Alcohol affects neuronal substrates of response inhibition but not of perceptual processing of stimuli signalling a stop response

Alcohol impairs inhibitory control, including the ability to terminate an initiated action. While there is increasing knowledge about neural mechanisms involved in response inhibition, the level at which alcohol impairs such mechanisms remains poorly understood. Thirty-nine healthy social drinkers received either 0.4g/kg or 0.8g/kg of alcohol, or placebo, and performed two variants of a Visual Stop-signal task during acquisition of functional magnetic resonance imaging (fMRI) data. The two task variants differed only in their instructions: in the classic variant (VSST), participants inhibited their response to a “Go-stimulus” when it was followed by a “Stop-stimulus”. In the control variant (VSST_C), participants responded to the “Go-stimulus” even if it was followed by a “Stop-stimulus”. Comparison of successful Stop-trials (Sstop)>Go, and unsuccessful Stop-trials (Ustop)>Sstop between the three beverage groups enabled the identification of alcohol effects on functional neural circuits supporting inhibitory behaviour and error processing. Alcohol impaired inhibitory control as measured by the Stop-signal reaction time, but did not affect other aspects of VSST performance, nor performance on the VSST_C. The low alcohol dose evoked changes in neural activity within prefrontal, temporal, occipital and motor cortices. The high alcohol dose evoked changes in activity in areas affected by the low dose but importantly induced changes in activity within subcortical centres including the globus pallidus and thalamus. Alcohol did not affect neural correlates of perceptual processing of infrequent cues, as revealed by conjunction analyses of VSST and VSST_C tasks. Alcohol ingestion compromises the inhibitory control of action by modulating cortical regions supporting attentional, sensorimotor and action-planning processes. At higher doses the impact of alcohol also extends to affect subcortical nodes of fronto-basal ganglia- thalamo-cortical motor circuits. In contrast, alcohol appears to have little impact on the early visual processing of infrequent perceptual cues. These observations clarify clinically-important effects of alcohol on behaviour

Effects of oxidized low density lipoprotein, lipid mediators and statins on vascular cell interactions

The integrin heterodimer CD11b/CD18 (alpha M beta 2, Mac-1, CR3) expressed on monocytes or polymorphonuclear leukocytes (PMN) is a receptor for iC3b, fibrinogen, heparin, and for intercellular adhesion molecule (ICAM)-1 on endothelium, crucially contributing to vascular cell interactions in inflammation and atherosclerosis. In this report, we summarize our findings on the effects of lipid mediators and lipid-lowering drugs. Exposure of endothelial cells to oxidized low density lipoprotein (oxLDL) induces upregulation of ICAM-1 and increases adhesion of monocytic cells expressing Mac-1. Inhibition experiments show that monocytes use distinct ligands, i.e. ICAM-1 and heparan sulfate proteoglycans for adhesion to oxLDL-treated endothelium. An albumin-transferable oxLDL activity is inhibited by the antioxidant pyrrolidine dithiocarbamate (PDTC), while 8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) or lysophosphatidylcholine had no effect, implicating yet unidentified radicals. Sequential adhesive! and signaling events lead to the firm adhesion of rolling PMN on activated and adherent platelets, which may occupy areas of endothelial denudation. Shear resistant arrest of PMN on thrombin-stimulated platelets in flow conditions requires distinct regions of Mac-1, involving its interactions with fibrinogen bound to platelet alpha llb beta 3, and with other platelet ligands. Both arrest and adhesion strengthening under flow are stimulated by platelet-activating factor and leukotriene B4, but not by the chemokine receptor CXCR2. We tested whether Mac-1-dependent monocyte adhesiveness is affected by inhibitors of hydroxy-methylglutaryl-Coenzyme A reductase (statins) which improve morbidity and survival of patients with coronary heart disease. As compared to controls, adhesion of isolated monocytes to endothelium ex vivo was increased in patients with hypercholesterolemia. Treatment with statins decreased total and low density lipoprotein (LDL) cholesterol plasma levels, surface expression of Mac-1, and resulted in a dramatic reduction of Mac,mediated monocyte adhesion to endothelium. The inhibition of monocyte adhesion was reversed by mevalonate but not LDL in vitro,indicating that isoprenoid precursors are crucial for adhesiveness of Mac-1. Such effects may crucially contribute to the clinical benefit of statins, independent of cholesterol-lowering, and may represent a paradigm for novel, anti-inflammatory mechanisms of action by this class of drugs

Does physical activity counselling enhance the effects of a pedometer-based intervention over the long-term : 12-month findings from the Walking for Wellbeing in the West study

Peer reviewedPublisher PD

Pneumococcal carriage in sub-Saharan Africa--a systematic review.

BACKGROUND: Pneumococcal epidemiology varies geographically and few data are available from the African continent. We assess pneumococcal carriage from studies conducted in sub-Saharan Africa (sSA) before and after the pneumococcal conjugate vaccine (PCV) era. METHODS: A search for pneumococcal carriage studies published before 2012 was conducted to describe carriage in sSA. The review also describes pneumococcal serotypes and assesses the impact of vaccination on carriage in this region. RESULTS: Fifty-seven studies were included in this review with the majority (40.3%) from South Africa. There was considerable variability in the prevalence of carriage between studies (I-squared statistic = 99%). Carriage was higher in children and decreased with increasing age, 63.2% (95% CI: 55.6-70.8) in children less than 5 years, 42.6% (95% CI: 29.9-55.4) in children 5-15 years and 28.0% (95% CI: 19.0-37.0) in adults older than 15 years. There was no difference in the prevalence of carriage between males and females in 9/11 studies. Serotypes 19F, 6B, 6A, 14 and 23F were the five most common isolates. A meta-analysis of four randomized trials of PCV vaccination in children aged 9-24 months showed that carriage of vaccine type (VT) serotypes decreased with PCV vaccination; however, overall carriage remained the same because of a concomitant increase in non-vaccine type (NVT) serotypes. CONCLUSION: Pneumococcal carriage is generally high in the African continent, particularly in young children. The five most common serotypes in sSA are among the top seven serotypes that cause invasive pneumococcal disease in children globally. These serotypes are covered by the two PCVs recommended for routine childhood immunization by the WHO. The distribution of serotypes found in the nasopharynx is altered by PCV vaccination

Population-Based Precision Cancer Screening: A Symposium on Evidence, Epidemiology, and Next Steps

Precision medicine, an emerging approach for disease treatment that takes into account individual variability in genes, environment, and lifestyle, is under consideration for preventive interventions, including cancer screening. On September 29, 2015, the National Cancer Institute sponsored a symposium entitled “Precision Cancer Screening in the General Population: Evidence, Epidemiology, and Next Steps”. The goal was two-fold: to share current information on the evidence, practices, and challenges surrounding precision screening for breast, cervical, colorectal, lung, and prostate cancers, and to allow for in-depth discussion among experts in relevant fields regarding how epidemiology and other population sciences can be used to generate evidence to inform precision screening strategies. Attendees concluded that the strength of evidence for efficacy and effectiveness of precision strategies varies by cancer site, that no one research strategy or methodology would be able or appropriate to address the many knowledge gaps in precision screening, and that issues surrounding implementation must be researched as well. Additional discussion needs to occur to identify the high priority research areas in precision cancer screening for pertinent organs and to gather the necessary evidence to determine whether further implementation of precision cancer screening strategies in the general population would be feasible and beneficial

R^4 counterterm and E7(7) symmetry in maximal supergravity

The coefficient of a potential R^4 counterterm in N=8 supergravity has been shown previously to vanish in an explicit three-loop calculation. The R^4 term respects N=8 supersymmetry; hence this result poses the question of whether another symmetry could be responsible for the cancellation of the three-loop divergence. In this article we investigate possible restrictions from the coset symmetry E7(7)/SU(8), exploring the limits as a single scalar becomes soft, as well as a double-soft scalar limit relation derived recently by Arkani-Hamed et al. We implement these relations for the matrix elements of the R^4 term that occurs in the low-energy expansion of closed-string tree-level amplitudes. We find that the matrix elements of R^4 that we investigated all obey the double-soft scalar limit relation, including certain non-maximally-helicity-violating six-point amplitudes. However, the single-soft limit does not vanish for this latter set of amplitudes, which suggests that the E7(7) symmetry is broken by the R^4 term.Comment: 33 pages, typos corrected, published versio

Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease

Nonequilibrium Singlet-Triplet Kondo Effect in Carbon Nanotubes

The Kondo-effect is a many-body phenomenon arising due to conduction electrons scattering off a localized spin. Coherent spin-flip scattering off such a quantum impurity correlates the conduction electrons and at low temperature this leads to a zero-bias conductance anomaly. This has become a common signature in bias-spectroscopy of single-electron transistors, observed in GaAs quantum dots as well as in various single-molecule transistors. While the zero-bias Kondo effect is well established it remains uncertain to what extent Kondo correlations persist in non-equilibrium situations where inelastic processes induce decoherence. Here we report on a pronounced conductance peak observed at finite bias-voltage in a carbon nanotube quantum dot in the spin singlet ground state. We explain this finite-bias conductance anomaly by a nonequilibrium Kondo-effect involving excitations into a spin triplet state. Excellent agreement between calculated and measured nonlinear conductance is obtained, thus strongly supporting the correlated nature of this nonequilibrium resonance.Comment: 21 pages, 5 figure

Integrating the promotion of physical activity within a smoking cessation programme: Findings from collaborative action research in UK Stop Smoking Services

Background: Within the framework of collaborative action research, the aim was to explore the feasibility of developing and embedding physical activity promotion as a smoking cessation aid within UK 6/7-week National Health Service (NHS) Stop Smoking Services. Methods: In Phase 1 three initial cycles of collaborative action research (observation, reflection, planning, implementation and re-evaluation), in an urban Stop Smoking Service, led to the development of an integrated intervention in which physical activity was promoted as a cessation aid, with the support of a theoretically based self-help guide, and self monitoring using pedometers. In Phase 2 advisors underwent training and offered the intervention, and changes in physical activity promoting behaviour and beliefs were monitored. Also, changes in clients’ stage of readiness to use physical activity as a cessation aid, physical activity beliefs and behaviour and physical activity levels were assessed, among those who attended the clinic at 4-week post-quit. Qualitative data were collected, in the form of clinic observation, informal interviews with advisors and field notes. Results: The integrated intervention emerged through cycles of collaboration as something quite different to previous practice. Based on field notes, there were many positive elements associated with the integrated intervention in Phase 2. Self-reported advisors’ physical activity promoting behaviour increased as a result of training and adapting to the intervention. There was a significant advancement in clients’ stage of readiness to use physical activity as a smoking cessation aid. Conclusions: Collaboration with advisors was key in ensuring that a feasible intervention was developed as an aid to smoking cessation. There is scope to further develop tailored support to increasing physical activity and smoking cessation, mediated through changes in perceptions about the benefits of, and confidence to do physical activity

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies