Non-homologous end-joining pathway associated with occurrence of myocardial infarction: gene set analysis of genome-wide association study data

<p>Purpose: DNA repair deficiencies have been postulated to play a role in the development and progression of cardiovascular disease (CVD). The hypothesis is that DNA damage accumulating with age may induce cell death, which promotes formation of unstable plaques. Defects in DNA repair mechanisms may therefore increase the risk of CVD events. We examined whether the joints effect of common genetic variants in 5 DNA repair pathways may influence the risk of CVD events.</p> <p>Methods: The PLINK set-based test was used to examine the association to myocardial infarction (MI) of the DNA repair pathway in GWAS data of 866 subjects of the GENetic DEterminants of Restenosis (GENDER) study and 5,244 subjects of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. We included the main DNA repair pathways (base excision repair, nucleotide excision repair, mismatch repair, homologous recombination and non-homologous end-joining (NHEJ)) in the analysis.</p> <p>Results: The NHEJ pathway was associated with the occurrence of MI in both GENDER (P = 0.0083) and PROSPER (P = 0.014). This association was mainly driven by genetic variation in the MRE11A gene (PGENDER = 0.0001 and PPROSPER = 0.002). The homologous recombination pathway was associated with MI in GENDER only (P = 0.011), for the other pathways no associations were observed.</p> <p>Conclusion: This is the first study analyzing the joint effect of common genetic variation in DNA repair pathways and the risk of CVD events, demonstrating an association between the NHEJ pathway and MI in 2 different cohorts.</p&gt

Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition

Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modelling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4BY358C mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioural assays, PDE4BY358C mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4BY358C mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 hours, was decreased at 7 days in PDE4BY358C mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signalling by PDE4B in a very late phase of consolidation. No effect of the PDE4BY358C mutation was observed in the pre-pulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory

Screen-detected colorectal cancers are associated with an improved outcome compared with stage-matched interval cancers

Background: Colorectal cancers (CRCs) detected through the NHS Bowel Cancer Screening Programme (BCSP) have been shown to have a more favourable outcome compared to non-screen-detected cancers. The aim was to identify whether this was solely due to the earlier stage shift of these cancers, or whether other factors were involved. Methods: A combination of a regional CRC registry (Northern Colorectal Cancer Audit Group) and the BCSP database were used to identify screen-detected and interval cancers (diagnosed after a negative faecal occult blood test, before the next screening round), diagnosed between April 2007 and March 2010, within the North East of England. For each Dukes' stage, patient demographics, tumour characteristics, and survival rates were compared between these two groups. Results: Overall, 322 screen-detected cancers were compared against 192 interval cancers. Screen-detected Dukes' C and D CRCs had a superior survival rate compared with interval cancers (P=0.014 and P=0.04, respectively). Cox proportional hazards regression showed that Dukes' stage, tumour location, and diagnostic group (HR 0.45, 95% CI 0.29-0.69, P<0.001 for screen-detected CRCs) were all found to have a significant impact on the survival of patients. Conclusions: The improved survival of screen-detected over interval cancers for stages C and D suggest that there may be a biological difference in the cancers in each group. Although lead-time bias may have a role, this may be related to a tumour's propensity to bleed and therefore may reflect detection through current screening tests

Design, fabrication and control of soft robots

Conventionally, engineers have employed rigid materials to fabricate precise, predictable robotic systems, which are easily modelled as rigid members connected at discrete joints. Natural systems, however, often match or exceed the performance of robotic systems with deformable bodies. Cephalopods, for example, achieve amazing feats of manipulation and locomotion without a skeleton; even vertebrates such as humans achieve dynamic gaits by storing elastic energy in their compliant bones and soft tissues. Inspired by nature, engineers have begun to explore the design and control of soft-bodied robots composed of compliant materials. This Review discusses recent developments in the emerging field of soft robotics.National Science Foundation (U.S.) (Grant IIS-1226883

Survival benefits of statins for primary prevention: a cohort study

Objectives: Estimate the effect of statin prescription on mortality in the population of England and Wales with no previous history of cardiovascular disease.  Methods: Primary care records from The Health Improvement Network 1987-2011 were used.Four cohorts of participants aged 60, 65, 70, or 75 years at baseline included 118,700,199,574, 247,149, and 194,085 participants; and 1.4, 1.9, 1.8, and 1.1 million person-years of data, respectively. The exposure was any statin prescription at any time before the participant reached the baseline age (60, 65, 70 or 75) and the outcome was all-cause mortality at any age above the baseline age. The hazard of mortality associated with statin prescription was calculated by Cox's proportional hazard regressions, adjusted for sex, year of birth, socioeconomic status, diabetes,antihypertensive medication, hypercholesterolaemia, body mass index, smoking status, and general practice. Participants were grouped by QRISK2 baseline risk of afirst cardiovascular event in the next ten years of <10%, 10-19%, or ≥20%.  Results: There was no reduction in all-cause mortality for statin prescription initiated in participants with a QRISK2 score <10% at any baseline age, or in participants aged 60at baseline in any risk group. Mortality was lower in participants with a QRISK2 score≥20% if statin prescription had been initiated by age 65 (adjusted hazard ratio (HR)0.86 (0.79-0.94)), 70 (HR 0.83 (0.79-0.88)), or 75 (HR 0.82 (0.79-0.86)). Mortality reduction was uncertain with a QRISK2 score of 10-19%: the HR was 1.00 (0.91-1.11)for statin prescription by age 65, 0.89 (0.81-0.99) by age 70, or 0.79 (0.52-1.19) by age75.  Conclusions: The current internationally recommended thresholds for statin therapy for primary prevention of cardiovascular disease in routine practice may be too low and may lead to overtreatment of younger people and those at low risk

Neuroanatomical Abnormalities in Violent Individuals with and without a Diagnosis of Schizophrenia

Several structural brain abnormalities have been associated with aggression in patients with schizophrenia. However, little is known about shared and distinct abnormalities underlying aggression in these subjects and non-psychotic violent individuals. We applied a region-of interest volumetric analysis of the amygdala, hippocampus, and thalamus bilaterally, as well as whole brain and ventricular volumes to investigate violent (n = 37) and non-violent chronic patients (n = 26) with schizophrenia, non-psychotic violent (n = 24) as well as healthy control subjects (n = 24). Shared and distinct volumetric abnormalities were probed by analysis of variance with the factors violence (non-violent versus violent) and diagnosis (non-psychotic versus psychotic), adjusted for substance abuse, age, academic achievement and negative psychotic symptoms. Patients showed elevated vCSF volume, smaller left hippocampus and smaller left thalamus volumes. This was particularly the case for non-violent individuals diagnosed with schizophrenia. Furthermore, patients had reduction in right thalamus size. With regard to left amygdala, we found an interaction between violence and diagnosis. More specifically, we report a double dissociation with smaller amygdala size linked to violence in non-psychotic individuals, while for psychotic patients smaller size was linked to non-violence. Importantly, the double dissociation appeared to be mostly driven by substance abuse. Overall, we found widespread morphometric abnormalities in subcortical regions in schizophrenia. No evidence for shared volumetric abnormalities in individuals with a history of violence was found. Finally, left amygdala abnormalities in non-psychotic violent individuals were largely accounted for by substance abuse. This might be an indication that the association between amygdala reduction and violence is mediated by substance abuse. Our results indicate the importance of structural abnormalities in aggressive individuals

A review of the distribution of particulate trace elements in urban terrestrial environments and its application to considerations of risk

We review the evolution, state of the art and future lines of research on the sources, transport pathways, and sinks of particulate trace elements in urban terrestrial environments to include the atmosphere, soils, and street and indoor dusts. Such studies reveal reductions in the emissions of some elements of historical concern such as Pb, with interest consequently focusing on other toxic trace elements such as As, Cd, Hg, Zn, and Cu. While establishment of levels of these elements is important in assessing the potential impacts of human society on the urban environment, it is also necessary to apply this knowledge in conjunction with information on the toxicity of those trace elements and the degree of exposure of human receptors to an assessment of whether such contamination represents a real risk to the city’s inhabitants and therefore how this risk can be addressed

Determination of the number of J/ψ events with J/ψ → inclusive decays

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