Age-dependence of urinary normal and modified nucleosides in childhood as determined by reversed-phase high-performance liquid chromatography

Modified nucleosides have been characterized as tumor markers for a number of malignant diseases. In order to use these markers in children, the age-dependence of the nucleoside levels in healthy children has to be established and taken into account in diagnostic decisions. In this study, the levels of 12 normal and modified nucleosides in urine of 166 healthy children and adolescents with an age between 1 day and 19 years are determined by reversed-phase HPLC, and age-dependent reference ranges are defined. The urinary nucleoside concentrations are related to the creatinine concentrations, which allows the use of randomly collected urine samples. All nucleoside levels in urine of children decrease with age, most pronounced during the first 4 years of life, and the age-dependence of the reference values of the individual nucleosides can be approximated by a mathematical function y = b(0) + b(1) (1/x) with the regression coefficients b(0) and b(1), the nucleoside levels y and the age x between 1 year and 19 years. In the very young children, the shifts in the nucleoside concentrations are more differentiated. Starting with low levels on the first day of life, the concentrations of all studied nucleosides rise up to an age of 1-2 months, when they reach their absolute maximum for all age periods, and then decrease. (C) 2004 Elsevier B.V. All rights reserved.

A framework for the transformation of the creative industries in a digital age.

The creative industries sector faces a constantly changing context characterised by the speed of the development and deployment of digital information systems and Information Communications Technologies (ICT) on a global scale. This continuous digital disruption has had significant impact on the whole value chain of the sector: creation and production; discovery and distribution; and consumption of cultural goods and services. As a result, creative enterprises must evolve business and operational models and practices to be sustainable. Enterprises of all scales, type, and operational model are affected, and all sectors face ongoing digital disruption. Management consultancy practitioners and business strategy academics have called for new strategy development frameworks and toolkits, fit for a continuously changing world. This thesis investigates a novel approach to organisational change appropriate to the digital age, in the context of the creative sector in Scotland. A set of concepts, methods, tools, and processes to generate theoretical learning and practical knowing was created to support enterprises to digitally adapt through undertaking journeys of change and organisational development. The framework is called The AmbITion Approach. It was developed by blending participatory action research (PAR) methods and modern management consultancy, design, and creative practices. Empirical work also introduced to the framework Coghlan and Rashford’s change categories. These enabled the definition and description of the extent to which organisations developed: whether they experienced first order (change), second order (adaptation) or third order (transformation) change. Digital research tools for inquiry were tested by a pilot study, and then embedded in a longitudinal study over two years of twentyone participant organisations from Scotland’s creative sector. The author applied and investigated the novel approach in a national digital development programme for Scotland’s creative industries. The programme was designed and delivered by the author and ran nationally between 2012-14. Detailed grounded thematic analysis of the data corpus was undertaken, along with analysis of rich media case studies produced by the organisations about their change journeys. The results of studies on participants, and validation criteria applied to the results, demonstrated that the framework triggers second (adaptation) and third order change (transformation) in creative industry enterprises. The AmbITion Approach framework is suitable for the continuing landscape of digital disruption within the creative sector. The thesis contributes to practice the concepts, methods, tools, and processes of The AmbITion Approach, which have been empirically tested in the field, and validated as a new framework for business transformation in a digital age. The thesis contributes to knowledge a theoretical and conceptual framework with a specific set of constructs and criteria that define first, second, and third order change in creative enterprises, and a robust research and action framework for the analysis of the quality, validity and change achieved by action research based development programmes. The thesis additionally contributes to the practice of research, adding to our understanding of the value of PAR and design thinking approaches and creative practices as methods for change.

Prediction of 30-day mortality in older patients with a first acute myocardial infarction

This study sought predictors of mortality in patients aged >or=75 years with a first ST-segment elevation myocardial infarction (STEMI) and evaluated the validity of the GUSTO-I and TIMI risk models. Clinical variables, treatment and mortality data from 433 consecutive patients were collected. Univariable and multivariable logistic regression analyses were applied to identify baseline factors associated with 30-day mortality. Subsequently a model predicting 30-day mortality was created and compared with the performance of the GUSTO-I and TIMI models. After adjustment, a higher Killip class was the most important predictor (OR 16.1; 95% CI 5.7-45.6). Elevated heart rate, longer time delay to admission, hyperglycemia and older age were also associated with increased risk. Patients with hypercholesterolemia had a significantly lower risk (OR 0.46; 95% CI 0.24-0.86). Discrimination (c-statistic 0.79, 95% CI 0.75-0.84) and calibration (Hosmer-Lemeshow 6, p = 0.5) of our model were good. The GUSTO-I and TIMI risk scores produced adequate discrimination within our dataset (c-statistic 0.76, 95% CI 0.71-0.81, and c-statistic 0.77, 95% CI 0.72-0.82, respectively), but calibration was not satisfactory (HL 21.8, p = 0.005 for GUSTO-I, and HL 20.6, p = 0.008 for TIMI). In conclusion, short-term mortality in elderly patients with a first STEMI depends most importantly on initial clinical and hemodynamic status. The GUSTO-I and TIMI models are insufficiently adequate for providing an exact estimate of 30-day mortality risk.

Age- and activity-related differences in the abundance of Myosin essential and regulatory light chains in human muscle

Traditional methods for phenotyping skeletal muscle (e.g., immunohistochemistry) are labor-intensive and ill-suited to multixplex analysis, i.e., assays must be performed in a series. Addressing these concerns represents a largely unmet research need but more comprehensive parallel analysis of myofibrillar proteins could advance knowledge regarding age- and activity-dependent changes in human muscle. We report a label-free, semi-automated and time efficient LC-MS proteomic workflow for phenotyping the myofibrillar proteome. Application of this workflow in old and young as well as trained and untrained human skeletal muscle yielded several novel observations that were subsequently verified by multiple reaction monitoring (MRM).We report novel data demonstrating that human ageing is associated with lesser myosin light chain 1 content and greater myosin light chain 3 content, consistent with an age-related reduction in type II muscle fibers. We also disambiguate conflicting data regarding myosin regulatory light chain, revealing that age-related changes in this protein more closely reflect physical activity status than ageing per se. This finding reinforces the need to control for physical activity levels when investigating the natural process of ageing. Taken together, our data confirm and extend knowledge regarding age- and activity-related phenotypes. In addition, the MRM transitions described here provide a methodological platform that can be fine-tuned to suite multiple research needs and thus advance myofibrillar phenotyping.

Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study

BACKGROUND: Family studies and heritability estimates provide evidence for a genetic contribution to variation in the human life span. METHODS:We conducted a genome wide association study (Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on 5 longevity and aging traits in up to 1345 Framingham Study participants from 330 families. Multivariable-adjusted residuals were computed using appropriate models (Cox proportional hazards, logistic, or linear regression) and the residuals from these models were used to test for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate [greater than or equal to]80%, minor allele frequency [greater than or equal to]10%, Hardy-Weinberg test p [greater than or equal to] 0.001).RESULTS:In family-based association test (FBAT) models, 8 SNPs in two regions approximately 500 kb apart on chromosome 1 (physical positions 73,091,610 and 73, 527,652) were associated with age at death (p-value < 10-5). The two sets of SNPs were in high linkage disequilibrium (minimum r2 = 0.58). The top 30 SNPs for generalized estimating equation (GEE) tests of association with age at death included rs10507486 (p = 0.0001) and rs4943794 (p = 0.0002), SNPs intronic to FOXO1A, a gene implicated in lifespan extension in animal models. FBAT models identified 7 SNPs and GEE models identified 9 SNPs associated with both age at death and morbidity-free survival at age 65 including rs2374983 near PON1. In the analysis of selected candidate genes, SNP associations (FBAT or GEE p-value < 0.01) were identified for age at death in or near the following genes: FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN. Top ranked SNP associations in the GEE model for age at natural menopause included rs6910534 (p = 0.00003) near FOXO3a and rs3751591 (p = 0.00006) in CYP19A1. Results of all longevity phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. CONCLUSION: Longevity and aging traits are associated with SNPs on the Affymetrix 100K GeneChip. None of the associations achieved genome-wide significance. These data generate hypotheses and serve as a resource for replication as more genes and biologic pathways are proposed as contributing to longevity and healthy aging.

Supplementary Material: PREMATURE EXPRESSION OF AN AGE-ASSOCIATED MUSCLE SENESCENCE PATHWAY IN HIV INFECTION

Supplement online material

An automated calibration tool for high performance wireless inertial measurement in professional sports

Traditional motion capture techniques, for instance, those employing optical technology, have long been used in the area of rehabilitation, sports medicine and performance analysis, where accurately capturing bio-mechanical data is of crucial importance. However their size, cost, complexity and lack of portability mean that their use is often impractical. Low cost MEMS inertial sensors when combined and assembled into a Wireless Inertial Measurement Unit (WIMU) present a possible solution for low cost and highly portable motion capture. However due to the large variability inherent to MEMS sensors, such a system would need extensive characterization to calibrate each sensor and ensure good quality data capture. A completely calibrated WIMU system would allow for motion capture in a wider range of real-world, non-laboratory based applications. Calibration can be a complex task, particularly for newer, multi-sensing range capable inertial sensors. As such we present an automated system for quickly and easily calibrating inertial sensors in a packaged WIMU, demonstrating some of the improvements in accuracy attainable.

History, revolution and the British popular novel: historical fiction in the romantic age

“History, Revolution and the British Popular Novel” takes as its focus the significant role which historical fiction played within the French Revolution debate and its aftermath. Examining the complex intersection of the genre with the political and historical dialogue generated by the French Revolution crisis, the thesis contends that contemporary fascination with the historical episode of the Revolution, and the fundamental importance of history to the disputes which raged about questions of tradition and change, and the meaning of the British national past, led to the emergence of increasingly complex forms of fictional historical narrative during the “war of ideas.” Considering the varying ways in which novelists such as Charlotte Smith, William Godwin, Mary Robinson, Helen Craik, Clara Reeve, John Moore, Edward Sayer, Mary Charlton, Ann Thomas, George Walker and Jane West engaged with the historical contexts of the Revolution debate, my discussion juxtaposes the manner in which English Jacobin novelists inserted the radical critique of the Jacobin novel into the wider arena of history with anti-Jacobin deployments of the historical to combat the revolutionary threat and internal moves for socio-political restructuring. I argue that the use of imaginative historical narrative to contribute to the ongoing dialogue surrounding the Revolution, and offer political and historical guidance to readers, represented a significant element within the literature of the Revolution crisis. The thesis also identifies the diverse body of historical fiction which materialised amidst the Revolution controversy as a key context within which to understand the emergence of Scott’s national historical novel in 1814, and the broader field of historical fiction in the era of Waterloo. Tracing the continued engagement with revolutionary and political concerns evident in the early Waverley novels, Frances Burney’s The Wanderer (1814), William Godwin’s Mandeville (1816), and Mary Shelley’s Valperga (1823), my discussion concludes by arguing that Godwin’s and Shelley’s extension of the mode of historical fiction initially envisioned by Godwin in the revolutionary decade, and their shared endeavour to retrieve the possibility enshrined within the republican past, appeared as a significant counter to the model of history and fiction developed by Walter Scott in the post-revolutionary epoch.

The Viking age glass beads of Ireland and their North Atlantic context

Hitherto, the majority of studies which have included the discussion of Viking glass beads have mainly focused on the assemblages from individual sites, with limited use of known parallels. Exceptions to this include recent publications regarding the Icelandic material and Callmer’s 1977 catalogue of the finds from mainland Scandinavia, now over thirty years old. Analysis of these finds from Ireland was, for the most part, non-existent. The aim of this research is to address this lack of analysis within Ireland, while incorporating the wider context of the beads within the Viking North Atlantic. The research thus examines the use of glass beads of diagnostically Scandinavian manufacture and import found in Ireland, particularly in relation to their context and distribution. The history of research from Ireland as well as from across the Viking world is considered and explored throughout the thesis, with critique of methods and discussions used. Focussed analysis of both published and unpublished material detailing artefacts from Scandinavia (especially Vestfold), Britain, Iceland, the Faroe Islands and L’Anse aux Meadows is presented within the thesis in order to provide the greater picture for the core section of the thesis, the glass beads found in Ireland. Three appendices are included within Volume 2, databases of the glass beads under discussion from Ireland, the Vestfold region graves in Norway and the topsoil finds from the Kaupang trading place, also located within Vestfold. These appendices therefore represent the first-hand analysis of glass beads by the author. In total, this research represents the most up-to-date analysis of Viking glass beads from Ireland and presents a new look at the patterns of use, trade and interpersonal contact that affected the everyday lives of individuals living within Viking Age Ireland.

Copper mining in Ireland during the later Bronze Age

Accepted Version