Systemic oxidative-nitrosative-inflammatory stress during acute exercise in hypoxia; implications for microvascular oxygenation and aerobic capacity

New Findings

What is the central question of this study?Exercise performance is limited during hypoxia by a critical reduction in cerebral and skeletal tissue oxygenation. To what extent an elevation in systemic free radical accumulation contributes to microvascular deoxygenation and the corresponding reduction in maximal aerobic capacity remains unknown.What is the main finding and its importance?We show that altered free radical metabolism is not a limiting factor for exercise performance in hypoxia, providing important insight into the fundamental mechanisms involved in the control of vascular oxygen transport.

Exercise performance in hypoxia may be limited by a critical reduction in cerebral and skeletal tissue oxygenation, although the underlying mechanisms remain unclear. We examined whether increased systemic free radical accumulation during hypoxia would be associated with elevated microvascular deoxygenation and reduced maximal aerobic capacity (). Eleven healthy men were randomly assigned single-blind to an incremental semi-recumbent cycling test to determine  in both normoxia (21% O_{2) and hypoxia (12% O2) separated by a week. Continuous-wave near-infrared spectroscopy was employed to monitor concentration changes in oxy- and deoxyhaemoglobin in the left vastus lateralis muscle and frontal cerebral cortex. Antecubital venous blood samples were obtained at rest and at  to determine oxidative (ascorbate radical by electron paramagnetic resonance spectroscopy), nitrosative (nitric oxide metabolites by ozone-based chemiluminescence and 3-nitrotyrosine by enzyme-linked immunosorbent assay) and inflammatory stress biomarkers (soluble intercellular/vascular cell adhesion 1 molecules by enzyme-linked immunosorbent assay). Hypoxia was associated with increased cerebral and muscle tissue deoxygenation and lower  (P < 0.05 versus normoxia). Despite an exercise-induced increase in oxidative–nitrosative–inflammatory stress, hypoxia per se did not have an additive effect (P > 0.05 versus normoxia). Consequently, we failed to observe correlations between any metabolic, haemodynamic and cardiorespiratory parameters (P > 0.05). Collectively, these findings suggest that altered free radical metabolism cannot explain the elevated microvascular deoxygenation and corresponding lower  in hypoxia. Further research is required to determine whether free radicals when present in excess do indeed contribute to the premature termination of exercise in hypoxia.}

Non-invasive ventilation for cystic fibrosis.

Non-invasive ventilation may be a means to temporarily reverse or slow the progression of respiratory failure in cystic fibrosis. To compare the effect of non-invasive ventilation versus no non-invasive ventilation in people with cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. We searched the reference lists of each trial for additional publications possibly containing other trials.Most recent search: 22 February 2013. Randomised controlled trials comparing a form of pressure preset or volume preset non-invasive ventilation to no non-invasive ventilation in people with acute or chronic respiratory failure in cystic fibrosis. Three reviewers independently assessed trials for inclusion criteria and methodological quality, and extracted data. Fifteen trials were identified; seven trials met the inclusion criteria with a total of 106 participants. Six trials evaluated single treatment sessions and one evaluated a six-week intervention.Four trials (79 participants) evaluated non-invasive ventilation for airway clearance compared with an alternative chest physiotherapy method and showed that airway clearance may be easier with non-invasive ventilation and people with cystic fibrosis may prefer it. We were unable to find any evidence that NIV increases sputum expectoration, but it did improve some lung function parameters.Three trials (27 participants) evaluated non-invasive ventilation for overnight ventilatory support, measuring lung function, validated quality of life scores and nocturnal transcutaneous carbon dioxide. Due to the small numbers of participants and statistical issues, there were discrepancies in the results between the RevMan and the original trial analyses. No clear differences were found between non-invasive ventilation compared with oxygen or room air except for exercise performance, which significantly improved with non-invasive ventilation compared to room air over six weeks. Non-invasive ventilation may be a useful adjunct to other airway clearance techniques, particularly in people with cystic fibrosis who have difficulty expectorating sputum. Non-invasive ventilation, used in addition to oxygen, may improve gas exchange during sleep to a greater extent than oxygen therapy alone in moderate to severe disease. These benefits of non-invasive ventilation have largely been demonstrated in single treatment sessions with small numbers of participants. The impact of this therapy on pulmonary exacerbations and disease progression remain unclear. There is a need for long-term randomised controlled trials which are adequately powered to determine the clinical effects of non-invasive ventilation in cystic fibrosis airway clearance and exercise.

Secondary prevention of cardiovascular disease in different primary healthcare systems with and without pay-for-performance

Objective: To compare baseline cardiovascular risk management between people recruited from two different healthcare systems, to a research trial of an intervention to optimize secondary prevention. Design: Cross-sectional study. Setting: General practices, randomly selected: 16 in Northern Ireland (NI) (UK NHS, ‘strong’ infrastructure); 32 in Republic of Ireland (RoI) (mixed healthcare economy, less infrastructure). Patients: 903 (mean age 67.5 years; 69.9% male); randomly selected, known coronary heart disease. Main outcome measures: Blood pressure, cholesterol, medications; validated questionnaires for diet (DINE), exercise (Godin), quality of life (SF12); healthcare usage. Results: More RoI than NI participants had systolic BP>140 mmHg (37% v 28%, p=0.01) and cholesterol >5mmol/l (24% v 17%, p=0.02): RoI mean systolic BP was higher (139 v 132 mm Hg). More RoI participants reported a high fibre intake (35% v 23%), higher levels of physical activity (62% v 44%), and better physical and mental health (SF12); they had more GP (5.6 v 4.4) and fewer nurse visits (1.6 v 2.1) in the previous year. Fewer in RoI (55% v 70%) were prescribed B blockers. Both groups’ ACE inhibitor (41%; 48%) prescribing was similar; high proportions were prescribed statins (84%; 85%) and aspirin (83%; 77%). Conclusions Blood pressure and cholesterol are better controlled among patients in a primary healthcare system with a ‘strong’ infrastructure supporting computerization and rewarding measured performance but this is not associated with healthier lifestyle or better quality of life. Further exploration of differences in professionals’ and patients’ engagement in secondary prevention in different healthcare systems is needed.

UK charity accounting: an exercise in widening stakeholder engagement

Given the economic and social impact of the charity sector in the United Kingdom (UK), the importance of good governance has been recognised as a basis for underpinning effective and ef?cient performance, and for ensuring that charities meet the legitimate aspirations of key stakeholders. A major aspect of this is high-quality accounting and reporting. Over the past 25 years attempts have been made to improve this through the medium of successive, evolving versions of a Statement of Recommended Practice (SORP) for charities. As a foundation for the future review of the SORP (expected to be published in 2015), the SORP Committee undertook its largest ever consultation on an accounting pronouncement. This paper presents the ?ndings of that consultation and, analysing them using stakeholder theory, concludes that this ambitious exercise facilitated much wider stakeholder engagement than had been experienced before and has the potential to legitimise further the SORP.

Exercise rehabilitation following intensive care unit discharge for recovery from critical illness

Background: Skeletal muscle wasting and weakness are significant complications of critical illness, associated with the degree of illness severity and periods of reduced mobility during mechanical ventilation. They contribute to the profound physical and functional deficits observed in survivors. These impairments may persist for many years following discharge from the intensive care unit (ICU) and may markedly influence health-related quality of life. Rehabilitation is a key strategy in the recovery of patients following critical illness. Exercise based interventions are aimed at targeting this muscle wasting and weakness. Physical rehabilitation delivered during ICU admission has been systematically evaluated and shown to be beneficial. However its effectiveness when initiated after ICU discharge has yet to be established. Objectives: To assess the effectiveness of exercise rehabilitation programmes, initiated after ICU discharge, on functional exercise capacity and health-related quality of life in adult ICU survivors who have been mechanically ventilated for more than 24 hours. Search methods:We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), OvidSP MEDLINE, Ovid SP EMBASE, and CINAHL via EBSCO host to 15th May 2014. We used a specific search strategy for each database. This included synonyms for ICU and critical illness, exercise training and rehabilitation. We searched the reference lists of included studies and contacted primary authors to obtain further information regarding potentially eligible studies. We also searched major clinical trials registries (Clinical Trials and Current Controlled Trials) and the personal libraries of the review authors. We applied no language or publication restriction. We reran the search in February 2015. We will deal with any studies of interest when we update the review.  Selection criteria:We included randomized controlled trials (RCTs), quasi-RCTs, and controlled clinical trials (CCTs) that compared an exercise interventioninitiated after ICU discharge to any other intervention or a control or ‘usual care’ programme in adult (≥18years) survivors ofcritical illness. Data collection and analysis:We used standard methodological procedures expected by The Cochrane Collaboration. Main results:We included six trials (483 adult ICU participants). Exercise-based interventions were delivered on the ward in two studies; both onthe ward and in the community in one study; and in the community in three studies. The duration of the intervention varied according to the length of stay in hospital following ICU discharge (up to a fixed duration of 12 weeks).Risk of bias was variable for all domains across all trials. High risk of bias was evident in all studies for performance bias, although blinding of participants and personnel in therapeutic rehabilitation trials can be pragmatically challenging. Low risk of bias was at least 50% for all other domains across all trials, although high risk of bias was present in one study for random sequence generation (selection bias), incomplete outcome data (attrition bias) and other sources. Risk of bias was unclear for remaining studies across the domains.All six studies measured effect on the primary outcome of functional exercise capacity, although there was wide variability in natureof intervention, outcome measures and associated metrics, and data reporting. Overall quality of the evidence was very low. Only two studies using the same outcome measure for functional exercise capacity, had the potential for pooling of data and assessment of heterogeneity. On statistical advice, this was considered inappropriate to perform this analysis and study findings were therefore qualitatively described. Individually, three studies reported positive results in favour of the intervention. A small benefit (versus. control)was evident in anaerobic threshold in one study (mean difference, MD (95% confidence interval, CI), 1.8 mlO2/kg/min (0.4 to 3.2),P value = 0.02), although this effect was short-term, and in a second study, both incremental (MD 4.7 (95% CI 1.69 to 7.75) Watts, P value = 0.003) and endurance (MD 4.12 (95% CI 0.68 to 7.56) minutes, P value = 0.021) exercise testing demonstrated improvement.Finally self-reported physical function increased significantly following a rehabilitation manual (P value = 0.006). Remaining studies found no effect of the intervention.Similar variability in with regard findings for the primary outcome of health-related quality of life were also evident. Only two studies evaluated this outcome. Following statistical advice, these data again were considered inappropriate for pooling to determine overall effect and assessment of heterogeneity. Qualitative description of findings was therefore undertaken. Individually, neither study reported differences between intervention and control groups for health-related quality of life as a result of the intervention. Overall quality of the evidence was very low.Mortality was reported by all studies, ranging from 0% to 18.8%. Only one non-mortality adverse event was reported across all patients in all studies (a minor musculoskeletal injury). Withdrawals, reported in four studies, ranged from 0% to 26.5% in control groups,and 8.2% to 27.6% in intervention groups. Loss to follow-up, reported in all studies, ranged from 0% to 14% in control groups, and 0% to 12.5% in intervention groups. Authors’ conclusions:We are unable, at this time, to determine an overall effect on functional exercise capacity, or health-related quality of life, of an exercise based intervention initiated after ICU discharge in survivors of critical illness. Meta-analysis of findings was not appropriate. This was due to insufficient study number and data. Individual study findings were inconsistent. Some studies reported a beneficial effect of the intervention on functional exercise capacity, and others not. No effect was reported on health-related quality of life. Methodological rigour was lacking across a number of domains influencing quality of the evidence. There was also wide variability in the characteristics of interventions, outcome measures and associated metrics, and data reporting.If further trials are identified, we may be able to determine the effect of exercise-based interventions following ICU discharge, on functional exercise capacity and health-related quality of life in survivors of critical illness.

Musculoskeletal (MSK) and Sport and Exercise Medicine (SEM) in General Practice (GP): A Novel GP-based MSK and SEM Clinic for Managing Musculoskeletal symptoms in a GP

Musculoskeletal (MSK) complaints are common within primary care (1) (2) (3) but some General Practitioners (GPs)/family physicians do not feel comfortable managing these symptoms (3), preferring to refer onto hospital specialists or Integrated Clinical Assessment and Treatment Services (ICATs). Long waiting times for hospital outpatient reviews are a major cause of patient inconvenience and complaints (4). We therefore aimed to establish a GP-ran MSK and sport and exercise medicine (SEM) clinic based within a Belfast GP surgery that would contribute to a sustainable improvement in managing these common conditions within primary care as well as reducing waiting times for patients with these conditions to see a specialist. This shift from hospital-based to community-based management is in-keeping with recent policy changes within the UK health-system, including Transforming Your Care within Northern Ireland (NI) (5). The GP-ran MSK and SEM clinic was held monthly within a Belfast GP practice, staffed by one GP with a specialist interest in MSK and SEM conditions and its performance was reviewed over a three month period. Parameters audited included cases seen, orthopaedic and x-ray referral rates and secondary care referrals comparing the GP practice’s performance to the same time period in the previous year as well as patient satisfaction questionnaires.

Novel ketone diet enhances physical and cognitive performance

Ketone bodies are the most energy-efficient fuel and yield more ATP per mole of substrate than pyruvate and increase the free energy released from ATP hydrolysis. Elevation of circulating ketones via high-fat, low-carbohydrate diets has been used for the treatment of drug-refractory epilepsy and for neurodegenerative diseases, such as Parkinson's disease. Ketones may also be beneficial for muscle and brain in times of stress, such as endurance exercise. The challenge has been to raise circulating ketone levels by using a palatable diet without altering lipid levels. We found that blood ketone levels can be increased and cholesterol and triglycerides decreased by feeding rats a novel ketone ester diet: chow that is supplemented with (R)-3-hydroxybutyl (R)-3-hydroxybutyrate as 30% of calories. For 5 d, rats on the ketone diet ran 32% further on a treadmill than did control rats that ate an isocaloric diet that was supplemented with either corn starch or palm oil (P < 0.05). Ketone-fed rats completed an 8-arm radial maze test 38% faster than did those on the other diets, making more correct decisions before making a mistake (P < 0.05). Isolated, perfused hearts from rats that were fed the ketone diet had greater free energy available from ATP hydrolysis during increased work than did hearts from rats on the other diets as shown by using [(31)P]-NMR spectroscopy. The novel ketone diet, therefore, improved physical performance and cognitive function in rats, and its energy-sparing properties suggest that it may help to treat a range of human conditions with metabolic abnormalities.