The effects of negative affectivity on self-reported activity limitations in stroke patients:testing the symptom perception, disability and psychosomatic hypotheses

This study investigated whether Negative Affectivity (NA) causes bias in self-report measures of activity limitations or whether NA has a real, non-artifactual association with activity limitations. The Symptom Perception Hypothesis (NA negatively biases self-reporting), Disability Hypothesis (activity limitations cause NA) and Psychosomatic Hypothesis (NA causes activity limitations) were examined longitudinally using both self-report and objective activity limitations measures. Participants were 101 stroke patients and their caregivers interviewed within two weeks of discharge, six weeks later and six months post-discharge. NA and self-report, proxy-report and observed performance activity (walking) limitations were assessed at each interview. NA was associated with activity limitations across measures. Both the Disability and Psychosomatic Hypotheses were supported: initial NA predicted objective activity limitations at six weeks but, additionally, activity limitations at six weeks predicted NA at six months. These results suggest that NA both affects and is affected by activity limitations and does not simply influence reporting.

Development of a near activity visual questionnaire to assess accommodating intraocular lenses

Purpose: To develop a questionnaire that subjectively assesses near visual function in patients with 'accommodating' intraocular lenses (IOLs). Methods: A literature search of existing vision-related quality-of-life instruments identified all questions relating to near visual tasks. Questions were combined if repeated in multiple instruments. Further relevant questions were added and item interpretation confirmed through multidisciplinary consultation and focus groups. A preliminary 19-item questionnaire was presented to 22 subjects at their 4-week visit post first eye phacoemulsification with 'accommodative' IOL implantation, and again 6 and 12 weeks post-operatively. Rasch Analysis, Frequency of Endorsement, and tests of normality (skew and kurtosis) were used to reduce the instrument. Cronbach's alpha and test-retest reliability (intraclass correlation coefficient, ICC) were determined for the final questionnaire. Construct validity was obtained by Pearson's product moment correlation (PPMC) of questionnaire scores to reading acuity (RA) and to Critical Print Size (CPS) reading speed. Criterion validity was obtained by receiver operating characteristic (ROC) curve analysis and dimensionality of the questionnaire was assessed by factor analysis. Results: Rasch Analysis eliminated nine items due to poor fit statistics. The final items have good separation (2.55), internal consistency (Cronbach's α = 0.97) and test-retest reliability (ICC = 0.66). PPMC of questionnaire scores with RA was 0.33, and with CPS reading speed was 0.08. Area under the ROC curve was 0.88 and Factor Analysis revealed one principal factor. Conclusion: The pilot data indicates the questionnaire to be internally consistent, reliable and a valid instrument that could be useful for assessing near visual function in patients with 'accommodating' IOLS. The questionnaire will now be expanded to include other types of presbyopic correction. © 2007 British Contact Lens Association.

Development of an intelligent quality management system using fuzzy association rules

In order to survive in the increasingly customer-oriented marketplace, continuous quality improvement marks the fastest growing quality organization’s success. In recent years, attention has been focused on intelligent systems which have shown great promise in supporting quality control. However, only a small number of the currently used systems are reported to be operating effectively because they are designed to maintain a quality level within the specified process, rather than to focus on cooperation within the production workflow. This paper proposes an intelligent system with a newly designed algorithm and the universal process data exchange standard to overcome the challenges of demanding customers who seek high-quality and low-cost products. The intelligent quality management system is equipped with the ‘‘distributed process mining” feature to provide all levels of employees with the ability to understand the relationships between processes, especially when any aspect of the process is going to degrade or fail. An example of generalized fuzzy association rules are applied in manufacturing sector to demonstrate how the proposed iterative process mining algorithm finds the relationships between distributed process parameters and the presence of quality problems.

Increased potential of a cationic liposome-based delivery system:enhancing stability and sustained immunological activity in pre-clinical development

The combination of dimethyl dioctadecyl ammonium bromide (DDA) and the synthetic cord factor trehalose dibehenate (TDB) with Ag85B-ESAT-6 (H1 fusion protein) has been found to promote strong protective immune responses against Mycobacterium tuberculosis. The development of a vaccine formulation that is able to facilitate the requirements of sterility, stability and generation of a vaccine product with acceptable composition, shelf-life and safety profile may necessitate selected alterations in vaccine formulation. This study describes the implementation of a sterilisation protocol and the use of selected lyoprotective agents in order to fulfil these requirements. Concomitantly, close analysis of any alteration in physico-chemical characteristics and parameters of immunogenicity have been examined for this promising DDA liposome-based tuberculosis vaccine. The study addresses the extensive guidelines on parameters for non-clinical assessment, suitable for liposomal vaccines and other vaccine delivery systems issued by the World Health Organisation (WHO) and the European Medicines Agency (EMEA). Physical and chemical stability was observed following alteration in formulations to include novel cryoprotectants and radiation sterilisation. Immunogenicity was maintained following these alterations and even improved by modification with lysine as the cryoprotective agent for sterilised formulations. Taken together, these results outline the successful alteration to a liposomal vaccine, representing improved formulations by rational modification, whilst maintaining biological activity.

EU governance of the internet:analyzing Europol’s role in the development of a EU cyber crime and cyber security policies

In recent years, the European Union has come to view cyber security, and in particular, cyber crime as one of the most relevant challenges to the completion of its Area of Freedom, Security and Justice. Given European societies’ increased reliance on borderless and decentralized information technologies, this sector of activity has been identified as an easy target for actors such as organised criminals, hacktivists or terrorist networks. Such analysis has been accompanied by EU calls to step up the fight against unlawful online activities, namely through increased cooperation among law enforcement authorities (both national and extra- communitarian), the approximation of legislations, and public- private partnerships. Although EU initiatives in this field have, so far, been characterized by a lack of interconnection and an integrated strategy, there has been, since the mid- 2000s, an attempt to develop a more cohesive and coordinated policy. An important part of this policy is connected to the activities of Europol, which have come to assume a central role in the coordination of intelligence gathering and analysis of cyber crime. The European Cybercrime Center (EC3), which will become operational within Europol in January 2013, is regarded, in particular, as a focal point of the EU’s fight against this phenomenon. Bearing this background in mind, the present article wishes to understand the role of Europol in the development of a European policy to counter the illegal use of the internet. The article proposes to reach this objective by analyzing, through the theoretical lenses of experimental governance, the evolution of this agency’s activities in the area of cyber crime and cyber security, its positioning as an expert in the field, and the consequences for the way this policy is currently developing and is expected to develop in the near future.

Are HRM practices related with patient mortality in NHS hospitals?:A study examining the underlying reasons for such an association

This thesis will report details of two studies conducted within the National Health Service in the UK that examined the association between HRM practices related to training and appraisal with health outcomes within NHS Trusts. Study one represents the organisational analysis of 61 NHS Trusts, and will report training and appraisal practices were significantly associated with lower patient mortality. Specifically, the research will show significantly lower patient mortality within NHS Trusts that: a) had achieved Investors in People accreditation; b) had a formal strategy document relating to training; c) had tailored training policy documents across occupational groups; d) had integrated training and appraisal practices; e) had a high percentage of staff receiving either an appraisal or updated personal development plan. There was also evidence of an additive effect where NHS Trusts that displayed more of these characteristics had significantly lower patient mortality. Study one in this thesis will also report significantly lower patient mortality within the NHS Trusts where there was broad level representation for the HR function. Study two will report details of a study conducted to examine the potential reasons why HR practices may be related to hospital performance. Details are given of the results of a staff attitudinal survey within five NHS Trusts. This study examined will show that a range of developmental activity, the favourability of the immediate work environment (in relation to social support and role stressors) and motivational outcomes are important antecedents to citizenship behaviours. Furthermore, the thesis will report that principles of the demand-control model were adopted to examine the relationship between workplace support and role stressors, and workplace support, influence, and an understanding of role expectation help mitigate against the negative effects of work demands upon motivational outcomes.

Trade union policy and new technology: the Civil and Public Services Association

The introduction of a micro-electronic based technology to the workplace has had a far reaching and widespread effect on the numbers and content of jobs. The importance of the implications of new technology were recognised by the trade unions, leading to a plethora of advice and literature in the late 70s and early 80s, notably the TUC 'Technology and Employment ' report. However, studies into the union response have consistently found an overall lack of influence by unions in the introduction of technology. Whilst the advent of new technology has coincided with an industrial relations climate of unprecedented hostility to union activity in the post-war period, there are structural weaknesses in unions in coming to terms with the process of technological change. In particular was the identification of a lack of suitable technological expertise. Addressing itself to this perceived weakness of the union response, this thesis is the outcome of a collaborative project between a national union and an academic institution. The thesis is based on detailed case studies concerning technology bargaining in the Civil Service and the response of the Civil and Public Services Associations (CPSA), the union that represents lower grade white collar civil servants. It is demonstrated that the application of expertise to union negotiators is insufficient on its own to extend union influence and that for unions to effectively come to terms with technology and influence its development requires a re-assessment across all spheres of union activity. It is suggested that this has repercussions for not only the internal organisation and quality of union policy formation and the extent, form and nature of collective bargaining with employer representatives, but also in the relationship with consumer and interest groups outside the traditional collective bargaining forum. Three policy options are developed in the thesis with the 'adversarial' and 'co~operative' options representing the more traditional reactive and passive forms of involvement. These are contrasted with an 'independent participative' form of involvement which was a 'pro-active' policy option and utilised the expertise of the Author in the CPSA's response to technological change.

Modulation of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase activity and oxidative modification during the development of adjuvant arthritis

Adjuvant arthritis (AA) was induced by intradermal administration of Mycobacterium butyricum to the tail of Lewis rats. In sarcoplasmic reticulum (SR) of skeletal muscles, we investigated the development of AA. SR Ca(2+)-ATPase (SERCA) activity decreased on day 21, suggesting possible conformational changes in the transmembrane part of the enzyme, especially at the site of the calcium binding transmembrane part. These events were associated with an increased level of protein carbonyls, a decrease in cysteine SH groups, and alterations in SR membrane fluidity. There was no alteration in the nucleotide binding site at any time point of AA, as detected by a FITC fluorescence marker. Some changes observed on day 21 appeared to be reversible, as indicated by SERCA activity, cysteine SH groups, SR membrane fluidity, protein carbonyl content and fluorescence of an NCD-4 marker specific for the calcium binding site. The reversibility may represent adaptive mechanisms of AA, induced by higher relative expression of SERCA, oxidation of cysteine, nitration of tyrosine and presence of acidic phospholipids such as phosphatidic acid. Nitric oxide may regulate cytoplasmic Ca(2+) level through conformational alterations of SERCA, and decreasing levels of calsequestrin in SR may also play regulatory role in SERCA activity and expression.

Structural basis for receptor activity-modifying protein-dependent selective peptide recognition by a G protein-coupled receptor

Association of receptor activity-modifying proteins (RAMP1-3) with the G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) enables selective recognition of the peptides calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) that have diverse functions in the cardiovascular and lymphatic systems. How peptides selectively bind GPCR:RAMP complexes is unknown. We report crystal structures of CGRP analog-bound CLR:RAMP1 and AM-bound CLR:RAMP2 extracellular domain heterodimers at 2.5 and 1.8 Å resolutions, respectively. The peptides similarly occupy a shared binding site on CLR with conformations characterized by a β-turn structure near their C termini rather than the α-helical structure common to peptides that bind related GPCRs. The RAMPs augment the binding site with distinct contacts to the variable C-terminal peptide residues and elicit subtly different CLR conformations. The structures and accompanying pharmacology data reveal how a class of accessory membrane proteins modulate ligand binding of a GPCR and may inform drug development targeting CLR:RAMP complexes.

Modulation of glucagon receptor pharmacology by Receptor Activity-modifying Protein-2 (RAMP2)

The glucagon and glucagon-like peptide-1 (GLP-1) receptors play important, opposing roles in regulating blood glucose levels. Consequently, these receptors have been identified as targets for novel diabetes treatments. However, drugs acting at the GLP-1 receptor, whilst having clinical efficacy, have been associated with severe adverse side-effects and targeting of the glucagon receptor has yet to be successful. Here we use a combination of yeast reporter assays and mammalian systems, to provide a more complete understanding of glucagon receptor signaling considering the effect of multiple ligands, association with the receptor-interacting protein, receptor activity modifying protein-2 (RAMP2) and individual G protein α-subunits. We demonstrate that RAMP2 alters both ligand selectivity and G protein preference of the glucagon receptor. Importantly, we also uncover novel cross-reactivity of therapeutically used GLP-1 receptor ligands at the glucagon receptor that is abolished by RAMP2 interaction. This study reveals the glucagon receptor as a previously unidentified target for GLP-1 receptor agonists and highlights a role for RAMP2 in regulating its pharmacology. Such previously unrecognized functions of RAMPs highlight the need to consider all receptor-interacting proteins in future drug development.