Infarct size and free fatty acids in the early phase of acute myocardial infarction

The management of acute myocardial infarction (AMI) has been improved by the realisation that the size of infarction can influence mortality (Sobel et al, 1972) and that the infarct size can be altered by subsequent therapy (Maroko et al, 1972). The identification of any factor which may have adverse effects on the ischaemic myocardium and which is amenable to treatment would therefore have important prognostic implications. Elevation of circulating free fatty acid (FFA) concentrations is a consistent feature (Kurien and Oliver, 1966; Oliver et al, 1968) of the profound, non-specific metabolic reaction associated with the onset of AMI (Opie, 1975). The FFA rise has been correlated with the development of arrhythmias (Oliver et al, 1968) after AMI, and with the severity of ischaemic damage (Oliver et al, 1968; Gupta et al, 1969; Russell & Oliver, 1978) on clinical grounds. The method of quantifying infarct size developed by Shell et al (1972) has provided a means of correlating the degree of metabolic disturbance with extent of myocardial damage, and of assessing the benefits of metabolic interventions. The purpose of the studies reported in this thesis was to examine in detail the FFA rise in the early phase of AMI and to correlate this rise with the development of arrhythmias and other complications of AMI and with enzymatically estimated infarct size, thus leading to a more rational approach to therapeutic interventions

Why, what, and how? case study on law, risk, and decision making as necessary themes in built environment teaching

The paper considers (and defends) the necessity of including legal studies as a core part of built environment undergraduate and postgraduate curricula. The writer reflects upon his own experience as a lawyer working alongside and advising built environment professionals in complex land remediation and site safety management situations in the United Kingdom and explains how themes of liability, risk, and decision making can be integrated into a practical simulation in order to underpin more traditional lecture-based law teaching. Through reflection upon the writer's experiments with simulation-based teaching, the paper suggests some innovations that may better orientate law teaching to engage these themes and, thereby, enhance the relevance of law studies to the future needs of built environment professionals in practice.</p

Deepening democracy within Ireland's social partnership

Ireland's social partnership process, now under attack from a number of quarters, has repeatedly been charged with being 'undemocratic' in that it undermines the sovereign position of elected political representatives, with key policy formulation and decision-making taking place in fora outside the institutions of representative democracy. These critiques echo those against new forms of networked governance more globally. A key question therefore is how (and if) democracy may be deepened within social partnership or its potential successor(s). This article addresses this question by employing a post-liberal democratic framework to examine social partnership in practice, and by drawing lessons from another partnership process, Malawi's PRSP. Drawing from Malawi's experience, it is argued that democracy can be deepened within social partnership when governance deliberations and negotiations are conducted under conditions of vibrant public debate and genuine perspective-based representation, and when the communicative and discursive norms are widened to allow for such representation

A Conditional Yeast E1 Mutant Blocks the Ubiquitin–Proteasome Pathway and Reveals a Role for Ubiquitin Conjugates in Targeting Rad23 to the Proteasome

E1 ubiquitin activating enzyme catalyzes the initial step in all ubiquitin-dependent processes. We report the isolation of uba1-204, a temperature-sensitive allele of the essential Saccharomyces cerevisiae E1 gene, UBA1. Uba1-204 cells exhibit dramatic inhibition of the ubiquitin–proteasome system, resulting in rapid depletion of cellular ubiquitin conjugates and stabilization of multiple substrates. We have employed the tight phenotype of this mutant to investigate the role ubiquitin conjugates play in the dynamic interaction of the UbL/UBA adaptor proteins Rad23 and Dsk2 with the proteasome. Although proteasomes purified from mutant cells are intact and proteolytically active, they are depleted of ubiquitin conjugates, Rad23, and Dsk2. Binding of Rad23 to these proteasomes in vitro is enhanced by addition of either free or substrate-linked ubiquitin chains. Moreover, association of Rad23 with proteasomes in mutant and wild-type cells is improved upon stabilizing ubiquitin conjugates with proteasome inhibitor. We propose that recognition of polyubiquitin chains by Rad23 promotes its shuttling to the proteasome in vivo

A genome-wide scan for common alleles affecting risk for autism

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C

Selective Remodeling: Refining Neural Connectivity at the Neuromuscular Junction

A primer on new research by Fuentes-Medel and colleagues explains the important role of non-neural cells in clearing neural debris, which is continuously produced during the normal remodeling processes that establish and maintain neural connectivity

Macroeconomic policy change: Ireland in comparative perspective

This paper sets out to develop an improved framework for examining critical junctures. This a priori framework is a significant improvement over existing critical juncture frameworks that lack any predictive element. It is an advance for historical institutionalism in particular, and political science in general. After the new framework is set out in detail here, it is tested. The framework is used to examine a number of potential critical junctures in macroeconomic policy, drawn from Ireland, Sweden, Britain, and America in the latter half of the twentieth century

DNA methylation in interleukin-11 predicts clinical response to antidepressants in GENDEP

Transcriptional differences in interleukin-11 (IL11) after antidepressant treatment have been found to correspond to clinical response in major depressive disorder (MDD) patients. Expression differences were partly mediated by a single-nucleotide polymorphism (rs1126757), identified as a predictor of antidepressant response as part of a genome-wide association study. Here we attempt to identify whether DNA methylation, another baseline factor known to affect transcription factor binding, might also predict antidepressant response, using samples collected from the Genome-based Therapeutic Drugs for Depression project (GENDEP). DNA samples from 113 MDD individuals from the GENDEP project, who were treated with either escitalopram (n=80) or nortriptyline (n=33) for 12 weeks, were randomly selected. Percentage change in Montgomery-� sberg Depression Rating Scale scores between baseline and week 12 were utilized as our measure of antidepressant response. The Sequenom EpiTYPER platform was used to assess DNA methylation across the only CpG island located in the IL11 gene. Regression analyses were then used to explore the relationship between CpG unit methylation and antidepressant response. We identified a CpG unit predictor of general antidepressant response, a drug by CpG unit interaction predictor of response, and a CpG unit by rs1126757 interaction predictor of antidepressant response. The current study is the first to investigate the potential utility of pharmaco-epigenetic biomarkers for the prediction of antidepressant response. Our results suggest that DNA methylation in IL11 might be useful in identifying those patients likely to respond to antidepressants, and if so, the best drug suited to each individual