Remembering the World War II Role of the Harvard Fatigue Laboratory

Edgar Folk (2010), the only living member of that laboratory, published an illustrated and interesting account and short bibliography of his and his colleagues' work there. The laboratory was created by biochemist Lawrence J. Henderson and physiologist David Bruce Dill in 1927. It was given the name "Fatigue Laboratory" because one of its missions was to work with industry to explain the physiology of fatigue. The Fatigue Laboratory was one of the first exercise laboratories in the United States and became the leading center in the United States devoted to research on exercise physiology. Many of its large-scale projects consisted of studying the effects of heat and cold on individuals. During the building of the Hoover Dam, workers in the extreme desert heat were succumbing to heat exhaustion and heatstroke, and there had been 13 deaths. Bruce Dill and John Talbott went to Nevada to make physiological and biochemical studies on themselves and healthy work crew volunteers in the heat. The war contributions of the Harvard Fatigue Laboratory in Cambridge, MA, were recorded in 169 Technical Reports, most of which were sent to the Office of the Quartermaster General. Earlier reports were sent to the National Research Council and the Office of Scientific Research and Development. Many of the reports from 1941 and later dealt with either physical fitness of soldiers or the energetic cost of military tasks in extreme heat and cold. New military emergency rations to be manufactured in large quantities were analyzed in the Fatigue Laboratory and then tested in the field. Newly designed cold weather clothing was tested in the cold chamber at −40°, and desired improvements were made and tested in the field by staff and soldiers in tents and sleeping bags. Electrically heated clothing was designed for high-altitude flight crews and tested both in laboratory chambers and field tests before being issued.

Genetic Variations in Tibetan and Andean Populations

Bigham et al. (2010) identified genes showing evidence of adaptation to hypoxia. Applying four population genetic statistics commonly used for detecting signatures of natural selection, they report that Tibetan and Andean patterns of genetic adaptation are largely distinct from one another and from low altitude controls, with both populations showing evidence of positive natural selection in different genes or gene regions. EGLN-1, related to oxygen sensing, shows evidence of positive selection in both Tibetans and Andeans with differences between the two populations. The authors suggest that several key HIF-regulatory and targeted genes are responsible for adaptation to high altitude in Andeans and Tibetans, and several different chromosomal regions are implicated in the putative response to selection.

Similar reports by Peng et al. (2010) and Xu et al. (2010) identified strong signals of selective sweep in two HIF-1α-related genes, EPAS-1 as well as in EGLN-1.

Scheinfeldt and Tishkoff (2010) conclude that these genome-wide scans demonstrate that genetic variants associated with high-altitude adaptation in Tibetans and Andeans arose independently as a result of convergent adaptation.

Since normal human responses to altitude are highly variable, it is probable that natural selection occurs by failure of some migrants to adapt to altitude living due to inherent genetic variations related to HIF, resulting in relocating to lower altitude, rather than implying a rapid genetic adaptation to life at high altitude.

Changes in Cardiac Mass, Function, and Energy Metabolism After 17 Days at Everest Base Camp

As part of the Caudwell Xtreme Everest Research Group, Holloway et al. (2010) studied 14 healthy volunteers immediately before and within 4 days of return from a 17-day trek to Mt. Everest Base Camp (5300 m). Total body weight fell by 3% while left ventricular mass decreased by 11%. Peak left ventricular filling rates and mitral inflow E/A fell 17% and 24% respectively. Cardiac PCr/ATP ratio by ³¹P magnetic resonance spectroscopy decreased by 18% supporting the authors' postulate of impaired cardiac high-energy metabolism. All returned to pre-trek levels after 6 months. These are similar to findings in patients with chronic hypoxia.

Intracranial Pressure Measurement by Ophthalmodynamometry on Everest

A recent development in non-invasive techniques to predict intracranial pressure (ICP) termed venous ophthalmodynamometry (vODM) has made measurements in absolute units possible (Querfurth et al., 2010). The vODM was calibrated against actual ICP in 12 neurosurgical patients while monitored by ventriculostomy/pressure transducers. Measurements were made in 42 trekkers and climbers scaling Mt. Everest. Mean ICP was estimated at several altitudes on the ascent. Estimated ICP increased normally with altitude from 10 ± 3 mm Hg at sea level to 20 ± 2 mm Hg at 6553 m. Acute mountain sickness symptoms did not correlate with raised ICP.

Ibuprofen and Acetazolamide Equally Reduce Headache in Acute Mountain Sickness

Gertsch et al. (2010) report a prospective, double-blind, randomized, placebo-controlled trial in the Nepal Himalaya comparing the effectiveness of ibuprofen and acetazolamide for the prevention of headache. Healthy western trekkers were recruited at altitudes of 4280 m and 4358 m and assigned to receive ibuprofen 600 mg, acetazolamide 85 mg, or placebo 3 times daily before continued ascent to 4928 m. In 265 subjects, headache incidence was similar when treated with acetazolamide (27.1%) or ibuprofen (27.5%), compared with placebo (45.3%). Acute mountain sickness incidence was similar when treated with acetazolamide (18.8%) or ibuprofen (13.7%) vs placebo (28.6%).

Beta Blockers May Lower SpO₂ at Altitude

Acute altitude exposure is known to increase systolic blood pressure in normals. To investigate the role of adrenergic response to hypoxia, healthy normotensive volunteers were treated with a beta-blocker (carvedilol) for two weeks at sea level and then exposed to 4559 m altitude. Twenty-four hour systolic blood pressure (BP) increased in all 24 participants, mainly due to increased night-time BP, but was lower (116 torr) than with placebo (126 torr). On the second-to-third day of altitude exposure, Bilo et al. (2010) observed a higher side effect score and an unexpected reduction of SpO₂ from 86% with placebo to 81% on drug (p = 0.04).

Free Radical Effect on Nitric Oxide in Altitude Pulmonary Hypertension

Bailey et al (2010) report that increased pulmonary arterial systolic pressure (PASP) at altitude is associated with a free radical-mediated reduction in pulmonary nitric oxide (NO) bioavailability. Twenty-six mountaineers provided central venous and radial arterial samples at low altitude (LA) and following active ascent to 4559 m. Electron paramagnetic resonance spectroscopy, ozone-based chemiluminescence, and ELISA were employed for plasma detection of the ascorbate free radical A*^-, NO metabolites, and 3-nitrotyrosine (3-NT). Fourteen subjects were diagnosed with acute mountain sickness and three of four high altitude pulmonary edema (HAPE)-susceptible subjects developed HAPE. Ascent decreased the arterio-central venous concentration difference (a-cv)D resulting in a net transpulmonary loss of ascorbate, alpha-tocopherol, and bioactive NO metabolites. This was accompanied by an increased (a-cv)D and net output of A*^- and lipid hydroperoxides that correlated against the rise in PASP and arterial 3-NT that was more pronounced in HAPE.

Exhaled Nitric Oxide Falls with Time at Altitude Even in Well-Acclimatized Miners

Eighty-one healthy gold miners, working for years at altitudes of 3800–4000 m, were studied during low altitude breaks and at altitude on day 1, day 3 and at the end of the 2- or 3-week shifts. When compared to the first day at altitude, exhaled nitric oxide (NO) was reduced by 17% on day 3 and 30% by the end of the shift. This gradual reduction in exhaled NO was unexpected in subjects with no signs of maladaptation (Vinnikov et al., 2010).

Effects of Preventing Normoxic Exercise Hypocapnia

Olin et al. (2010) find that maintaining isocapnia during strenuous exercise increases middle cerebral arterial blood flow velocity (CBFv) but decreases peak work capacity. Ten cyclists performed two incremental exercise tests, one as control and one with isocapnia (P_ETCO₂ 40 mmHg vs. 30 mmHg). In isocapnia, CBFv was 26% higher, cerebral oxygenation (transcranial infrared spectroscopy) was unchanged, and peak work capacity was 6% lower, rejecting the hypothesis that hypocapnia limits work capacity.

Hypoxia and Hypohydration Additively Degrade Time Trial Performance

To assess the roles of combining hypoxia and hydration on performance, 7 lowlander men completed 4 separate experimental trials. At both sea level and altitude (3048 m, chamber), subjects were either normally hydrated or were dehydrated by 4% of body mass. After 30 min of submaximal exercise they performed a 30 min performance time-trial (TT). At sea level, dehydration reduced TT by 19%. Altitude alone reduced TT 11%, and combined with dehydration, 34%. Hypohydration at 3048 m did not appear to increase the prevalence/severity of acute mountain sickness symptoms (Castellani et al., 2010).

Role of Pro-inflammatory Cytokine Interleukin 1β in Maintaining Andean Altitude Fetal Growth

The balance between pro- and anti-inflammatory cytokines is important for successful pregnancy. Chronic high altitude (HA) hypoxia alters cytokine levels and increases the frequency of fetal growth restriction (FGR) especially in European newcomers (EU). Multigenerational Andeans (AN) are protected from altitude-associated FGR. To address whether ancestry group differences in cytokine levels were involved, Davila et al. (2010) conducted serial studies in 56 low altitude (29 AN and 27 EU) and in 42 HA (19 AN and 23 EU) residents (3600–4100 m). Pregnancy raised both pro- and anti-inflammatory cytokines, IL-1β, and IL-10. There were no ancestry group differences in cytokine levels at any time. HA reduced IL-1β in EU but not in AN, until near term. Higher IL-1β levels correlated with uterine artery blood flow at 20 weeks in AN at HA, suggesting that IL-1β may play a role in AN protection from altitude-associated reductions in fetal growth.

Ovine Gestation at High Altitude Results in Neonatal Pulmonary Hypertension Persisting at Sea Level

Herrera et al. (2010) show that postnatal pulmonary hypertension induced by spending 70% of pregnancy at high altitude promotes cardiopulmonary remodeling that persists at sea level. Pregnant ewes were kept at 3600 m from 30% of gestation until delivery and then brought with lambs back to low altitude. Compared with low altitude controls, the lambs had higher basal pulmonary arterial pressure (PAP) and a greater increment in PAP after L-NAME. Small pulmonary arteries had a greater maximal contraction to K⁺, higher sensitivity to endothelin-1 and nitroprusside, higher right heart mass ratio, greater muscle area, and greater protein expression of eNOS, PDE5, and calcium-activated potassium channels.

Leukocyte Oxygen Consumption Falls After 24 Hours at 4559 m Altitude

Faoro et al. (2010) report that leukocytic O₂ consumption was decreased about 70% in blood sampled from 15 normal volunteers 24 h after climbing to high altitude (4559 m), and was only slightly further decreased by acute in-vitro hypoxia. Before the climb, acute in-vitro hypoxia (20 torr) decreases leukocyte metabolic activity about 40%. Leukocyte normoxic O₂ consumption was not affected by 24 h of 20 torr hypoxia in-vitro. mRNA expression of COX-1 and COX-2 in leukocytes was increased at high altitude but not by in-vitro hypoxia. Whether this effect was caused by the exercise during ascent or systemic effects of hypoxia at high altitude remains unknown.

Chronic Hypoxia Increases Insulin-Stimulated Glucose Uptake in Mouse Soleus Muscle

Humans living at high altitude generally have lower blood glucose levels and decreased incidence of diabetes. Since skeletal muscle is by far the largest glucose sink in mammals, Gamboa, Garcia-Cazarin and Andrade (2010) show that 4 weeks of chronic normobaric 10% hypoxia in adult male mice increases insulin-stimulated glucose uptake in soleus muscles 30%, lowers blood glucose 30%, lowers plasma insulin 40%, and increases insulin sensitivity 80%. AKT phosphorylation following insulin stimulation in soleus muscle was 25% increased. The authors conclude that the adaptation of skeletal muscles to chronic hypoxia includes increased insulin-stimulated glucose uptake.

Altitude Effects the Hormonal Response to Hypothalamic Factors

Richalet, Letournel and Souberbielle (2010) investigated whether hypophyseal hormones show a hypoxia-induced decrease in their response to hypothalamic factors. In eight men after 3–4 days at 4350 m altitude, basal levels of thyroid hormones were elevated 16–21%, while TSH levels were unchanged. Basal FSH and prolactin decreased while LH was unchanged. Norepinephrine and cortisol were elevated while no change was observed in epinephrine, dopamine, GH, IGF-1, and IGF-BP3. The response of prolactin was inversely related to the changes in plasma dopamine. The authors conclude that prolonged exposure to altitude hypoxia induces contrasted changes in hormonal levels, but the hypophyseal response to hypothalamic factors does not appear to be blunted.

High Altitude Resident College Students Show Impaired Memory Center Responses by Functional Magnetic Resonance Imaging

Yan et al. (2010) compared regional blood flow responses in the verbal working memory areas of 28 high altitude residents and 30 sea level residents using blood level oxygen dependent (BOLD) functional magnetic resonance imaging (fMRI). All of the subjects were healthy college students, matched for age, gender ratio, socioeconomic status, and hemoglobin level. All studies were done in the same laboratory in the location where the students lived during school terms. The high altitude subjects showed longer reaction time and decreased response accuracy in behavioral performance. With group comparison statistics, the high altitude subjects showed decreased activation at the inferior and middle frontal gyrus, the middle occipital and the lingual gyrus, the pyramids of vermis, as well as the thalamus.

Adaptation to Intermittent Hypoxia Protects Rats Against Experimental Alzheimer's Disease

Goryacheva et al. (2010) report that adaptation to intermittent hypoxia (AIH) can prevent overproduction of nitric oxide (NO) in brain and neurodegeneration induced by β-amyloid (Aβ). AIH was induced by simulated altitude of 4000 m, 14 days, 4 h daily. AIH significantly alleviated memory impairment of rats after Aβ injection. Histological examination confirmed the protective effect of AIH. Degenerating neurons, which were numerous in the cortex of Aβ-injected, unadapted rats, were essentially absent in the brain of hypoxia-adapted rats. Injections of Aβ resulted in significant increases in NOx and in expression of all NOS isoforms in brain; AIH blunted these increases. NO overproduction was associated with increased amounts of 3-nitrotyrosine in the cortex and hippocampus. AIH alone did not significantly influence tissue 3-nitrotyrosine, but significantly restricted its increase after the Aβ injection. The authors conclude that AIH affords significant protection against experimental Alzheimer's disease, and this protection correlates with restricted NO overproduction.

Brain Tissue PO₂ Measurement in Awake Unrestrained Rats

Ortiz-Prado et al. (2010) present a novel fiber optic method to measure absolute brain P_tO₂ in unanesthetized, unrestrained animals. A sensor was chronically implanted in the frontal cortex of eight Wistar rats. It contained a crystal on the end of a fiber optic probe that, after a light pulse, fluoresces with an oxygen tension dependent lifetime. Mean P_tO₂ within the cortex was 24–30 torr. After 28 days of hypoxic acclimatization to 375 torr air pressure, P_tO₂ breathing ambient air (Calgary P_IO₂ = 139 torr) was 39 torr, approximately 30% higher than before acclimatization. Acute chamber administration of 8% O₂ reduced P_tO₂ by 80% and 76% pre- and post-acclimatization. P_tO₂ was a nearly linear function of inspired PO₂. These cortical P_tO₂ values are higher than most prior published values that range from 12 – 22 torr with P_IO₂ ≈ 150 torr.