Investigating the effects of antiepileptic drugs on the electrophysiology of vision

The principal aim of this work was to examine the effects of antiepileptic drugs (AEDs) on vision. Vigabatrin acts by increasing GABA at brain inhibitory synapses by irreversibly binding to GABA-transaminase. Remacemide is a novel non-competitive NMDA receptor antagonist and fast sodium channel inhibitor that results in the inhibition of the NMDA receptors located in the neuronal membrane calcium channels increasing glutamate in the brain. Vigabatrin has been shown to cause a specific pattern of visual field loss, as one in three adults taking vigabatrin have shown a bilateral concentric constriction. Remacemide has unknown effects on vision. The majority of studies of the effects of AEDs on vision have not included the paediatric population due to difficulties assessing visual field function using standard perimetry testing. Evidently an alternative test is required to establish and monitor visual field problems associated with AEDs both in children and in adults who cannot comply with perimetry. In order to test paediatric patients exposed to vigabatrin, a field-specific visual evoked potential was developed. Other tests performed on patients taking either vigabatrin or remacemide were electroretinograms, electro-oculograms, multifocal VEPs and perimetry. Comparing these tests to perimetry results from vigabatrin patients the field specific VEP was found to have a high sensitivity and specificity, as did the 30Hz flicker amplitude. The modified VEP was also found to provide useful results in vigabatrin patients. Remacemide did not produce a similar visual field loss to vigabatrin although macular vision was affected. The field specific VEP is a useful method for detecting vigabatrin associated visual field loss that is well tolerated by young children. This technique combined with the ERG under light adapted (30Hz flicker) condition is presently the superior method for detecting vigabatrin-attributed peripheral field defects present in children below the developmental age of 9. The effects of AEDs on vision should be monitored carefully and the use of multifocal stimulation allows for specific areas of the retina and visual pathway to be monitored.

Cellular delivery of hammerhead ribozymes

Hammerhead ribozymes are potent RNA molecules which have the potential to specifically inhibit gene expression by catalysing the trans-cleavage of mRNAs. However, they are unstable in biological fluids and cellular delivery poses a problem. Site-specific chemical modification of hammerhead ribozymes was evaluated as a means of enhancing biological stability. Chimeric, 2'-O-methylated ribozymes, containing only five unmodified ribonucleotides, were catalytically active in vitro (kcat = 1.46 min-1) and were significantly more stable in serum and lysosomal enzymes than unmodified (all-RNA) counterparts. Furthermore, they remained undegraded in cell-containing media for up to 8 hours. Stability enhancement allowed cellular uptake properties of radiolabelled ribozymes to be assessed following exogenous delivery. Studies in vulval and glial cell lines indicated that chimeric ribozymes became cell-associated via an inefficient process, which was energy and concentration dependant. A considerable proportion of ribozymes remained bound to cell-surface components, however, a small proportion (<1%) were internalised via mechanisms of adsorptive and / or receptor mediated endocytosis. Fluorescent microscopy indicated that ribozymes were localised within endosomal / lysosomal vesicles following cell entry. This was confirmed by immuno-electron microscopy, which allowed the detection of biotin-labelled ribozymes within the cell ultrastructure. Despite the predominant localisation within endocytic vesicles, a small proportion of internalised ribozymes appeared able to exit these compartments and penetrate target sites within the nucleus and cytoplasm. The ribozymes designed in this report were directed against the epidermal growth factor receptor mRNA, which is over-expressed in a malignant brain disease called glioblastoma multiforme. In order to examine the fate of ribozymes in the brain, the distribution of FITC-labelled ribozymes was examined following intra-cerebro ventricular injection to mice. FITC-ribozymes demonstrated high punctate pattern of distribution within the striatum and cortex, which appeared to represent localisation within cell bodies and dendritic processes. This suggested that delivery to glial cells in vivo may be possible. Finally, strategies were investigated to enhance the cellular delivery of ribozymes. Conjugation of ribozymes to anti~transferrin receptor antibodies improved cellular uptake 3-fold as a result of a specific interaction with transferrin receptors. Complexation with cationic liposomes also significantly improved cell association, however, some toxiclty was observed and this could be a limitation to their use. Overall, it would appear that hammerhead ribozymes can be chemically stabilised to allow direct exogenous administration in vivo. However, additional delivery strategies are probably required to improve cellular uptake, and thus, allow ribozymes to achieve their full potential as pharmaceutical agents. KEYWORDS: Catalytic

The design of a support department simulator for use in the design of manufacturing systems

Manufacturing firms are driven by competitive pressures to continually improve the effectiveness and efficiency of their organisations. For this reason, manufacturing engineers often implement changes to existing processes, or design new production facilities, with the expectation of making further gains in manufacturing system performance. This thesis relates to how the likely outcome of this type of decision should be predicted prior to its implementation. The thesis argues that since manufacturing systems must also interact with many other parts of an organisation, the expected performance improvements can often be significantly hampered by constraints that arise elsewhere in the business. As a result, decision-makers should attempt to predict just how well a proposed design will perform when these other factors, or 'support departments', are taken into consideration. However, the thesis also demonstrates that, in practice, where quantitative analysis is used to evaluate design decisions, the analysis model invariably ignores the potential impact of support functions on a system's overall performance. A more comprehensive modelling approach is therefore required. A study of how various business functions interact establishes that to properly represent the kind of delays that give rise to support department constraints, a model should actually portray the dynamic and stochastic behaviour of entities in both the manufacturing and non-manufacturing aspects of a business. This implies that computer simulation be used to model design decisions but current simulation software does not provide a sufficient range of functionality to enable the behaviour of all of these entities to be represented in this way. The main objective of the research has therefore been the development of a new simulator that will overcome limitations of existing software and so enable decision-makers to conduct a more holistic evaluation of design decisions. It is argued that the application of object-oriented techniques offers a potentially better way of fulfilling both the functional and ease-of-use issues relating to development of the new simulator. An object-oriented analysis and design of the system, called WBS/Office, are therefore presented that extends to modelling a firm's administrative and other support activities in the context of the manufacturing system design process. A particularly novel feature of the design is the ability for decision-makers to model how a firm's specific information and document processing requirements might hamper shop-floor performance. The simulator is primarily intended for modelling make-to-order batch manufacturing systems and the thesis presents example models created using a working version of WBS/Office that demonstrate the feasibility of using the system to analyse manufacturing system designs in this way.

Evaluation of public housing strategies in Mexico City : an exploratory goal programming approach

This thesis describes the development and use of a goal programming methodology for the evaluation of public housjng strategies in Mexico City, The methodology responds to the need to incorporate the location, size and densities of housing projects on the one hand, and "external" constraints such as the ability of low income families to pay for housing, and the amounts of capital and land available, on the other. The provision of low cost housing by public housing agencies in Mexico City is becoming increasingly difficult because there are so many constraints to be met and overcome, the most important of which is the ability of families to pay for housing. Other important limiting factors are the availability of capital and of land plots of the right size in desired locations. The location of public housing projects is significant because it determines the cost and pattern of work trips, which in a metropolitan area such as Mexico City are of considerable importance to both planners and potential. house owners. In addition, since the price of land is closely related to its location, the last factor is also significant in determining the price of the total housing package. Consequently there is a major trade-off between a housing strategy based on the provision of housing at locations close to employment, and the opposite one based on the provjsion of housjng at locations where employment accessibility is poorer but housing can be provided at a lower price. The goal programming evaluation methodology presented in this thesis was developed to aid housing planners to evaluate housing strategies which incorporate the issues raised above,

Settlement of fill with particular reference to opencast coal mining sites

A study of information available on the settlement characteristics of backfill in restored opencast coal mining sites and other similar earthworks projects has been undertaken. In addition, the methods of opencast mining, compaction controls, monitoring and test methods have been reviewed. To consider and develop the methods of predicting the settlement of fill, three sites in the West Midlands have been examined; at each, the backfill had been placed in a controlled manner. In addition, use has been made of a finite element computer program to compare a simple two-dimensional linear elastic analysis with field observations of surface settlements in the vicinity of buried highwalls. On controlled backfill sites, settlement predictions have been accurately made, based on a linear relationship between settlement (expressed as a percentage of fill height) against logarithm of time. This `creep' settlement was found to be effectively complete within 18 months of restoration. A decrease of this percentage settlement was observed with increasing fill thickness; this is believed to be related to the speed with which the backfill is placed. A rising water table within the backfill is indicated to cause additional gradual settlement. A prediction method, based on settlement monitoring, has been developed and used to determine the pattern of settlement across highwalls and buried highwalls. The zone of appreciable differential settlement was found to be mainly limited to the highwall area, the magnitude was dictated by the highwall inclination. With a backfill cover of about 15 metres over a buried highwall the magnitude of differential settlement was negligible. Use has been made of the proposed settlement prediction method and monitoring to control the re-development of restored opencase sites. The specifications, tests and monitoring techniques developed in recent years have been used to aid this. Such techniques have been valuable in restoring land previously derelict due to past underground mining.

Background levels of urban land contamination

The research work reported in this thesis is concerned with the development and application of an urban scale sampling methodology for measuring and assessing background levels of heavy metal soil contamination in large and varied urban areas. The policy context of the work is broadly the environmental health problems posed by contaminated land and their implications for urban development planning. Within this wider policy context, the emphasis in the research has been placed on issues, related to the determination and application of 'guidelines' for assessing the significance of contaminated land for environmental planning. In concentrating on background levels of land contamination, the research responds to the need for additional techniques which address both the problems of measuring soil contamination at the urban scale and which are also capable of providing detailed information for use in the assessment of contaminated sites. Therefore, a key component of the work has been the development of a land-use based sampling framework for generating spatially comprehensive data on heavy metals in soil. The utility of the information output of the sampling method is demonstrated in two alternative ways. Firstly, it has been used to map the existing pattern of typical levels of heavy metals in urban soils. Secondly, it can be used to generate both generalised data in the form of 'reference levels' from which the overall significance of .background contamination may be assessed and detailed data, termed 'normal limit levels' for use in the assessment of site specific investigation data. The fieldwork was conducted in the West Midlands Metropolitan County and surface soil has been sampled and analysed for a measure of plant-available' and 'total' lead cadmium, copper and zinc. The research contrasts with much of the previous work on contaminated land which has generally concentrated on either the detailed investigation of individual sites suspected of being contaminated or the appraisal of land contamination resulting from specific point sources.

Topographic studies of scalp potentials evoked by pattern presentation

The waveform and scalp distribution of the visual evoked potentials elicited by stimuli in the foveal and parafoveal regions have been investigated in a group of normal humans using a 16-channel `brain mapping' system. The waveform and topography of the responses to pattern onset and pattern reversal stimulation were investigated, using 4 x 4o full field and 4 x 2o lateral and altitudinal half-field stimuli. The responses were composed of several successive peaks which are in some respects consistent with those demonstrated by other workers using larger field sizes. The differences in the behaviour of these components with respect to the position of the stimulus in the visual field were suggestive of origins in different areas of the visual cortex and/or different visual mechanism. Of particular interest were the major early positive components `P90' and `P95' of the responses to pattern onset and pattern reversal stimulation respectively. More detailed exploration of the behaviour of these major early positive components was carried out using `M-scaled' stimuli selected to activate one square centimetre patches of striate cortex and associated extrastriate re-projections, positioned at different points in the foveal and parafoveal area of the visual field. The inter- and intra-subject variability in amplitude and localisation of the signals elicited by these targets was considered to be a reflection of the individual variations in relationship of visual field projections with the pattern of gyri and fissures on the proximal surface of the occipital lobe. The behaviour of component P90 of the onset response is consistent with a lateral origin in extrastriate visual cortex; that of P95 of the pattern reversal response is consistent in some respects with a striate cortical origin, but in others with a partial origin in extrastriate cortex.

Adults with dyslexia exhibit large effects of crowding, increased dependence on cues, and detrimental effects of distractors in visual search tasks

Difficulties in visual attention are increasingly being linked to dyslexia. To date, the majority of studies have inferred functionality of attention from response times to stimuli presented for an indefinite duration. However, in paradigms that use reaction times to investigate the ability to orient attention, a delayed reaction time could also indicate difficulties in signal enhancement or noise exclusion once oriented. Thus, in order to investigate attention modulation and visual crowding effects in dyslexia, this study measured stimulus discrimination accuracy to rapidly presented displays. Adults with dyslexia (AwD) and controls discriminated the orientation of a target in an array of different numbers of - and differently spaced - vertically orientated distractors. Results showed that AwD: were disproportionately impacted by (i) close spacing and (ii) increased numbers of stimuli, (iii) did use pre-cues to modulate attention, but (iv) used cues less successfully to counter effects of increasing numbers of distractors. A greater dependence on pre-cues, larger effects of crowding and the impact of increased numbers of distractors all correlated significantly with measures of literacy. These findings extend previous studies of visual crowding of letters in dyslexia to non-complex stimuli. Overall, AwD do not use cues less, but they do use cues less successfully. We conclude that visual attention is an important factor to consider in the aetiology of dyslexia. The results challenge existing theoretical accounts of visual attention deficits, which alone are unable to comprehensively explain the pattern of findings demonstrated here.

The pro-reform movement led by Avenir de la Francaise:a point of leverage in the French political process?

The study examines factors influencing language planning decisions in contemporary France. It focuses upon the period 1992-1994, which witnessed the introduction of two major language policy measures, the first an amendment to the French Constitution, in 1992, proclaiming the language of the Republic as French, the second, in 1994, legislation to extend the ambit of the loi Bas-Lauriol, governing the use of the French language in France. The thesis posits a significant role for the pro-reform movement led by the French language association Avenir de la Langue Francaise (ALF) in the introduction and formulation of the policy measures concerned. The movement is depicted as continuing the traditional pattern of intellectual involvement in language planning, whilst also marking the beginning of a highly proactive, and increasingly political approach. Detailed examination of the movement's activities reveals that contextual factors and strategic strength combined to facilitate access to the levers of power, and enabled those involved to exert an impact on policy initiation, formulation, and ultimately implementation. However, ALF's decision to pursue the legislative route led to the expansion of the network of actors involved in language policymaking, and the development of counter-pressure from sectoral groups. It is suggested that this more interventionist approach destabilised the traditionally consensual language policy community, and called into question the quasi-monopoly of the intelligentsia in respect of language policymaking. It raised broader questions relating to freedom of expression and the permissible limits of language regulation in a democracy such as France. It also exposed ongoing ambiguities and inconsistencies in the interpretation of the tenets of language planning.

Evolving forms of manufacturing strategy development:evidence and implications

This paper outlines, using evidence from several case studies, the use of alternative forms of manufacturing strategy processes. Our investigation shows that the manufacturing strategy development practices of manufacturers are evolving in many directions; we found several alternatives to the formal top-down planning process. Manufacturers use one or more of the following alternatives with or without the top-down manufacturing strategy process: a coherent pattern of actions; manufacturing/process improvement programs; or the pursuit of core manufacturing capabilities. It appears that the various manufacturing strategy development processes may be tied to the strategic role of manufacturing in a company. This paper offers a framework that captures the relationship between the strategic role of manufacturing and the process of manufacturing strategy development. An in-depth case from a UK company illustrates the evolving forms of manufacturing strategy development processes.

Shaping strategic action through the rhetorical construction and exploitation of ambiguity

This paper extends existing understandings of how actors' constructions of ambiguity shape the emergent process of strategic action. We theoretically elaborate the role of rhetoric in exploiting strategic ambiguity, based on analysis of a longitudinal case study of an internationalization strategy within a business school. Our data show that actors use rhetoric to construct three types of strategic ambiguity: protective ambiguity that appeals to common values in order to protect particular interests, invitational ambiguity that appeals to common values in order to invite participation in particular actions, and adaptive ambiguity that enables the temporary adoption of specific values in order to appeal to a particular audience at one point in time. These rhetorical constructions of ambiguity follow a processual pattern that shapes the emergent process of strategic action. Our findings show that (1) the strategic actions that emerge are shaped by the way actors construct and exploit ambiguity, (2) the ambiguity intrinsic to the action is analytically distinct from ambiguity that is constructed and exploited by actors, and (3) ambiguity construction shifts over time to accommodate the emerging pattern of actions.

Multiple component patient safety intervention in English hospitals:controlled evaluation of second phase

Objective: To independently evaluate the impact of the second phase of the Health Foundation's Safer Patients Initiative (SPI2) on a range of patient safety measures. Design: A controlled before and after design. Five substudies: survey of staff attitudes; review of case notes from high risk (respiratory) patients in medical wards; review of case notes from surgical patients; indirect evaluation of hand hygiene by measuring hospital use of handwashing materials; measurement of outcomes (adverse events, mortality among high risk patients admitted to medical wards, patients' satisfaction, mortality in intensive care, rates of hospital acquired infection). Setting: NHS hospitals in England. Participants: Nine hospitals participating in SPI2 and nine matched control hospitals. Intervention The SPI2 intervention was similar to the SPI1, with somewhat modified goals, a slightly longer intervention period, and a smaller budget per hospital. Results: One of the scores (organisational climate) showed a significant (P=0.009) difference in rate of change over time, which favoured the control hospitals, though the difference was only 0.07 points on a five point scale. Results of the explicit case note reviews of high risk medical patients showed that certain practices improved over time in both control and SPI2 hospitals (and none deteriorated), but there were no significant differences between control and SPI2 hospitals. Monitoring of vital signs improved across control and SPI2 sites. This temporal effect was significant for monitoring the respiratory rate at both the six hour (adjusted odds ratio 2.1, 99% confidence interval 1.0 to 4.3; P=0.010) and 12 hour (2.4, 1.1 to 5.0; P=0.002) periods after admission. There was no significant effect of SPI for any of the measures of vital signs. Use of a recommended system for scoring the severity of pneumonia improved from 1.9% (1/52) to 21.4% (12/56) of control and from 2.0% (1/50) to 41.7% (25/60) of SPI2 patients. This temporal change was significant (7.3, 1.4 to 37.7; P=0.002), but the difference in difference was not significant (2.1, 0.4 to 11.1; P=0.236). There were no notable or significant changes in the pattern of prescribing errors, either over time or between control and SPI2 hospitals. Two items of medical history taking (exercise tolerance and occupation) showed significant improvement over time, across both control and SPI2 hospitals, but no additional SPI2 effect. The holistic review showed no significant changes in error rates either over time or between control and SPI2 hospitals. The explicit case note review of perioperative care showed that adherence rates for two of the four perioperative standards targeted by SPI2 were already good at baseline, exceeding 94% for antibiotic prophylaxis and 98% for deep vein thrombosis prophylaxis. Intraoperative monitoring of temperature improved over time in both groups, but this was not significant (1.8, 0.4 to 7.6; P=0.279), and there were no additional effects of SPI2. A dramatic rise in consumption of soap and alcohol hand rub was similar in control and SPI2 hospitals (P=0.760 and P=0.889, respectively), as was the corresponding decrease in rates of Clostridium difficile and meticillin resistant Staphylococcus aureus infection (P=0.652 and P=0.693, respectively). Mortality rates of medical patients included in the case note reviews in control hospitals increased from 17.3% (42/243) to 21.4% (24/112), while in SPI2 hospitals they fell from 10.3% (24/233) to 6.1% (7/114) (P=0.043). Fewer than 8% of deaths were classed as avoidable; changes in proportions could not explain the divergence of overall death rates between control and SPI2 hospitals. There was no significant difference in the rate of change in mortality in intensive care. Patients' satisfaction improved in both control and SPI2 hospitals on all dimensions, but again there were no significant changes between the two groups of hospitals. Conclusions: Many aspects of care are already good or improving across the NHS in England, suggesting considerable improvements in quality across the board. These improvements are probably due to contemporaneous policy activities relating to patient safety, including those with features similar to the SPI, and the emergence of professional consensus on some clinical processes. This phenomenon might have attenuated the incremental effect of the SPI, making it difficult to detect. Alternatively, the full impact of the SPI might be observable only in the longer term. The conclusion of this study could have been different if concurrent controls had not been used.

Consumer trial, continuous use, and economic benefits of a retail service innovation:the case of the personal shopping assistant

Service innovations in retailing have the potential to benefit consumers as well as retailers. This research models key factors associated with the trial and continuous use of a specific self-service technology (SST), the personal shopping assistant (PSA), and estimates retailer benefits from implementing that innovation. Based on theoretical insights from prior SST studies, diffusion of innovation literature, and the technology acceptance model (TAM), this study develops specific hypotheses and tests them on a sample of 104 actual users of the PSA and 345 nonusers who shopped at the retail store offering the PSA device. Results indicate that factors affecting initial trial are different from those affecting continuous use. More specifically, consumers' trust toward the retailer, novelty seeking, and market mavenism are positively related to trial, while technology anxiety hinders the likelihood of trying the PSA. Perceived ease of use of the device positively impacts continuous use while consumers' need for interaction in shopping environments reduces the likelihood of continuous use. Importantly, there is evidence on retailer benefits from introducing the innovation since consumers using the PSA tend to spend more during each shopping trip. However, given the high costs of technology, the payback period for recovery of investments in innovation depends largely upon continued use of the innovation by consumers. Important implications are provided for retailers considering investments in new in-store service innovations. Incorporation of technology within physical stores affords opportunities for the retailer to reduce costs, while enhancing service provided to consumers. Therefore, service innovations in retailing have the potential to benefit consumers as well as retailers. This research models key factors associated with the trial and continuous use of a specific SST in the retail context, the PSA, and estimates retailer benefits from implementing that innovation. In so doing, the study contributes to the nascent area of research on SSTs in the retail sector. Based on theoretical insights from prior SST studies, diffusion of innovation literature, and the TAM, this study develops specific hypotheses regarding the (1) antecedent effects of technological anxiety, novelty seeking, market mavenism, and trust in the retailer on trial of the service innovation; (2) the effects of ease of use, perceived waiting time, and need for interaction on continuous use of the innovation; and (3) the effect of use of innovation on consumer spending at the store. The hypotheses were tested on a sample of 104 actual users of the PSA and 345 nonusers who shopped at the retail store offering the PSA device, one of the early adopters of PSA in Germany. Data were analyzed using logistic regression (antecedents of trial), multiple regression (antecedents of continuous use), and propensity score matching (assessing retailer benefits). Results indicate that factors affecting initial trial are different from those affecting continuous use. More specifically, consumers' trust toward the retailer, novelty seeking, and market mavenism are positively related to trial, while technology anxiety hinders the likelihood of trying the PSA. Perceived ease of use of the device positively impacts continuous use, while consumers' need for interaction in shopping environments reduces the likelihood of continuous use. Importantly, there is evidence on retailer benefits from introducing the innovation since consumers using the PSA tend to spend more during each shopping trip. However, given the high costs of technology, the payback period for recovery of investments in innovation depends largely upon continued use of the innovation by consumers. Important implications are provided for retailers considering investments in new in-store service innovations. The study contributes to the literature through its (1) simultaneous examination of antecedents of trial and continuous usage of a specific SST, (2) the demonstration of economic benefits of SST introduction for the retailer, and (3) contribution to the stream of research on service innovation, as against product innovation.

Assessing the motivation of MDs to use computer-based support at the point-of-care in the emergency department

A significant body of research investigates the acceptance of computer-based support (including devices and applications ranging from e-mail to specialized clinical systems, like PACS) among clinicians. Much of this research has focused on measuring the usability of systems using characteristics related to the clarity of interactions and ease of use. We propose that an important attribute of any clinical computer-based support tool is the intrinsic motivation of the end-user (i.e. a clinician) to use the system in practice. In this paper we present the results of a study that investigated factors motivating medical doctors (MDs) to use computer-based support. Our results demonstrate that MDs value computer-based support, find it useful and easy to use, however, uptake is hindered by perceived incompetence, and pressure and tension associated with using technology.

The adoption and use of diagnostic and prognostic technology within UK-based manufacturers

Manufacturers are seeking increasingly innovative ways to achieve competitive advantage. An emerging trend is to exploit diagnostic and prognostic technology to support service-led competitive strategies where the emphasis is put on the 'sale of use' rather than the 'sale of product'. However, little is known about the extent to which this technology is being exploited, the drivers and inhibitors, and the sectors where adoption is most prolific. This paper introduces the results of a survey conducted across the UK manufacturing sector to explore the extent, motivations, benefits, and challenges of deploying diagnostic and prognostic technology as an element of competitive strategy.