The effects of aetiology on outcome in patients treated with cardiac resynchronization therapy in the CARE-HF trial

Aims: Cardiac dyssynchrony is common in patients with heart failure, whether or not they have ischaemic heart disease (IHD). The effect of the underlying cause of cardiac dysfunction on the response to cardiac resynchronization therapy (CRT) is unknown. This issue was addressed using data from the CARE-HF trial.Methods and resultsPatients (n = 813) were grouped by heart failure aetiology (IHD n = 339 vs. non-IHD n = 473), and the primary composite (all-cause mortality or unplanned hospitalization for a major cardiovascular event) and principal secondary (all-cause mortality) endpoints analysed. Heart failure severity and the degree of dyssynchrony were compared between the groups by analysing baseline clinical and echocardiographic variables. Patients with IHD were more likely to be in NYHA class IV (7.5 vs. 4.0; P = 0.03) and to have higher NT-proBNP levels (2182 vs. 1725 pg/L), indicating more advanced heart failure. The degree of dyssynchrony was more pronounced in patients without IHD (assessed using mean QRS duration, interventricular mechanical delay, and aorta-pulmonary pre-ejection time). Left ventricular ejection fraction and left ventricular end-systolic volume improved to a lesser extent in the IHD group (4.53 vs. 8.50 and -35.68 vs. -58.52 cm 3). Despite these differences, CRT improved all-cause mortality, NYHA class, and hospitalization rates to a similar extent in patients with or without IHD.ConclusionThe benefits of CRT in patients with or without IHD were similar in relative terms in the CARE-HF study but as patients with IHD had a worse prognosis, the benefit in absolute terms may be greater

Mitochondrial precursor proteins are imported through a hydrophilic membrane environment

We have analyzed how translocation intermediates of imported mitochondrial precursor proteins, which span contact sites, interact with the mitochondrial membranes. F1-ATPase subunit β(F1β) was trapped at contact sites by importing it into Neurospora mitochondria in the presence of low levels of nucleoside triphosphates. This F1β translocation intermediate could be extracted from the membranes by treatment with protein denaturants such as alkaline pH or urea. By performing import at low temperatures, the ADP/ATP carrier was accumulated in contact sites of Neurospora mitochondria and cytochrome b2 in contact sites of yeast mitochondria. These translocation intermediates were also extractable from the membranes at alkaline pH. Thus, translocation of precursor proteins across mitochondrial membranes seems to occur through an environment which is accessible to aqueous perturbants. We propose that proteinaceous structures are essential components of a translocation apparatus present in contact sites

Risk and promotive effects in the explanation of persistent serious delinquency in boys

Risk and promotive effects were investigated as predictors of persistent serious delinquency in male participants of the Pittsburgh Youth Study (R. Loeber, D. P. Farrington, M. Stouthamer-Loeber, & W. B. van Kammen, 1998), living in different neighborhoods. Participants were studied over ages 13–19 years for the oldest sample and 7–13 years for the youngest sample. Risk and promotive effects were studied in 6 domains: child behavior, child attitudes, school and leisure activities, peer behaviors, family functioning, and demographics. Regression models improved when promotive effects were included with risk effects in predicting persistent serious delinquency. Disadvantaged neighborhoods, compared with better neighborhoods, had a higher prevalence of risk effects and a lower prevalence of promotive effects. However, predictive relations between risk and promotive effects and persistent serious delinquency were linear and similar across neighborhood socioeconomic status. Although advances have been made in the study of predictors of serious delinquency (Hawkins et al., 1998; Lipsey & Derzon, 1998), little is known about predictors of persistent serious offend-ing, which from a societal point of view is of particular concern. Most youth commit some delinquent acts in childhood or adoles

Redox-induced activation of the proton pump in the respiratory complex I

Significance Complex I is a redox-driven proton pump, central for aerobic energy transduction. We show here by large-scale quantum and classical molecular simulations how reduction of quinone (Q) in the hydrophilic domain of complex I activates the proton pump in the membrane domain. Our simulations indicate that reduction of Q leads to local charge redistributions that trigger conformational changes via an array of alternating charged residues in the membrane domain, nearly 40 Å away. These mechanistic observations are supported by site-directed mutagenesis of a key residue triggering the activation process. The combined data provide molecular insight into how the long-range energy transduction is accomplished by complex I.</jats:p

Young people, crime and school exclusion: a case of some surprises

During the 1990s the number of young people being permanently excluded from schools in England and Wales increased dramatically from 2,910 (1990/91) to a peak of 12,700 (1996/97). Coinciding with this rise was a resurgence of the debate centring on lawless and delinquent youth. With the publication of Young People and Crime (Graham and Bowling 1995) and Misspent Youth (Audit Commission 1996) the 'common sense assumption' that exclusion from school inexorably promoted crime received wide support, with the school excludee portrayed as another latter day 'folk devil'. This article explores the link between school exclusion and juvenile crime, and offers some key findings from a research study undertaken with 56 young people who had experience of being excluded from school. Self-report interview questions reveal that whilst 40 of the young people had offended, 90% (36) reported that the onset of their offending commenced prior to their first exclusion. Moreover, 50 (89.2% of the total number of young people in the sample), stated that they were no more likely to offend subsequent to being excluded and 31 (55.4%) stated that they were less likely to offend during their exclusion period. Often, this was because on being excluded, they were 'grounded' by their parents

The politics of the digital single market:Culture vs. competition vs. copyright

This paper examines the implications for European music culture of the European Union’s Digital Single Market strategy. It focuses on the regulatory framework being created for the management of copyright policy, and in particular the role played by Collective Management Organisations (or Collecting Societies). One of the many new opportunities created by digitalization has been the music streaming services. These depend on consumers being able to access music wherever they are, but such a system runs counter to the management of rights on a national basis and through collecting organisations who act as monopolies within their own territories. The result has been ‘geo-blocking’. The EU has attempted to resolve this problem in a variety of ways, most recently in a Directive designed to reform the CMOs. In this paper, we document these various efforts, showing them to be motivated by a deep-seated and persisting belief in the capacity of ‘competition’ to resolve problems that, we argue, actually lie elsewhere - in copyright policy itself. The result is that the EU’s intervention fails to address its core concern and threatens the diversity of European music culture by rewarding those who are already commercially successful

Annihilation vs. Decay: Constraining dark matter properties from a gamma-ray detection

Most proposed dark matter candidates are stable and are produced thermally in the early Universe. However, there is also the possibility of unstable (but long-lived) dark matter, produced thermally or otherwise. We propose a strategy to distinguish between dark matter annihilation and/or decay in the case that a clear signal is detected in gamma-ray observations of Milky Way dwarf spheroidal galaxies with gamma-ray experiments. The sole measurement of the energy spectrum of an indirect signal would render the discrimination between these cases impossible. We show that by examining the dependence of the intensity and energy spectrum on the angular distribution of the emission, the origin could be identified as decay, annihilation, or both. In addition, once the type of signal is established, we show how these measurements could help to extract information about the dark matter properties, including mass, annihilation cross section, lifetime, dominant annihilation and decay channels, and the presence of substructure. Although an application of the approach presented here would likely be feasible with current experiments only for very optimistic dark matter scenarios, the improved sensitivity of upcoming experiments could enable this technique to be used to study a wider range of dark matter models.Comment: 29 pp, 8 figs; replaced to match published version (minor changes and some new references

Young People’s Differential Vulnerability to Criminogenic Exposure: Bridging The Gap Between People and Place Oriented Approaches in the Study of Crime Causation

The overall purpose of this study is to contribute to bridging the gap between people and place oriented approaches in the study of crime causation. To achieve this we will explore some core hypotheses derived from Situational Action Theory (SAT) about what makes young people crime prone and places criminogenic, and about the interaction between crime propensity and criminogenic exposure predicting crime events. We will also calculate the expected reduction in aggregate levels of crime that will occur as a result of successful interventions targeting crime propensity and criminogenic exposure. To test the hypotheses we will utilise a unique set of space-time budget, small area community survey, land use and interviewer-led questionnaire data from the prospective longitudinal Peterborough Adolescent and Young Adult Development Study (PADS+) and an Artificial Neural Network approach to modelling. The results show that people’s crime propensity (based on their personal morals and abilities to exercise self-control) has the bulk of predictive power, but also that including criminogenic exposure (being unsupervised with peers and engaged in unstructured activities in residential areas of poor collective efficacy or commercial centres) demonstrates a substantial increase in predictive power (in addition to crime propensity). Moreover, the results show that the probability of crime is strongest when a crime prone person takes part in a criminogenic setting and, crucially, that the higher a person’s crime propensity the more vulnerable he or she is to influences of criminogenic exposure. Finally, the findings suggest that a reduction in people’s crime propensity has a much bigger impact on their crime involvement than a reduction in their exposure to criminogenic settings.This research was supported by grants from the UK Economic & Social Research Council (ESRC grant ES/K010646/1); the European Research Council (grants IDCAB 220/104702003 and Momentum 324247) and Riksbankens Jubileumsfond - the Swedish Foundation for Humanities and Social Sciences

Limits on the high-energy gamma and neutrino fluxes from the SGR 1806-20 giant flare of December 27th, 2004 with the AMANDA-II detector

On December 27th 2004, a giant gamma flare from the Soft Gamma-ray Repeater 1806-20 saturated many satellite gamma-ray detectors. This event was by more than two orders of magnitude the brightest cosmic transient ever observed. If the gamma emission extends up to TeV energies with a hard power law energy spectrum, photo-produced muons could be observed in surface and underground arrays. Moreover, high-energy neutrinos could have been produced during the SGR giant flare if there were substantial baryonic outflow from the magnetar. These high-energy neutrinos would have also produced muons in an underground array. AMANDA-II was used to search for downgoing muons indicative of high-energy gammas and/or neutrinos. The data revealed no significant signal. The upper limit on the gamma flux at 90% CL is dN/dE < 0.05 (0.5) TeV^-1 m^-2 s^-1 for gamma=-1.47 (-2). Similarly, we set limits on the normalization constant of the high-energy neutrino emission of 0.4 (6.1) TeV^-1 m^-2 s^-1 for gamma=-1.47 (-2).Comment: 14 pages, 3 figure