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UBC-Nepal Expedition: An experimental overview of the 2016 University of British Columbia Scientific Expedition to Nepal Himalaya.
Willie, CK, Stembridge, M, Hoiland, RL, Tymko, MM, Tremblay, JC, Patrician, A, Steinback, C, Moore, J, Anholm, J, Subedi, P, et al
PloS one. 2018;(10):e0204660
Abstract
The University of British Columbia Nepal Expedition took place over several months in the fall of 2016 and was comprised of an international team of 37 researchers. This paper describes the objectives, study characteristics, organization and management of this expedition, and presents novel blood gas data during acclimatization in both lowlanders and Sherpa. An overview and framework for the forthcoming publications is provided. The expedition conducted 17 major studies with two principal goals-to identify physiological differences in: 1) acclimatization; and 2) responses to sustained high-altitude exposure between lowland natives and people of Tibetan descent. We performed observational cohort studies of human responses to progressive hypobaric hypoxia (during ascent), and to sustained exposure to 5050 m over 3 weeks comparing lowlander adults (n = 30) with Sherpa adults (n = 24). Sherpa were tested both with (n = 12) and without (n = 12) descent to Kathmandu. Data collected from lowlander children (n = 30) in Canada were compared with those collected from Sherpa children (n = 57; 3400-3900m). Studies were conducted in Canada (344m) and the following locations in Nepal: Kathmandu (1400m), Namche Bazaar (3440m), Kunde Hospital (3480m), Pheriche (4371m) and the Ev-K2-CNR Research Pyramid Laboratory (5050m). The core studies focused on the mechanisms of cerebral blood flow regulation, the role of iron in cardiopulmonary regulation, pulmonary pressures, intra-ocular pressures, cardiac function, neuromuscular fatigue and function, blood volume regulation, autonomic control, and micro and macro vascular function. A total of 335 study sessions were conducted over three weeks at 5050m. In addition to an overview of this expedition and arterial blood gas data from Sherpa, suggestions for scientists aiming to perform field-based altitude research are also presented. Together, these findings will contribute to our understanding of human acclimatization and adaptation to the stress of residence at high-altitude.
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Fructose metabolism, cardiometabolic risk, and the epidemic of coronary artery disease.
Mirtschink, P, Jang, C, Arany, Z, Krek, W
European heart journal. 2018;(26):2497-2505
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Abstract
Despite strong indications that increased consumption of added sugars correlates with greater risks of developing cardiometabolic syndrome (CMS) and cardiovascular disease (CVD), independent of the caloric intake, the worldwide sugar consumption remains high. In considering the negative health impact of overconsumption of dietary sugars, increased attention is recently being given to the role of the fructose component of high-sugar foods in driving CMS. The primary organs capable of metabolizing fructose include liver, small intestine, and kidneys. In these organs, fructose metabolism is initiated by ketohexokinase (KHK) isoform C of the central fructose-metabolizing enzyme KHK. Emerging data suggest that this tissue restriction of fructose metabolism can be rescinded in oxygen-deprived environments. In this review, we highlight recent progress in understanding how fructose metabolism contributes to the development of major systemic pathologies that cooperatively promote CMS and CVD, reference recent insights into microenvironmental control of fructose metabolism under stress conditions and discuss how this understanding is shaping preventive actions and therapeutic approaches.
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[Is Oxygen Deficiency Always Harmful?].
Schläpfer, M
Praxis. 2018;(21):1155-1159
Abstract
Is Oxygen Deficiency Always Harmful? Abstract. The role of the cardiovascular circulation is to supply tissue with oxygen and nutrients. Oxygen deficiency (hypoxia) is considered life-threatening, since cells die, either through apoptotic or necrotic processes. Tissue tries to counteract this by means of evolutionary signalling pathways, such as the nuclear hypoxia-inducible factor, which protects the tissue by promoting cell survival strategies and simultaneously intervening in angiogenesis, haematogenesis and metabolic processes. Recent findings indicate that these conserved signalling pathways can also function as therapeutic approaches in wound healing of bones and skin, as well as in the regeneration of tissues, e.g. in the liver, and in the hematopoietic system.
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Nitrite mediated vasorelaxation in human chorionic plate vessels is enhanced by hypoxia and dependent on the NO-sGC-cGMP pathway.
Tropea, T, Wareing, M, Greenwood, SL, Feelisch, M, Sibley, CP, Cottrell, EC
Nitric oxide : biology and chemistry. 2018;:82-88
Abstract
Adequate perfusion of the placental vasculature is essential to meet the metabolic demands of fetal growth and development. Lacking neural control, local tissue metabolites, circulating and physical factors contribute significantly to blood flow regulation. Nitric oxide (NO) is a key regulator of fetoplacental vascular tone. Nitrite, previously considered an inert end-product of NO oxidation, has been shown to provide an important source of NO. Reduction of nitrite to NO may be particularly relevant in tissue when the oxygen-dependent NO synthase (NOS) activity is compromised, e.g. in hypoxia. The contribution of this pathway in the placenta is currently unknown. We hypothesised that nitrite vasodilates human placental blood vessels, with enhanced efficacy under hypoxia. Placentas were collected from uncomplicated pregnancies and the vasorelaxant effect of nitrite (10-6-5x10-3 M) was assessed using wire myography on isolated pre-constricted chorionic plate arteries (CPAs) and veins (CPVs) under normoxic (pO2 ∼5%) and hypoxic (pO2 ∼1%) conditions. The dependency on the NO-sGC-cGMP pathway and known nitrite reductase (NiR) activities was also investigated. Nitrite caused concentration-dependent vasorelaxation in both arteries and veins, and this effect was enhanced by hypoxia, significantly in CPVs (P < 0.01) and with a trend in CPAs (P = 0.054). Pre-incubation with NO scavengers (cPTIO and oxyhemoglobin) attenuated (P < 0.01 and P < 0.0001, respectively), and the sGC inhibitor ODQ completely abolished nitrite-mediated vasorelaxation, confirming the involvement of NO and sGC. Inhibition of potential NiR enzymes xanthine oxidoreductase, mitochondrial aldehyde dehydrogenase and mitochondrial bc1 complex did not attenuate vasorelaxation. This data suggests that nitrite may provide an important reservoir of NO bioactivity within the placenta to enhance blood flow when fetoplacental oxygenation is impaired, as occurring in pregnancy diseases such as pre-eclampsia and fetal growth restriction.
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Hypoxia imaging and radiotherapy: bridging the resolution gap.
Grimes, DR, Warren, DR, Warren, S
The British journal of radiology. 2017;(1076):20160939
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Abstract
Oxygen distribution is a major determinant of treatment success in radiotherapy, with well-oxygenated tumour regions responding by up to a factor of three relative to anoxic volumes. Conversely, tumour hypoxia is associated with treatment resistance and negative prognosis. Tumour oxygenation is highly heterogeneous and difficult to measure directly. The recent advent of functional hypoxia imaging modalities such as fluorine-18 fluoromisonidazole positron emission tomography have shown promise in non-invasively determining regions of low oxygen tension. This raises the prospect of selectively increasing dose to hypoxic subvolumes, a concept known as dose painting. Yet while this is a promising approach, oxygen-mediated radioresistance is inherently a multiscale problem, and there are still a number of substantial challenges that must be overcome if hypoxia dose painting is to be successfully implemented. Current imaging modalities are limited by the physics of such systems to have resolutions in the millimetre regime, whereas oxygen distribution varies over a micron scale, and treatment delivery is typically modulated on a centimetre scale. In this review, we examine the mechanistic basis and implications of the radiobiological oxygen effect, the factors influencing microscopic heterogeneity in tumour oxygenation and the consequent challenges in the interpretation of clinical hypoxia imaging (in particular fluorine-18 fluoromisonidazole positron emission tomography). We also discuss dose-painting approaches and outline challenges that must be addressed to improve this treatment paradigm.
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Effects of oral sodium nitrate on forearm blood flow, oxygenation and exercise performance during acute exposure to hypobaric hypoxia (4300 m).
Gasier, HG, Reinhold, AR, Loiselle, AR, Soutiere, SE, Fothergill, DM
Nitric oxide : biology and chemistry. 2017;:1-9
Abstract
A reduction in oxygen transport contributes to impaired exercise capacity at high altitude. Since blood flow is mediated, in part, by nitric oxide (NO), we hypothesized that sodium nitrate provided before forearm grip exercise performed at a simulated altitude of 4300 m (hypobaric hypoxia (HH)) would increase forearm blood flow and oxygenation, and decrease the decrement in grip performance. In a double-blind, randomized crossover study, 10 healthy subjects (9 males and 1 female) performed continuous (CGrip) and repeated rhythmic (RGrip) isometric forearm exercise until task failure in normobaric normoxia (NN), 2.5 h following consumption of placebo and sodium nitrate (15 mmol) in HH, and then again post-HH at sea-level pressure. Measurements included forearm blood flow (FBF) and anterior forearm tissue oxygenation (StO2), mean arterial blood pressure (MAP), arterial blood O2 saturation (SpO2), plasma NO reaction products (NOx) and nitrite, and exhaled NO (PENO). Compared to baseline testing in NN, performing CGrip and RGrip exercise in HH resulted in significant reductions in forearm blood flow, SaO2 and StO2, responses that were accompanied by significant performance decrements (∼10%) in both CGrip and RGrip exercise. In spite of a 10-fold increase in plasma NOx levels and a significant decrease in MAP during CGrip exercise following nitrate consumption, there were no significant main effects of treatment (placebo vs. sodium nitrate) for forearm blood flow, SpO2, StO2, or grip performance. PENO remained unchanged between NN, HH and post-HH conditions with placebo, but increased (∼24%) following nitrate supplementation in HH and post-HH. These data do not support a benefit in consuming a single dose of supplemental nitrate on forearm blood flow and isometric exercise in healthy adults at a simulated altitude of 4300 m.
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Dietary nitrate supplementation increases acute mountain sickness severity and sense of effort during hypoxic exercise.
Rossetti, GMK, Macdonald, JH, Wylie, LJ, Little, SJ, Newton, V, Wood, B, Hawkins, KA, Beddoe, R, Davies, HE, Oliver, SJ
Journal of applied physiology (Bethesda, Md. : 1985). 2017;(4):983-992
Abstract
Dietary nitrate supplementation enhances sea level performance and may ameliorate hypoxemia at high altitude. However, nitrate may exacerbate acute mountain sickness (AMS), specifically headache. This study investigated the effect of nitrate supplementation on AMS symptoms and exercise responses with 6-h hypoxia. Twenty recreationally active men [age, 22 ± 4 yr, maximal oxygen consumption (V̇o2max), 51 ± 6 ml·min-1·kg-1, means ± SD] completed this randomized double-blinded placebo-controlled crossover study. Twelve participants were classified as AMS- on the basis of Environmental Symptoms Questionnaire [Acute Cerebral Mountain Sickness score (AMS-C)] <0.7 in both trials, and five participants were classified as AMS+ on the basis of AMS-C ≥0.7 on placebo. Five days of nitrate supplementation (70-ml beetroot juice containing ~6.4 mmol nitrate daily) increased plasma NO metabolites by 182 µM compared with placebo but did not reduce AMS or improve exercise performance. After 4-h hypoxia [inspired O2 fraction ([Formula: see text]) = 0.124], nitrate increased AMS-C and headache severity (visual analog scale; whole sample ∆10 [1, 20] mm, mean difference [95% confidence interval]; P = 0.03) compared with placebo. In addition, after 5-h hypoxia, nitrate increased sense of effort during submaximal exercise (∆7 [-1, 14]; P = 0.07). In AMS-, nitrate did not alter headache or sense of effort. In contrast, in AMS+, nitrate increased headache severity (∆26 [-3, 56] mm; P = 0.07), sense of effort (∆14 [1, 28]; P = 0.04), oxygen consumption, ventilation, and mean arterial pressure during submaximal exercise. On the next day, in a separate acute hypoxic exercise test ([Formula: see text] = 0.141), nitrate did not improve time to exhaustion at 80% hypoxic V̇o2max In conclusion, dietary nitrate increases AMS and sense of effort during exercise, particularly in those who experience AMS. Dietary nitrate is therefore not recommended as an AMS prophylactic or ergogenic aid in nonacclimatized individuals at altitude.NEW & NOTEWORTHY This is the first study to identify that the popular dietary nitrate supplement (beetroot) does not reduce acute mountain sickness (AMS) or improve exercise performance during 6-h hypoxia. The consumption of nitrate in those susceptible to AMS exacerbates AMS symptoms (headache) and sense of effort and raises oxygen cost, ventilation, and blood pressure during walking exercise in 6-h hypoxia. These data question the suitability of nitrate supplementation during altitude travel in nonacclimatized people.
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Effects of caffeine on neuromuscular fatigue and performance during high-intensity cycling exercise in moderate hypoxia.
Smirmaul, BP, de Moraes, AC, Angius, L, Marcora, SM
European journal of applied physiology. 2017;(1):27-38
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Abstract
PURPOSE To investigate the effects of caffeine on performance, neuromuscular fatigue and perception of effort during high-intensity cycling exercise in moderate hypoxia. METHODS Seven adult male participants firstly underwent an incremental exercise test on a cycle ergometer in conditions of acute normobaric hypoxia (fraction inspired oxygen = 0.15) to establish peak power output (PPO). In the following two visits, they performed a time to exhaustion test (78 ± 3% PPO) in the same hypoxic conditions after caffeine ingestion (4 mg kg-1) and one after placebo ingestion in a double-blind, randomized, counterbalanced cross-over design. RESULTS Caffeine significantly improved time to exhaustion by 12%. A significant decrease in subjective fatigue was found after caffeine consumption. Perception of effort and surface electromyographic signal amplitude of the vastus lateralis were lower and heart rate was higher in the caffeine condition when compared to placebo. However, caffeine did not reduce the peripheral and central fatigue induced by high-intensity cycling exercise in moderate hypoxia. CONCLUSION The caffeine-induced improvement in time to exhaustion during high-intensity cycling exercise in moderate hypoxia seems to be mediated by a reduction in perception of effort, which occurs despite no reduction in neuromuscular fatigue.
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Living and Training at 825 m for 8 Weeks Supplemented With Intermittent Hypoxic Training at 3,000 m Improves Blood Parameters and Running Performance.
Wonnabussapawich, P, Hamlin, MJ, Lizamore, CA, Manimmanakorn, N, Leelayuwat, N, Tunkamnerdthai, O, Thuwakum, W, Manimmanakorn, A
Journal of strength and conditioning research. 2017;(12):3287-3294
Abstract
Wonnabussapawich, P, Hamlin, MJ, Lizamore, CA, Manimmanakorn, N, Leelayuwat, N, Tunkamnerdthai, O, Thuwakum, W, and Manimmanakorn, A. Living and training at 825 m for 8 weeks supplemented with intermittent hypoxic training at 3,000 m improves blood parameters and running performance. J Strength Cond Res 31(12): 3287-3294, 2017-We aimed to investigate the effect of an 8-week low-altitude training block supplemented with intermittent hypoxic training, on blood and performance parameters in soccer players. Forty university-level male soccer players were separated into altitude (n = 20, 825 m) or sea-level (n = 20, 125 m) groups. Before (1-2 days ago) and after (1 and 14 days later) training, players were asked to give a resting venous blood sample and complete a series of performance tests. Compared with sea level, the altitude group increased erythropoietin, red blood cell (RBC) count, and hematocrit 1 day after training (42.6 ± 24.0%, 1.8 ± 1.3%, 1.4 ± 1.1%, mean ± 95% confidence limits (CL), respectively). By 14 days after training, only RBC count and hemoglobin were substantially higher in the altitude compared with the sea-level group (3.2 ± 1.8%, 2.9 ± 2.1% respectively). Compared with sea level, the altitude group 1-2 days after training improved their 50-m (-2.9 ± 1.4%) and 2,800-m (-2.9 ± 4.4%) run times and demonstrated a higher maximal aerobic speed (4.7 ± 7.4%). These performance changes remained at 14 days after training with the addition of a likely higher estimated V[Combining Dot Above]O2max in the altitude compared with the sea-level group (3.2 ± 3.0%). Eight weeks of low-altitude training, supplemented with regular bouts of intermittent hypoxic training at higher altitude, produced beneficial performance improvements in team-sport athletes, which may increase the viability of such training to coaches and players that cannot access more traditional high altitude venues.
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Effects of normoxic and hypoxic exercise regimens on lymphocyte apoptosis induced by oxidative stress in sedentary males.
Wang, JS, Chen, YC, Chen, WL, Lin, CP
European journal of applied physiology. 2017;(12):2445-2455
Abstract
PURPOSE Oxidative stress-induced lymphocyte apoptosis is linked to hypoxemic individuals suffering from cardiopulmonary disorders or exposed to hypoxic environments. What kind of the exercise strategy under hypoxic condition improves exercise performance and simultaneously minimizes lymphocyte dysfunction caused by oxidative stress has not yet been established. This study elucidates how various exercises regimens with/without hypoxia affect lymphocyte apoptosis induced by oxidative stress. METHODS A total of 60 sedentary males were randomly divided into five groups. Each group (n = 12) received one of the five interventions: hypoxic-absolute exercise (HAT, 50%W max under 15%O2), hypoxic-relative exercise (HRT, 50% heart rate reserve under 15%O2), normoxic exercise (NT, 50%W max under 21%O2), hypoxic control (HC, resting under 15%O2), or normoxic control (NC, resting under 21%O2) for 30 min/day, 5 days/week for 4 weeks. RESULTS Before the intervention, the graded exercise test (GXT, progressive exercise up to VO2max) decreased the surface thiol level on lymphocytes and subsequently augmented the extents of H2O2-induced mitochondria transmembrane potential (MTP) diminishing, caspase 3/8/9 activations, and phosphotidyl serine (PS) exposure in lymphocytes. However, 4 weeks of NT, HRT, or HAT reduced the extents of surface thiol decreasing on lymphocytes and H2O2-induced MTP diminishing, caspase 3/8/9 activations, and PS exposure in lymphocytes following GXT. Moreover, the HAT group exhibited greater improvements in pulmonary ventilation and VO2max than either NT or HRT group did. CONCLUSIONS Exercise training with/without hypoxic exposure effectively alleviates lymphocyte apoptosis induced by oxidative stress following strenuous exercise. However, the HAT is superior to the NT or HRT for enhancing aerobic capacity.