Homocysteine from endothelial cells promotes LDL nitration and scavenger receptor uptake

We recently reported that methionine-loaded human umbilical vein endothelial cells (HUVECs) exported homocysteine (Hcy) and were associated with hydroxyl radical generation and oxidation of lipids in LDL. Herein we have analysed the Hcy-induced posttranslational modifications (PTMs) of LDL protein. PTMs have been characterised using electrophoretic mobility shift, protein carbonyl ELISA, HPLC with electrochemical detection and Western blotting of 3-nitrotyrosine, and LDL uptake by scavenger receptors on monocyte/macrophages. We have also analysed PTMs in LDL isolated from rheumatoid (RA) and osteo-(OA) arthritis patients with cardiovascular disease (CVD). While reagent Hcy (<50 μM) promoted copper-catalysed LDL protein oxidation, Hcy released from methionine-loaded HUVECs promoted LDL protein nitration. In addition, LDL nitration was associated with enhanced monocyte/macrophage uptake when compared with LDL oxidation. LDL protein nitration and uptake by monocytes, but not carbonyl formation, was elevated in both RA and OA patients with CVD compared with disease-matched patients that had no evidence of CVD. Moreover, a direct correlation between plasma total Hcy (tHcy) and LDL uptake was observed. The present studies suggest that elevated plasma tHcy may promote LDL nitration and increased scavenger receptor uptake, providing a molecular mechanism that may contribute to the clinical link between CVD and elevated plasma tHcy. © 2005 Elsevier Inc. All rights reserved.

Downstream effects on human low density lipoprotein of homocysteine exported from endothelial cells in an in vitro system

A model system is presented using human umbilical vein endothelial cells (HUVECs) to investigate the role of homocysteine (Hcy) in atherosclerosis. HUVECs are shown to export Hcy at a rate determined by the flux through the methionine/Hcy pathway. Additional methionine increases intracellular methionine, decreases intracellular folate, and increases Hcy export, whereas additional folate inhibits export. An inverse relationship exists between intracellular folate and Hcy export. Hcy export may be regulated by intracellular S-adenosyl methionine rather than by Hcy. Human LDLs exposed to HUVECs exporting Hcy undergo time-related lipid oxidation, a process inhibited by the thiol trap dithionitrobenzoate. This is likely to be related to the generation of hydroxyl radicals, which we show are associated with Hcy export. Although Hcy is the major oxidant, cysteine also contributes, as shown by the effect of glutamate. Finally, the LDL oxidized in this system showed a time-dependent increase in uptake by human macrophages, implying an upregulation of the scavenger receptor. These results suggest that continuous export of Hcy from endothelial cells contributes to the generation of extracellular hydroxyl radicals, with associated oxidative modification of LDL and incorporation into macrophages, a key step in atherosclerosis. Factors that regulate intracellular Hcy metabolism modulate these effects. Copyright © 2005 by the American Society for Biochemistry and Molecular Biology, Inc.

An examination of the role of the concept of the community within the current reorganisation of English local government

The thesis will examine the role and impact of the concept of the community within the structural reorganisation of English local government between 1992 and 1995. The methodological approach adopted within this thesis has been to compare the use, application and significance of the community with a case study of a specific local authority and its preparations for reorganisation. The authority in question was Wychavon District Council located in the County of Hereford and Worcester. The conclusions from this case study were then compared to the role and significance of the community in the reviews of other local authorities in England. This study produced two important results. These were that there was an established body of literature which argued that the community could be of value to local government and that the community should be identified by measuring individuals sense of belonging and feelings of attachment, as well as such daily activities as shopping and working (which help to stimulate these feelings). The then Conservative Government even instructed the specially appointed Commission to apply this particular interpretation of the community to their reviews, and to attempt to base any new unitary authorities upon the social and spatial area it created. The Conservative Government also gave the Commission a Community Index to assist with the identification of communities, and appointed the pollsters MORI to support the Commission with the task of identifying the emotional and more subjective senses of community. The Commission eventually came to rely entirely on the MORI polls, and whilst these polls attempted to faithfully apply the Governments interpretation of the community, they unfortunately produced small and often complex communities, which the Commission felt could not be applied to its reviews. This therefore led to the community becoming a secondary consideration to the factors of cost and efficiency. Furthermore the problematic nature of the community - that is, the production of small and complex communities - was repeated in this thesis' own survey of community identities in the District of Wychavon. In fact this authority's proposals for reorganisation were based almost entirely upon the factors of cost, size and efficiency.

The impact of board independence and ownership structure on the timeliness of corporate internet reporting of Irish-listed companies

Purpose – This study seeks to provide valuable new insight into the timeliness of corporate internet reporting (TCIR) by a sample of Irish-listed companies. Design/methodology/approach – The authors apply an updated version of Abdelsalam et al. TCIR index to assess the timeliness of corporate internet reporting. The index encompasses 13 criteria that are used to measure the TCIR for a sample of Irish-listed companies. In addition, the authors assess the timeliness of posting companies’ annual and interim reports to their web sites. Furthermore, the study examines the influence of board independence and ownership structure on the TCIR behaviour. Board composition is measured by the percentage of independent directors, chairman’s dual role and average tenure of directors. Ownership structure is represented by managerial ownership and blockholder ownership. Findings – It is found that Irish-listed companies, on average, satisfy only 46 per cent of the timeliness criteria assessed by the timeliness index. After controlling for size, audit fees and firm performance, evidence that TCIR is positively associated with board of director’s independence and chief executive officer (CEO) ownership is provided. Furthermore, it is found that large companies are faster in posting their annual reports to their web sites. The findings suggest that board composition and ownership structure influence a firm’s TCIR behaviour, presumably in response to the information asymmetry between management and investors and the resulting agency costs. Practical implications – The findings highlight the need for improvement in TCIR by Irish-listed companies in many areas, especially in regard to the regular updates of information provided on their web sites. Originality/value – This study represents one of the first comprehensive examinations of the important dimension of the TCIR in Irish-listed companies.

Knowledge management: a review of the field and of OR's contribution

This paper examines the field of knowledge management (KM) and identifies the role of operational research (OR) in key milestones and in KM's future. With the presence of the OR Society journal Knowledge Management Research and Practice and with the INFORMS journal Organization Science, OR may be assumed to have an explicit and a leading role in KM. Unfortunately, the origins and the evidence of recent research efforts do not fully support this assumption. We argue that while OR has been inside many of the milestones there is no explicit recognition of its role and while OR research on KM has considerably increased in the last 5 years, it still forms a rather modest explicit contribution to KM research. Nevertheless, the depth of OR's experience in decision-making models and decision support systems, soft systems with hard systems and in risk management suggests that OR is uniquely placed to lead future KM developments. We suggest that a limiting aspect of whether OR will be seen to have a significant profile will be the extent to which developments are recognized as being informed by OR.

The role of monocytes in atherosclerotic coronary artery disease

Inflammation plays a key role in the pathogenesis of atherosclerosis. The more we discover about the molecular pathways involved in atherosclerosis, the more we perceive the importance of monocytes in this process. Circulating monocytes are components of innate immunity, and many pro-inflammatory cytokines and adhesion molecules facilitate their adhesion and migration to the vascular endothelial wall. In addition to the accumulation of lipids and formation of atherogenic 'foam' cells, monocytes may promote atherosclerotic plaque growth by production of inflammatory cytokines, matrix metalloproteinases, and reactive oxidative species. However, the contribution of monocytes to atherogenesis is not only limited to tissue destruction. Monocyte subsets are also involved in intraplaque angiogenesis and tissue reparative processes. The aim of this overview is to discuss the mechanisms of monocyte activation, the pivotal role and importance of activated monocytes in atherosclerotic coronary artery disease, their implication in the development of acute coronary events, and their potential in cardiovascular reparative processes such angiogenesis.

Immunological and biochemical techniques in the analysis of tear proteins

This study is concerned with the analysis of tear proteins, paying particular attention to the state of the tears (e.g. non-stimulated, reflex, closed), created during sampling, and to assess their interactions with hydrogel contact lenses. The work has involved the use of a variety of biochemical and immunological analytical techniques for the measurement of proteins, (a), in tears, (b), on the contact lens, and (c), in the eluate of extracted lenses. Although a diverse range of tear components may contribute to contact lens spoilation, proteins were of particular interest in this study because of their theoretical potential for producing immunological reactions. Although normal host proteins in their natural state are generally not treated as dangerous or non-self, those which undergo denaturation or suffer a conformational change may provoke an excessive and unnecessary immune response. A novel on-lens cell based assay has been developed and exploited in order to study the role of the ubiquitous cell adhesion glycoprotein, vitronectin, in tears and contact lens wear under various parameters. Vitronectin, whose levels are known to increase in the closed eye environment and shown here to increase during contact lens wear, is an important immunoregulatory protein and may be a prominent marker of inflammatory activity. Immunodiffusion assays were developed and optimised for use in tear analysis, and in a series of subsequent studies used for example in the measurement of albumin, lactoferrin, IgA and IgG. The immunodiffusion assays were then applied in the estimation of the closed eye environment; an environment which has been described as sustaining a state of sub-clinical inflammation. The role and presence of a lesser understood and investigated protein, kininogen, was also estimated, in particular, in relation to contact lens wear. Difficulties arise when attempting to extract proteins from the contact lens in order to examine the individual nature of the proteins involved. These problems were partly alleviated with the use of the on-lens cell assay and a UV spectrophotometry assay, which can analyse the lens surface and bulk respectively, the latter yielding only total protein values. Various lens extraction methods were investigated to remove protein from the lens and the most efficient was employed in the analysis of lens extracts. Counter immunoelectrophoresis, an immunodiffusion assay, was then applied to the analysis of albumin, lactoferrin, IgA and IgG in the resultant eluates.

Learning with other health professions in the United Kingdom MPharm degree:Multidisciplinary and placement education

This paper reviews the approach to multidisciplinary and placement education in UK schools of pharmacy. The methodology involved triangulation of course documentation, staff interviews and a final year student survey. Staff members were supportive of multidisciplinary learning. The advantages were development of a wider appreciation of the students? future professional role and better understanding of the roles of other professional groups. The barriers were logistics (student numbers; multiple sites; different timetables), the achievement of balanced numbers between disciplines and engagement of students from all participating disciplines. Placement education was offered by all schools, predominantly in hospital settings. Key problems were funding and the lack of staff resources. Currently, multidisciplinary learning within the UK for pharmacy students is inadequate and is coupled with relatively low levels of placement education. In order for things to change, there should be a review of funding and support from government and the private sector employers.

Informal boundary-spanning links and networks in successful technological innovation

The sources of ideas embodied within successful technological innovation has been a subject of interest in many studies since the 1950s. This research suggests that sources external to the innovating organisation account for between one and two-thirds of the inputs important to the innovation process. In addition, studies have long highlighted the important role played by the personal boundary-spanning relationships of engineers and scientists as a channel for the transference of such inputs. However, research concerning the role and nature of personal boundary-spanning links in the innovation process have either been primarily structurally orientated, seeking to map out the informal networks of scientists and engineers, or more typically, anecdotal. The objective of this research was to reveal and build upon our knowledge of the role, nature and importance of informal exchange activity in the innovation process. In order to achieve this, an empirical study was undertaken to determine the informal sources, channels and mechanisms employed in the development of thirty five award-winning innovations. Through the adoption of the network perspective, the multiple sources and pluralistic patterns of collaboration and communication in the innovation process were systematically explored. This approach provided a framework that allowed for the detailed study of both the individual dyadic links and morphology of the innovation action-sets in which these dyads were embedded. The research found, for example, that the mobilisation of boundary-spanning links and networks was an important or critical factor in nineteen (54%) of the development projects. Of these, informal boundary-spanning exchange activity was considered to be important or critical in eight (23%).

Investigating the supply and demand relationship in a profession: the English and Welsh schools of librarianship and information Studies and the Higher Education Library and Information Services employment sector in England and Wales.

Concern has been expressed in the professional literature - borne out by professional experience and observation - that the supply and demand relationship existing between the 13 English and Welsh Library and Information Studies (LIS) Schools (as providers of `First Professional' staff) and the Higher Education Library and Information Services (HE LIS) sector of England and Wales (as one group of employers of such staff) is unsatisfactory and needs attention. An appropriate methodology to investigate this problem was devised. A basic content analysis of Schools' curricular and recruitment material intended for public consumption was undertaken to establish an overview of the LIS initial professional education system in England and Wales, and to identify and analyse any covert messages imparted to readers. This was followed by a mix of Main Questionnaires and Semi-Structured Interviews with appropriate populations. The investigation revealed some serious areas of dissatisfaction by the HE LIS Chiefs with the role and function of the Schools. Considerable divergence of views emerged on the state of the working relationships between the two sectors and on the Schools' successes in meeting the needs of the HE LIS sector and on CPD provision. There were, however, areas of substantial and consistent agreement between the two sectors. The main implications of the findings were that those areas encompassing divergence of views were worrying and needed addressing by both sides. Possible ways forward included recommendations on improving the image of the profession purveyed by the Schools; the forming of closer and more effective inter-sectoral relationships; recognising fully the importance of `practicum' and increasing and sustaining the network of `practicum' providers.

The effects of varying forms and degrees of government intervention upon the effective competitiveness of UK small businesses

This doctoral thesis responds to the need for greater understanding of small businesses and their inherent unique problem-types. Integral to the investigation is the theme that for governments to effectively influence small business, a sound understanding of the factors they are seeking to influence is essential. Moreover, the study, in its recognition of the many shortcomings in management research and, in particular that the research methods and approaches adopted often fail to give adequate understanding of issues under study, attempts to develop an innovative and creative research approach. The aim thus being to produce, not only advances in small business management knowledge from the standpoints of government policy makers and `lq recipient small business, but also insights into future potential research method for the continued development of that knowledge. The origins of the methodology lay in the non-acceptance of traditional philosophical positions in epistemology and ontology, with a philosophical standpoint of internal realism underpinning the research. Internal realism presents the basis for the potential co-existence of qualitative and quantitative research strategy and underlines the crucial contributory role of research method in provision of ultimate factual status of the assertions of research findings. The concept of epistemological bootstrapping is thus used to develop a `lq partial research framework to foothold case study research, thereby avoiding limitations of objectivism and brute inductivism. The major insights and issues highlighted by the `lq bootstrap, guide the researcher around the participant case studies. A novel attempt at contextualist (linked multi-level and processual) analysis was attempted in the major in-depth case study, with two further cases playing a support role and contributing to a balanced emphasis of empirical research within the context of time constraints inherent within part-time research.

Status and professional association councils. Available in 4 volumes.

This thesis examines the predictive value of a conceptual distinction between status-seeking associations and status-maintaining associations for enhancing understanding of ten selected professional associations and of the attitudes, values, behaviour and policies of their governing organs. Thirty four specific hypotheses have been tested by such research methods as questionnaires administered to individuals and associations, participant observation and an examination of association minutes and publications. Certain hypotheses have been found to be valid for particular matched pairs and/or groups of associations. The findings of the study suggest that the present conceptualisation of profession, the individual professional, professionalism, professionalisation, professional status and that relating to the role of the professions in society needs to be refined and modified in varying degrees in application to accounting associations, business graduate associations and management associations. The concept of the `ideal type' profession is shown to be of limited value in understanding certain aspects of the activities of business graduate and management associations. The findings of the study suggest that in future the professional associations examined may attach less importance to their qualifying role and lay more stress upon their representational role. The professional association faces a managerial challenge to adjust and adapt to a range of `external' pressures and `internal' demands from members and may increasingly need to be regarded as an organisation that possesses certain combinations or sets of characteristics rather than as a type of organisation that possesses a particular or relatively exclusive set. With a blurring of the distinction between the professional and state sector vocational education, and a growing customer/market orientation associated with the changing nature of work, membership of a professional association may, in future, come to be associated rather more with securing access to a relevant range of services and less with qualification for a particular career.

A study of new product market search and user adoption

The research was carried out in the Aviation Division of Dunlop Limited and was initiated as a search for more diverse uses for carbon/carbon composites. An assumed communication model of adoption was refined by introducing the concept of a two way search after making cross industry comparisons of supplier and consumer behaviour. This research has examined methods of searching for new uses for advanced technology materials. Two broad approaches were adopted. First, a case history approach investigated materials that had been in a similar oosition to carbon/carbon to see how other material producing firms had tackled the problem. Second, a questionnaire survey among industrialists examined: the role and identity of material decision makers in different sized firms; the effectiveness of various information sources and channels; and the material adoption habits of different industries. The effectiveness of selected information channels was further studied by monitoring the response to publicity given to carbon/carbon. A flow chart has been developed from the results of this research which should help any material producing firm that is contemplating the introduction of a new material to the world market. Further benefit to our understanding of the innovation and adoption of new materials would accrue from work in the followino areas: "micro" type case histories; understanding more fully the role of product champions or promoters; investigating the phase difference between incremental and radical type innovations for materials; examining the relationship between the adoption rate of new materials and the advance of technology; studying the development of cost per unit function methods for material selection; and reviewing the benefits that economy of scale studies can have on material developments. These are all suggested areas for further work.

Political leadership:character and performance. A comparative analysis of British political leadership, 1997-2010.

Classical and contemporary scholarship on leadership has referred to political performance and the ability of political actors to deploy the self to political purpose. Literature on contemporary British politics (Hennessy, 2001; Marquand, 2008, King, 2009) has highlighted the qualitative shift in political leadership from the mid-1990s towards a focus upon the image, style, celebrity and performance of political leaders, and the shift towards the presidentialisation or semi-presidentialisation of the prime minister (Foley, 2001). However, the literature has lacked a focus upon political performance and a methodology for assessing leadership performance within cultural and institutional contexts. This thesis assesses British political leadership performance from 1997-2010 through the proposal of a framework of political performance to suit comparative purpose. The framework consisting of culture, institutions and performance is used to assess the performance of the case studies (Tony Blair, Gordon Brown and David Cameron, and Gordon Brown, David Cameron and Nick Clegg in the televised Leaders’ Debates of 2010). The application of the framework to the case studies will allow us to a) analyse political performance within given cultural and institutional contexts; b) establish the character traits and other aspects of a politician’s political persona; and c) appraise the role and effects of performance and persona upon the political process.

Which factors drive firm survival within an industry boundary over time?:the UK onshore oil and gas production industry 1984-1999

This thesis looks at the UK onshore oil and gas production industry and follows the history of a population of firms over a fifteen-year period following the industry's renaissance. It examines the linkage between firm survival, selection pressures and adaptation responses at the firm level, especially the role of discretionary adaptation, specifically exploration and exploitation strategies.Taking a Realist approach and using quantitative and qualitative methods for triangulation on a new data base derived from archival data, as well as informant interviews, it tests seven hypotheses' about post-entry survival of firms. The quantitative findings suggest that firm survival within this industry is linked to discretionary adaptation, when measured at the firm level, and to a mixture of selection and adaptation forces when measured for each firm for each individual year. The qualitative research suggests that selection factors dominate. This difference in views is unresolved. However the small, sparse population and the nature of the oil and gas industry compared with other common research contexts such as manufacturing or service firms suggests the results be treated with caution as befits a preliminary investigation. The major findings include limited support for the theory that the external environment is the major determinant of firm survival, though environment components affect firms differentially; resolution of apparent literature differences relating to the sequencing of exploration and exploitation and potential tangible evidence of coevolution. The research also finds that, though selection may be considered important by industry players, discretionary adaptation appears to play the key role, and that the key survival drivers for thispopulation are intra-industry ties, exploitation experience and a learning/experience component. Selection has a place, however, in determining the life-cycle of the firm returning to be a key survival driver at certain ages of the firm inside the industry boundary.