Differential effects of high-altitude exposure on markers of oxidative stress, antioxidant capacity, and iron profiles.

High-altitude (HA) exposure may stimulate significant physiological and molecular changes, resulting in HA-related illnesses. HA may impact oxidative stress, antioxidant capacity, and iron homeostasis, yet it is unclear how both repeated exposure and HA acclimatization may modulate such effects. Therefore, we assessed the effects of weeklong repeated daily HA exposure (2,900-5,050 m) in altitude-naïve individuals (n = 21 individuals, 13 females, mean ± SD, 25.3 ± 3.7 yr) to mirror the working schedule of HA workers (n = 19 individuals, all males, 41.1 ± 9.4 yr) at the Atacama Large Millimeter Array (ALMA) Observatory (San Pedro de Atacama, Chile). Markers of oxidative stress, antioxidant capacity, and iron homeostasis were measured in blood plasma. Levels of protein oxidation (P < 0.001) and catalase activity (P = 0.023) increased and serum iron (P < 0.001), serum ferritin (P < 0.001), and transferrin saturation (P < 0.001) levels decreased with HA exposure in both groups. HA workers had lower levels of oxidative stress, and higher levels of antioxidant capacity, iron supply, and hemoglobin concentration as compared with altitude-naïve individuals. On a second week of daily HA exposure, changes in levels of protein oxidation, glutathione peroxidase, and nitric oxide metabolites were lower as compared with the first week in altitude-naïve individuals. These results indicate that repeated exposure to HA may significantly alter oxidative stress and iron homeostasis, and the degree of such changes may be dependent on if HA is visited naïvely or routinely. Further studies are required to fully elucidate differences in HA-induced changes in oxidative stress and iron homeostasis profiles among visitors of HA.

Effect of aerobic exercise on white matter microstructure in the aging brain.

Aging is associated with decline in white matter (WM) microstructure, decreased cognitive functioning, and increased risk of Alzheimer's disease and related dementias. Recent research has identified aerobic physical exercise as a promising intervention for increasing white matter microstructure in aging, with the aim of increasing cognitive abilities, and protecting against neurodegenerative processes. However, the degree to which white matter microstructure can be protected or improved with exercise remains incompletely understood. Here, a sub-group of 25 healthy, sedentary participants (aged 57 to 86 years; M = 67.1; SD = 7.9; 11 female, 14 male) from the larger Brain in Motion Study (Tyndall et al., 2013) underwent diffusion tensor imaging (DTI) before and after a six-month aerobic exercise intervention. DTI data were analysed with FSL's Tract-Based Spatial Statistics (TBSS) to determine whether WM microstructure improved, as defined by increased fractional anisotropy (FA) and/or decreased mean diffusivity (MD), after the aerobic exercise intervention. Neither FA nor MD of the cerebral WM were significantly correlated with either age or cardiovascular fitness at baseline. Whole-brain WM mean FA decreased over the intervention while mean MD showed no significant change. Longitudinal TBSS analyses revealed decreased FA in the left uncinate fasciculus, left anterior corona radiata, left inferior fronto-occipital fasciculus, and left anterior thalamic radiation. MD increased in the left forceps major, left inferior longitudinal fasciculus, and left superior longitudinal fasciculus. Results indicate that six months of aerobic exercise in healthy, sedentary older adults was not associated with improvements in FA or MD measures of cerebral WM microstructure.

Medication use by middle-aged and older participants of an exercise study: results from the Brain in Motion study.

BACKGROUND: Over the past 50 years, there has been an increase in the utilization of prescribed, over-the-counter (OTC) medications, and natural health products. Although it is known that medication use is common among older persons, accurate data on the patterns of use, including the quantity and type of medications consumed in a generally healthy older population from a Canadian perspective are lacking. In this study, we study the pattern of medication use in a sedentary but otherwise healthy older persons use and determined if there was an association between medication use and aerobic fitness level. METHODS: All participants enrolled in the Brain in Motion study provided the name, formulation, dosage and frequency of any medications they were consuming at the time of their baseline assessment. Maximal aerobic capacity (VO2max) was determined on each participant. RESULTS: Two hundred seventy one participants (mean age 65.9 ± 6.5 years; range 55-92; 54.6% females) were enrolled. Most were taking one or more (1+) prescribed medication (n = 204, 75.3%), 1+ natural health product (n = 221, 81.5%) and/or 1+ over-the-counter (OTC) drug (n = 174, 64.2%). The most commonly used prescribed medications were HMG-CoA reductase inhibitors (statins) (n = 52, 19.2%). The most common natural health product was vitamin D (n = 201, 74.2%). For OTC drugs, non-steroidal anti-inflammatories (n = 82, 30.3%) were the most common. Females were more likely than males to take 1+ OTC medications, as well as supplements. Those over 65 years of age were more likely to consume prescription drugs than their counterparts (p ≤ 0.05). Subjects taking more than two prescribed or OTC medications were less physically fit as determined by their VO2max. The average daily Vitamin D intake was 1896.3 IU per participant. CONCLUSIONS: Medication use was common in otherwise healthy older individuals. Consumption was higher among females and those older than 65 years. Vitamin D intake was over two-fold higher than the recommended 800 IU/day for older persons, but within the tolerable upper intake of 4,000 IU/day. The appropriateness of the high rate of medication use in this generally healthy population deserves further investigation.

Effects of exercise on markers of oxidative stress: an Ancillary analysis of the Alberta Physical Activity and Breast Cancer Prevention Trial.

BACKGROUND: Oxidative stress may contribute to cancer aetiology through several mechanisms involving damage to DNA, proteins and lipids leading to genetic mutations and genomic instability. The objective of this study was to determine the effects of aerobic exercise on markers of oxidative damage and antioxidant enzymes in postmenopausal women. METHODS: The Alberta Physical Activity and Breast Cancer Prevention Trial (ALPHA) was a two-centre, two-armed randomised trial of 320 inactive, healthy, postmenopausal women aged 50-74 years. Participants were randomly assigned to a year-long exercise intervention (225 min/week) or a control group while being asked to maintain a normal diet. Fasting blood samples were obtained and plasma concentrations of two oxidative damage markers (8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-isoprostaglandin F2α (8-Iso-PGF2α)) and two antioxidant enzymes (superoxide dismutase and catalase) were measured at baseline, 6 months and 12 months. Intention-to-treat (ITT) and per-protocol analyses were performed using linear mixed models adjusted for baseline biomarker concentrations. A further exercise adherence analysis, based on mean minutes of exercise per week, was also performed. RESULTS: In the ITT and per-protocol analyses, the exercise intervention did not have any statistically significant effect on either oxidative damage biomarkers or antioxidant enzyme activity. CONCLUSIONS: A year-long aerobic exercise intervention did not have a significant impact on oxidative stress in healthy, postmenopausal women. TRIAL REGISTRATION NUMBER: NCT00522262.

Human intermittent hypoxia-induced respiratory plasticity is not caused by inflammation.

Ventilatory instability, reflected by enhanced acute hypoxic (AHVR) and hypercapnic (AHCVR) ventilatory responses is a fundamental component of obstructive sleep apnoea (OSA) pathogenesis. Intermittent hypoxia-induced inflammation is postulated to promote AHVR enhancement in OSA, although the role of inflammation in intermittent hypoxia-induced respiratory changes in humans has not been examined. Thus, this study assessed the role of inflammation in intermittent hypoxia-induced respiratory plasticity in healthy humans.In a double-blind, placebo-controlled, randomised crossover study design, 12 males were exposed to 6 h of intermittent hypoxia on three occasions. Prior to intermittent hypoxia exposures, participants ingested (for 4  days) either placebo or the nonsteroidal anti-inflammatory drugs indomethacin (nonselective cyclooxygenase (COX) inhibitor) and celecoxib (selective COX-2 inhibitor). Pre- and post-intermittent hypoxia resting ventilation, AHVR, AHCVR and serum concentration of the pro-inflammatory cytokine tumour necrosis factor (TNF)-α were assessed.Pre-intermittent hypoxia resting ventilation, AHVR, AHCVR and TNF-α concentrations were similar across all three conditions (p≥0.093). Intermittent hypoxia increased resting ventilation and the AHVR similarly across all conditions (p=0.827), while the AHCVR was increased (p=0.003) and TNF-α was decreased (p=0.006) with only selective COX-2 inhibition.These findings indicate that inflammation does not contribute to human intermittent hypoxia-induced respiratory plasticity. Moreover, selective COX-2 inhibition augmented the AHCVR following intermittent hypoxia exposure, suggesting that selective COX-2 inhibition could exacerbate OSA severity by increasing ventilatory instability.

Relationship between oxidative stress and HIF-1 alpha mRNA during sustained hypoxia in humans.

The aim of this study was to investigate the relations among reactive oxygen species (ROS), hypoxia inducible factor (HIF-1 alpha) gene expression, HIF-1 alpha target gene erythropoietin (EPO), and vascular endothelium growth factor (VEGF) in humans. Five healthy men (32+/-7 years, mean+/-SD) were exposed to 12 h of sustained poikilocapnic hypoxia (P(ET)O(2)=60 mmHg). DNA oxidation (8-hydroxy-2'-deoxyguanosine, 8-OHdG), advanced oxidation protein products (AOPP), EPO, and VEGF were measured in plasma and HIF-1 alpha mRNA was assessed in leukocytes before and after 1, 2, 4, 6, 8, 10, and 12 h of exposure to hypoxia. HIF-1 alpha mRNA amount increased during the first two hours of hypoxic exposure and then returned to baseline levels. The findings reveal an up-regulation of HIF-1 alpha (+68%), VEGF (+46%), and EPO (+74%). AOPP increased continuously from 4 h (+69%) to 12 h (+216%) of hypoxic exposure while 8-OHdG increased after 6 h (+78%) and remained elevated until 12 h. During the "acute" increase phase of HIF-1 alpha (between 0 and 2 h), 8-OHdG was positively correlated with HIF-1 alpha (r=0.55). These findings suggest that hypoxia induces oxidative stress via an overgeneration of reactive oxygen species (ROS). Finally, this study in humans corroborates the previous in vitro findings demonstrating that ROS is involved in HIF-1 alpha transcription.

Effects of ovarian hormones and aging on respiratory sinus arrhythmia and breathing patterns in women.

We investigated the effect of ovarian hormones and aging on breathing pattern [pulmonary minute ventilation (V(E))], tidal volume (V(T)), breathing frequency (F(b)), and respiratory sinus arrhythmia (RSA) in women. Recordings of V(E) and electrocardiogram (ECG) were obtained from 23 healthy women (10 premenopausal, 13 postmenopausal) under resting, isocapnic hypoxia (IH), and euoxic hypercapnia (EH) conditions. Premenopausal women were tested on three different days, each day corresponding to a specific phase of the menstrual cycle (follicular, mid-cycle, and luteal); postmenopausal women (PMW) were tested on 1 day only. On each test day, subjects were challenged with IH and EH. The order of the two tests was randomized and separated by at least 1 hour. Due to the low F (b) of several PMW, the band limits for RSA analysis had to be adjusted. The spectral coherence between respiratory flow and ECG RR-interval was used to determine the spectral band. Within the spectral band, there was a consistent phase relationship between the two variables where high values of spectral coherence indicate a well-defined phase relationship between respiratory flow and RR-interval variability. The main findings in this study for RSA are fourfold. First, RSA did not change with different levels of ovarian hormones (progesterone, serum 17beta-estradiol) during the menstrual cycle. Second, RSA was not influenced by hormone replacement therapy. Third, RSA did not change with age. Fourth, RSA did not change with IH and EH-induced changes in breathing patterns. Finally, high individual variability of average RR-interval change per breath was found.

Differential responses of circulating amylin to high-fat vs. high-carbohydrate meal in healthy men.

OBJECTIVE: The success of an amylin analogue in weight loss trials has generated interest in amylin as a physiological satiety signal. Little is known about how plasma amylin responds to macronutrients. This study examined the effects of a high-carbohydrate meal (CHO), a high-fat meal (FAT) or a continued fast (FAST) on amylin concentrations and correlations among other satiety hormones and measures of appetite. DESIGN/PATIENTS: In a randomized, crossover design, 10 healthy males consumed a meal high in carbohydrate or fat or continued fasted. MEASUREMENTS: Blood samples and subjective hunger scores were obtained at baseline and 30, 90 and 210 min postprandial. RESULTS: After CHO, amylin, insulin and C-peptide were greater and des-acyl ghrelin lower compared to FAT (P < 0.001). Area under the curve (AUC) was greater for amylin and insulin and lower for des-acyl ghrelin following CHO. Subjective satiety and fullness were higher for CHO and FAT than FAST at 30 and 90 min but only for CHO at 210 min (P < 0.01). Hunger and desire to eat were lower for CHO and FAT than FAST at 30 and 90 min but only for CHO at 210 min (P < 0.005). Amylin was negatively correlated to hunger, desire to eat, and nausea and positively related to satiety and insulin. Des-acyl ghrelin was negatively associated with C-peptide, insulin and GLP-1 and satiety. CONCLUSIONS: CHO enhances amylin and suppresses des-acyl ghrelin to a greater extent than FAT in healthy men. The mechanisms responsible for these changes and their implications in the physiology of satiety remain to be elucidated.

Cerebrovascular responses to altitude.

The regulation of cerebral blood flow (CBF) is a complex process that is altered significantly with altitude exposure. Acute exposure produces a marked increase in CBF, in proportion to the severity of the hypoxia and mitigated by hyperventilation-induced hypocapnia when CO(2) is uncontrolled. A number of mediators contribute to the hypoxia-induced cerebral vasodilation, including adenosine, potassium channels, substance P, prostaglandins, and NO. Upon acclimatization to altitude, CBF returns towards normal sea-level values in subsequent days and weeks, mediated by a progressive increase in PO2, first through hyperventilation followed by erythropoiesis. With long-term altitude exposure, a number of mechanisms play a role in regulating CBF, including acid-base balance, hematological modifications, and angiogenesis. Finally, several cerebrovascular disorders are associated with altitude exposure. Existing gaps in our knowledge of CBF and altitude, and areas of future investigation include effects of longer exposures, intermittent hypoxia, and gender differences in the CBF responses to altitude.

Dietary and metabolic differences in pre- versus postmenopausal women taking or not taking hormone replacement therapy.

While hormonal fluctuations during the menstrual cycle are known to affect energy intake, changes in dietary intake at menopause and specifically with hormone replacement therapy (HRT) are less well understood. Our objective was to assess dietary macro- and micronutrient intakes in premenopausal women (PEMW) in the luteal and follicular phases and postmenopausal women (PSMW) taking or not taking HRT. Serum estradiol and progesterone as well as resting energy expenditure (REE) and respiratory exchange ratio (RER) were measured. In the 9 PEMW, daily energy intake was 19% higher during the luteal versus follicular phase (2089+/-178 vs. 1752+/-158 kcal/day, p<0.05). The luteal phase was characterized by higher intake of total and saturated fat and a lower micronutrient density. In the 7 PSMW not taking HRT and 6 women taking HRT, there was no significant difference in total energy or macronutrient intake. Neither PEMW nor PSMW met national nutritional recommendations for folate, vitamin D, vitamin E and calcium. Serum progesterone levels were positively correlated with protein intake and negatively correlated with percent carbohydrate in the diet. REE was lower (p<0.05) in PSMW not taking HRT, but not in those taking HRT compared to young women. We confirm increased energy intake in the luteal phase in PEMW but found no difference in energy intake between PSMW taking or not taking HRT. While the quality of the diet in PSMW women was closer to national nutritional recommendations, several at risk nutrients that have been linked to health and disease were found in both groups.