Evaluation of a standard provision versus an autonomy promotive exercise referral programme: rationale and study design

Background The National Institute of Clinical Excellence in the UK has recommended that the effectiveness of ongoing exercise referral schemes to promote physical activity should be examined in research trials. Recent empirical evidence in health care and physical activity promotion contexts provides a foundation for testing the utility of a Self Determination Theory (SDT) -based exercise referral consultation. Methods/Design Design: An exploratory cluster randomised controlled trial comparing standard provision exercise on prescription with a Self Determination Theory-based (SDT) exercise on prescription intervention. Participants: 347 people referred to the Birmingham Exercise on Prescription scheme between November 2007 and July 2008. The 13 exercise on prescription sites in Birmingham were randomised to current practice (n=7) or to the SDT-based intervention (n=6). Outcomes measured at 3 and 6-months: Minutes of moderate or vigorous physical activity per week assessed using the 7-day Physical Activity Recall; physical health: blood pressure and weight; health status measured using the Dartmouth CO-OP charts; anxiety and depression measured by the Hospital Anxiety and Depression Scale and vitality measured by the subjective vitality score; motivation and processes of change: perceptions of autonomy support from the advisor, satisfaction of the needs for competence, autonomy, and relatedness via physical activity, and motivational regulations for exercise. Discussion This trial will determine whether an exercise referral programme based on Self Determination Theory increases physical activity and other health outcomes compared to a standard programme and will test the underlying SDT-based process model (perceived autonomy support, need satisfaction, motivation regulations, outcomes) via structural equation modelling. Trial registration The trial is registered as Current Controlled trials ISRCTN07682833

Synaptic Dysbindin-1 Reductions in Schizophrenia Occur in an Isoform-Specific Manner Indicating Their Subsynaptic Location

Background: An increasing number of studies report associations between variation in DTNBP1, a top candidate gene in schizophrenia, and both the clinical symptoms of the disorder and its cognitive deficits. DTNBP1 encodes dysbindin-1, reduced levels of which have been found in synaptic fields of schizophrenia cases. This study determined whether such synaptic reductions are isoform-specific. Methodology/Principal Findings: Using Western blotting of tissue fractions, we first determined the synaptic localization of the three major dysbindin-1 isoforms (A, B, and C). All three were concentrated in synaptosomes of multiple brain areas, including auditory association cortices in the posterior half of the superior temporal gyrus (pSTG) and the hippocampal formation (HF). Tests on the subsynaptic tissue fractions revealed that each isoform is predominantly, if not exclusively, associated with synaptic vesicles (dysbindin-1B) or with postsynaptic densities (dysbindin-1A and -1C). Using Western blotting on pSTG (n = 15) and HF (n = 15) synaptosomal fractions from schizophrenia cases and their matched controls, we discovered that synaptic dysbindin-1 is reduced in an isoform-specific manner in schizophrenia without changes in levels of synaptophysin or PSD-95. In pSTG, about 92% of the schizophrenia cases displayed synaptic dysbindin-1A reductions averaging 48% (p = 0.0007) without alterations in other dysbindin-1 isoforms. In the HF, by contrast, schizophrenia cases displayed normal levels of synaptic dysbindin-1A, but 67% showed synaptic reductions in dysbindin-1B averaging 33% (p = 0.0256), while 80% showed synaptic reductions in dysbindin-1C averaging 35% (p = 0.0171). Conclusions/Significance: Given the distinctive subsynaptic localization of dysbindin-1A, -1B, and -1C across brain regions, the observed pSTG reductions in dysbindin-1A are postsynaptic and may promote dendritic spine loss with consequent disruption of auditory information processing, while the noted HF reductions in dysbindin-1B and -1C are both presynaptic and postsynaptic and could promote deficits in spatial working memory

A Measurement of Rb using a Double Tagging Method

The fraction of Z to bbbar events in hadronic Z decays has been measured by the OPAL experiment using the data collected at LEP between 1992 and 1995. The Z to bbbar decays were tagged using displaced secondary vertices, and high momentum electrons and muons. Systematic uncertainties were reduced by measuring the b-tagging efficiency using a double tagging technique. Efficiency correlations between opposite hemispheres of an event are small, and are well understood through comparisons between real and simulated data samples. A value of Rb = 0.2178 +- 0.0011 +- 0.0013 was obtained, where the first error is statistical and the second systematic. The uncertainty on Rc, the fraction of Z to ccbar events in hadronic Z decays, is not included in the errors. The dependence on Rc is Delta(Rb)/Rb = -0.056*Delta(Rc)/Rc where Delta(Rc) is the deviation of Rc from the value 0.172 predicted by the Standard Model. The result for Rb agrees with the value of 0.2155 +- 0.0003 predicted by the Standard Model.Comment: 42 pages, LaTeX, 14 eps figures included, submitted to European Physical Journal

Measurement of the B+ and B-0 lifetimes and search for CP(T) violation using reconstructed secondary vertices

The lifetimes of the B+ and B-0 mesons, and their ratio, have been measured in the OPAL experiment using 2.4 million hadronic Z(0) decays recorded at LEP. Z(0) --> b (b) over bar decays were tagged using displaced secondary vertices and high momentum electrons and muons. The lifetimes were then measured using well-reconstructed charged and neutral secondary vertices selected in this tagged data sample. The results aretau(B+) = 1.643 +/- 0.037 +/- 0.025 pstau(Bo) = 1.523 +/- 0.057 +/- 0.053 pstau(B+)/tau(Bo) = 1.079 +/- 0.064 +/- 0.041,where in each case the first error is statistical and the second systematic.A larger data sample of 3.1 million hadronic Z(o) decays has been used to search for CP and CPT violating effects by comparison of inclusive b and (b) over bar hadron decays, No evidence fur such effects is seen. The CP violation parameter Re(epsilon(B)) is measured to be Re(epsilon(B)) = 0.001 +/- 0.014 +/- 0.003and the fractional difference between b and (b) over bar hadron lifetimes is measured to(Delta tau/tau)(b) = tau(b hadron) - tau((b) over bar hadron)/tau(average) = -0.001 +/- 0.012 +/- 0.008

The Population Impact of a Large School-Based Influenza Vaccination Campaign

The optimal vaccination strategy to mitigate the impact of influenza epidemics is unclear. In 2005, a countywide school-based influenza vaccination campaign was launched in Knox County, Tennessee (population 385,899). Approximately 41% and 48% of eligible county children aged 5-17 years were immunized with live attenuated influenza vaccine before the 2005-2006 and 2006-2007 influenza seasons, respectively. We sought to determine the population impact of this campaign.Laboratory-confirmed influenza data defined influenza seasons. We calculated the incidence of medically attended acute respiratory illness attributable to influenza in Knox and Knox-surrounding counties (concurrent controls) during consecutive seasons (5 precampaign and 2 campaign seasons) using negative binomial regression and rate difference methods. Age-stratified analyses compared the incidence of emergency department (ED) visits and hospitalizations attributable to influenza.During precampaign seasons, estimated ED visit rates attributable to influenza were 12.39 (95% CI: 10.34-14.44) per 1000 Knox children aged 5-17 years and similar in Knox-surrounding counties. During the campaign seasons, annual Knox influenza-associated ED visit rates declined relative to rates in Knox-surrounding counties: rate ratios 0.55 (95% CI: 0.27-0.83) and 0.70 (95% CI: 0.56-0.84) for the first and second campaign seasons, respectively. Overall, there were about 35% or 4.86 per 1000 fewer influenza-associated ED visits among Knox County children aged 5-17 years attributable to the campaign. No significant declines in Knox compared to surrounding counties were detected for influenza associated ED visits in children aged <5 years, all adults combined or selected adult age subgroups, although power for these analyses was limited. Alternate rate-difference analyses yielded consistent results.Vaccination of approximately 45% of Knox school-aged children with influenza vaccine was associated with a 35% annual reduction (4.86 per 1000) in ED visit rates attributable to influenza. Higher vaccination coverage and/or larger studies would be needed to determine whether similar interventions have indirect benefits in other age groups

Comparative Genome Analysis of Filamentous Fungi Reveals Gene Family Expansions Associated with Fungal Pathogenesis

Fungi and oomycetes are the causal agents of many of the most serious diseases of plants. Here we report a detailed comparative analysis of the genome sequences of thirty-six species of fungi and oomycetes, including seven plant pathogenic species, that aims to explore the common genetic features associated with plant disease-causing species. The predicted translational products of each genome have been clustered into groups of potential orthologues using Markov Chain Clustering and the data integrated into the e-Fungi object-oriented data warehouse (http://www.e-fungi.org.uk/). Analysis of the species distribution of members of these clusters has identified proteins that are specific to filamentous fungal species and a group of proteins found only in plant pathogens. By comparing the gene inventories of filamentous, ascomycetous phytopathogenic and free-living species of fungi, we have identified a set of gene families that appear to have expanded during the evolution of phytopathogens and may therefore serve important roles in plant disease. We have also characterised the predicted set of secreted proteins encoded by each genome and identified a set of protein families which are significantly over-represented in the secretomes of plant pathogenic fungi, including putative effector proteins that might perturb host cell biology during plant infection. The results demonstrate the potential of comparative genome analysis for exploring the evolution of eukaryotic microbial pathogenesis

A Novel Ecdysone Receptor Mediates Steroid-Regulated Developmental Events during the Mid-Third Instar of Drosophila

The larval salivary gland of Drosophila melanogaster synthesizes and secretes glue glycoproteins that cement developing animals to a solid surface during metamorphosis. The steroid hormone 20-hydroxyecdysone (20E) is an essential signaling molecule that modulates most of the physiological functions of the larval gland. At the end of larval development, it is known that 20E—signaling through a nuclear receptor heterodimer consisting of EcR and USP—induces the early and late puffing cascade of the polytene chromosomes and causes the exocytosis of stored glue granules into the lumen of the gland. It has also been reported that an earlier pulse of hormone induces the temporally and spatially specific transcriptional activation of the glue genes; however, the receptor responsible for triggering this response has not been characterized. Here we show that the coordinated expression of the glue genes midway through the third instar is mediated by 20E acting to induce genes of the Broad Complex (BRC) through a receptor that is not an EcR/USP heterodimer. This result is novel because it demonstrates for the first time that at least some 20E-mediated, mid-larval, developmental responses are controlled by an uncharacterized receptor that does not contain an RXR-like component

The benefits and risks of bacille Calmette-Guérin vaccination among infants at high risk for both tuberculosis and severe combined immunodeficiency: assessment by Markov model

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccine is given to Canadian Aboriginal neonates in selected communities. Severe reactions and deaths associated with BCG have been reported among infants born with immunodeficiency syndromes. The main objective of this study was to estimate threshold values for severe combined immunodeficiency (SCID) incidence, above which BCG is associated with greater risk than benefit. METHODS: A Markov model was developed to simulate the natural histories of tuberculosis (TB) and SCID in children from birth to 14 years. The annual risk of tuberculous infection (ARI) and SCID incidence were varied in analyses. The model compared a scenario of no vaccination to intervention with BCG. Appropriate variability and uncertainty analyses were conducted. Outcomes included TB incidence and quality-adjusted life years (QALYs). RESULTS: In sensitivity analyses, QALYs were lower among vaccinated infants if the ARI was 0.1% and the rate of SCID was higher than 4.2 per 100,000. Assuming an ARI of 1%, this threshold increased to 41 per 100,000. In uncertainty analyses (Monte Carlo simulations) which assumed an ARI of 0.1%, QALYs were not significantly increased by BCG unless SCID incidence is 0. With this ARI, QALYs were significantly decreased among vaccinated children if SCID incidence exceeds 23 per 100,000. BCG is associated with a significant increase in QALYs if the ARI is 1%, and SCID incidence is below 5 per 100,000. CONCLUSION: The possibility that Canadian Aboriginal children are at increased risk for SCID has serious implications for continued BCG use in this population. In this context, enhanced TB Control – including early detection and treatment of infection – may be a safer, more effective alternative

Aconitase Regulation of Erythropoiesis Correlates with a Novel Licensing Function in Erythropoietin-Induced ERK Signaling

Erythroid development requires the action of erythropoietin (EPO) on committed progenitors to match red cell output to demand. In this process, iron acts as a critical cofactor, with iron deficiency blunting EPO-responsiveness of erythroid progenitors. Aconitase enzymes have recently been identified as possible signal integration elements that couple erythropoiesis with iron availability. In the current study, a regulatory role for aconitase during erythropoiesis was ascertained using a direct inhibitory strategy.In C57BL/6 mice, infusion of an aconitase active-site inhibitor caused a hypoplastic anemia and suppressed responsiveness to hemolytic challenge. In a murine model of polycythemia vera, aconitase inhibition rapidly normalized red cell counts, but did not perturb other lineages. In primary erythroid progenitor cultures, aconitase inhibition impaired proliferation and maturation but had no effect on viability or ATP levels. This inhibition correlated with a blockade in EPO signal transmission specifically via ERK, with preservation of JAK2-STAT5 and Akt activation. Correspondingly, a physical interaction between ERK and mitochondrial aconitase was identified and found to be sensitive to aconitase inhibition.Direct aconitase inhibition interferes with erythropoiesis in vivo and in vitro, confirming a lineage-selective regulatory role involving its enzymatic activity. This inhibition spares metabolic function but impedes EPO-induced ERK signaling and disturbs a newly identified ERK-aconitase physical interaction. We propose a model in which aconitase functions as a licensing factor in ERK-dependent proliferation and differentiation, thereby providing a regulatory input for iron in EPO-dependent erythropoiesis. Directly targeting aconitase may provide an alternative to phlebotomy in the treatment of polycythemia vera

Behavioral genomics of honeybee foraging and nest defense

The honeybee has been the most important insect species for study of social behavior. The recently released draft genomic sequence for the bee will accelerate honeybee behavioral genetics. Although we lack sufficient tools to manipulate this genome easily, quantitative trait loci (QTLs) that influence natural variation in behavior have been identified and tested for their effects on correlated behavioral traits. We review what is known about the genetics and physiology of two behavioral traits in honeybees, foraging specialization (pollen versus nectar), and defensive behavior, and present evidence that map-based cloning of genes is more feasible in the bee than in other metazoans. We also present bioinformatic analyses of candidate genes within QTL confidence intervals (CIs). The high recombination rate of the bee made it possible to narrow the search to regions containing only 17–61 predicted peptides for each QTL, although CIs covered large genetic distances. Knowledge of correlated behavioral traits, comparative bioinformatics, and expression assays facilitated evaluation of candidate genes. An overrepresentation of genes involved in ovarian development and insulin-like signaling components within pollen foraging QTL regions suggests that an ancestral reproductive gene network was co-opted during the evolution of foraging specialization. The major QTL influencing defensive/aggressive behavior contains orthologs of genes involved in central nervous system activity and neurogenesis. Candidates at the other two defensive-behavior QTLs include modulators of sensory signaling (Am5HT(7) serotonin receptor, AmArr4 arrestin, and GABA-B-R1 receptor). These studies are the first step in linking natural variation in honeybee social behavior to the identification of underlying genes