Long-term safety and efficacy of lowering low-density lipoprotein cholesterol with statin therapy : 20-year follow-up of West of Scotland Coronary Prevention Study

The study was supported by a grant from Merck, Sharp & Dohme, Kenilworth, NJ, as part of an Investigator Initiated Program.BACKGROUND Extended follow-up of statin-based low-density lipoprotein cholesterol lowering trials improves the understanding of statin safety and efficacy. Examining cumulative cardiovascular events (total burden of disease) gives a better appreciation of the clinical value of statins. This article evaluates the long-term impact of therapy on mortality and cumulative morbidity in a high-risk cohort of men. METHODS AND RESULTS The West of Scotland Coronary Prevention Study was a primary prevention trial in 45- to 64-year-old men with high low-density lipoprotein cholesterol. A total of 6595 men were randomized to receive pravastatin 40 mg once daily or placebo for an average of 4.9 years. Subsequent linkage to electronic health records permitted analysis of major incident events over 20 years. Post trial statin use was recorded for 5 years after the trial but not for the last 10 years. Men allocated to pravastatin had reduced all-cause mortality (hazard ratio, 0.87; 95% confidence interval, 0.80-0.94; P=0.0007), attributable mainly to a 21% decrease in cardiovascular death (hazard ratio, 0.79; 95% confidence interval, 0.69-0.90; P=0.0004). There was no difference in noncardiovascular or cancer death rates between groups. Cumulative hospitalization event rates were lower in the statin-treated arm: by 18% for any coronary event (P=0.002), by 24% for myocardial infarction (P=0.01), and by 35% for heart failure (P=0.002). There were no significant differences between groups in hospitalization for noncardiovascular causes. CONCLUSION Statin treatment for 5 years was associated with a legacy benefit, with improved survival and a substantial reduction in cardiovascular disease outcomes over a 20-year period, supporting the wider adoption of primary prevention strategies.Publisher PDFPeer reviewe

Modest enhancements to conventional grassland diversity improve the provision of pollination services

Grassland for livestock production is a major form of land use throughout Europe and its intensive management threatens biodiversity and ecosystem functioning in agricultural landscapes. Modest increases to conventional grassland biodiversity could have considerable positive impacts on the provision of ecosystem services, such as pollination, to surrounding habitats. Using a field-scale experiment in which grassland seed mixes and sward management were manipulated, complemented by surveys on working farms and phytometer experiments, the impact of conventional grassland diversity and management on the functional diversity and ecosystem service provision of pollinator communities were investigated. Increasing plant richness, by the addition of both legumes and forbs, was associated with significant enhancements in the functional diversity of grassland pollinator communities. This was associated with increased temporal stability of flower–visitor interactions at the community level. Visitation networks revealed pasture species Taraxacum sp. (Wigg.) (dandelion) and Cirsium arvense (Scop.) (creeping thistle) to have the highest pollinator visitation frequency and richness. Cichorium intybus (L.) (chichory) was highlighted as an important species having both high pollinator visitation and desirable agronomic properties. Increased sward richness was associated with an increase in the pollination of two phytometer species; Fragaria × ananassa (strawberry) and Silene dioica (red campion), but not Vicia faba (broad bean). Enhanced functional diversity, richness and abundance of the pollinator communities associated with more diverse neighbouring pastures were found to be potential mechanisms for improved pollination. Synthesis and applications. A modest increase in conventional grassland plant diversity with legumes and forbs, achievable with the expertise and resources available to most grassland farmers, could enhance pollinator functional diversity, richness and abundance. Moreover, our results suggest that this could improve pollination services and consequently surrounding crop yields (e.g. strawberry) and wildflower reproduction in agro-ecosystems

The Emerging Role of Protein Phosphorylation as a Critical Regulatory Mechanism Controlling Cellulose Biosynthesis

Plant cell walls are extracellular matrices that surround plant cells and critically influence basic cellular processes, such as cell division and expansion. Cellulose is a major constituent of plant cell walls, and this paracrystalline polysaccharide is synthesized at the plasma membrane by a large protein complex known as the cellulose synthase complex (CSC). Recent efforts have identified numerous protein components of the CSC, but relatively little is known about regulation of cellulose biosynthesis. Numerous phosphoproteomic surveys have identified phosphorylation events in CSC associated proteins, suggesting that protein phosphorylation may represent an important regulatory control of CSC activity. In this review, we discuss the composition and dynamics of the CSC in vivo, the catalogue of CSC phosphorylation sites that have been identified, the function of experimentally examined phosphorylation events, and potential kinases responsible for these phosphorylation events. Additionally, we discuss future directions in cellulose synthase kinase identification and functional analyses of CSC phosphorylation sites

Expressing functional siRNAs in mammalian cells using convergent transcription

BACKGROUND: The use of small interfering RNAs (siRNAs) as genetic inhibitors of gene expression has been shown to be an effective way of studying gene function in mammalian cells. Recently, different DNA vectors for expression of small hairpin RNAs (shRNAs) or co-expression of sense and antisense RNAs have been developed that direct siRNA-mediated gene silencing. One expression cassette design that has been used to express long sense and antisense RNAs in non-mammalian cell types is symmetric transcription using convergent promoters. However, convergent transcription as a way to generate functional siRNAs in mammalian cells has not been reported. This vector design permits the generation of expression constructs containing no repeat sequences, but capable of inducing RNA interference (RNAi)-mediated gene silencing. RESULTS: With the aim of simplifying the construction of RNAi expression vectors, we report on the production and application of a novel convergent promoter cassette capable of expressing sense and antisense RNAs, that form double-stranded RNA, and mediate gene silencing in mammalian cells. We use this cassette to inhibit the expression of both the EGFP transgene and the endogenous TP53 gene. The gene silencing effect is Dicer-dependent and the level of gene inactivation achieved is comparable to that produced with synthetic siRNA. Furthermore, this expression system can be used for both short and long-term control of specific gene expression in mammalian cells. CONCLUSION: The experiments performed in this study demonstrate that convergent transcription can be used in mammalian cells to invoke gene-specific silencing via RNAi. This method provides an alternative to expression of shRNAs and co-expression of sense and antisense RNAs from independent cassettes or a divergent promoter. The main advantage of the present vector design is the potential to produce a functional siRNA expression cassette with no repeat sequences. Furthermore, the cassette design reported is ideal for both routine use in controlling specific gene expression and construction of randomised RNAi expression libraries for use in unbiased forward genetic selections

Multivariate neuroanatomical classification of cognitive subtypes in schizophrenia: A support vector machine learning approach

AbstractHeterogeneity in the structural brain abnormalities associated with schizophrenia has made identification of reliable neuroanatomical markers of the disease difficult. The use of more homogenous clinical phenotypes may improve the accuracy of predicting psychotic disorder/s on the basis of observable brain disturbances. Here we investigate the utility of cognitive subtypes of schizophrenia – ‘cognitive deficit’ and ‘cognitively spared’ – in determining whether multivariate patterns of volumetric brain differences can accurately discriminate these clinical subtypes from healthy controls, and from each other. We applied support vector machine classification to grey- and white-matter volume data from 126 schizophrenia patients previously allocated to the cognitive spared subtype, 74 cognitive deficit schizophrenia patients, and 134 healthy controls. Using this method, cognitive subtypes were distinguished from healthy controls with up to 72% accuracy. Cross-validation analyses between subtypes achieved an accuracy of 71%, suggesting that some common neuroanatomical patterns distinguish both subtypes from healthy controls. Notably, cognitive subtypes were best distinguished from one another when the sample was stratified by sex prior to classification analysis: cognitive subtype classification accuracy was relatively low (<60%) without stratification, and increased to 83% for females with sex stratification. Distinct neuroanatomical patterns predicted cognitive subtype status in each sex: sex-specific multivariate patterns did not predict cognitive subtype status in the other sex above chance, and weight map analyses demonstrated negative correlations between the spatial patterns of weights underlying classification for each sex. These results suggest that in typical mixed-sex samples of schizophrenia patients, the volumetric brain differences between cognitive subtypes are relatively minor in contrast to the large common disease-associated changes. Volumetric differences that distinguish between cognitive subtypes on a case-by-case basis appear to occur in a sex-specific manner that is consistent with previous evidence of disrupted relationships between brain structure and cognition in male, but not female, schizophrenia patients. Consideration of sex-specific differences in brain organization is thus likely to assist future attempts to distinguish subgroups of schizophrenia patients on the basis of neuroanatomical features

Control of the stop band of an acoustic double fishnet

Copyright © 2013 Acoustical Society of AmericaThe acoustic transmittance of two closely spaced solid plates, each perforated with a square array of cylindrical holes, exhibits a band of near-perfect acoustic attenuation originating from hybridization between a resonance in the gap separating the plates and pipe resonances in the holes. Displacement of one plate relative to the other, such that the holes are no longer aligned, or an increase in the plate separation leads to an increased center frequency of the stop band. This ability to easily tune the frequency of the stop band may prove advantageous.The authors acknowledge funding of ARJM by EPSRC and Sonardyne International