Synthesis and evaluation of N1-substituted-3-propyl-1,4-benzodiazepine-2-ones as cholecystokinin (CCK2) receptor ligands

A novel synthetic approach towards N1-alkylated 3-propyl-1,4-benzodiazepines was developed in five synthetic steps from 2-amino-4-chlorobenzophenone, in which the N-oxide 4 served as a key intermediate. The structure-activity relationship optimization of this 3-prophyl-1,4-benzodiazepine template was carried out on the N1-position by selective alkylation reactions and resulted in a ligand with an improved affinity on the cholecystokinin (CCK2) receptor. The N-allyl-3-propyl-benzodiazepine 6d displayed an affinity towards the CCK2 (CCK-B) receptor of 170 nM in a radiolabelled receptor-binding assay. The anxiolytic activity of this allyl-3-propyl-1,4-benzodiazepine 6d was subsequently determined in in-vivo psychotropic assays. This novel ligand had ED50 values of 4.7 and 5.2 mg kg-1 in the black and white box test and the x-maze, respectively, and no significant sedation/muscle relaxation was observed.

Modelling data and voice traffic over IP networks using continuous-time Markov models

Common approaches to IP-traffic modelling have featured the use of stochastic models, based on the Markov property, which can be classified into black box and white box models based on the approach used for modelling traffic. White box models, are simple to understand, transparent and have a physical meaning attributed to each of the associated parameters. To exploit this key advantage, this thesis explores the use of simple classic continuous-time Markov models based on a white box approach, to model, not only the network traffic statistics but also the source behaviour with respect to the network and application. The thesis is divided into two parts: The first part focuses on the use of simple Markov and Semi-Markov traffic models, starting from the simplest two-state model moving upwards to n-state models with Poisson and non-Poisson statistics. The thesis then introduces the convenient to use, mathematically derived, Gaussian Markov models which are used to model the measured network IP traffic statistics. As one of the most significant contributions, the thesis establishes the significance of the second-order density statistics as it reveals that, in contrast to first-order density, they carry much more unique information on traffic sources and behaviour. The thesis then exploits the use of Gaussian Markov models to model these unique features and finally shows how the use of simple classic Markov models coupled with use of second-order density statistics provides an excellent tool for capturing maximum traffic detail, which in itself is the essence of good traffic modelling. The second part of the thesis, studies the ON-OFF characteristics of VoIP traffic with reference to accurate measurements of the ON and OFF periods, made from a large multi-lingual database of over 100 hours worth of VoIP call recordings. The impact of the language, prosodic structure and speech rate of the speaker on the statistics of the ON-OFF periods is analysed and relevant conclusions are presented. Finally, an ON-OFF VoIP source model with log-normal transitions is contributed as an ideal candidate to model VoIP traffic and the results of this model are compared with those of previously published work.

New technology, industrial relations and white collar trade unions : the case of the National and Local Government Officers Association

The decade since 1979 has seen the most rapid introduction of microelectronic technology in the workplace. In particular, the scope offered for the application of this new technology to the area of white collar work has meant that it is a sector where trade unions have been confronted with major challenges. However the application of this technology has also provided trade unions with opportunities for exerting influence to reshape traditional attitudes to both industrial relations and the nature of work. Recent academic research on the trade union response to the introduction of new technology at the workplace suggests that, despite the resources and apparent sophistication of modern trade unions, they have not in general been able to take advantage of the opportunities offered during this period of radical technological change,the argument being that this is due both to structural weaknesses and the inappropriateness of the system of collective bargaining where new technology issues are concerned. Despite the significance of the Public Sector in employment terms, research into the response of public sector white collar trade unions to technological change has been fairly limited. This thesis sets out the approach of the National and Local Government Officers Association (NALGO), the largest solely white collar union in the world with over three quarters of a million members employed in a wide range of public service industries. The thesis examines NALGO's response at national level and, through detailed case studies, at local level in respect of Local Government and Water Industry NALGO members. The response is then evaluated and conclusions drawn in terms of a framework based upon an assessment of the key factors relevant in judging the ability of NALGO to respond effectively to the challenges brought about by the technological revolution of the last ten years.

The black middle class: middle class Afro-Caribbeans: a racial fraction of the British middle class or a class fraction of a racial group

This research examines the relationship between 'race' and class in Britain. This is achieved by considering how these two concepts articulate in the overall structuring of class relationships in a society which is typified by the incorporatation of black labour into a majority white society, This relationship is examined through an investigation of those black workers who occupy a position in the objectively defined middle class. The basic theme underlying this research is that 'race, in the form of structural racism, plays a significant role at two levels. Firstly, it serves to structure the class position of black labour in Britain. Secondly, it serves to determine the type of race, class and political consciousness generated by black labour. The study was carried out in the London area. Occupation was used as an indicator of 'objective' class position when selecting respondents to be included in the two survey populations required for the research. A 'network' approach was used to actually locate the respondents. In-depth interviews were carried out with all the respondents. The study concludes that the concepts of 'race' and class are not independent of each other in the overall structuring of class relationships between black and white labour. It is argued that the inter-relationship identified between these two concepts serves to highlight the fact that the structural position of black labour, the type of consciousness generated and the type of decisions taken by those who took part in the research are to a large extent a result of the structural constraints deriving from the effects of structural racism in Britain.

Black and minority ethnic graduate entrepreneurs: motivations, characteristics and access to finance

This paper draws upon four case studies to examine characteristics, entrepreneurial motivations and access to finance of black and minority ethnic (BME) graduates in the UK. We find that BME graduates starting a business are motivated by a desire to “do better”, and rely heavily on personal savings and family sources for start-up capital. In addition: • There is no conclusive evidence that suggests in this study that BME graduates entered entrepreneurship because of unemployment; with the exception of a few, all had jobs prior to entering self employment. • “Glass ceilings” were often cited by participants of the case studies as a kind of barrier, but there was reluctance to specify exactly what that meant. • Also, lack of satisfaction from working for others is considered to be a strong motivator for entering self-employment but other reasons, to be one’s own boss and the prospect of higher earnings, are also strong motivators. There is, therefore, a need for support agencies and universities to recognise the distinctive nature of BME graduate enterprise in order to provide effective solutions for different groups. This might include a) work experience, b) advice on an adequate capital structure at start up, c) adequate funding and training, and d) appropriate training for all graduates in basic business education.

Comparative risk of microalbuminuria and proteinuria in UK residents of south Asian and white European ethnic background with type 2 diabetes:a report from UKADS

Objective - This study investigated and compared the prevalence of microalbuminuria and overt proteinuria and their determinants in a cohort of UK resident patients of white European or south Asian ethnicity with type 2 diabetes mellitus. Research design and methods - A total of 1978 patients, comprising 1486 of south Asian and 492 of white European ethnicity, in 25 general practices in Coventry and Birmingham inner city areas in England were studied in a cross-sectional study. Demographic and risk factor data were collected and presence of microalbuminuria and overt proteinuria assessed. Main outcome measures - Prevalences of microalbuminuria and overt proteinuria. Results - Urinary albumin:creatinine measurements were available for 1852 (94%) patients. The south Asian group had a lower prevalence of microalbuminuria, 19% vs. 23% and a higher prevalence of overt proteinuria, 8% vs. 3%, X2?=?15.85, 2df, P?=?0.0004. In multiple logistic regression models, adjusted for confounding factors, significantly increased risk for the south Asian vs. white European patients for overt proteinuria was shown; OR (95% CI) 2.17 (1.05, 4.49), P?=?0.0365. For microalbuminuria, an interaction effect for ethnicity and duration of diabetes suggested that risk for south Asian patients was lower in early years following diagnosis; OR for SA vs. WH at durations 0 and 1 year were 0.56 (0.37, 0.86) and 0.59 (0.39, 0.89) respectively. After 20 years’ duration, OR?=?1.40 (0.63, 3.08). Limitations - Comparability of ethnicity defined groups; statistical methods controlled for differences between groups, but residual confounding may remain. Analyses are based on a single measure of albumin:creatinine ratio. Conclusions - There were significant differences between ethnicity groups in risk factor profiles and microalbuminuria and overt proteinuria outcomes. Whilst south Asian patients had no excess risk of microalbuminuria, the risk of overt proteinuria was elevated significantly, which might be explained by faster progression of renal dysfunction in patients of south Asian ethnicity.

The dyslexia candidate locus on 2p12 is associated with general cognitive ability and white matter structure

Independent studies have shown that candidate genes for dyslexia and specific language impairment (SLI) impact upon reading/language-specific traits in the general population. To further explore the effect of disorder-associated genes on cognitive functions, we investigated whether they play a role in broader cognitive traits. We tested a panel of dyslexia and SLI genetic risk factors for association with two measures of general cognitive abilities, or IQ, (verbal and non-verbal) in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N>5,000). Only the MRPL19/C2ORF3 locus showed statistically significant association (minimum P = 0.00009) which was further supported by independent replications following analysis in four other cohorts. In addition, a fifth independent sample showed association between the MRPL19/C2ORF3 locus and white matter structure in the posterior part of the corpus callosum and cingulum, connecting large parts of the cortex in the parietal, occipital and temporal lobes. These findings suggest that this locus, originally identified as being associated with dyslexia, is likely to harbour genetic variants associated with general cognitive abilities by influencing white matter structure in localised neuronal regions.

The impact of general intellectual ability and white matter volume on the functional outcome of patients with bipolar disorder and their relatives

Background: There is substantial evidence that cognitive deficits and brain structural abnormalities are present in patients with Bipolar Disorder (BD) and in their first-degree relatives. Previous studies have demonstrated associations between cognition and functional outcome in BD patients but have not examined the role of brain morphological changes. Similarly, the functional impact of either cognition or brain morphology in relatives remains unknown. Therefore we focused on delineating the relationship between psychosocial functioning, cognition and brain structure, in relation to disease expression and genetic risk for BD. Methods: Clinical, cognitive and brain structural measures were obtained from 41 euthymic BD patients and 50 of their unaffected first-degree relatives. Psychosocial function was evaluated using the General Assessment of Functioning (GAF) scale. We examined the relationship between level of functioning and general intellectual ability (IQ), memory, attention, executive functioning, symptomatology, illness course and total gray matter, white matter and cerebrospinal fluid volumes. Limitations: Cross-sectional design. Results: Multiple regression analyses revealed that IQ, total white matter volume and a predominantly depressive illness course were independently associated with functional outcome in BD patients, but not in their relatives, and accounted for a substantial proportion (53%) of the variance in patients' GAF scores. There were no significant domain-specific associations between cognition and outcome after consideration of IQ. Conclusions: Our results emphasise the role of IQ and white matter integrity in relation to outcome in BD and carry significant implications for treatment interventions. © 2010 Elsevier B.V.

Ties that bind:understanding why and how diversity management relates to black and ethnic minority employees’ experience of organisational life

Despite much anecdotal and oftentimes empirical evidence that black and ethnic minority employees do not feel integrated into organisational life and the implications of this lack of integration for their career progression, there is a dearth of research on the nature of the relationship black and ethnic minority employees have with their employing organisations. Additionally, research examining the relationship between diversity management and work outcomes has returned mixed findings. Scholars have attributed this to the lack of an empirically validated measure of workforce diversity management. Accordingly, I sought to address these gaps in the extant literature in a two-part study grounded in social exchange theory. In Study 1, I developed and validated a measure of workforce diversity management practices. Data obtained from a sample of ethnic minority employees from a cross section of organisations provided support for the validity of the scale. In Study 2, I proposed and tested a social-exchange-based model of the relationship between black and ethnic minority employees’ and their employing organisations, as well as assessed the implications of this relationship for their work outcomes. Specifically, I hypothesised: (i) perception of support for diversity, perception of overall justice, and developmental experiences (indicators of integration into organisational life) as mediators of the relationship between diversity management and social exchange with organisation; (ii) the moderating influence of diversity climate on the relationship between diversity management and these indicators of integration; and (iii) the work outcomes of social exchange with organisation defined in terms of career satisfaction, turnover intention and strain. SEM results provide support for most of the hypothesised relationships. The findings of the study contribute to the literature on workforce diversity management in a number of ways. First, the development and validation of a diversity management practice scale constitutes a first step in resolving the difficulty in operationalising and measuring the diversity management construct. Second, it explicates how and why diversity management practices influence a social exchange relationship with an employing organisation, and the implications of this relationship for the work outcomes of black and ethnic minority employees. My study’s focus on employee work outcomes is an important corrective to the predominant focus on organisational-level outcomes of diversity management. Lastly, by focusing on ethno-racial diversity my research complements the extant research on such workforce diversity indicators as age and gender.

Image enhancement of real-time television to benefit the visually impaired

Purpose: To examine the use of real-time, generic edge detection, image processing techniques to enhance the television viewing of the visually impaired. Design: Prospective, clinical experimental study. Method: One hundred and two sequential visually impaired (average age 73.8 ± 14.8 years; 59% female) in a single center optimized a dynamic television image with respect to edge detection filter (Prewitt, Sobel, or the two combined), color (red, green, blue, or white), and intensity (one to 15 times) of the overlaid edges. They then rated the original television footage compared with a black-and-white image displaying the edges detected and the original television image with the detected edges overlaid in the chosen color and at the intensity selected. Footage of news, an advertisement, and the end of program credits were subjectively assessed in a random order. Results: A Prewitt filter was preferred (44%) compared with the Sobel filter (27%) or a combination of the two (28%). Green and white were equally popular for displaying the detected edges (32%), with blue (22%) and red (14%) less so. The average preferred edge intensity was 3.5 ± 1.7 times. The image-enhanced television was significantly preferred to the original (P < .001), which in turn was preferred to viewing the detected edges alone (P < .001) for each of the footage clips. Preference was not dependent on the condition causing visual impairment. Seventy percent were definitely willing to buy a set-top box that could achieve these effects for a reasonable price. Conclusions: Simple generic edge detection image enhancement options can be performed on television in real-time and significantly enhance the viewing of the visually impaired. © 2007 Elsevier Inc. All rights reserved.

Pain management programmes for non-English-speaking black and minority ethnic groups with long-term or chronic pain

Increasing ethnic diversity in the UK means that there is a growing need for National Health Service care to be delivered to non-English-speaking patients. The aims of the present systematic review were to: (1) better understand the outcomes of chronic pain management programmes (PMPs) for ethnic minority and non-English-speaking patients and (2) explore the perspectives on and experiences of chronic pain for these groups. A systematic review identified 26 papers meeting the inclusion criteria; no papers reported on the outcomes of PMPs delivered in the UK. Of the papers obtained, four reported on PMPs conducted outside the UK; eight reported on ethnic differences in patients seeking support from pain management services in America; and the remaining papers included literature reviews, an experimental pain study, a collaborative enquiry, and a survey of patient and clinician ratings of pain. The findings indicate a lack of research into UK-based pain management for ethnic minorities and non-English-speaking patients. The literature suggests that effective PMPs must be tailored to meet cultural experiences of pain and beliefs about pain management. There is a need for further research to explore these cultural beliefs in non-English-speaking groups in the UK. Culturally sensitive evaluations of interpreted PMPs with long-term follow-up are needed to assess the effectiveness of current provision. Copyright © 2015 John Wiley & Sons, Ltd.