Microtubule Dependent Mechano-Transduction Drives Oxidative Stress and Calcium Dysregulation in Dystrophic Skeletal Muscle

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Myosin-binding protein C corrects an intrinsic inhomogeneity in cardiac excitation-contraction coupling

The beating heart exhibits remarkable contractile fidelity over a lifetime, which reflects the tight coupling of electrical, chemical, and mechanical elements within the sarcomere, the elementary contractile unit. On a beat-to-beat basis, calcium is released from the ends of the sarcomere and must diffuse toward the sarcomere center to fully activate the myosin- and actin-based contractile proteins. The resultant spatial and temporal gradient in free calcium across the sarcomere should lead to nonuniform and inefficient activation of contraction. We show that myosin-binding protein C (MyBP-C), through its positioning on the myosin thick filaments, corrects this nonuniformity in calcium activation by exquisitely sensitizing the contractile apparatus to calcium in a manner that precisely counterbalances the calcium gradient. Thus, the presence and correct localization of MyBP-C within the sarcomere is critically important for normal cardiac function, and any disturbance of MyBP-C localization or function will contribute to the consequent cardiac pathologies

Values for preventing influenza-related morbidity and vaccine adverse events in children

BACKGROUND: Influenza vaccination recently has been recommended for children 6–23 months old, but is not currently recommended for routine use in non-high-risk older children. Information on disease impact, costs, benefits, risks, and community preferences could help guide decisions about which age and risk groups should be vaccinated and strategies for improving coverage. The objective of this study was to measure preferences and willingness-to-pay for changes in health-related quality of life associated with uncomplicated influenza and two rarely-occurring vaccination-related adverse events (anaphylaxis and Guillain-Barré syndrome) in children. METHODS: We conducted telephone interviews with adult members selected at random from a large New England HMO (n = 112). Respondents were given descriptions of four health outcomes: uncomplicated influenza in a hypothetical 1-year-old child of their own, uncomplicated influenza in a hypothetical 14-year-old child of their own, anaphylaxis following vaccination, and Guillain-Barré syndrome. "Uncomplicated influenza" did not require a physician's visit or hospitalization. Preferences (values) for these health outcomes were measured using time-tradeoff and willingness-to-pay questions. Time-tradeoff questions asked the adult to assume they had a child and to consider how much time from the end of their own life they would be willing to surrender to avoid the health outcome in the child. RESULTS: Respondents said they would give a median of zero days of their lives to prevent an episode of uncomplicated influenza in either their (hypothetical) 1-year-old or 14-year-old, 30 days to prevent an episode of vaccination-related anaphylaxis, and 3 years to prevent a vaccination-related case of Guillain-Barré syndrome. Median willingness-to-pay to prevent uncomplicated influenza in a 1-year-old was $175, uncomplicated influenza in a 14-year-old was$100, anaphylaxis $400, and Guillain-Barré syndrome$4000. The median willingness-to-pay for an influenza vaccination for their children with no risk of anaphylaxis or Guillain-Barré syndrome was $50 and$100, respectively. CONCLUSION: Most respondents said they would not be willing to trade any time from their own lives to prevent uncomplicated influenza in a child of their own, and the time traded did not vary by the age of the hypothetical affected child. However, adults did indicate a willingness-to-pay to prevent uncomplicated influenza in children, and that they would give more money to prevent the illness in a 1-year-old than in a 14-year-old. Respondents also indicated a willingness to pay a premium for a vaccine without any risk of severe complications

Health Benefits, Risks, and Cost-Effectiveness of Influenza Vaccination of Children

Vaccinating children aged 6–23 months, plus all other children at high-risk, will likely be more effective than vaccinating all children against influenza

Tuberculosis in badgers where the bovine tuberculosis epidemic is expanding in cattle in England.

Bovine tuberculosis (bTB) is an important animal health and economic problem for the cattle industry and a potential zoonotic threat. Wild badgers (Meles meles) play a role on its epidemiology in some areas of high prevalence in cattle, particularly in the UK and Republic of Ireland and increasingly in parts of mainland Europe. However, little is known about the involvement of badgers in areas on the spatial edge of the cattle epidemic, where increasing prevalence in cattle is seen. Here we report the findings of a study of found-dead (mainly road-killed) badgers in six counties on the edge of the English epidemic of bTB in cattle. The overall prevalence of Mycobacterium tuberculosis complex (MTC) infection detected in the study area was 51/610 (8.3%, 95% CI 6.4-11%) with the county-level prevalence ranging from 15 to 4-5%. The MTC spoligotypes of recovered from badgers and cattle varied: in the northern part of the study area spoligotype SB0129 predominated in both cattle and badgers, but elsewhere there was a much wider range of spoligotypes found in badgers than in cattle, in which infection was mostly with the regional cattle spoligotype. The low prevalence of MTC in badgers in much of the study area, and, relative to in cattle, the lower density of sampling, make firm conclusions difficult to draw. However, with the exception of Cheshire (north-west of the study area), little evidence was found to link the expansion of the bTB epidemic in cattle in England to widespread badger infection

Contractile Function during Angiotensin-II Activation:Increased Nox2 Activity Modulates Cardiac Calcium Handling via Phospholamban Phosphorylation

AbstractBackgroundRenin-angiotensin system activation is a feature of many cardiovascular conditions. Activity of myocardial reduced nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2 or Nox2) is enhanced by angiotensin II (Ang II) and contributes to increased hypertrophy, fibrosis, and adverse remodeling. Recent studies found that Nox2-mediated reactive oxygen species production modulates physiological cardiomyocyte function.ObjectivesThis study sought to investigate the effects of cardiomyocyte Nox2 on contractile function during increased Ang II activation.MethodsWe generated a cardiomyocyte-targeted Nox2-transgenic mouse model and studied the effects of in vivo and ex vivo Ang II stimulation, as well as chronic aortic banding.ResultsChronic subpressor Ang II infusion induced greater cardiac hypertrophy in transgenic than wild-type mice but unexpectedly enhanced contractile function. Acute Ang II treatment also enhanced contractile function in transgenic hearts in vivo and transgenic cardiomyocytes ex vivo. Ang II–stimulated Nox2 activity increased sarcoplasmic reticulum (SR) Ca2+ uptake in transgenic mice, increased the Ca2+ transient and contractile amplitude, and accelerated cardiomyocyte contraction and relaxation. Elevated Nox2 activity increased phospholamban phosphorylation in both hearts and cardiomyocytes, related to inhibition of protein phosphatase 1 activity. In a model of aortic banding–induced chronic pressure overload, heart function was similarly depressed in transgenic and wild-type mice.ConclusionsWe identified a novel mechanism in which Nox2 modulates cardiomyocyte SR Ca2+ uptake and contractile function through redox-regulated changes in phospholamban phosphorylation. This mechanism can drive increased contractility in the short term in disease states characterized by enhanced renin-angiotensin system activation

The Impact of Pandemic Influenza H1N1 on Health-Related Quality of Life: A Prospective Population-Based Study

BACKGROUND: While the H1N1v influenza pandemic in 2009 was clinically mild, with a low case-fatality rate, the overall disease burden measured in quality-adjusted life years (QALY) lost has not been estimated. Such a measure would allow comparison with other diseases and assessment of the cost-effectiveness of pandemic control measures. METHODS AND FINDINGS: Cases of H1N1v confirmed by polymerase chain reaction (PCR) and PCR negative cases with similar influenza-like illness (ILI controls) in 7 regions of England were sent two questionnaires, one within a week of symptom onset and one two weeks later, requesting information on duration of illness, work loss and antiviral use together with EQ-5D questionnaires. Results were compared with those for seasonal influenza from a systematic literature review. A total QALY loss for the 2009 pandemic in England was calculated based on the estimated total clinical cases and reported deaths. A total of 655 questionnaires were sent and 296 (45%) returned. Symptoms and average illness duration were similar between confirmed cases and ILI controls (8.8 days and 8.7 days respectively). Days off work were greater for cases than ILI controls (7.3 and 4.9 days respectively, p  =  0.003). The quality-adjusted life days lost was 2.92 for confirmed cases and 2.74 for ILI controls, with a reduction in QALY loss after prompt use of antivirals in confirmed cases. The overall QALY loss in the pandemic was estimated at 28,126 QALYs (22,267 discounted) of which 40% was due to deaths (24% with discounting). CONCLUSION: Given the global public health significance of influenza, it is remarkable that no previous prospective study of the QALY loss of influenza using standardised and well validated methods has been performed. Although the QALY loss was minor for individual patients, the estimated total burden of influenza over the pandemic was substantial when compared to other infectious diseases

MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca^(2+) Stress

Mitochondria shape cytosolic calcium ([Ca^(2+)]_c) transients and utilize the mitochondrial Ca_2^+ ([Ca^(2+)]_m) in exchange for bioenergetics output. Conversely, dysregulated [Ca^(2+)]_c causes [Ca^(2+)]_m overload and induces permeability transition pore and cell death. Ablation of MCU-mediated Ca^(2+) uptake exhibited elevated [Ca^(2+)]_c and failed to prevent stress-induced cell death. The mechanisms for these effects remain elusive. Here, we report that mitochondria undergo a cytosolic Ca^(2+)-induced shape change that is distinct from mitochondrial fission and swelling. [Ca^(2+)]_c elevation, but not MCU-mediated Ca^(2+) uptake, appears to be essential for the process we term mitochondrial shape transition (MiST). MiST is mediated by the mitochondrial protein Miro1 through its EF-hand domain 1 in multiple cell types. Moreover, Ca^(2+)-dependent disruption of Miro1/KIF5B/tubulin complex is determined by Miro1 EF1 domain. Functionally, Miro1-dependent MiST is essential for autophagy/mitophagy that is attenuated in Miro1 EF1 mutants. Thus, Miro1 is a cytosolic Ca^(2+) sensor that decodes metazoan Ca^(2+) signals as MiST