Metabolism of ticagrelor in patients with acute coronary syndromes.

© The Author(s) 2018Ticagrelor is a state-of-the-art antiplatelet agent used for the treatment of patients with acute coronary syndromes (ACS). Unlike remaining oral P2Y12 receptor inhibitors ticagrelor does not require metabolic activation to exert its antiplatelet action. Still, ticagrelor is extensively metabolized by hepatic CYP3A enzymes, and AR-C124910XX is its only active metabolite. A post hoc analysis of patient-level (n = 117) pharmacokinetic data pooled from two prospective studies was performed to identify clinical characteristics affecting the degree of AR-C124910XX formation during the first six hours after 180 mg ticagrelor loading dose in the setting of ACS. Both linear and multiple regression analyses indicated that ACS patients presenting with ST-elevation myocardial infarction or suffering from diabetes mellitus are more likely to have decreased rate of ticagrelor metabolism during the acute phase of ACS. Administration of morphine during ACS was found to negatively influence transformation of ticagrelor into AR-C124910XX when assessed with linear regression analysis, but not with multiple regression analysis. On the other hand, smoking appears to increase the degree of ticagrelor transformation in ACS patients. Mechanisms underlying our findings and their clinical significance warrant further research.Peer reviewedFinal Published versio

Common variants of ZNF750, RPTOR and TRAF3IP2 genes and psoriasis risk

Psoriasis vulgaris is a genetically heterogenous disease with unclear molecular background. We assessed the association of psoriasis and its main clinical phenotypes with common variants of three potential psoriasis susceptibility genes: ZNF750, RPTOR and TRAF31P2. We genotyped 10 common variants in a cohort of 1,034 case–control individuals using Taqman genotyping assays and sequencing. Minor alleles of all four TRAF3IP2 variants were more frequent among cases. The strongest, significant association was observed for rs33980500 (OR = 2.5, p = 0.01790). Minor allele of this SNP was always present in two haplotypes found to be associated with increased psoriasis risk: rs13196377_G + rs13190932_G + rs33980500_T + rs13210247_A (OR = 2.7, p = 0.0054) and rs13196377_A + rs13190932_A + rs33980500_T + rs13210247_G (OR = 1.8, p = 0.0008). Analyses of clinically relevant phenotypes revealed association of rs33980500 with pustular psoriasis (OR = 1.2, p = 0.0109). We observed significant connection of severity of cutaneous disease with variation at rs13190932 and suggestive with three remaining TRAF3IP2 SNPs. Another positive associations were found between age of onset and familial aggregation of disease: smoking and younger age of onset, smoking and occurrence of pustular psoriasis, nail involvement and arthropatic psoriasis, nail involvement and more severe course of psoriasis. We found no statistically significant differences in the prevalence of the examined variants of RPTOR and ZNF750 genes among our cases and controls. We have replicated the association of TRAF3IP2-_rs33980500 variant with the susceptibility to psoriasis. We have found new associations with clinically relevant subphenotypes such as pustular psoriasis or moderate-to-severe cases. We ascertain no connection of RPTOR and ZNF750 variants with psoriasis or its subphenotypes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00403-013-1407-9) contains supplementary material, which is available to authorized users

Monitoring Stresses on the Pv-4 Isostatic Press From 1960 to 1997

The PV-4 isostatic press has a very large working volume (98 ft{sup 3}) that was designed for routine operations at internal pressures up to 30 ksi and is, therefore, a unique and valuable component of the U.S. DOE Y-12 manufacturing capability. More than 13,000 pressing operations have been conducted since initiation of operations in September 1960. The pressure vessel portion consists of three concentric cylinders of high-strength steel with the outer two cylinders shrink-fitted on the imermost cylinder to minimize tensile stresses on the inner surface of the vessel. The third, outermost cylinder consists of two sections; each section is one-half the length of the pressure vessel. The vessel is contained within a large frame which is made of T-1 steel. In 1982 and 1983 precision strain gauges were mounted at selected locations on the frame and the outer surface of the pressure vessel to monitor the operating stresses. Where possible, locations of the gauges mounted in 1982 and 1983 were at or near the same locations as the strain gauges mounted in 1960 to monitor stresses on the frame and vessel during preoperational testing and design verification of the press. This report presents the information obtained with these strain gauges for tests conducted in September 1960 prior to any operation of the press and for the period July 1983 to August 1997. On September 8 and 9, 1960, Sturm & Krouse used 120 strain gauges on the frame and 20 strain gauges on the outer surface of the pressure vessel to measure strains in PV-4 as a function of operating pressure from O to 33 ksi. Although the design maximum operating pressure of the press was 30 ksi, to provide a safety factor for operations at 30 ksi and to assure totally elastic behavior of the steel components of the frame and pressure vessel at pressures above the design pressure, strains were also measured at operating pressures of 32 and 33 ksi. Sturm & Krouse observed that the stresses on the frame and vessel were a linear function of operating pressure over the test range from O to 33 ksi. They verified the design performance and parameters of the press and linear elastic behavior to at least 10% higher than the design operating pressure. Stresses calculated from strain gauge measurements taken between July 29, 1983, and August 5, 1997, at an operating pressure of 30 ksi are in good to excellent agreement with those obtained in September 1960 on the frame and are in excellent agreement with those obtained on the pressure vessel. In addition, slopes of the measured strain as a function of internal pressure have remained the same from preoperational testing on September 8 and 9, 1960, through August 5, 1997, the last date on which strain measurements were conducted. Also, there have been no systematic changes in the zero strain values for measurements taken with the same data acquisitions ystem. The excellent agreement of the stresses and slopes measured from 1983 to 1997 with those measured in 1960 indicates that no cracks, defects, or other flaws have developed in the pressure vessel that could affect the integrity of the pressure vessel. Also, this excellent agreement indicates that there has not been any relaxation of the original shrink-fit pressures that were employed in fabrication of the vessel. Therefore, the original shrink-fit pressures may be used for stress analysis of the pressure vessel and for estimating the fatigue life of the vessel. The excellent agreement of the stresses and slopes of strain as a function of internal pressure obtained for the period 1983 to 1997 with those obtained in 1960 are exactly as expected for the metallurgical structure of the steels of which the press frame and pressure vessel were constructed. To assure long-term integrity of the pressure vessel and that the shrink-fit pressures are not relaxed, continued monitoring of the vessel with precision strain gauges is required

Increased amino acids levels and the risk of developing of hypertriglyceridemia in a 7-year follow-up

BACKGROUND: Recently, five branched-chain and aromatic amino acids were shown to be associated with the risk of developing type 2 diabetes (T2D). AIM: We set out to examine whether amino acids are also associated with the development of hypertriglyceridemia. MATERIALS AND METHODS: We determined the serum amino acids concentrations of 1,125 individuals of the KORA S4 baseline study, for which follow-up data were available also at the KORA F4 7 years later. After exclusion for hypertriglyceridemia (defined as having a fasting triglyceride level above 1.70 mmol/L) and diabetes at baseline, 755 subjects remained for analyses. RESULTS: Increased levels of leucine, arginine, valine, proline, phenylalanine, isoleucine and lysine were significantly associated with an increased risk of hypertriglyceridemia. These associations remained significant when restricting to those individuals who did not develop T2D in the 7-year follow-up. The increase per standard deviation of amino acid level was between 26 and 40 %. CONCLUSIONS: Seven amino acids were associated with an increased risk of developing hypertriglyceridemia after 7 years. Further studies are necessary to elucidate the complex role of these amino acids in the pathogenesis of metabolic disorders

Measurements, Models, Systems and Design

531 s.

The Rise of the Resilient Local Authority?

The term resilience is increasingly being utilised within the study of public policy to depict how individuals, communities and organisations can adapt, cope, and ‘bounce back’ when faced with external shocks such as climate change, economic recession and cuts in public expenditure. In focussing on the local dimensions of the resilience debate, this article argues that the term can provide useful insights into how the challenges facing local authorities in the UK can be reformulated and reinterpreted. The article also distinguishes between resilience as ‘recovery’ and resilience as ‘transformation’, with the latter's focus on ‘bouncing forward’ from external shocks seen as offering a more radical framework within which the opportunities for local innovation and creativity can be assessed and explained. While also acknowledging some of the weaknesses of the resilience debate, the dangers of conceptual ‘stretching’, and the extent of local vulnerabilities, the article highlights a range of examples where local authorities – and crucially, local communities – have enhanced their adaptive capacity, within existing powers and responsibilities. From this viewpoint, some of the barriers to the development of resilient local government are not insurmountable, and can be overcome by ‘digging deep’ to draw upon existing resources and capabilities, promoting a strategic approach to risk, exhibiting greater ambition and imagination, and creating space for local communities to develop their own resilience

Phenotypic variation of erythrocyte linker histone H1.c in a pheasant (Phasianus colchicus L.) population

Our goal was to characterize a phenotypic variation of the pheasant erythrocyte linker histone subtype H1.c. By using two-dimensional polyacrylamide gel electrophoresis three histone H1.c phenotypes were identified. The differently migrating allelic variants H1.c1 and H1.c2 formed either two homozygous phenotypes, c1 and c2, or a single heterozygous phenotype, c1c2. In the pheasant population screened, birds with phenotype c2 were the most common (frequency 0.761) while individuals with phenotype c1 were rare (frequency 0.043)

A roadmap for gene functional characterisation in wheat

To adapt to the challenges of climate change and the growing world population, it is vital to increase global crop production. Understanding the function of genes within staple crops will accelerate crop improvement by allowing targeted breeding approaches. Despite the importance of wheat, which provides 20 % of the calories consumed by humankind, a lack of genomic information and resources has hindered the functional characterisation of genes in this species. The recent release of a high-quality reference sequence for wheat underpins a suite of genetic and genomic resources that support basic research and breeding. These include accurate gene model annotations, gene expression atlases and gene networks that provide background information about putative gene function. In parallel, sequenced mutation populations, improved transformation protocols and structured natural populations provide rapid methods to study gene function directly. We highlight a case study exemplifying how to integrate these resources to study gene function in wheat and thereby accelerate improvement in this important crop. We hope that this review provides a helpful guide for plant scientists, especially those expanding into wheat research for the first time, to capitalise on the discoveries made in Arabidopsis and other plants. This will accelerate the improvement of wheat, a complex polyploid crop, of vital importance for food and nutrition security

Potential range of impact of an ecological trap network: the case of timber stacks and the Rosalia longicorn

Although the negative impact of timber stacks on populations of saproxylic beetles is a well-known phenomenon, there is relatively little data concerning the scale of this impact and its spatial aspect. Beech timber stored in the vicinity of the forest can act as an ecological trap for the Rosalia longicorn (Rosalia alpina), so in this study we have attempted to determine the spatial range of the impact of a network of timber stacks. Timber stacks in the species’ range in the study area were listed and monitored during the adult emergence period in 2014–2016. Based on published data relating to the species’ dispersal capabilities, buffers of four radii (500, 1000, 1600, 3000 m) were delineated around the stacks and the calculated ranges of potential impact. The results show that the percentage of currently known localities of the Rosalia longicorn impacted by stacks varies from 19.7 to 81.6%, depending on the assumed impact radius. The percentage of forest influenced by timber stacks was 77% for the largest-radius buffer. The overall impact of the ecological trap network is accelerated by fragmentation of the impact-free area. It was also found that forests situated close to the timber stacks where the Rosalia longicorn was recorded were older and more homogeneous in age and species composition than those around stacks where the species was absent. Such results suggest that timber stacks act as an ecological trap in the source area of the local population

Potential Use of Gluconate in Cancer Therapy

We have recently discovered that cancer cells take up extracellular citrate through plasma membrane citrate transporter (pmCiC) and advantageously use citrate for their metabolism. Citrate uptake can be blocked with gluconate and this results in decreased tumor growth and altered metabolic characteristics of tumor tissue. Interestingly, gluconate, considered to be physiologically neutral, is incidentally used in medicine as a cation carrier, but not as a therapeutically active substance. In this review we discuss the results of our recent research with available literature and suggest that gluconate may be useful in the treatment of cancer