Hemoglobin and cerebral hypoxic vasodilation in humans:Evidence for nitric oxide-dependent and S-nitrosothiol mediated signal transduction

Cerebral hypoxic vasodilation is poorly understood in humans, which undermines the development of therapeutics to optimize cerebral oxygen delivery. Across four investigations (total n = 195) we investigated the role of nitric oxide (NO) and hemoglobin-based S-nitrosothiol (RSNO) and nitrite ((Formula presented.)) signaling in the regulation of cerebral hypoxic vasodilation. We conducted hemodilution (n = 10) and NO synthase inhibition experiments (n = 11) as well as hemoglobin oxygen desaturation protocols, wherein we measured cerebral blood flow (CBF), intra-arterial blood pressure, and in subsets of participants trans-cerebral release/uptake of RSNO and (Formula presented.). Higher CBF during hypoxia was associated with greater trans-cerebral RSNO release but not (Formula presented.), while NO synthase inhibition reduced cerebral hypoxic vasodilation. Hemodilution increased the magnitude of cerebral hypoxic vasodilation following acute hemodilution, while in 134 participants tested under normal conditions, hypoxic cerebral vasodilation was inversely correlated to arterial hemoglobin concentration. These studies were replicated in a sample of polycythemic high-altitude native Andeans suffering from excessive erythrocytosis (n = 40), where cerebral hypoxic vasodilation was inversely correlated to hemoglobin concentration, and improved with hemodilution (n = 6). Collectively, our data indicate that cerebral hypoxic vasodilation is partially NO-dependent, associated with trans-cerebral RSNO release, and place hemoglobin-based NO signaling as a central mechanism of cerebral hypoxic vasodilation in humans.</p

Acute reductions in hematocrit increase flow-mediated dilation independent ofresting nitric oxide bioavailability in humans

Hemoglobin (Hb) may impact the transduction of endothelium‐dependent and nitric oxide (NO) mediated vasodilator activity, given its contribution to shear stress stimuli and diverse biochemical reactions with NO. We hypothesized that an acute reduction in [Hb] and hematocrit (Hct) would increase brachial artery flow‐mediated dilation (FMD). In eleven healthy males (28 ± 7 years; 23 ± 2 kg m−2), FMD (Duplex ultrasound), arterial blood gases, Hct and [Hb], blood viscosity, and NO metabolites (ozone‐based chemiluminescence) were measured before and after isovolumic hemodilution, where ∼20% of whole blood was removed and replaced with 5% human serum albumin. Hemodilution reduced Hct by 18 ± 2% (P < 0.001) and whole blood viscosity by 22 ± 5% (P < 0.001). Plasma nitrite (P = 0.01), S‐nitrosothiols (P = 0.03), and total red blood cell NO (P = 0.001) were collectively reduced by ∼15–40%. Brachial artery FMD increased by ∼160% from 3.8 ± 2.1 to 9.7 ± 4.5% (P = 0.004). Statistical covariation for the shear stress stimulus did not alter FMD, indicating that the increase in FMD was not directly related to alterations in whole blood viscosity and the shear stimulus. Collectively, these findings indicate that hemoglobin scavenging of NO appears to be an important factor in the regulation of FMD under normal conditions through constraint of endothelium‐dependent NO‐mediated vasodilation in healthy humans

Global REACH 2018: The influence of acute and chronic hypoxia on cerebral haemodynamics and related functional outcomes during cold and heat stress

Real-world settings are composed of multiple environmental stressors, yet the majority of research in environmental physiology investigates these stressors in isolation. The brain is central in both behavioural and physiological responses to threatening stimuli and, given its tight metabolic and haemodynamic requirements, is particularly susceptible to environmental stress. We measured cerebral blood flow (CBF, duplex ultrasound), cerebral oxygen delivery (CDO2), oesophageal temperature, and arterial blood gases during exposure to three commonly experienced environmental stressors –heat, cold and hypoxia –in isolation, and in combination. Twelve healthy male subjects (27±11 years) underwent core cooling by 1.0ºC and core heating by 1.5ºC in randomized order at sea-level; acute hypoxia (PetO2= 50mmHg) was imposed at baseline and at each thermal extreme. Core cooling and heating protocols were repeated after 16±4 days residing at 4330m to investigate any interactions with high altitude acclimatization. Cold stress decreased CBF by 20–30% and CDO2 by 12–19%(both p0.08). The increases in CBF with acute hypoxia during thermal stress were appropriate to maintain CDO2 at normothermic, normoxic values. Reaction time was faster and slower by 6-9%with heating and cooling, respectively(both p<0.01), but central (brain) processes were not impaired by any combination of environmental stressors. These findings highlight the powerful influence of core cooling in reducing CDO2. Despite these large reductions in CDO2 with cold stress, gross indices of cognition remained stable

The 2018 Global Research Expedition on Altitude-related Chronic Health (REACH) to Cerro de Pasco, Peru: An Experimental Overview

In 2016, the international research team - Global Research Expedition onAltitude-related Chronic Health (REACH) - was established and executed a high altituderesearch expedition to Nepal. The team consists of ~45 students, principal investigatorsand physicians with the common objective of conducting experiments focused on highaltitude adaptation in lowlanders, and highlanders with lifelong exposure to high altitude.In 2018, Global REACH traveled to Peru where we performed a series of experiments inthe Andean highlanders. The experimental objectives, organization and characteristics,and key cohort data from Global REACH's latest research expedition are outlined herein.Herein, fifteen major studies are described that aimed to elucidate the physiologicaldifferences in high altitude acclimatization between lowlanders (n=30) and Andean bornhighlanders with (n=22) and without (n=45) Excessive Erythrocytosis (EE). Afterbaseline testing in Kelowna, BC, Canada (344m), Global REACH travelled to Lima, Peru(~80 m), and then ascended by automobile to Cerro de Pasco, Peru (~4300m) whereexperiments were conducted over 25 days. The core studies focused on elucidating themechanism(s) governing cerebral and peripheral vascular function, cardiopulmonaryregulation, exercise performance, and autonomic control. Despite encountering seriouslogistical challenges, each of the proposed studies were completed at both sea level andhigh altitude amounting to ~780 study sessions and >3000 hrs of experimental testing.Participant demographics and data related to acid-base balance and exercise capacityare presented. The collective findings will contribute to our understanding of howlowlanders and Andean highlanders have adapted under high altitude stress

Information discernment, mis-information and pro-active scepticism

A participatory action research approach was employed to investigate school students’ information discernment capabilities. Placing school student participants at the centre of the research process enabled them to define the problem in their own words and begin to find solutions to the issue of how to choose good quality information. Findings confirmed the results of many studies - that school students adopt a cognitive default position of trust and are relatively unquestioning when using information sources for their work (in this case the Extended Project Qualification or EPQ). Results also showed that with an appropriate embedded learning and teaching intervention, which includes aspects of information and digital literacy, school students adopt a cognitive questioning state, which leads to pro-active scepticism, enhancing their information discernment and in turn enables them to make better information choices. This has implications not only for school teachers and librarians but for educational policy makers also

Mechanisms and applications of acute heat stress on vascular function

Passive heat stress shows promise as an effective strategy to reduce the risk of cardiovascular diseases (CVD) as an alternative or adjunct to exercise and/or medication. Improving function of the endothelium is one of the key targets underlying the reduction in CVD risk. Therefore, this thesis aimed to evaluate potential mechanisms of acute heat-related improvement of endothelial function and investigate the effectiveness of heat in selected clinical groups. Endothelial function was measured via the technique of flow-mediated dilation (FMD) and shear stress was estimated using duplex Doppler ultrasound imaging of large arteries. In study #1, we compared forearm vs. whole-body heating in in 12 young, healthy individuals. In addition to elevated shear stress, skin and core temperatures independently increased endothelial function. In study #2, we compared peripheral and cerebrovascular responses to whole-body heating with oral ingestion of an α-1 adrenergic antagonist (Prazosin) or placebo. Although α-1 adrenergic antagonism did not influence hyperthermia-induced reductions in cerebral blood flow or affect post-heating FMD, preliminary trends indicate a potential impact of sympathetic nervous system activity on FMD in the brachial artery. In order to test the effectiveness of passive heating in extremely sedentary individuals in study #3, we measured FMD in 15 participants with cervical spinal cord injuries (SCI) and 15 uninjured controls before and after acute leg heating. There was no change in either brachial or superficial femoral artery FMD in SCI or controls; however, systemically circulating microparticles reflective of endothelial activation were reduced by ~60% after heating in SCI but not controls These reductions in endothelial microparticles were associated with improved shear patterns. Study #4 demonstrated that FMD was not different between older adults who are habitually exposed to passive heat stress (via regular sauna use) compared to those who are not. Furthermore, an exploratory analysis suggested there was no difference in FMD in sauna users compared to non-users with coronary artery disease; these data help direct towards other mechanisms as factors underlying lower CVD risk with sauna use. Collectively, the findings within this thesis highlight thermal and hemodynamic responses to heating that acutely influence endothelial function in health and disease. These findings have implications on the design of future studies that will contribute to reducing CVD risk with aging and various disease states.Health and Social Development, Faculty of (Okanagan)Health and Exercise Sciences, School of (Okanagan)Graduat

Unsung heroes: exploring the roles of school-based professional experience coordinators in Australian preservice teacher education

The literature on practicum in preservice teacher education provides varied and detailed accounts of the roles of the student teacher, the supervising teacher, and the university-based teacher educator. However, the school-based professional experience coordinator, usually the principal or deputy principal, has been dismissed as an administrative outsider to the essential triad of supervision. Feedback from the field suggested that the coordinator's role may in fact be crucial in ensuring that practicum is an occasion for quality learning. This paper reports on a study to explore ways in which a small selection of professional experience coordinators contribute to the establishment, support and appraisal of high quality practicum experience in a variety of settings. The research fills a gap in the existing literature on the practicum by providing some illumination of the varied ways the school-based coordinator role is filled. In addition, the paper raises questions about selection and support of coordinators, about ownership of the practicum, and argues for a reconceptualisation of the practicum as the site where all shareholders engage in the partnership, with continual opportunities for construction, reconstruction and renewal of the teaching profession