Associations of time of day with cardiovascular disease risk factors measured in older men: results from the British Regional Heart Study.

OBJECTIVE: We estimated associations of time of day with cardiovascular disease (CVD) risk factors measured in older men. METHODS: CVD risk factors (markers of inflammation and haemostasis, and cardiac markers) were measured on one occasion between 08:00 and 19:00 hours in 4252 men aged 60-79 years from the British Regional Heart Study. Linear models were used to estimate associations between time of day and risk factors. When an association was found, we examined whether the relationship between risk factors and cardiovascular mortality was affected by the adjustment for time of day using survival analyses. RESULTS: N-terminal pro-brain natriuretic peptide (NT-proBNP) levels increased by 3.3% per hour (95% CI 1.9% to 4.8%), interleukin-6 (IL-6) increased by 2.6% per hour (95% CI 1.8% to 3.4%), while tissue plasminogen activator (t-PA) decreased by 3.3% per hour (95% CI 3.7% to 2.9%); these associations were unaffected by adjustment for possible confounding factors. The percentages of variation in these risk factors attributable to time of day were less than 2%. In survival analyses, the association of IL-6, NT-proBNP and t-PA with cardiovascular mortality was not affected by the adjustment for time of day. C reactive protein, fibrinogen, D-dimer, von Willebrand factor and cardiac troponin T showed no associations with time of day. CONCLUSIONS: In older men, markers of inflammation (IL-6), haemostasis (t-PA) and a cardiac marker (NT-proBNP) varied by time of day. The contribution of time of day to variations in these markers was small and did not appear to be relevant for the CVD risk prediction

Enforced expression of PPP1R13L increases tumorigenesis and invasion through p53-dependent and p53-independent mechanisms.

PPP1R13L was initially identified as a protein that binds to the NF-[kappa]B subunit p65/RelA and inhibits its transcriptional activity. It also binds p53 and inhibits its action. One set of experimental findings based on over-expression of PPP1R13L indicates that PPP1R13L blocks apoptosis. Another set of experiments, based on endogenous production of PPP1R13L, suggests that the protein may sometimes be pro-apoptotic. We have used primary mouse embryonic fibroblasts (MEFs), dually transformed by H-ras and Adenovirus E1A and differing in their p53 status, to explore the effects of PPP1R13L over-expression, thus examining the ability of PPP1R13L to act as an oncoprotein. We found that over-expression of PPP1R13L strongly accelerated tumor formation by ras/E1A and also resulted in an increased metastatic potential of the tumors. PPP1R13L over-expressing cells were depleted for both p53 and active p65/RelA and we found that both p53 dependent and independent apoptosis pathways were regulated by PPP1R13L. Finally, studies with the proteasome inhibitor MG132 revealed that over-expression of PPP1R13L causes faster p53 degradation, a likely explanation for the depletion of p53. Taken together, our results show that increased levels of PPP1R13L can increase tumorigenesis and furthermore pinpoint PPP1R13L as a gene that influences metastasis

Relationship between outdoor temperature and cardiovascular disease risk factors in older people.

Background Previous studies demonstrated that lower outdoor temperatures increase the levels of established cardiovascular disease risk factors, such as blood pressure and lipids. Whether or not low temperatures increase novel cardiovascular disease risk factors levels is not well studied. The aim was to investigate associations of outdoor temperature with a comprehensive range of established and novel cardiovascular disease risk factors in two large Northern European studies of older adults, in whom cardiovascular disease risk is increased. Design and methods Data came from the British Regional Heart Study (4252 men aged 60-79 years) and the Prospective Study of Pravastatin in the Elderly at Risk (5804 men and women aged 70-82 years). Associations between outdoor temperature and cardiovascular disease risk factors were quantified in each study and then pooled using a random effects model. Results With a 5℃ lower mean temperature, total cholesterol was 0.04 mmol/l (95% confidence interval (CI) 0.02-0.07) higher, low density lipoprotein cholesterol was 0.02 mmol/l (95% CI 0.01-0.05) higher and SBP was 1.12 mm Hg (95% CI 0.60-1.64) higher. Among novel cardiovascular disease risk factors, C-reactive protein was 3.3% (95% CI 1.0-5.6%) higher, interleukin-6 was 2.7% (95% CI 1.1-4.3%) higher, and vitamin D was 11.2% (95% CI 1.0-20.4%) lower. Conclusions Lower outdoor temperature was associated with adverse effects on cholesterol, blood pressure, circulating inflammatory markers, and vitamin D in two older populations. Public health approaches to protect the elderly against low temperatures could help in reducing the levels of several cardiovascular disease risk factors

Interleukin 18 and coronary heart disease: Prospective study and systematic review

Aim Previous studies suggest that circulating levels of interleukin-18 (IL-18) may be prospectively related to risk of coronary heart disease (CHD) in the general population. We report new data from the largest prospective study to date, which are combined with data from all published prospective studies in a meta-analysis. Methods We measured baseline IL-18 levels in stored serum samples of subjects from a case–control study nested within a prospective study of 5661 men aged 40–59 years recruited from general practices in 18 British towns in 1978–1980 and followed-up for up to 16 years (median time to event 8.4 years) for fatal CHD and non-fatal myocardial infarction (595 cases, 1238 controls). Results IL-18 concentrations were strongly related to cigarette smoking, triglyceride, HDL-cholesterol (inversely) and to circulating levels of several inflammatory and haemostatic markers. Men in the top third of baseline IL-18 levels had an age-adjusted odds ratio (OR) for CHD of 1.55 (95% CI 1.21, 1.98) compared with those in the lowest third; this was reduced to 1.30 (95% CI 0.99, 1.69) after additional adjustment for vascular risk factors and 1.12 (95% CI 0.84, 1.49) after further adjustment for CRP and IL-6. In meta-analyses of CVD, associations (or effect sizes) were consistent between studies; RRs were 1.63 (95% CI 1.46, 1.82) after age adjustment, 1.39 (95% CI 1.24, 1.55) after additional risk factor adjustment and 1.34 (95% CI 1.17, 1.54) after additional adjustment for inflammatory markers. Conclusions Circulating IL-18 is prospectively and independently associated with CVD risk

The Rx for Change database: a first-in-class tool for optimal prescribing and medicines use

<p>Abstract</p> <p>Background</p> <p>Globally, suboptimal prescribing practices and medication errors are common. Guidance to health professionals and consumers alone is not sufficient to optimise behaviours, therefore strategies to promote evidence-based decision making and practice, such as decision support tools or reminders, are important. The literature in this area is growing, but is of variable quality and dispersed across sources, which makes it difficult to identify, access, and assess. To overcome these problems, by synthesizing and evaluating the data from systematic reviews, we have developed <it>Rx for Change </it>to provide a comprehensive, online database of the evidence for strategies to improve drug prescribing and use.</p> <p>Methods</p> <p>We use reliable and valid methods to search and screen the literature, and to appraise and analyse the evidence from relevant systematic reviews. We then present the findings in an online format which allows users to easily access pertinent information related to prescribing and medicines use. The database is a result of the collaboration between the Canadian Agency for Drugs and Technologies in Health (CADTH) and two Cochrane review groups.</p> <p>Results</p> <p>To capture the body of evidence on interventions to improve prescribing and medicines use, we conduct comprehensive and regular searches in multiple databases, and hand-searches of relevant journals. We screen articles to identify relevant systematic reviews, and include them if they are of moderate or high methodological quality. Two researchers screen, assess quality, and extract data on demographic details, intervention characteristics, and outcome data. We report the results of our analysis of each systematic review using a standardised quantitative and qualitative format. <it>Rx for Change </it>currently contains over 200 summarised reviews, structured in a multi-level format. The reviews included in the database are diverse, covering various settings, conditions, or diseases and targeting a range of professional and consumer behaviors.</p> <p>Conclusions</p> <p><it>Rx for Change </it>is a novel database that synthesizes current research evidence about the effects of interventions to improve drug prescribing practices and medicines use.</p

A gene-centric analysis of activated partial thromboplastin time and activated protein C resistance using the HumanCVD focused genotyping array.

Activated partial thromboplastin time (aPTT) is an important routine measure of intrinsic blood coagulation. Addition of activated protein C (APC) to the aPTT test to produce a ratio, provides one measure of APC resistance. The associations of some genetic mutations (eg, factor V Leiden) with these measures are established, but associations of other genetic variations remain to be established. The objective of this work was to test for association between genetic variants and blood coagulation using a high-density genotyping array. Genetic association with aPTT and APC resistance was analysed using a focused genotyping array that tests approximately 50 000 single-nucleotide polymorphisms (SNPs) in nearly 2000 cardiovascular candidate genes, including coagulation pathway genes. Analyses were conducted on 2544 European origin women from the British Women's Heart and Health Study. We confirm associations with aPTT at the coagulation factor XII (F12)/G protein-coupled receptor kinase 6 (GRK6) and kininogen 1 (KNG1)/histidine-rich glycoprotein (HRG) loci, and identify novel SNPs at the ABO locus and novel locus kallikrein B (KLKB1)/F11. In addition, we confirm association between APC resistance and factor V Leiden mutation, and identify novel SNP associations with APC resistance in the HRG and F5/solute carrier family 19 member 2 (SLC19A2) regions. In conclusion, variation at several genetic loci influences intrinsic blood coagulation as measured by both aPTT and APC resistance

Zinc intake, status and indices of cognitive function in adults and children: a systematic review and meta-analysis

In developing countries, deficiencies of micronutrients are thought to have a major impact on child development; however, a consensus on the specific relationship between dietary zinc intake and cognitive function remains elusive. The aim of this systematic review was to examine the relationship between zinc intake, status and indices of cognitive function in children and adults. A systematic literature search was conducted using EMBASE, MEDLINE and Cochrane Library databases from inception to March 2014. Included studies were those that supplied zinc as supplements or measured dietary zinc intake. A meta-analysis of the extracted data was performed where sufficient data were available. Of all of the potentially relevant papers, 18 studies met the inclusion criteria, 12 of which were randomised controlled trials (RCTs; 11 in children and 1 in adults) and 6 were observational studies (2 in children and 4 in adults). Nine of the 18 studies reported a positive association between zinc intake or status with one or more measure of cognitive function. Meta-analysis of data from the adult’s studies was not possible because of limited number of studies. A meta-analysis of data from the six RCTs conducted in children revealed that there was no significant overall effect of zinc intake on any indices of cognitive function: intelligence, standard mean difference of <0.001 (95% confidence interval (CI) –0.12, 0.13) P=0.95; executive function, standard mean difference of 0.08 (95% CI, –0.06, 022) P=0.26; and motor skills standard mean difference of 0.11 (95% CI –0.17, 0.39) P=0.43. Heterogeneity in the study designs was a major limitation, hence only a small number (n=6) of studies could be included in the meta-analyses. Meta-analysis failed to show a significant effect of zinc supplementation on cognitive functioning in children though, taken as a whole, there were some small indicators of improvement on aspects of executive function and motor development following supplementation but high-quality RCTs are necessary to investigate this further

FMRI resting slow fluctuations correlate with the activity of fast cortico-cortical physiological connections

Recording of slow spontaneous fluctuations at rest using functional magnetic resonance imaging (fMRI) allows distinct long-range cortical networks to be identified. The neuronal basis of connectivity as assessed by resting-state fMRI still needs to be fully clarified, considering that these signals are an indirect measure of neuronal activity, reflecting slow local variations in de-oxyhaemoglobin concentration. Here, we combined fMRI with multifocal transcranial magnetic stimulation (TMS), a technique that allows the investigation of the causal neurophysiological interactions occurring in specific cortico-cortical connections. We investigated whether the physiological properties of parieto-frontal circuits mapped with short-latency multifocal TMS at rest may have some relationship with the resting-state fMRI measures of specific resting-state functional networks (RSNs). Results showed that the activity of fast cortico-cortical physiological interactions occurring in the millisecond range correlated selectively with the coupling of fMRI slow oscillations within the same cortical areas that form part of the dorsal attention network, i.e., the attention system believed to be involved in reorientation of attention. We conclude that resting-state fMRI ongoing slow fluctuations likely reflect the interaction of underlying physiological cortico-cortical connections

RNA-Seq improves annotation of protein-coding genes in the cucumber genome

<p>Abstract</p> <p>Background</p> <p>As more and more genomes are sequenced, genome annotation becomes increasingly important in bridging the gap between sequence and biology. Gene prediction, which is at the center of genome annotation, usually integrates various resources to compute consensus gene structures. However, many newly sequenced genomes have limited resources for gene predictions. In an effort to create high-quality gene models of the cucumber genome (<it>Cucumis sativus </it>var. <it>sativus</it>), based on the EVidenceModeler gene prediction pipeline, we incorporated the massively parallel complementary DNA sequencing (RNA-Seq) reads of 10 cucumber tissues into EVidenceModeler. We applied the new pipeline to the reassembled cucumber genome and included a comparison between our predicted protein-coding gene sets and a published set.</p> <p>Results</p> <p>The reassembled cucumber genome, annotated with RNA-Seq reads from 10 tissues, has 23, 248 identified protein-coding genes. Compared with the published prediction in 2009, approximately 8, 700 genes reveal structural modifications and 5, 285 genes only appear in the reassembled cucumber genome. All the related results, including genome sequence and annotations, are available at <url>http://cmb.bnu.edu.cn/Cucumis_sativus_v20/</url>.</p> <p>Conclusions</p> <p>We conclude that RNA-Seq greatly improves the accuracy of prediction of protein-coding genes in the reassembled cucumber genome. The comparison between the two gene sets also suggests that it is feasible to use RNA-Seq reads to annotate newly sequenced or less-studied genomes.</p

Stage-Specific Inhibition of MHC Class I Presentation by the Epstein-Barr Virus BNLF2a Protein during Virus Lytic Cycle

gamma-herpesvirus Epstein-Barr virus (EBV) persists for life in infected individuals despite the presence of a strong immune response. During the lytic cycle of EBV many viral proteins are expressed, potentially allowing virally infected cells to be recognized and eliminated by CD8+ T cells. We have recently identified an immune evasion protein encoded by EBV, BNLF2a, which is expressed in early phase lytic replication and inhibits peptide- and ATP-binding functions of the transporter associated with antigen processing. Ectopic expression of BNLF2a causes decreased surface MHC class I expression and inhibits the presentation of indicator antigens to CD8+ T cells. Here we sought to examine the influence of BNLF2a when expressed naturally during EBV lytic replication. We generated a BNLF2a-deleted recombinant EBV (ΔBNLF2a) and compared the ability of ΔBNLF2a and wild-type EBV-transformed B cell lines to be recognized by CD8+ T cell clones specific for EBV-encoded immediate early, early and late lytic antigens. Epitopes derived from immediate early and early expressed proteins were better recognized when presented by ΔBNLF2a transformed cells compared to wild-type virus transformants. However, recognition of late antigens by CD8+ T cells remained equally poor when presented by both wild-type and ΔBNLF2a cell targets. Analysis of BNLF2a and target protein expression kinetics showed that although BNLF2a is expressed during early phase replication, it is expressed at a time when there is an upregulation of immediate early proteins and initiation of early protein synthesis. Interestingly, BNLF2a protein expression was found to be lost by late lytic cycle yet ΔBNLF2a-transformed cells in late stage replication downregulated surface MHC class I to a similar extent as wild-type EBV-transformed cells. These data show that BNLF2a-mediated expression is stage-specific, affecting presentation of immediate early and early proteins, and that other evasion mechanisms operate later in the lytic cycle