Cardiopulmonary response and body composition changes after prolonged high altitude exposure in women

Weight loss in men is commonly observed during prolonged high altitude exposure as a result of a daily negative energy balance. Its amount depends mainly on duration of exposure, altitude reached, and level of physical activity. This reduction in body weight often comes with a loss of muscular mass, likely contributing to the decreased physical performance generally reported. Limited data is, however, available on body composition, functional capacity, and cardiopulmonary response to exercise after high altitude exposure in women. The aim of this study was to evaluate the effects of prolonged high altitude exposure on body composition and on cardiopulmonary response to maximal exercise in a group of young, moderately active women. Twelve female subjects, aged 21.5 ± 3.1 (mean ± SD), BMI 22.1 ± 1.9 kg · m(-2) and Vo(2max) 33.8 ± 3.5 mL · kg(-1) · min(-1), participated in this study, by residing for 21 days at high altitude (5050 m, Pyramid, EV-K(2)-CNR laboratory). Before and after high altitude exposure, all subjects underwent both a body composition evaluation using two methods (bioimpedance analysis and DEXA) and a functional evaluation based on a maximal exercise test on a cycle ergometer with breath-by-breath gas analysis. After high altitude exposure, data showed a slight, nonsignificant reduction in body weight, with an average 3:2 reduction ratio between fat and fat-free mass evaluated by DEXA, in addition to a significant decrease in Vo(2max) on the cycle ergometer test (p<0.01). Changes in Vo(2max) correlated to changes of leg muscle mass, evaluated by DEXA (r(2) = 0.72; p<0.0001). No changes were observed in the maximal heart rate, work capacity, and ventilatory thresholds, while the Vo(2)/W slope was significantly reduced (p<0.05). Finally, Ve/Vo(2) and VE/Vco(2max) slopes were increased (p<0.01), suggesting a possible long-term modulation of the exercise ventilatory response after prolonged high altitude exposure.     

Changes in ventilatory threshold at high altitude: effect of antioxidants

PURPOSE: To investigate the effects of prolonged hypoxia and antioxidant supplementation on ventilatory threshold (VT) during high-altitude (HA) exposure (4300 m). METHODS: Sixteen physically fit males (25 +/- 5 yr; 77.8 +/- 8.5 kg) performed an incremental test to maximal exertion on a cycle ergometer at sea level (SL). Subjects were then matched on VO2peak, ventilatory chemosensitivity, and body mass and assigned to either a placebo (PL) or antioxidant (AO) supplement group in a randomized, double-blind manner. PL or AO (12 mg of beta-carotene, 180 mg of alpha-tocopherol acetate, 500 mg of ascorbic acid, 100 mug of selenium, and 30 mg of zinc daily) were taken 21 d prior to and for 14 d at HA. During HA, subjects participated in an exercise program designed to achieve an energy deficit of approximately 1400 kcal.d(-1). VT was reassessed on the second and ninth days at HA (HA2, HA9). RESULTS: Peak power output (Wpeak) and VO2peak decreased (28%) in both groups upon acute altitude exposure (HA2) and were unchanged with acclimatization and exercise (HA9). Power output at VT (WVT) decreased from SL to HA2 by 41% in PL, but only 32% in AO (P < 0.05). WVT increased in PL only during acclimatization (P < 0.05) and matched AO at HA9. Similar results were found when VT was expressed in terms of % Wpeak and % VO2peak. CONCLUSIONS: VT decreases upon acute HA exposure but improves with acclimatization. Prior AO supplementation improves VT upon acute, but not chronic altitude exposure.     

Chilean miners commuting from sea level to 4500 m: a prospective study

The development of mining activities in North Chile involves a great number of workers intermittently exposed to high altitude for a long period of time (chronic intermittent hypoxia, CIH). A 2(1/2)-year prospective study aimed to characterize this model of exposure to CIH and to know whether this condition may progressively lead to a chronic pattern. Twenty-nine miners, aged 25 +/- 5 yr, working 7 days at HA (3800 to 4600 m) and resting 7 days at sea level (SL) were studied. Subjects underwent a physical examination, EKG, hematological status, maximal exercise test, ventilatory and cardiac response to hypoxia (F(iO2) = 0.114) at rest and exercise, pulmonary vascular response to hypoxia by echocardiography, and 24-h monitoring of EKG and arterial pressure. Basal evaluations were performed at SL before the first exposure to hypoxia. HA measurements were daily AMS score, sleep status, and 24-h monitoring of EKG and arterial pressure. All these measurements were repeated after a mean period of 12, 19, and 31 months. Hematocrit increased but reached values lower than those observed in chronic permanent exposure. Systemic and pulmonary arterial pressures measured at SL did not change, but were higher in hypoxia. Right ventricle showed a slight dilatation. Exercise performance at SL declined with exposure to CIH to reach a 12.3% decrease after 31 months of CIH, associated with a 6.8% decrease in maximal heart rate. Signs of ventilatory acclimatization were observed after 12 months. Symptoms of AMS and sleep disturbances were still seen on the first 2 days at HA, whatever the time of exposure to CIH. In conclusion, CIH induced a clear acclimatization process. Subjects did not reach a health status comparable to that seen in permanent residents at HA and remained at risk of acute altitude-induced illnesses.     

The effect of long endurance running on natural killer cells in marathoners

Ten experienced marathoners were exercised 3 h in the laboratory. Blood samples were collected at 0 h baseline, 1 h exercise, and 5 min, 1.5 h, 6 h, and 21 h recovery and were analyzed for total number of lymphocytes expressing membrane antigens found on natural killer (NK) cells. NK activity was also measured. Four of the seven subpopulations of lymphocytes studied, Leu-11+19+, Leu-11+19-, Leu-11+7-, and Leu-19+11-, showed significant within-subject effects over time, using repeated measures ANOVA. Simple contrasts with baseline values showed that, at 1.5 h and 21 h recovery, total number of lymphocytes bearing three different combinations of NK markers, Leu-11+19+, Leu-11+19-, and Leu-11+7-, were significantly decreased when compared with baseline values. At 1.5 h recovery, NK activity was significantly decreased below baseline levels for four of the six effector NK cell/target K562 myelogenous leukemia cell (E:T) ratios tested. At 6 h recovery, NK activity was still decreased significantly with the 12.5:1 and 3:1 E:T ratios. By 21 h recovery, NK activity did not differ significantly from baseline levels. Cortisol levels at 5 min post-exercise were negatively correlated with NK activity at 1.5 h recovery (r = -0.62, P = 0.05, 50:1 E:T ratio; r = -0.66, P = 0.04, 25:1 E:T ratio). Further research is needed to elucidate the effect these changes have on host immunosurveillance and immunoresponsiveness in vivo.     

Italian high altitude laboratories: past and present

Italy is a mountainous country with a total of 88 huts and bivouacs at altitudes higher than 3,000 m. Starting in the 19th century a great deal of research in high altitude pathophysiology has been carried out in Italy and many Italian physicians have been involved in mountain medicine. Most of the Italian research has been carried out at two locations: the scientific laboratories "Angelo Mosso" on Monte Rosa (Capanna Regina Margherita and Laboratorio Angelo Mosso), and the "Pyramid" in Nepal. The Capanna Regina Margherita, located on the top of Punta Gnifetti (Monte Rosa, 4,559 m), was inaugurated in 1893. With the support of Queen Margherita of Savoy, an Observatory for scientific studies was built beside this hut in 1894. In 1980 the hut was completely rebuilt by the Italian Alpine Club. The Istituto Angelo Mosso at Col d'Olen, at the base of Monte Rosa (at 2,900 m) was inaugurated in 1907. The high altitude laboratory named the "Pyramid" was built in 1990. Made of glass and aluminium, this pyramid-shaped structure is situated in Nepal at 5,050 m. The scientific laboratories "Angelo Mosso" on Monte Rosa (mainly the Capanna Regina Margherita) and the Pyramid form a nucleus for high altitude research: the former is especially devoted to research regarding acute mountain sickness and the response to subacute hypoxia, whereas the latter is a unique facility for research responses to chronic hypoxia, the effect of exposure to very high altitude, and the study of the resident population living in the Himalayas for at least 25,000 years.     

Acute versus chronic hypoxia in tumors

Background

Many tumors contain hypoxic regions. Hypoxia, in turn, is known to increase aggressiveness and to be associated with treatment resistance. The two most frequently described and investigated subtypes of tumor hypoxia are acute and chronic. These two subtypes can lead to completely different hypoxia-related responses within the tumor, which could have a direct effect on tumor development and response to treatment. In order to accurately assess the specific biological consequences, it is important to understand which time frames best define acute and chronic hypoxia.

Materials and methods

This article provides an overview of the kinetics of in vitro and in vivo acute and chronic tumor hypoxia. Special attention was paid to differentiate between methods to detect spontaneous in vivo hypoxia and to describe the biological effects of experimental in vitro and in vivo acute and chronic tumor hypoxia.

Results and conclusions

There are large variations in reported spontaneous fluctuations in acute hypoxia that are dependent on the cell lines investigated and the detection method used. In addition to differing hypoxia levels, exposure times used to induce in vitro and in vivo experimental acute and chronic hypoxia range from 30?min to several weeks with no clear boundaries separating the two. Evaluation of the biological consequences of each hypoxia subtype revealed a general trend that acute hypoxia leads to a more aggressive phenotype. Importantly, more information on the occurrence of acute and chronic hypoxia in human tumors is needed to help our understanding of the clinical consequences.     

急性放射病患者恢复期外周血淋巴细胞表型及功能分析

了解急性放射病患者恢复期间外周血淋巴细胞功能。方法用流式细胞仪分析淋巴细胞表型，３Ｈ－ＴｄＲ掺入法分别分析Ｔ细胞和ＮＫ细胞功能。结果照后４．５年，患者外周血ＣＤ＋４Ｔ细胞仍有不同程度低于正常对照；受照剂量大于２Ｇｙ者ＣＤ＋８Ｔ细胞数明显高于正常，而受照时年龄为５４岁者ＣＤ＋８Ｔ细胞明显低于对照；多数患者外周血ＮＫ细胞数和功能都高于正常对照。结论受照者外周血Ｔ细胞功能恢复与受照剂量大小及年龄因素有关，恢复期ＮＫ细胞数量和活性增高，对于弥补Ｔ细胞功能不足具有积极意义     

Low dose radiation induced immunomodulation: effect on macrophages and CD8+ T cells

PURPOSE: The aim of the present investigation was to study the effect of fractionated whole body low dose ionizing radiation (LDR) on the functional responses of T lymphocytes, their subpopulations and macrophages. MATERIALS AND METHODS: C57BL/6 mice were exposed to 4 cGy from a (60)Co source, at 0.31 cGy/min, at 24 h intervals for 5 days (total dose 20 cGy). Phagocytic activity was measured by flow cytometry using Bioparticles and nitric oxide generation was estimated by spectrophotometry. Proliferation of lymphocytes in response to concanavalin A (con A) and alloantigens was measured by (3)H thymidine incorporation. Expression of cell surface markers was assessed by flow cytometric analysis of antibody labeled cells. Target cell killing by cytotoxic T cells (CTL) generated against allogenic cells was assessed by flow cytometry using PKH26 labeled target cells. Cytokines were estimated by enzyme linked immunosorbent assay. RESULTS: Exposure to LDR enhanced nitric oxide secretion and phagocytosis. The expression of early activation antigen, CD69, was enhanced in CD8(+) T lymphocytes concomitant with enhanced proliferation in response to con A. In addition, mixed lymphocyte reaction (MLR) and CTL response were augmented and secretion of interferon gamma (IFN-gamma) was suppressed following LDR exposure. CONCLUSIONS: LDR exposure enhanced the function of macrophages and responses of CD8(+) T cells in C57BL/6 mice.     

Antitumorale Wirkung von Interferonen und Interleukinen in Kombination mit Strahlentherapie

BACKGROUND: During the last 2 decades, cytokines such as interferons (IFN) have been used to modulate tumor response in radiotherapy. Initially, the focus was on antiviral and radiosensitizing effects of interferons but increasingly, the function of interferons and interleukins (IL) within the immune response to tumor cells is becoming important. METHOD: The cellular immune response toward tumor cells is reviewed. The role of cytokines in antigen presentation and activation of effector cells and their interactions with radiation are described. Preclinical strategies of the antitumor action of cytokines are presented and discussed based on the induction of IFN-gamma by IL-12. RESULTS: Recent advances in immunology have demonstrated the importance of local interactions between antigen-presenting cells (APC) and effector cells such as natural killer (NK) cells and T-lymphocytes for an effective immune reaction against tumors. Interferons stimulate such interactions, while IL-2 plays a central role in the activation of NK cells and T-lymphocytes. The interactions between APC and effector cells are suppressed by many tumors but can be stimulated by irradiation. Since systemic application of interferons is quite toxic, present strategies aim at local expression, e. g., the induction of IFN-gamma expression in Th1 cells by IL-12. CONCLUSION: The improved understanding of immunologic mechanisms has emphasized the role of the cytokine network in the interaction between tumor cells and effector cells such as NK cells and T-lymphocytes. This opens new possibilities for the application of cytokines as biological response modifiers, which may eventually help widening the therapeutic window in radiotherapy.     

FISH examination of lymphocytes from Mayak workers for assessment of translocation induction rate under chronic radiation exposures

Purpose: To estimate the translocation-induction rate under chronic exposure conditions by measuring chromosome aberration frequencies in lymphocytes from Mayak nuclear workers using fluorescence in situ hybridization (FISH). Materials and methods: Lymphocytes were examined from 27 nuclear workers at the Mayak Production Association and two control individuals using FISH with probes for chromosomes 1, 2 and 4. Official doses derived from worker film-badge records varied from 0 to 8.50 Gy. Results: The mean (- SD) genome-equivalent translocation frequency (F G) was 2.30 (- 0.75)% in the zero-dose group (n = 7), and Poisson regression analysis provided the best-fit equation of F G (%) = 2.96 (- 0.39) + 0.69 (- 0.14) D + 0.12 (- 0.05) A, where D is the film-badge-derived dose (Gy), and A is age centred at 67 years. The induction rate would increase to nearly 1% Gy -1 if the radiation dose to bone marrow, one of the major organs for lymphocytes and where their precursor cells reside, is considered. Conclusion: The estimated induction rate in vivo appeared substantially smaller than linear coefficients estimated from various in vitro studies.     

Alpha coefficient of dose-response for chromosome translocations measured by FISH in human lymphocytes exposed to chronic 60Co gamma rays at body temperature.

PURPOSE: To measure the alpha coefficient, the initial slope of the translocation dose-response curve, for 60Co gamma-rays in human lymphocytes. MATERIALS AND METHODS: Human lymphocytes were exposed to 0, 0.32, 0.62 and 0.92 Gy of chronic 60Co gamma-rays under conditions that reduce the metabolic stress to the cells. Chromosome translocation frequencies were measured using fluorescence in situ hybridization with a whole-chromosome probe cocktail specific for chromosomes 1, 2, 4 (orange) and 3, 5, 6 (green). RESULTS: A total of 72,383 metaphases were analysed (33,429 in exposed cells) in two individuals. The shape of the dose-response curves for translocations was linear, and alpha coefficient was measured as 0.024 +/- 0.002 translocations per cell per Gy for the combined data for two 24 year old male donors. CONCLUSION: The alpha coefficients measured after chronic exposure were in good agreement with that reported in the literature for acute, low-dose exposure of human lymphocytes to 60Co gamma-rays.     

Radiobiological and immunohistochemical assessment of hypoxia in human melanoma xenografts: acute and chronic hypoxia in individual tumours

Purpose: Tumour hypoxia causes resistance to treatment and may promote the development of metastatic disease. The mean fraction of radiobiologically hypoxic cells has been determined for a large number of tumour cell lines, but quantitative information on intertumour heterogeneity in radiobiological hypoxia is sparse, and it is not known whether radiobiological hypoxia is mainly either chronic or acute in nature. The purpose of the work reported here was (1) to determine the fraction of radiobiologically hypoxic cells in individual tumours and (2) to differentiate quantitatively between chronic and acute hypoxia. Materials and methods: Four human melanoma xenograft lines (A-07, D-12, R-18, U-25) were included. A radiobiological assay based on the paired survival curve method was established to measure the fraction of radiobiologically hypoxic cells. An immunohistochemical assay using the hypoxia marker pimonidazole was developed to determine the fraction of chronically hypoxic cells. The fraction of acutely hypoxic cells was estimated from the fraction of radiobiologically hypoxic cells and the fraction of chronically hypoxic cells. Results: The fractions of radiobiologically hypoxic cells were in the ranges of 1-49% (A-07), 10-69% (D-12), 22-87% (R-18) and 23-85% (U-25); the fractions of chronically hypoxic cells were in the ranges of 0-15% (A-07), 5-25% (D-12), 4-17% (R-18) and 9-25% (U-25); the fractions of acutely hypoxic cells were in the ranges of 1-47% (A-07), 1-57% (D-12), 9-80% (R-18) and 5-69% (U-25). The fraction of acutely hypoxic cells was higher than the fraction of chronically hypoxic cells in most A-07, R-18 and U-25 tumours. The fraction of chronically hypoxic cells was higher than the fraction of acutely hypoxic cells in 16 of 25 D-12 tumours. Conclusion: This study indicates that acute hypoxia in tumours is a far more serious problem than chronic hypoxia and, consequently, it may be beneficial to focus on acute hypoxia rather than chronic hypoxia when searching for clinically useful predictive assays of hypoxia-induced radiation resistance and malignant progression and for methods to overcome treatment resistance caused by hypoxia.     

Radiobiological and immunohistochemical assessment of hypoxia in human melanoma xenografts: acute and chronic hypoxia in individual tumours

PURPOSE: Tumour hypoxia causes resistance to treatment and may promote the development of metastatic disease. The mean fraction of radiobiologically hypoxic cells has been determined for a large number of tumour cell lines, but quantitative information on intertumour heterogeneity in radiobiological hypoxia is sparse, and it is not known whether radiobiological hypoxia is mainly either chronic or acute in nature. The purpose of the work reported here was (1) to determine the fraction of radiobiologically hypoxic cells in individual tumours and (2) to differentiate quantitatively between chronic and acute hypoxia. MATERIALS AND METHODS: Four human melanoma xenograft lines (A-07, D-12, R-18, U-25) were included. A radiobiological assay based on the paired survival curve method was established to measure the fraction of radiobiologically hypoxic cells. An immunohistochemical assay using the hypoxia marker pimonidazole was developed to determine the fraction of chronically hypoxic cells. The fraction of acutely hypoxic cells was estimated from the fraction of radiobiologically hypoxic cells and the fraction of chronically hypoxic cells. RESULTS: The fractions of radiobiologically hypoxic cells were in the ranges of 1-49% (A-07), 10-69% (D-12), 22-87% (R-18) and 23 85% (U-25); the fractions of chronically hypoxic cells were in the ranges of 0-15% (A-07), 5-25% (D-12), 4-17% (R-18) and 9-25% (U-25); the fractions of acutely hypoxic cells were in the ranges of 1-47% (A-07), 1-57% (D-12), 9-80% (R-18) and 5-69% (U-25). The fraction of acutely hypoxic cells was higher than the fraction of chronically hypoxic cells in most A-07, R-18 and U-25 tumours. The fraction of chronically hypoxic cells was higher than the fraction of acutely hypoxic cells in 16 of 25 D-12 tumours. CONCLUSION: This study indicates that acute hypoxia in tumours is a far more serious problem than chronic hypoxia and, consequently, it may be beneficial to focus on acute hypoxia rather than chronic hypoxia when searching for clinically useful predictive assays of hypoxia-induced radiation resistance and malignant progression and for methods to overcome treatment resistance caused by hypoxia.     

大鼠缺氧过程中脑线粒体超微结构变化及形态计量学研究

目的：观察及定量分析急、慢性缺氧后大鼠脑线粒体形态变化。方法：动物分别在低压舱内模拟４０００ｍ高原连续缺氧３天和４０天后,取大脑皮质组织,作超薄切片后透射电镜观察,图像经计算机扫描后做生物体视学测量。结果：急性缺氧线粒体体积增大,部分出现嵴肿胀,线粒体平均直径、截面积在,比表面积减小（Ｐ〈０．０５）。慢性缺氧后线粒体形态及体积密度与面数密度未见显著变化（Ｐ〉０．０５）,与急性缺氧组比较,线粒体平均     

高强度间歇训练对武警战士T淋巴细胞稳态的影响

 目的 探讨高强度间歇训练(high-intensity interval training,HIIT)对武警战士T淋巴细胞稳态(Th1/Th2和TH17/Treg)的影响。方法 选取23名武警男性战士分别进行急性(1次)和短期(4周、3次/周)HIIT,于1次HIIT运动前、运动后即刻、运动后60 min及4周HIIT前后取静脉血利用流式细胞术测定细胞因子IFN-γ(Th1亚群)、IL-4(Th2亚群)、IL-17A(Th17亚群)、TGF-β(Treg亚群),以及Treg细胞活化标志物CD39、LAP和GARP相对表达量(用阳性细胞率表示)。结果 1次HIIT后即刻,Th1细胞IFN-γ表达上调(P<0.05),60 min后,Treg细胞GARP、LAP和CD39表达量升高(P<0.05),IFN-γ恢复(P>0.05);IL-4在各时间点均无显著性变化(P>0.05)。4周HIIT后,Treg细胞LAP表达下调(P<0.05)。未检测到IL-17A和TGF-β表达量。结论 1次急性HIIT暂时性破坏Th1/Th2稳态并使Th1/Th2平衡向Th1漂移,运动后恢复期具有免疫抑制作用的Treg细胞被动员,其作用可能参与T细胞稳态的调节与重建。短期(4周)HIIT诱导Treg细胞免疫抑制能力减弱,但T细胞稳态平衡无显著性改变。     

离体淋巴细胞经低氧及低氧预处理后免疫指标的变化

目的　观察急性低氧及低氧预处理后淋巴细胞 [Ca2 ]i的变化及与淋巴细胞增殖活化的关系。　方法　取正常人外周静脉血 ,用Ficoll Hypaque密度梯度离心法分离淋巴细胞。实验分 3组 :正常对照组、急性低氧组和低氧预处理组。用Fura 2 /AM荧光分光光度法检测 [Ca2 ]i。用ELISA法检测上清液中IgG和IL 2的分泌量。用MTT法检测淋巴细胞增殖率。　结果　急性低氧后淋巴细胞 [Ca2 ]i明显下降 ,与对照组比较差异有非常显著性意义 (P <0 0 1) ,同时淋巴细胞IgG和IL 2的分泌量以及淋巴细胞增殖反应也明显下降 ,与各自的对照组相比差异有非常显著性意义(P <0 0 1) ;低氧预处理后再进行急性低氧时 ,淋巴细胞 [Ca2 ]i、IgG和IL 2的分泌量以及淋巴细胞增殖反应均恢复到与对照组相近的水平 ,且与急性低氧组比较差异有非常显著性意义 (P <0 0 1)。　结论　急性低氧后淋巴细胞免疫功能下降 ,低氧预处理能改善淋巴细胞的免疫功能 ,其中 [Ca2 ]i的适应性变化发挥了重要作用。