Platelet function and ageing

There are clear age-related changes in platelet count and function, driven by changes in hematopoietic tissue, the composition of the blood and vascular health. Platelet count remains relatively stable during middle age (25–60 years old) but falls in older people. The effect of age on platelet function is slightly less clear. The longstanding view is that platelet reactivity increases with age in an almost linear fashion. There are, however, serious limitations to the data supporting this dogma. We can conclude that platelet function increases during middle age, but little evidence exists on the changes in platelet responsiveness in old age (>75 years old). This change in platelet function is driven by differential mRNA and microRNA expression, an increase in oxidative stress and changes in platelet receptors. These age-related changes in platelets are particularly pertinent given that thrombotic disease and use of anti-platelet drugs is much more prevalent in the elderly population, yet the majority of platelet research is carried out in young to middle-aged (20–50 years old) human volunteers and young mice (2–6 months old). We know relatively little about exactly how platelets from people over 75 years old differ from those of middle-aged subjects, and we know even less about the mechanisms that drive these changes. Addressing these gaps in our knowledge will provide substantial understanding in how cell signalling changes during ageing and will enable the development of more precise anti-platelet therapies

Calculation of the free-free transitions in the electron-hydrogen scattering S-wave model

The S-wave model of electron-hydrogen scattering is evaluated using the convergent close-coupling method with an emphasis on scattering from excited states including an initial state from the target continuum. Convergence is found for discrete excitations and the elastic free-free transition. The latter is particularly interesting given the corresponding potential matrix elements are divergent

A model-based assessment of the cost-utility of strategies to identify Lynch syndrome in early-onset colorectal cancer patients.

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.BACKGROUND: Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2. Individuals with Lynch syndrome have an increased risk of colorectal cancer, endometrial cancer, ovarian and other cancers. Lynch syndrome remains underdiagnosed in the UK. Reflex testing for Lynch syndrome in early-onset colorectal cancer patients is proposed as a method to identify more families affected by Lynch syndrome and offer surveillance to reduce cancer risks, although cost-effectiveness is viewed as a barrier to implementation. The objective of this project was to estimate the cost-utility of strategies to identify Lynch syndrome in individuals with early-onset colorectal cancer in the NHS. METHODS: A decision analytic model was developed which simulated diagnostic and long-term outcomes over a lifetime horizon for colorectal cancer patients with and without Lynch syndrome and for relatives of those patients. Nine diagnostic strategies were modelled which included microsatellite instability (MSI) testing, immunohistochemistry (IHC), BRAF mutation testing (methylation testing in a scenario analysis), diagnostic mutation testing and Amsterdam II criteria. Biennial colonoscopic surveillance was included for individuals diagnosed with Lynch syndrome and accepting surveillance. Prophylactic hysterectomy with bilateral salpingo-oophorectomy (H-BSO) was similarly included for women diagnosed with Lynch syndrome. Costs from NHS and Personal Social Services perspective and quality-adjusted life years (QALYs) were estimated and discounted at 3.5% per annum. RESULTS: All strategies included for the identification of Lynch syndrome were cost-effective versus no testing. The strategy with the greatest net health benefit was MSI followed by BRAF followed by diagnostic genetic testing, costing £5,491 per QALY gained over no testing. The effect of prophylactic H-BSO on health-related quality of life (HRQoL) is uncertain and could outweigh the health benefits of testing, resulting in overall QALY loss. CONCLUSIONS: Reflex testing for Lynch syndrome in early-onset colorectal cancer patients is predicted to be a cost-effective use of limited financial resources in England and Wales. Research is recommended into the cost-effectiveness of reflex testing for Lynch syndrome in other associated cancers and into the impact of prophylactic H-BSO on HRQoL.NIH

Reprocessing with GANEX:Methodology for Ligand Radiation Tolerance Testing

Results demonstrating the methodology for testing the radiation tolerance of organic ligands are presented. A high activity sealed source was used to irradiate samples which were sequentially removed and analysed using a sensitive mass spectrometer. The degradation of a candidate ligand for a new reprocessing process “GANEX” was found to be around 50% after 567 kGy exposure to gamma from Cs-137.<br/

Tangeretin regulates platelet function through inhibition of phosphoinositide 3-Kinase and cyclic nucleotide signaling

OBJECTIVE: Dietary flavonoids have long been appreciated in reducing cardiovascular disease risk factors, but their mechanisms of action are complex in nature. In this study, the effects of tangeretin, a dietary flavonoid, were explored on platelet function, signaling, and hemostasis. APPROACH AND RESULTS: Tangeretin inhibited agonist-induced human platelet activation in a concentration-dependent manner. It inhibited agonist-induced integrin αIIbβ3 inside-out and outside-in signaling, intracellular calcium mobilization, and granule secretion. Tangeretin also inhibited human platelet adhesion and subsequent thrombus formation on collagen-coated surfaces under arterial flow conditions in vitro and reduced hemostasis in mice. Further characterization to explore the mechanism by which tangeretin inhibits platelet function revealed distinctive effects of platelet signaling. Tangeretin was found to inhibit phosphoinositide 3-kinase-mediated signaling and increase cGMP levels in platelets, although phosphodiesterase activity was unaffected. Consistent with increased cGMP levels, tangeretin increased the phosphorylation of vasodilator-stimulated phosphoprotein at S239. CONCLUSIONS: This study provides support for the ability and mechanisms of action of dietary flavonoids to modulate platelet signaling and function, which may affect the risk of thrombotic disease

A high-density immunoblotting methodology for quantification of total protein levels and phosphorylation modifications

The components of many signaling pathways have been identified and there is now a need to conduct quantitative data-rich temporal experiments for systems biology and modeling approaches to better understand pathway dynamics and regulation. Here we present a modified Western blotting method that allows the rapid and reproducible quantification and analysis of hundreds of data points per day on proteins and their phosphorylation state at individual sites. The approach is of particular use where samples show a high degree of sample-to-sample variability such as primary cells from multiple donors. We present a case study on the analysis of >800 phosphorylation data points from three phosphorylation sites in three signaling proteins over multiple time points from platelets isolated from ten donors, demonstrating the technique's potential to determine kinetic and regulatory information from limited cell numbers and to investigate signaling variation within a population. We envisage the approach being of use in the analysis of many cellular processes such as signaling pathway dynamics to identify regulatory feedback loops and the investigation of potential drug/inhibitor responses, using primary cells and tissues, to generate information about how a cell's physiological state changes over time

Comparison of resource use by COPD patients on inhaled therapies with long-acting bronchodilators: a database study

<p>Abstract</p> <p>Background</p> <p>The purpose of this analysis was to compare health care costs and utilization among COPD patients who had long-acting beta-2 agonist (LABA) OR long-acting muscarinic antagonist (LAMA); LABA AND LAMA; or LABA, LAMA, AND inhaled corticosteroid (ICS) prescription claims.</p> <p>Methods</p> <p>This was a 12 month pre-post, retrospective analysis using COPD patients in a national administrative insurance database. Propensity score and exact matching were used to match patients 1:1:1 between the LABA or LAMA (formoterol, salmeterol, or tiotropium), LABA and LAMA (tiotropium/formoterol or tiotropium/salmeterol), and LABA, LAMA and ICS (bronchodilators plus steroid) groups. Post-period comparisons were evaluated with analysis of covariance. Costs were evaluated from a commercial payer perspective.</p> <p>Results</p> <p>A total of 523 patients were matched using 29 pre-period variables (e.g., demographics, medication exposure). Post-match assessments indicated balance among the cohorts. COPD-related costs differed among groups (LABA or LAMA $2,051 SE = 91; LABA and LAMA$2,823 SE = 62; LABA, LAMA and ICS $3,546 SE = 89; all p < .0001) with the differences driven by study medication costs. However, non-study COPD medication costs were higher for the LABA or LAMA therapy group ($911 SE = 91) compared to the LABA and LAMA therapy group ($668 SE = 58; p = 0.0238) and non-study respiratory medications were approximately$100 greater for the LABA or LAMA therapy group relative to both LABA and LAMA (p = .0018) and LABA, LAMA, and ICS (p = .0071) therapy groups. While there was no observed difference in outpatient costs, there was a slightly higher number of outpatient visits per patient in the LABA and LAMA (25.5 SE = 0.9, p = 0.0070) relative to the LABA or LAMA therapy group (22.3 SE = 0.8) and higher utilization (89.7% of patients) with COPD visits in the LABA and LAMA therapy group relative to both the LABA or LAMA (73.8%; p < .0001) and LABA, LAMA and ICS therapy groups (85.3; p = 0.0305).</p> <p>Conclusions</p> <p>Significant cost differences driven mainly by pharmaceuticals were observed among LABA or LAMA, LABA and LAMA and LABA, LAMA and ICS therapies. A COPD-related cost offset was observed from single bronchodilator to two bronchodilators. Addition of an ICS with two bronchodilators resulted in higher treatment costs without reduction in other COPD-related costs compared with two bronchodilators.</p

Platelet endothelial cell adhesion molecule-1 inhibits platelet response to thrombin and von Willebrand factor by regulating the internalization of glycoprotein Ib via AKT/glycogen synthase kinase-3/dynamin and integrin αIIbβ3

OBJECTIVE: Platelet endothelial cell adhesion molecule-1 (PECAM-1) regulates platelet response to multiple agonists. How this immunoreceptor tyrosine-based inhibitory motif-containing receptor inhibits G protein-coupled receptor-mediated thrombin-induced activation of platelets is unknown. APPROACH AND RESULTS: Here, we show that the activation of PECAM-1 inhibits fibrinogen binding to integrin αIIbβ3 and P-selectin surface expression in response to thrombin (0.1-3 U/mL) but not thrombin receptor-activating peptides SFLLRN (3×10(-7)-1×10(-5) mol/L) and GYPGQV (3×10(-6)-1×10(-4) mol/L). We hypothesized a role for PECAM-1 in reducing the tethering of thrombin to glycoprotein Ibα (GPIbα) on the platelet surface. We show that PECAM-1 signaling regulates the binding of fluorescein isothiocyanate-labeled thrombin to the platelet surface and reduces the levels of cell surface GPIbα by promoting its internalization, while concomitantly reducing the binding of platelets to von Willebrand factor under flow in vitro. PECAM-1-mediated internalization of GPIbα was reduced in the presence of both EGTA and cytochalasin D or latrunculin, but not either individually, and was reduced in mice in which tyrosines 747 and 759 of the cytoplasmic tail of β3 integrin were mutated to phenylalanine. Furthermore, PECAM-1 cross-linking led to a significant reduction in the phosphorylation of glycogen synthase kinase-3β Ser(9), but interestingly an increase in glycogen synthase kinase-3α pSer(21). PECAM-1-mediated internalization of GPIbα was reduced by inhibitors of dynamin (Dynasore) and glycogen synthase kinase-3 (CHIR99021), an effect that was enhanced in the presence of EGTA. CONCLUSIONS: PECAM-1 mediates internalization of GPIbα in platelets through dual AKT/protein kinase B/glycogen synthase kinase-3/dynamin-dependent and αIIbβ3-dependent mechanisms. These findings expand our understanding of how PECAM-1 regulates nonimmunoreceptor signaling pathways and helps to explains how PECAM-1 regulates thrombosis

Nanotechnology in construction and demolition: What we know, what we don’t

Self-cleaning windows, very high strength concrete and thin, super-efficient insulation are just three examples of new building materials promised by nanotechnology, which manipulates matter at the atomic level. But for all their purported benefits, little is known about the risks posed by very small, engineered particles and fibres. Some long and very thin strands might act like asbestos if they are inhaled, for instance. To begin addressing this knowledge gap, the Institution of Occupational Safety and Health (IOSH) sponsored a research team at Loughborough University, led by Professor Alistair Gibb and Dr Wendy Jones, to investigate where these materials are used, how widespread this use is, what the potential risks are and how workers in construction and demolition might manage them. The executive summary of that report, released in January, is reproduced here with IOSH’s permission