Are mice good models for human neuromuscular disease? Comparing muscle excursions in walking between mice and humans

The mouse is one of the most widely used animal models to study neuromuscular diseases and test new therapeutic strategies. However, findings from successful pre-clinical studies using mouse models frequently fail to translate to humans due to various factors. Differences in muscle function between the two species could be crucial but often have been overlooked. The purpose of this study was to evaluate and compare muscle excursions in walking between mice and humans

Upregulated IL-1β in dysferlin-deficient muscle attenuates regeneration by blunting the response to pro-inflammatory macrophages.

BACKGROUND: Loss-of-function mutations in the dysferlin gene (DYSF) result in a family of muscle disorders known collectively as the dysferlinopathies. Dysferlin-deficient muscle is characterized by inflammatory foci and macrophage infiltration with subsequent decline in muscle function. Whereas macrophages function to remove necrotic tissue in acute injury, their prevalence in chronic myopathy is thought to inhibit resolution of muscle regeneration. Two major classes of macrophages, classical (M1) and alternative (M2a), play distinct roles during the acute injury process. However, their individual roles in chronic myopathy remain unclear and were explored in this study. METHODS: To test the roles of the two macrophage phenotypes on regeneration in dysferlin-deficient muscle, we developed an in vitro co-culture model of macrophages and muscle cells. We assayed the co-cultures using ELISA and cytokine arrays to identify secreted factors and performed transcriptome analysis of molecular networks induced in the myoblasts. RESULTS: Dysferlin-deficient muscle contained an excess of M1 macrophage markers, compared with WT, and regenerated poorly in response to toxin injury. Co-culturing macrophages with muscle cells showed that M1 macrophages inhibit muscle regeneration whereas M2a macrophages promote it, especially in dysferlin-deficient muscle cells. Examination of soluble factors released in the co-cultures and transcriptome analysis implicated two soluble factors in mediating the effects: IL-1β and IL-4, which during acute injury are secreted from M1 and M2a macrophages, respectively. To test the roles of these two factors in dysferlin-deficient muscle, myoblasts were treated with IL-4, which improved muscle differentiation, or IL-1β, which inhibited it. Importantly, blockade of IL-1β signaling significantly improved differentiation of dysferlin-deficient cells. CONCLUSIONS: We propose that the inhibitory effects of M1 macrophages on myogenesis are mediated by IL-1β signals and suppression of the M1-mediated immune response may improve muscle regeneration in dysferlin deficiency. Our studies identify a potential therapeutic approach to promote muscle regeneration in dystrophic muscle

5 Remote method invocation (RMI

This article gives a U.K.-based perspective on the involvement of forensic psychiatry organizations in questions of political controversy. Medical professional bodies are fundamentally concerned to uphold good standards of clinical practice and patient welfare, and to uphold professional medical ethics. In our specialty, when acting as individual expert witnesses, we seek to serve the courts with objectivity and respect for the law. However, as members of our professional bodies we have a legitimate medical concern about how the law affects the mentally disordered as a class. We should articulate a collective view about what treating the mentally disordered justly and appropriately in the legal system means and should challenge the law when it fails to achieve this

Understanding clinical and non-clinical decisions under uncertainty: a scenario-based survey

BACKGROUND: Prospect theory suggests that when faced with an uncertain outcome, people display loss aversion by preferring to risk a greater loss rather than incurring certain, lesser cost. Providing probability information improves decision making towards the economically optimal choice in these situations. Clinicians frequently make decisions when the outcome is uncertain, and loss aversion may influence choices. This study explores the extent to which prospect theory, loss aversion, and probability information in a non-clinical domain explains clinical decision making under uncertainty. METHODS: Four hundred sixty two participants (n = 117 non-medical undergraduates, n = 113 medical students, n = 117 resident trainees, and n = 115 medical/surgical faculty) completed a three-part online task. First, participants completed an iced-road salting task using temperature forecasts with or without explicit probability information. Second, participants chose between less or more risk-averse (“defensive medicine”) decisions in standardized scenarios. Last, participants chose between recommending therapy with certain outcomes or risking additional years gained or lost. RESULTS: In the road salting task, the mean expected value for decisions made by clinicians was better than for non-clinicians(−ce:para,022 vs -ce:para,061; < 0.001). Probability information improved decision making for all participants, but non-clinicians improved more (mean improvement of $64 versus$33; p = 0.027). Mean defensive decisions decreased across training level (medical students 2.1 ± 0.9, residents 1.6 ± 0.8, faculty1.6 ± 1.1; p-trend < 0.001) and prospect-theory-concordant decisions increased (25.4%, 33.9%, and 40.7%;p-trend = 0.016). There was no relationship identified between road salting choices with defensive medicine and prospect-theory-concordant decisions. CONCLUSIONS: All participants made more economically-rational decisions when provided explicit probability information in a non-clinical domain. However, choices in the non-clinical domain were not related to prospect-theory concordant decision making and risk aversion tendencies in the clinical domain. Recognizing this discordance may be important when applying prospect theory to interventions aimed at improving clinical care