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Glucose tolerance of lowlanders during prolonged stay at high altitude and among high altitude natives.

The fasting blood sugar level and glucose tolerance were investigated in seven amle lowlanders at sea level, during their stay at an altitude of 4,000 m at intervals of 2 weeks, 10, 15, 20, and 24 months and again on return to sea level during the first week and after 1 month. For comparison, the glucose tolerance of six male Ladakhis (natives of high altitude area) was also determined at altitude. The fasting blood sugar among lowlanders increased to 136.0 plus or minus 4.39 mg per 100 ml during 10 months of stay at altitude followed with a gradual decrease to a value of 76.4 plus or minus 3.8 at the end of 24 months. On return to sea level, the blood glucose showed a tendency to increase. Ladakhis had a lower blood sugar level at altitude (86.4 plus or minus 7.28) as compared with lowlanders at sea level (92.6 plus or minus 2.29). The glucose tolerance curves of lowlanders ran paralell to each other at altitude and at sea level. However, the peak of the glucose tolerance curve shifted towards the left during the 20th and 24th months of stay at altitude and at sea level. However, the peak of the glucose tolerance curve shifted towards the left during the 20th and 24th months of stay at altitude and on return to sea level. The tolerance curve of Ladakhis was similar to that of lowlanders at altitude, but showed a sharper blood sugar decline rate.

Acclimatization

Accentuated hypoxemia at high altitude in subjects susceptible to high-altitude pulmonary edema.

To investigate the hypotheses that activated coagulation, catecholamine release, or arginine vasopressin release are involved in the pathogenesis of high-altitude pulmonary edema (HAPE), we measured these variables in seven subjects susceptible to HAPE and in nine control subjects at an altitude of 1,600 m, and after 6 and 12 h at a simulated altitude of 4,150 m. Each subject was studied twice, once after 3 days of placebo medication and once after 3 days of premedication with aspirin and dipyridamole. At high altitude, HAPE-susceptible subjects showed significantly exaggerated hypoxemia and a slightly higher end-tidal carbon dioxide partial pressure that did not account fully for the hypoxemia. Fibrinolytic activity was significantly accelerated in both groups at high altitude, whereas other coagulation measurements, catecholamines and arginine vasopressin levels, and pulmonary function tests were not significantly changed. Similar findings were obtained after both placebo and platelet-inhibitor premedication. The results indicate that none of the three hypothesized mechanisms, i.e., activated coagulation, excessive catecholamine release, or antidiuresis, would account for HAPE susceptibility. Instead, HAPE-susceptible subjects exhibited exaggerated hypoxemia associated with relative hypoventilation and a widened alveolar-arterial gas pressure difference.

Adolescent

Pulmonary gas exchange, diffusing capacity in natives and newcomers at high altitude.

At high altitude, in resting conditions, no differences have been observed between High Altitude Natives (HAN) and acclimatized Sea Level Natives (SLN) in AaDO2, aADCO2 or venous admixture. In acclimatized SLN, AaDO2 is smaller than at sea level because of: (1) The minor effect on arterial oxygenation of the probably constant venous admixture. (2) The reduction of VA/Q inequality as shown by a smaller aADCO2. In HAN, DLCO is greater than in SLN; the contribution of DM or VC in this difference remains unsettled, mainly because of the difficulties of measurement of DM and VC in HAN suddenly exposed to acute hyperoxia. In SLN, in acute hypoxia, DLCO increased transitorily. Asynchronous mechanisms of adaptation to high altitude are evoked.

Acclimatization

[Altitude adaptation. IV. Fertility and reproduction at high altitudes].

High altitude populations have been reproducing for thousands of years. The mean total fertility is comparable to the respective mean values of the whole populations or is even higher. On the other hand, newcomers from sea level seem to have difficulties reproducing in high altitude, especially if they are caucasian. Cattle and other animals fail to reproduce to some extent (due to degeneration of the testes, asoospermia, abortation etc.), which can only be avoided after crossbreeding with aclimatized strains in several generations. But successful gestation in altitudes above 3000 metres is different from sea level gestation in several aspects, which may be important for the survival of mother and child, thus leaving open the question of selective pressure. The mean birth weight of man and animals is reduced, while the mean palcental weight is greater (relatively and absolutely) due to enlargement of the capillary volume. Placenta proves to be on higher risk for developing infarcts (the more in number and extetion, the greater the caucasian admixture). Due to the tendency to a greater extention of the surface, the rate of placenta praevia is extremely high (27%). The lower birth weight corresponds to a higher neonatal mortality, progressing with increasing altitude. Additional to the high altitude stress including the factors to which the newborn are exposed, such as cold, nuturtional deficiencies etc., particular socio-economic conditions influence the differential mortality. In the Bolivian mining-areas, mortality during the first year of life rises to 50%. Only high fertility rates compensate this loss so that high altitude population growth rates do not vary with the altitude.

Acclimatization

[Exposure to high altitude: ventilatory control in relation to syndromes of high altitude].

To investigate the role of hypoxic ventilatory response (HVR) in the pathogenesis of acute mountain sickness (AMS) and high-altitude pulmonary edema (HAPE), we performed two studies. In the first study, nine healthy male lowlanders were exposed to a simulated altitude of 3,700 m (485 Torr) for 24 h in a hypobaric chamber. Subjects (n = 4) with lower alveolar ventilation on arrival at 3,700 m subsequently developed more severe AMS 24 h after the exposure. The relative hypoventilation was related to the lower HVR measured at low altitude, suggesting a possible role of low HVR in AMS. In the second study nine lowlanders with a previous history of HAPE (HAPE-S) and six control subjects were exposed to a simulated altitude of 3,200 m (515 Torr). At low altitude, HVR (delta VE/delta SaO2) in HAPE-S was significantly lower than that of controls (-0.40 +/- 0.20 vs. -0.85 +/- 0.21 L/min/%, p < 0.01). At high altitude HAPE-S showed lower PaO2, higher PaCO2 and lower PAO2, compared with controls, i.e., relative hypoventilation. In one of the HAPE-S, who showed the lowest PaO2 at the simulated altitude, oxygen breathing resulted in a paradoxical increase in ventilation, suggesting hypoxic ventilatory depression. These two studies suggest that low HVR may a contributing rather than a critical factor in the pathogenesis of AMS and HAPE.

Acute Disease

Further studies on pulmonary oedema of high altitude. Abnormal responses to hypoxia of men who had developed pulmonary oedema at high altitude.

101 Indian soldiers, 57 of whom had developed pulmonary oedema of high altitude (POHA) and 44 who had not developed this condition in spite of being at high altitudes for over 2 years, were investigated for observing the differences, if any, in their reaction to acute hypoxic stress. Each subject was made to breathe a 10% hypoxic mixture for 5 min. Haemodynamic parameters like pulmonary artery pressure (systolic, diastolic and mean), brachial artery pressure, wedge pressure, cardiac output, minute ventilation, arterial oxygen saturation and oxygen uptake before and at the end of hypoxic breathing were estimated. In addition, results of the cold pressor test were recorded and the Vd/Vt ratio was estimated. The results obtained in the present study confirmed those obtained in our previous studies. In addition, it was observed that oxygen uptake was significantly higher and oxygen saturation lower after hypoxia in the POHA subjects than in the controls. Certain parameters for screening of subjects possibly susceptible to POHA have been suggested.

Adult

[Digestive physiology and pathology in high altitude].

In the high altitude environment the oxygen and air density are decreased, the temperature and humidity are low, there es an increase in radioactivity. These environmental factors influence on the human body; it has been known for many years that people born and living at high altitude have different morphological and physiological characteristic than those at low altitude. The digestive mechanism for adaptation or acclimation to high altitude has interested physiologist and clinicians for many years. The objective of this article is to present a brief overview of the digestive physiology and pathology in the high altitude.

Altitude

Integrated Cytokine and Immune Cell Profiling Reveals a Distinct Immune Signature Associated with High-Altitude Pulmonary Edema.

High-altitude pulmonary edema (HAPE) is a rapidly progressive, life-threatening disorder arising in otherwise healthy individuals upon ascent to high altitude, yet the mechanisms underlying maladaptive vascular leak remain poorly defined. Although elevated pulmonary arterial pressure and capillary stress failure are recognized as central hemodynamic drivers, accumulating evidence indicates that innate immune dysregulation is an equally critical, largely unexplored determinant of HAPE. To systematically delineate the immune and molecular programs that distinguish pathological responses to hypobaric hypoxia from acclimatization, peripheral blood along with clinical details was collected from low-altitude controls (LA-Cntrl, number of participants, (n = 19), healthy high-altitude sojourners (HA-Cntrl, n = 47), and HAPE patients (n = 90). Plasma proteomic markers were quantified using a targeted panel, while monocyte and dendritic cell subsets in peripheral blood mononuclear cells were immunophenotyped by multicolor flow cytometry. HA-Cntrl subjects displayed an anti-inflammatory profile, marked by the suppression of CXC chemokine receptor 3 axis chemokines. HAPE patients, in contrast, exhibited a pro-inflammatory, vascular injury signature, with elevated levels of inflammatory interleukins and myeloid and chemotactic factors. This inflammatory signature was accompanied by the expansion of classical monocytes, implicating a myeloid vascular program associated with HAPE.

Humans

Plasma Proteomic Profiling Reveals ITGA2B as A Key Regulator of Heart Health in High-altitude Settlers.

Myocardial injury is a common disease in the plateau, especially in the lowlanders who have migrated to the plateau, in which the pathogenesis is not well understood. Here, we established a cohort of lowlanders comprising individuals from both low-altitude and high-altitude areas and conducted plasma proteomic profiling. Proteomic data showed that there was a significant shift in energy metabolism and inflammatory response in individuals with myocardial abnormalities at high altitude. Notably, integrin alpha-&#x2161;b (ITGA2B) emerged as a potential key player in this context. Functional studies demonstrated that ITGA2B upregulated the transcription and secretion of interleukin-6 (IL-6) through the integrin-linked kinase (ILK)/nuclear factor-&#x3ba;B (NF-&#x3ba;B) signaling axis under hypoxic conditions. Moreover, ITGA2B disrupted mitochondrial structure and function, increased glycolytic capacity, and aggravated energy reprogramming from oxidative phosphorylation to glycolysis. Leveraging the therapeutic potential of traditional Chinese medicine in cardiac diseases, we discovered that tanshinone &#x2161;A (Tan&#x2161;A) effectively alleviated the myocardial injury caused by the abnormally elevated expression of ITGA2B and hypobaric hypoxia exposure in mice, thus providing a novel candidate therapeutic strategy for the prevention and treatment of high-altitude myocardial injury.

Animals

Effects of high altitude hypoxia on left ventricular systolic time intervals in man.

Effects of high altitude hypoxia on systolic time intervals were examined in 34 healthy men: 20 sea level residents studied at rest and at the end of 3 minutes steady isometric (handgrip) exercise at sea level and then serially for the first 5 days and on the tenth day, at an altitude of 3658 m, and I4 permanent residents at high altitude studied at high altitude. In the sea level residents there was a significant increase in the pre-ejection period (PEP), abbreviation of the left ventricular ejection time (LVET), both corrected for heart rate, and prolongation of the PEP/LVET ratio at high altitude. The maximum changes were seen on days 2 and 3; these parameters tended to approach sea level control values by the tenth day. The systolic time interval values of high altitude residents were similar to the control values of the sea level residents obtained at sea level but significantly different from the changes in the sea level values seen in the first 4 days at high altitude. It thus appears that while the high altitude residents do not show any left ventricular dysfunction as determined by systolic time intervals, healthy sea level residents when exposed to high altitude hypoxia show a significant depression of the left ventricular function for at least the first 4 days. This might be a contributing factor in the genesis of high altitude pulmonary oedema.

Adult

[Hormonal variation during physical exertion at high altitude].

The influence of the physical exercise at high altitude on the endocrine function was studied in 8 normal native men of sea level and in 8 natives men of high altitude. The sea level dwellers were studied both, at sea level, during an acute exposure to low barometric pressure and after 3 months of acclimatization to altitudes over 3,500 meters above the sea level. The experiments at high altitude were conducted at an altitude of 4,500 meters above the sea level. Two types of exercise were carried out, sub-maximal and maximal, at fasting state, between 8 and 10 a.m. During an acute exposure to altitude the physical exercise produced a marked rise of glucose, cortisol and growth hormone and a fall in the insulin content of plasma. In the sea level dwellers, acclimatized to altitude during 3 months, an elevation of growth hormone was observed only during maximal physical effort. Marked variation in glucose and cortisol were observed during both types of exercise. This shows that in these subjects some adaptative changes have ocurred but of lesser extent as those observed in altitude natives. In the high altitude native higher basal concentrations of growth hormone and glucagón as well as a lower glucose concentration in blood, were found. During exercise the high altitude dweller showed no significant changes in somatotropin, meanwhile an important elevation of cortisol occurred. These findings indicate that the high altitude native has metabolic and endocrine responses to exercise similar to those found in well fitted atletes of sea level. The exposure to altitude provoked a rise in glucagon concentration directly proportional to the time of exposition ot altitude. The physical exercise did not elucidate any change in the glucagon content of blood.

Adult

Sustained venoconstriction in man supplemented with CO2 at high altitude.

Venoconstriction occurs at high altitude. This study sought to determine whether hypoxia or hypocapnia is the cause of the venoconstriction. Five male subjects were exposed to 4,000-4,400 m (PB 440-465 mmHg) with supplemental 3.77 +/- 0.02% CO2 in a hypobaric chamber for 4 days. Similar alveolar O2 tensions were obtained in four control subjects exposed to 3,500-4,100 m (PB 455-492 mmHg) without CO2. A water-filled plethysmograph was used to determine forearm flow and venous compliance. Systemic blood pressure was measured with the cuff procedure. Catecholamines were measured in 24-h urine collections. Venous compliance fell at high altitude in both groups and was less (P less than 0.01) than control values. Forearm flow and resistance were unaltered at altitude in the group with CO2 supplementation while forearm flow decreased and resistance increased in the hypocapnic group at 72 h of exposure. Urinary catecholamines increased in the group with CO2 and remained unaltered in the hypocapnic group. It is concluded that hypoxia is responsible for decreasing venous compliance, and hypocapnia for increasing resistance and decreasing flow. Group differences observed in urinary catecholamines may be explained by differences in arterial pH.

Adolescent

High altitude medical problems.

Increased travel to high altitude areas by mountaineers and nonclimbing tourists has emphasized the clinical problems associated with rapid ascent. Acute mountain sickness affects most sojourners at elevations above 10,000 feet. Symptoms are usually worse on the second or third day after arrival. Gradual ascent, spending one to three days at an intermediate altitude, and the use of acetazolamide (Diamox) will prevent or ameliorate symptoms in most instances. Serious and potentially fatal problems, such as high altitude pulmonary edema or cerebral edema, occur in approximately 0.5 percent to 1.0 percent of visitors to elevations above 10,000 feet-especially with heavy physical exertion on arrival, such as climbing or skiing. Early recognition, high flow oxygen therapy and prompt descent are crucially important in management. Our knowledge of the causes of these and other high altitude problems, such as retinal hemorrhage, systemic edema and pulmonary hypertension, is still incomplete. Even less is known of the effect of high altitudes on medical conditions common at sea level or on the action of commonly used drugs.

Adolescent

Changes in transthoracic electrical impedance at high altitude.

Mean transthoracic electrical impedance (impedance) which is inversely related to intrathoracic extravascular fluid volume was measured in 121 normal healthy volunteers at sea-level and at 3658 metres altitude. Fifty (group A) reached the high altitude location after an hour's journey in a pressurised aircraft. Twenty-five (group D) underwent slow road ascent including acclimatisation en route. Thirty permanent residents (group B) and 16 temporary residents at high altitude (group C) were also studied. Serial studies in the 30 subjects of group A who developed symptoms of high altidue sickness showed a significant decrease of impedance up to the fourth day of exposure to high altitude which later returned to normal. The 4 volunteers who developed severe symptoms showed the largest drop in impedance. A case of acute pulmonary oedema developing at 4300 metres showed an impedance value of 24-1 ohms on admission. After effective treatment the impedance increased by 11-9 to 36-0 ohms. Twenty asymptomatic subjects of group A and 25 of group D showed a small average increase in impedance values at high altitude. These obstructions suggest that measurement of transthoracic electrical impedance may be a valuable means of detecting incipient high altitude pulmonary oedema.

Acclimatization

Evidence for increased intrathoracic fluid volume in man at high altitude.

To determine if subclinical pulmonary edema occurs commonly at high altitude, 25 soldiers participated in two consecutive 72-h field exercises, the first at low altitude (200-875 m) and the second at high altitude (3,000-4,300 m). Various aspects of ventilatory function and pulmonary mechanics were measured at 0, 36, and 72 h of each exercise. Based on physical examination and chest radiographs there was no evidence of pulmonary edema at high altitude. There was, however, an immediate and sustained decrease in vital capacity and transthoracic electrical impedance as well as a clockwise rotation of the transpulmonary pressure-volume curve. In contrast, closing capacity and residual volume did not change immediately upon arrival at high altitude but did increase later during the exposure. These observations are consistent with an abrupt increase in thoracic intravascular fluid volume upon arrival at high altitude followed by a more gradual increase in extravascular fluid volume in the peribronchial spaces of dependent lung regions.

Adolescent

High altitude pulmonary edema. Epidemiologic observations in Peru.

The incidence of high altitude pulmonary edema was examined by a survey (via questionnaire) of residents living at 3,750 meters (12,303 feet) in the mining community of La Oroya, Peru. Ninety-seven subjects made a total of 1,157 ascents to high altitude after a stay at sea level of longer than 14 days. Sixty-four subjects experienced at least one episode of high-altitude pulmonary edema. The incidence was higher in subjects aged 13 to 20 years, where 17 percent (15) of 90 ascents resulted in episodes of high-altitude pulmonary edema, than in subjects 21 years or older (3 percent; 18/686 ascents). Young subjects (2 to 12 years old) had more severe episodes of high-altitude pulmonary edema (81 percent; 30/37 episodes) than adults (22 percent; 4/18 episodes). No episodes were observed in children under two years old. Five subjects under 21 years of age experienced recurrent episodes. Our estimated incidence of severe episodes of high altitude pulmonary edema per ascent in adults (0.6 percent; 4/686) is similar to that reported by other workers (incidence of 0.15 to 0.57 percent) in various parts of the world.

Adolescent

High-altitude hypoxia alters the visual control of standing balance in lowlanders and Tibetan highlanders.

High-altitude hypoxia affects both visual function and postural control, yet the influence of optic-flow perturbations on standing balance under hypoxic stress remains unclear. Tibetan highlanders (TH) exhibit adaptations to chronic hypoxia, but whether their visually driven postural responses differ from those of lowlanders (LL) has not been investigated. We examined how high-altitude exposure and acclimatization influence static and dynamic visual contributions to balance by delivering sinusoidal optic-flow perturbations in virtual reality at low altitude (1,400 m) and after incremental ascent to high altitude (4,300 m) in acclimatizing LL (n = 15) and TH (n = 14). Anteroposterior center of pressure (AP CoP) velocity and mean power frequency (MPF) were measured during three visual-field conditions (full-, central-, and peripheral-vision) and two optic-flow velocities (peak 1 m/s and 8 m/s at 0.25 Hz). At high altitude, both groups showed attenuated responses to optic flow compared with 1,400 m, reflected by reduced AP CoP velocity and lower MPF across visual-field conditions, consistent with reduced responsiveness to dynamic visual-motion cues under high altitude hypoxia. In contrast, during eyes-open quiet stance [no virtual reality (VR)], TH but not LL exhibited increased AP CoP velocity and MPF at 4,300 m, and no altitude effect was observed with eyes-closed in either group. This finding indicates that TH adopt a visually dependent postural strategy at altitude, whereas LL show minimal changes in static visual balance control but reduced responsiveness to fast dynamic motion. Together, these findings demonstrate that high-altitude hypoxia disrupts dynamic visual processing for balance control in both groups, while revealing group differences in the use of static visual cues during quiet stance.NEW & NOTEWORTHY This is the first study to investigate how high-altitude hypoxia alters visually driven postural control using virtual reality (VR) optic-flow perturbations. We show that hypoxia attenuates sway responses to optic-flow in both lowlanders and Tibetan highlanders, and that visual weighting differs between these groups. These findings reveal altitude- and population-related changes in sensory weighting during standing balance, advancing sensorimotor understanding of postural control in hypoxia.

Humans