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

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

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

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

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

LRP-1 functionalized polymersomes enhance the efficacy of carnosine in experimental stroke

Stroke is one of the commonest causes of death with limited treatment options. L-Carnosine has shown great promise as a neuroprotective agent in experimental stroke, but translation to the clinic is impeded by the large doses needed. We developed and evaluated the therapeutic potential of a novel delivery vehicle which encapsulated carnosine in lipoprotein receptor related protein-1 (LRP-1)-targeted functionalized polymersomes in experimental ischemic stroke. We found that following ischemic stroke, polymersomes encapsulating carnosine exhibited remarkable neuroprotective effects with a dose of carnosine 3 orders of magnitude lower than free carnosine. The LRP-1-targeted functionalization was essential for delivery of carnosine to the brain, as non-targeted carnosine polymersomes did not exhibit neuroprotection. Using Cy3 fluorescence in vivo imaging, we showed that unlike non-targeted carnosine polymersomes, LRP-1-targeted carriers accumulated in brain in a time dependent manner. Our findings suggest that these novel carriers have the ability to deliver neuroprotective cargo effectively to the brain

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

Association between hip joint impingement and lumbar disc disease in elite rowers

Objectives Lumbar disc disease is a known cause of back pain. Increasingly it is thought that cam morphology of the hip may have a causal role in development of lumbar disc disease. The aim of this study was to describe the morphology of the hip and investigate the association of cam morphology with lumbar disc disease observed on MRI in elite rowers. Methods Cross-sectional observational study of 20 elite rowers (12 male, 8 female, mean age 24.45, SD 2.1). Assessment included clinical examination, questionnaires, 3T MRI scans of the hips and lumbar spine. Alpha angle of the hips and Pfirrmann score of lumbar discs were measured. Results 85% of rowers had a cam morphology in at least one hip. Alpha angle was greatest at the 1 o’clock position ((bone 70.9 (SD 16.9), cartilage 71.4 (16.3)). 95% of the group were noted to have labral tears, but only 50% of the group had history of groin pain. 85% of rowers had at least one disc with a Pfirrmann score of 3 or more and 95% had a history of back pain. A positive correlation was observed between the alpha angle and radiological degenerative disc disease (correlation coefficient=3.13, p=0.012). A negative correlation was observed between hip joint internal rotation and radiological degenerative disc disease (correlation coefficient=−2.60, p=0.018). Conclusions Rowers have a high prevalence of labral tears, cam morphology and lumbar disc disease. There is a possible association between cam morphology and radiological lumbar degenerative disc disease, however, further investigation is required

Antiplatelet use in ischemic stroke

Objective: A literature review of antiplatelet agents for primary and secondary stroke prevention, including mechanism of action, cost, and reasons for lack of benefit. Data sources: Articles were gathered from MEDLINE, Cochrane Reviews, and PubMed databases (1980-2021). Abstracts from scientific meetings were considered. Search terms included ischemic stroke, aspirin, clopidogrel, dipyridamole, ticagrelor, cilostazol, prasugrel, glycoprotein IIb/IIIa inhibitors. Study selection and data extraction: English-language original and review articles were evaluated. Guidelines from multiple countries were reviewed. Articles were evaluated independently by 2 authors. Data synthesis: An abundance of evidence supports aspirin and clopidogrel use for secondary stroke prevention. In the acute phase (first 21 days postinitial stroke), these medications have higher efficacy for preventing further stroke when combined, but long-term combination therapy is associated with higher hemorrhage rates. Antiplatelet treatment failure is influenced by poor adherence and genetic polymorphisms. Antiplatelet agents such as cilostazol may provide extra benefit over clopidogrel and aspirin, in certain racial groups, but further research in more diverse ethnic populations is needed. Relevance to patient care and clinical practice: This review presents the data available on the use of different antiplatelet agents poststroke. Dual therapy, recurrence after initiation of secondary preventative therapy, and areas for future research are discussed. Conclusions: Although good evidence exists for the use of certain antiplatelet agents postischemic stroke, there are considerable opportunities for future research to investigate personalized therapies. These include screening patients for platelet polymorphisms that confer antiplatelet resistance and for randomized trials including more racially diverse populations