significant correlations between age and the reserves of the cardiovascular system in the group of climbers. Reflexometry in normoxic conditions showed an improvement in the orientation of subjects in the sensory flow as compared with the initial level. The sensorimotor integration (as a response of sensorimotor responses) was more stable during hypoxia as compared with the same indices in normoxia. Noticeable correlation was observed between the results of the humeral test and the reserves of the cardiovascular system defined by orthostatic hypotension: the reserves were higher in the subjects with a higher level of left-hand preference. The regulation of the autonomic nervous system is correlated with left-handedness, which results in more effective adaptation to the high altitude in left-handers. The parameter of handedness can be used as a phenotypic predictor of the level of the cardiovascular system reserves in climbers. It is suggested that the factor of hypoxia with small exposure has a stimulating effect on sensorimotor integration in climbers.     

Physiological premises and mechanisms of normalizing effect of normobaric hypoxia and inhalation therapy]

Pathogenetic and physiological aspects of hypoxia problems have been considered. An opinion is stated that normalizing effect of intermittent normobaric hypoxia (INH) with short-term respiration of gaseous mixture containing at least 10% of oxygen in nitrogen is based on biorhythm inherent in all the living organisms with replacement of the high functional activity periods by the periods of rest and restoration with temporary physiological hypoxia as their typical companion. It is shown that for numerous diseases the course of INH or sessions of staying in the chamber of artificial mountain climate normalize the state of central nervous system, blood circulation, respiration, hemopoiesis and immunological reactivity, activate natural protective mechanisms and increase functional reserves of the organism. Allowing for anthropogenic pollution of the environment and its consequences for the health, it is advisable to widely adopt hypoxytherapy and orrhotherapy.     

Neuroprotective Role of Intermittent Hypobaric Hypoxia in Unpredictable Chronic Mild Stress Induced Depression in Rats

Hypoxic exposure results in several pathophysiological conditions associated with nervous system, these include acute and chronic mountain sickness, loss of memory, and high altitude cerebral edema. Previous reports have also suggested the role of hypoxia in pathogenesis of depression and related psychological conditions. On the other hand, sub lethal intermittent hypoxic exposure induces protection against future lethal hypoxia and may have beneficial effect. Therefore, the present study was designed to explore the neuroprotective role of intermittent hypobaric hypoxia (IHH) in Unpredictable Chronic Mild Stress (UCMS) induced depression like behaviour in rats. The IHH refers to the periodic exposures to hypoxic conditions interrupted by the normoxic or lesser hypoxic conditions. The current study examines the effect of IHH against UCMS induced depression, using elevated plus maze (EPM), open field test (OFT), force swim test (FST), as behavioural paradigm and related histological and molecular approaches. The data indicated the UCMS induced depression like behaviour as evident from decreased exploration activity in OFT with increased anxiety levels in EPM, and increased immobility time in the FST; whereas on providing the IHH (5000m altitude, 4hrs/day for two weeks) these behavioural changes were ameliorated. The morphological and molecular studies also validated the neuroprotective effect of IHH against UCMS induced neuronal loss and decreased neurogenesis. Here, we also explored the role of Brain-Derived Neurotrophic Factor (BDNF) in anticipatory action of IHH against detrimental effect of UCMS as upon blocking of BDNF-TrkB signalling the beneficial effect of IHH was nullified. Taken together, the findings of our study demonstrate that the intermittent hypoxia has a therapeutic potential similar to an antidepressant in animal model of depression and could be developed as a preventive therapeutic option against this pathophysiological state.     

Effect of L-arginine and N(omega)-nitro-L-arginine on oxidative phosphorylation and lipid peroxidation in rats with various tolerance to hypoxia under stressful conditions

The influence of L-arginine (600 mg/kg) and NO-synthase blocator N omega-nitro-L-arginine L-NNA (35 mg/kg) on processes of ADP-stimulated respiration (under using 0.35 mM succinate, 1 mM alpha-ketoglutarate, 2 mM pyruvate, 2 mM glutamate, 2 Mm malate and succinate dehydrohenase blocator--2 mM malonate as substrates of oxidation), lipid peroxidation (concentration of DK and MDA), activities of succinate dehydrohenase and aminotransferases in rats tissues with different resistance to hypoxia under stress conditions have been investigated. It have been shown that the energy metabolism indices (respiration rate and efficiency of phosphorilation ADP/O) are higher in high resistent (HR) animals in the control group. Stress causes the increase of ADP-stimulated respiration in low resistent (LR) under succinate oxidation and decrease of NADPH-dependent utilization, indicative of more effort of energy system in LR animals. Stress conditions are connected with the increase of lipid peroxidation products in blood both in LR and in HR animals, though in hepar their concentration change unimportantly. Injection of L-arginine decreases aerobic component of energy metabolism on the background decreasing aminotransferases ways of oxidation and succinate dehydrohenase activity. L-arginine causes decrease of lipid peroxidation products in LR, in HR the same effect reaches by L-NNA injection. The has been made conclusion about tight correlation between energy metabolism, processes of lipid peroxidation with resistance to hypoxia and functioning of nitric oxide cycle under stress conditions.     

Hypobaric hypoxia and catecholaminuria in normal humans

Consequences of hypoxic hypobaric chemostimulation have been analyzed in six normal subjects arriving in excellent ambient conditions in a mountain scientific station (Jungfraujoch, 3,580 m). During the first two days of the sojourn, neither systemic blood pressure, nor catecholamines urinary excretion were modified in comparison with their values at the sea level. It is concluded that the chemostimulation due to hypobaric hypoxia does not affect orthosympathetic activities as far as other stressing solicitations are avoided (muscular exercise, temperature modifications, psychic alertness...etc.).     

The reaction of thymocytes to hypoxic stress

The reaction of thymocytes to hypoxic stress has been investigated according to indices of nucleic acid exchange. Acute and moderate, though long-term, hypoxia noticeably depresses DNA and RNA syntheses in rat thymocytes. Activation of nucleic acid repair synthesis during restoration of the organ takes place only if the hypoxic effect alternates with periods of normoxia. Under conditions of continuous prolonged hypoxia (high altitude), the adaptation is achieved by a decrease in thymocyte nucleic acid exchange. The role of thymocytes in the homeostasis-maintaining mechanisms, as the organism becomes adapted to hypoxia through different training conditions, is discussed.     

External respiration and the functional state of the respiratory center in hypoxia developing against a background of inactivated carbonic anhydrase]

Experiments were conducted on cats; inactivation of carboanhydrase with diamox prevented developmento f hypocapnia and disturbances of the rhythmic activity of the respiratory neurons associated with it in acute hypoxia. However, comparision of electrophysiological data, external respiration indices, of the acid-base balance, pO2 and pCO2 of arterial blood demonstrated that, preventing development of pathological Cheyne-Stokes respiration under conditions of hypoxia, inactivation of carboanhydrase with diamox caused dissociation of the thoracic and abdominal respiration and dyspnea. The latter led to shifts in the metabolic processes and to disturbance of the electrolyte metabolism at the cell level.     

The lung at high altitude

Men and mammals (excluding the indigenous mountain species) who are born at high altitude, or who ascend to live there for a long period, have to undergo acclimatization which affects virtually every system in the body. Since chronic hypoxia is the most important adverse factor in the mountain environment, the lung plays a major part in the process and shows many alterations in structure and function. However, we remain ignorant about many aspects of acclimatization of the lung to hypoxia especially at the ultrastructural level with respect to those cells whose normal function is not yet established. An account of what is known is given in this paper.     

Operation Everest. II: Nutrition and body composition

Progressive body weight loss occurs during high mountain expeditions, but whether it is due to hypoxia, inadequate diet, malabsorption, or the multiple stresses of the harsh environment is unknown. To determine whether hypoxia due to decompression causes weight loss, six men, provided with a palatable ad libitum diet, were studied during progressive decompression to 240 Torr over 40 days in a hypobaric chamber where hypoxia was the major environmental variable. Caloric intake decreased 43.0% from 3,136 to 1,789 kcal/day (P less than 0.001). The percent carbohydrate in the diet decreased from 62.1 to 53.2% (P less than 0.001). Over the 40 days of the study the subjects lost 7.4 +/- 2.2 (SD) kg and 1.6% (2.5 kg) of the total body weight as fat. Computerized tomographic scans indicated that most of the weight loss was derived from fat-free weight. The data indicated that prolonged exposure to the increasing hypoxia was associated with a reduction in carbohydrate preference and body weight despite access to ample varieties and quantities of food. This study suggested that hypoxia can be sufficient cause for the weight loss and decreased food consumption reported by mountain expeditions at high altitude.     

Botanical and geographical characteristics of forest steppe of the Altai-Sayan mountain region

Four types of mountain forest steppes have been specified in the Altai-Sayan mountain region. It has been shown that each type corresponds to a particular bioclimatic sector. The pattern of the mountain forest-steppe belt vegetation has been characterized for each of the types. The peculiarities of mountain forest- steppe vegetation changes with the increase of climate aridity conditions are described within 3 series: the primary Altaian, the primary Khakas-Tuvinian, and the secondary Khakas-Tuvinian series.     

The relation of the reactivity of the human respiratory system, mental and physical work capacity and metabolic characteristics during a 1-year stay in the mountains

People with the highest rates of mental working capacity staying for a year at an altitude of 1680 m below sea level are characterized by less pronounced responses of respiration to moderate hypoxia and great ventilatory response to maximally endured hypoxic action, by higher glucose content in blood and physical working capacity. Many relationships typical of the middle mountains are inverse ones under conditions of a one-year stay at an altitude of 3650 m below sea level. In the case of a total decrease in indices of mental and physical working capacity people with the highest rate of information processing are characterized by less reactivity of the respiratory system, greater resistance to ultimate hypoxia, lower glucose concentration, less physical working capacity.     

On the origin of Tibetans and their genetic basis in adapting high-altitude environments

Since their arrival in the Tibetan Plateau during the Neolithic Age, Tibetans have been well-adapted to extreme environmental conditions and possess genetic variation that reflect their living environment and migratory history. To investigate the origin of Tibetans and the genetic basis of adaptation in a rigorous environment, we genotyped 30 Tibetan individuals with more than one million SNP markers. Our findings suggested that Tibetans, together with the Yi people, were descendants of Tibeto-Burmans who diverged from ancient settlers of East Asia. The valleys of the Hengduan Mountain range may be a major migration route. We also identified a set of positively-selected genes that belong to functional classes of the embryonic, female gonad, and blood vessel developments, as well as response to hypoxia. Most of these genes were highly correlated with population-specific and beneficial phenotypes, such as high infant survival rate and the absence of chronic mountain sickness.     

Secondary polycythemia: a boon or a burden?

The development of a secondary erythrocytosis is usually considered a compensatory effort to counteract tissue hypoxia. However, the associated increase in viscosity tends to decrease blood flow and in theory should augment rather than relieve tissue hypoxia. Clinical observations have supported this concern and phlebotomies have been used to treat cardiopulmonary patients with high hematocrits and to prepare acclimatized mountain climbers for strenuous exercises. Direct measurements of tissue tension in rats and mice have shown that a moderate increase in hematocrit does increase the tissue tension of oxygen, probably due to a concomital increase in blood volume, and only severe increases in hematocrit are detrimental. In contrast, it was found that erythropoietin production in mice and man is decreased at even the most extreme hematocrits, suggesting that the tissue tension in the kidneys is not affected by high hematocrits and sluggish blood flow. This lack of renal hypoxia at high blood viscosities appears to serve an important purpose by preventing a vicious circle in which hypoxia will cause erythrocytosis leading to more hypoxia and more erythrocytosis and so on. However, well maintained secondary erythrocytosis cannot always be considered optimal for overall oxygen transport and has to be evaluated clinically for its potential benefit or harm.     

Pathophysiologic mechanisms of cardiorespiratory system dysfunction in high school children with chronic obstructive pulmonary diseases]

The basic indices of the cardiorespiratory system function, gas exchange, regional pulmonary functions have been studied. It is stated that a group of children with a higher level of oxygen consumption (hyperergic type) as against a control group is characterized by disorder in permeability of terminal branches of a bronchial tree, by the development of acute obstructive emphysema, increase in alveolar ventilation with relative decrease in minute blood volume, arterial hypoxemia with possible emergence of tissue hypoxia. A decrease in permeability of large bronchi were observed in a group of children with a low level of oxygen consumption (hypoergic type). Due to this decrease the hypoventilation zones appeared. It caused the development of arterial hypoxemia, but a risk of the tissue hypoxia emergence was insignificant.     

Cyclooxygenase-Mediated Generation of Free Radicals During Hypoxia in the Cerebral Cortex of Newborn Piglets

Previous studies have demonstrated that free radicals are formed under hypoxic conditions in newborn piglet brain. To test the hypothesis that the cyclooxygenase pathway serves as a source of free radical generation during hypoxia studies were performed on 24 piglets divided into four groups. Six saline (group 3) and six indomethacin treated (group 4) were exposed to hypoxia (FiO2 0.05-0.07) for 60 min. Cerebral hypoxia was documented biochemically by determination of ATP and phosphocreatine. Fluorescent compounds and conjugated dienes were determined as indices of lipid peroxidation. Free radical formation was determined by using n-tert butyl phenyl nitrone (PBN) as a spin trap agent and measuring spin adduct formation in duplicate using a Varian E-109 spectrometer. Groups 1 and 2 (normoxic) showed no spin adduct formation. Group 3 showed a significant increase in spin adduct formation compared to normoxia (372+/-125 vs. 63+/-15, P<0.001). Hypoxic animals pretreated with indomethacin had a spin adduct level of 197+/-132 and were similar to normoxic animals. ATP/PCr levels were the same in groups 3 and 4 denoting the same degree of cerebral hypoxia in all hypoxic animals. Conjugated dienes increased significantly during hypoxia as compared to normoxia (0.142+/-0.017 vs. 0.0+/-0.0) and were decreased insignificantly with indomethacin treatment. Fluorescent compounds were not significantly different among the four groups. Na+,K+-ATPase activity decreased during hypoxia but was not preserved in hypoxic animals pretreated with indomethacin. These data provide direct evidence of the presence of free radicals during hypoxia and the contribution of cyclooxygenase metabolism to their formation.     

血管紧张素原基因多态性与低氧习服效果的关联研究

目的：研究血管紧张素原基因（AGT） G-217A和T174M两个位点的多态性与急性高原反应（AMS）的发生及其低氧习服效果的关系。方法：阶段1：61名北方汉族大学生,在低氧室急性低氧暴露6 h（模拟海拔4 800 m）,入室后先安静休息30 min,再仰卧蹬车20 min,蹬车负荷定量为60 r/min、80 W,用路易斯湖评分系统（LLS）评价AMS,并记录运动过程中HR、动态血压、SpO₂等生理指标的值;阶段2：进行3周模拟低氧训练,氧含量分别相当于海拔2 500 m、3 500 m、4 800 m,同时以中等强度负荷量运动,2 h/d、4 d/周。3周后,再以阶段1的试验条件测试相应指标;采用PCR-RFLP法检测受试者AGT基因G-217A和T174M位点的基因型和等位基因频率。结果：第1次低氧暴露,在AGT基因的G-217A位点上,GG与GA+AA基因型受试者的各项生理指标无显著性差异;第2次低氧暴露,GG基因型受试者的SpO₂明显低于GA+AA基因型（P<0.05）;T174M位点的不同基因型和等位基因携带者在2次暴露中其AMS发生率、VE、SpO₂、HR和血压等生理指标均无显著性差异。结论：G-217A位点可能是低氧习服的遗传学标记;T174M位点的多态性与AMS的发生及低氧习服未见明显关联。     

Hypoxia and its effect on the cellular system

Eukaryotic cells utilize oxygen for different functions of cell organelles owing to cellular survival. A balanced oxygen homeostasis is an essential requirement to maintain the regulation of normal cellular systems. Any changes in the oxygen level are stressful and can alter the expression of different homeostasis regulatory genes and proteins. Lack of oxygen or hypoxia results in oxidative stress and formation of hypoxia inducible factors (HIF) and reactive oxygen species (ROS). Substantial cellular damages due to hypoxia have been reported to play a major role in various pathological conditions. There are different studies which demonstrated that the functions of cellular system are disrupted by hypoxia. Currently, study on cellular effects following hypoxia is an important field of research as it not only helps to decipher different signaling pathway modulation, but also helps to explore novel therapeutic strategies. On the basis of the beneficial effect of hypoxia preconditioning of cellular organelles, many therapeutic investigations are ongoing as a promising disease management strategy in near future. Hence, the present review discusses about the effects of hypoxia on different cellular organelles, mechanisms and their involvement in the progression of different diseases.     

Replication catastrophe induced by cyclic hypoxia leads to increased APOBEC3B activity

Tumor heterogeneity includes variable and fluctuating oxygen concentrations, which result in the accumulation of hypoxic regions in most solid tumors. Tumor hypoxia leads to increased therapy resistance and has been linked to genomic instability. Here, we tested the hypothesis that exposure to levels of hypoxia that cause replication stress could increase APOBEC activity and the accumulation of APOBEC-mediated mutations. APOBEC-dependent mutational signatures have been well-characterized, although the physiological conditions which underpin them have not been described. We demonstrate that fluctuating/cyclic hypoxic conditions which lead to replication catastrophe induce the expression and activity of APOBEC3B. In contrast, stable/chronic hypoxic conditions which induce replication stress in the absence of DNA damage are not sufficient to induce APOBEC3B. Most importantly, the number of APOBEC-mediated mutations in patient tumors correlated with a hypoxia signature. Together, our data support the conclusion that hypoxia-induced replication catastrophe drives genomic instability in tumors, specifically through increasing the activity of APOBEC3B.