Alterations in Redox Homeostasis During Recovery From Unexplained Underperformance Syndrome in an Elite International Rower.

This case study of an international rower examines a diagnosis of Unexplained Under Performance Syndrome (UUPS or Overtraining Syndrome) describing a full recovery and return to elite competition the same year. On diagnosis and 4 and 14 months post-diagnosis, detailed assessments including physiological, nutritional, and biomarkers were made. Clinical examination and laboratory results for haematology, biochemistry, thyroid function, immunology, vitamins and minerals were unremarkable and did not explain the presentation and diagnosis. Redox biomarkers including hydroperoxides, plasma antioxidant capacity, red blood cell glutathione, superoxide dismutase, co-enzyme Q10, vitamin E (α and γ-tocopherol), and carotenoids (lutein, α-carotene, β-carotene) provided evidence of altered redox homeostasis. The recovery strategy began with 12 days of training abstinence and nutritional interventions, followed by 6-weeks of modified training. Four months post-intervention performance had recovered strongly, resulting in the athlete becoming European champion that same year. Further improvements in physiological and performance indices were observed at 14 months post-intervention. Physiologically relevant increases in concentrations of carotenoids were achieved at each post-intervention time point, exceeding the reported critical difference values. We conclude that increasing athlete phytonutrient intake may enhance recovery and tolerance to training and environmental stressors, reducing the risk of unexplained under performance syndrome. Alterations in redox homeostasis should be considered as part of the medical management in unexplained under performance syndrome. This is the first reported case study of an elite athlete with alterations in redox homeostasis in conjunction with a diagnosis of unexplained under performance syndrome

Action Experience and Action Discovery in Medicated Individuals with Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder that markedly affects voluntary action. While regular dopamine treatment can help restore motor function, dopamine also influences cognitive portions of the action system. Previous studies have demonstrated that dopamine medication boosts action-effect associations, which are crucial for the discovery of new voluntary actions. In the present study, we investigated whether neural processes involved in the discovery of new actions are altered in PD participants on regular dopamine treatment, compared to healthy age-matched controls. We recorded brain electroencephalography (EEG) activity while PD patients and age-matched controls performed action discovery (AD) and action control tasks. We found that the novelty P3, a component normally present when there is uncertainty about the occurrence of the sensory effect, was enhanced in PD patients. However, AD was maintained in PD patients, and the novelty P3 demonstrated normal learning-related reductions. Crucially, we found that in PD patients the causal association between an action and its resulting sensory outcome did not modulate the amplitude of the feedback correct-related positivity (fCRP), an EEG component sensitive to the association between an action and its resulting effect. Collectively, these preliminary results suggest that the formation of long-term action-outcome representations may be maintained in PD patients on regular dopamine treatment, but the initial experience of action-effect association may be affected

Increased Oxidative Stress in Injured and Ill Elite International Olympic Rowers

Identifying strategies that reduce the risk of illness and injury is an objective of sports science and medicine teams. No studies have examined the relationship between oxidative stress (OS) and illness or injury in international athletes undergoing periods of intensified training and competition. Purpose: We aimed to identify relationships between illness, injury and OS. Methods: A longitudinal, observational study of elite male rowers (n=10) was conducted over 18-weeks leading into World Championships. Following a recovery day and a 12-hour fast, hydroperoxides (FORT) and total anti-oxidant capacity (FORD) were measured in venous blood, with the ratio calculated as the oxidative stress index (OSI). At all study time points, athletes were independently dichotomized as ill or not ill, injured or not injured. OS data were compared between groups using independent t-tests. A Cox proportional hazard model was used to assess the association of OS with injury and illness while adjusting for age and body mass index. Results: FORD was lower (p<0.02) and OSI was higher (p<0.001) with illness than without illness. FORT and OSI were higher with injury than without injury (p<0.001). FORD exerts a protective effect on illness with 0.5 mmol•L-1 increase related to a 30.6% illness risk reduction (p=0.014), and OSI exerts a harmful effect on illness risk with a 0.5 unit increase in OSI related to an 11.3% increased risk (p=0.036). Conclusion: OS is increased in injured and ill athletes. Monitoring OS may be advantageous in assessing recovery from, and in reducing injury and illness risk given the association

Remote ischaemic conditioning for stroke: unanswered questions and future directions

Remote ischaemic conditioning (RIC) refers to a process whereby periods of intermittent ischaemia, typically via the cyclical application of a blood pressure cuff to a limb at above systolic pressure, confers systemic protection against ischaemia in spatially distinct vascular territories. The mechanisms underlying this have not been characterised fully but have been shown to involve neural, hormonal and systemic inflammatory signalling cascades. Preclinical and early clinical studies have been promising and suggest beneficial effects of RIC in acute ischaemic stroke, symptomatic intracranial stenosis and vascular cognitive impairment. Through systematic searches of several clinical trials databases we identified 48 active clinical trials of RIC in ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage. We summarise the different RIC protocols and outcome measures studied in ongoing clinical trials and highlight which studies are most likely to elucidate the underlying biological mechanisms of RIC and characterise its efficacy in the near future. We discuss the uncertainties of RIC including the optimal frequency and duration of therapy, target patient groups, cost-effectiveness, the confounding impact of medications and the absence of a clinically meaningful biomarker of the conditioning response. With several large clinical trials of RIC expected to report their outcomes within the next 2 years, this review aims to highlight the most important studies and unanswered questions that will need to be addressed before this potentially widely accessible and low-cost intervention can be used in clinical practice

Quinolone-resistant gyrase mutants demonstrate decreased susceptibility to triclosan

Objectives: Cross-resistance between antibiotics and biocides is a potentially important driver of MDR. A relationship between susceptibility of Salmonella to quinolones and triclosan has been observed. This study aimed to: (i) investigate the mechanism underpinning this; (ii) determine whether the phenotype is conserved in Escherichia coli; and (iii) evaluate the potential for triclosan to select for quinolone resistance. Methods: WT E. coli, Salmonella enterica serovar Typhimurium and gyrA mutants were used. These were characterized by determining antimicrobial susceptibility, DNA gyrase activity and sensitivity to inhibition. Expression of stress response pathways (SOS, RpoS, RpoN and RpoH) was measured, as was the fitness of mutants. The potential for triclosan to select for quinolone resistance was determined. Results: All gyrase mutants showed increased triclosan MICs and altered supercoiling activity. There was no evidence for direct interaction between triclosan and gyrase. Identical substitutions in GyrA had different impacts on supercoiling in the two species. For both, there was a correlation between altered supercoiling and expression of stress responses. This was more marked in E. coli, where an Asp87Gly GyrA mutant demonstrated greatly increased fitness in the presence of triclosan. Exposure of parental strains to low concentrations of triclosan did not select for quinolone resistance. Conclusions: Our data suggest gyrA mutants are less susceptible to triclosan due to up-regulation of stress responses. The impact of gyrA mutation differs between E. coli and Salmonella. The impacts of gyrA mutation beyond quinolone resistance have implications for the fitness and selection of gyrA mutants in the presence of non-quinolone antimicrobials

The Potential of Adaptive Design in Animal Studies

Clinical trials are the backbone of medical research, and are often the last step in the development of new therapies for use in patients. Prior to human testing, however, preclinical studies using animal subjects are usually performed in order to provide initial data on the safety and effectiveness of prospective treatments. These studies can be costly and time consuming, and may also raise concerns about the ethical treatment of animals when potentially harmful procedures are involved. Adaptive design is a process by which the methods used in a study may be altered while it is being conducted in response to preliminary data or other new information. Adaptive design has been shown to be useful in reducing the time and costs associated with clinical trials, and may provide similar benefits in preclinical animal studies. The purpose of this review is to summarize various aspects of adaptive design and evaluate its potential for use in preclinical research

Comparative cerebroprotective potential of d- and l-carnosine following ischemic stroke in mice

l-carnosine is an attractive therapeutic agent for acute ischemic stroke based on its robust preclinical cerebroprotective properties and wide therapeutic time window. However, large doses are needed for efficacy because carnosine is rapidly degraded in serum by carnosinases. The need for large doses could be particularly problematic when translating to human studies, as humans have much higher levels of serum carnosinases. We hypothesized that d-carnosine, which is not a substrate for carnosinases, may have a better pharmacological profile and may be more efficacious at lower doses than l-carnosine. To test our hypothesis, we explored the comparative pharmacokinetics and neuroprotective properties of d- and L-carnosine in acute ischaemic stroke in mice. We initially investigated the pharmacokinetics of d- and L-carnosine in serum and brain after intravenous (IV) injection in mice. We then investigated the comparative efficacy of d- and l-carnosine in a mouse model of transient focal cerebral ischemia followed by in vitro testing against excitotoxicity and free radical generation using primary neuronal cultures. The pharmacokinetics of d- and l-carnosine were similar in serum and brain after IV injection in mice. Both d- and l-carnosine exhibited similar efficacy against mouse focal cerebral ischemia. In vitro studies in neurons showed protection against excitotoxicity and the accumulation of free radicals. d- and l-carnosine exhibit similar pharmacokinetics and have similar efficacy against experimental stroke in mice. Since humans have far higher levels of carnosinases, d-carnosine may have more favorable pharmacokinetics in future human studies

Loss of endothelial endoglin promotes high-output heart failure through peripheral arteriovenous shunting driven by VEGF signaling

Rationale: ENG (endoglin) is a coreceptor for BMP (bone morphogenetic protein) 9/10 and is strongly expressed in endothelial cells. Mutations in ENG lead to the inherited vascular disorder hereditary hemorrhagic telangiectasia characterized by local telangiectases and larger arteriovenous malformations (AVMs); but how ENG functions to regulate the adult vasculature is not understood. Objective: The goal of the work was to determine how ENG maintains vessel caliber in adult life to prevent AVM formation and thereby protect heart function. Methods and Results: Genetic depletion of endothelial Eng in adult mice led to a significant reduction in mean aortic blood pressure. There was no evidence of hemorrhage, anemia, or AVMs in major organs to explain the reduced aortic pressure. However, large AVMs developed in the peripheral vasculature intimately associated with the pelvic cartilaginous symphysis—a noncapsulated cartilage with a naturally high endogenous expression of VEGF (vascular endothelial growth factor). The increased blood flow through these peripheral AVMs explained the drop in aortic blood pressure and led to increased cardiac preload, and high stroke volumes, ultimately resulting in high-output heart failure. Development of pelvic AVMs in this region of high VEGF expression occurred because loss of ENG in endothelial cells leads to increased sensitivity to VEGF and a hyperproliferative response. Development of AVMs and associated progression to high-output heart failure in the absence of endothelial ENG was attenuated by targeting VEGF signaling with an anti-VEGFR2 (VEGF receptor 2) antibody. Conclusions: ENG promotes the normal balance of VEGF signaling in quiescent endothelial cells to maintain vessel caliber—an essential function in conditions of increased VEGF expression such as local hypoxia or inflammation. In the absence of endothelial ENG, increased sensitivity to VEGF drives abnormal endothelial proliferation in local regions of high VEGF expression, leading to AVM formation and a rapid injurious impact on heart function