Nitric oxide availability is increased in contracting skeletal muscle from aged mice, but does not differentially decrease muscle superoxide

Reactive oxygen and nitrogen species have been implicated in the loss of skeletal muscle mass and function that occurs during aging. Nitric oxide (NO) and superoxide are generated by skeletal muscle and where these are generated in proximity their chemical reaction to form peroxynitrite can compete with the superoxide dismutation to hydrogen peroxide. Changes in NO availability may therefore theoretically modify superoxide and peroxynitrite activities in tissues, but published data are contradictory regarding aging effects on muscle NO availability. We hypothesised that an age-related increase in NO generation might increase peroxynitrite generation in muscles from old mice, leading to an increased nitration of muscle proteins and decreased superoxide availability. This was examined using fluorescent probes and an isolated fiber preparation to examine NO content and superoxide in the cytosol and mitochondria of muscle fibers from adult and old mice both at rest and following contractile activity. We also examined the 3-nitrotyrosine (3-NT) and peroxiredoxin 5 (Prx5) content of muscles from mice as markers of peroxynitrite activity. Data indicate that a substantial age-related increase in NO levels occurred in muscle fibers during contractile activity and this was associated with an increase in muscle eNOS. Muscle proteins from old mice also showed an increased 3-NT content. Inhibition of NOS indicated that NO decreased superoxide bioavailability in muscle mitochondria, although this effect was not age related. Thus increased NO in muscles of old mice was associated with an increased 3-NT content that may potentially contribute to age-related degenerative changes in skeletal muscle

Elevated hematocrit enhances platelet accumulation following vascular injury

Red blood cells (RBCs) demonstrate procoagulant properties in vitro, and elevated hematocrit is associated with reduced bleeding and increased thrombosis risk in humans. These observations suggest RBCs contribute to thrombus formation. However, effects of RBCs on thrombosis are difficult to assess because humans and mice with elevated hematocrit typically have coexisting pathologies. Using an experimental model of elevated hematocrit in healthy mice, we measured effects of hematocrit in 2 in vivo clot formation models. We also assessed thrombin generation, platelet-thrombus interactions, and platelet accumulation in thrombi ex vivo, in vitro, and in silico. Compared with controls, mice with elevated hematocrit (RBCHIGH) formed thrombi at a faster rate and had a shortened vessel occlusion time. Thrombi in control and RBCHIGH mice did not differ in size or fibrin content, and there was no difference in levels of circulating thrombin-antithrombin complexes. In vitro, increasing the hematocrit increased thrombin generation in the absence of platelets; however, this effect was reduced in the presence of platelets. In silico, direct numerical simulations of whole blood predicted elevated hematocrit increases the frequency and duration of interactions between platelets and a thrombus.Whenhumanwhole blood was perfused over collagen at arterial shear rates, elevating the hematocrit increased the rate of platelet deposition and thrombus growth. These data suggest RBCs promote arterial thrombosis by enhancing platelet accumulation at the site of vessel injury. Maintaining a normal hematocrit may reduce arterial thrombosis risk in humans

Social learning in LEADER: Exogenous, endogenous and hybrid evaluation in rural development

This paper considers the relationship between the centralised exogenous, institutions and the embedded, endogenous institutions of rural governance in Europe through an examination the evaluation procedures of the European LEADER programme. LEADER is presented in the literature as progressive in terms of innovation and stakeholder engagement. Yet while the planning and management of LEADER embraces heterogeneity and participation, programmatic evaluation is centralised and held at arms length from delivery organisations. The paper reviews previous efforts to improve evaluation in LEADER and considers alternative strategies for evaluation, contrasting LEADER practice with participatory evaluation methodologies in the wider international context. Can evaluation in itself be valuable as a mode of social learning and hence a driver for endogenous development in rural communities in Europe? The paper concludes by examining the challenges in producing a hybrid form of evaluation which accommodates endogenous and exogenous values

Capabilities for Uniqueness and Borrowing

An important application of unique object references is safe and efficient message passing in concurrent object-oriented programming. However, to prevent the ill effects of aliasing, practical systems often severely restrict the shape of messages passed by reference. Moreover, the problematic interplay between destructive reads--often used to implement unique references--and temporary aliasing through "borrowed" references is exacerbated in a concurrent setting, increasing the potential for unpredictable run-time errors. This paper introduces a new approach to uniqueness. The idea is to use capabilities for enforcing both at-most-once consumption of unique references, and a flexible notion of uniqueness. The main novelty of our approach is a model of uniqueness and borrowing based on simple, unstructured capabilities. The advantages are: first, it provides simple foundations for uniqueness and borrowing. Second, it can be formalized using a relatively simple type system, for which we provide a complete soundness proof. Third, it avoids common problems involving borrowing and destructive reads, since unique references subsume borrowed references. We have implemented our type system as an extension to Scala. Practical experience suggests that our system allows type checking real-world actor-based concurrent programs with only a small number of additional type annotations

Functional Neuroimaging Correlates of Burnout among Internal Medicine Residents and Faculty Members

Contains fulltext : 125473.pdf (publisher's version ) (Open Access)Burnout is prevalent in residency training and practice and is linked to medical error and suboptimal patient care. However, little is known about how burnout affects clinical reasoning, which is essential to safe and effective care. The aim of this study was to examine how burnout modulates brain activity during clinical reasoning in physicians. Using functional Magnetic Resonance Imaging (fMRI), brain activity was assessed in internal medicine residents (n = 10) and board-certified internists (faculty, n = 17) from the Uniformed Services University (USUHS) while they answered and reflected upon United States Medical Licensing Examination and American Board of Internal Medicine multiple-choice questions. Participants also completed a validated two-item burnout scale, which includes an item assessing emotional exhaustion and an item assessing depersonalization. Whole brain covariate analysis was used to examine blood-oxygen-level-dependent (BOLD) signal during answering and reflecting upon clinical problems with respect to burnout scores. Higher depersonalization scores were associated with less BOLD signal in the right dorsolateral prefrontal cortex and middle frontal gyrus during reflecting on clinical problems and less BOLD signal in the bilateral precuneus while answering clinical problems in residents. Higher emotional exhaustion scores were associated with more right posterior cingulate cortex and middle frontal gyrus BOLD signal in residents. Examination of faculty revealed no significant influence of burnout on brain activity. Residents appear to be more susceptible to burnout effects on clinical reasoning, which may indicate that residents may need both cognitive and emotional support to improve quality of life and to optimize performance and learning. These results inform our understanding of mental stress, cognitive control as well as cognitive load theory

Sound Sonification describing the life expectancy and premium for insurance around the world

Sound design describing the life expectance of a country and its respective premium for insurance coverage around the worl