We do not known the optimum amount of physiotherapy for individual patients and recent trials have been inconclusive. We conducted an individual-patient-data meta-analysis of trials testing increased levels of physiotherapy input. Results: We incorporated 9 trials (951 subjects). We found no statistically significant differences between patients receiving intensive or standard amounts of physiotherapy, in terms of overall disability or overall impairment scores, length of hospital stay or survival. Secondary analyses showed improvements on Motricity Index scores for the upper limbs (5.2 units, 95% CI 1.5 to 8.8, P=0.0058) and lower limbs (6.8 units, 95% CI 2.2-11.4, P=0.0042), Improvements were also seen in Action Research Arm Test scores (1.8 units, 95% CI – 1.2 to 4.8, P=0.25) in younger patients (under 70 years) and those with higher baseline Barthel scores, and in recovery of walking speed (increase of 0.0.56 m/s, 95% CI -0.018 to 0.130, P=0.14) (when the target of treatment was lower limb or gait focused). There was no significant difference in change in ADL (measured by BI (7 trials)) between the groups (0.15 units of change in BI, 95% CI -0.38 to 0.67, P=0.58). There were increased odds of a “good recovery” i.e. (improvement of 6 points or up to the maximum of 20 / 20 on BI), (odds ratio 1.33; 0.96 – 1.85; P=0.09) and of “excellent recovery” (> 8 points or up to the maximum on BI), (odds ratio 1.47; 1.03 – 2.05; P=0.04) in the augmented group. The higher contrast trials in our study (typically 15 – 44 hrs additional physiotherapy, with earlier onset at 7-10 days after admission, higher daily contrast and longer duration) are more likely to show treatment effects than lower contrast trials, with respect to impairment measured by the Motricity index and disability measured by the BI.

The studies of hypertension, described herein, combined complementary strategies to examine the relevance of human chromosome 5q31.1-qter to blood pressure as a quantitative trait, and hypertension as a qualitative trait. This distal region of chromosome 5 was focused upon due to its implication by other human and animal model studies and the cluster of cardiovascular candidate genes located there. Eleven microsatellites across 55 cM of 5q31.1 to qter were genotyped in 212 hypertensive nuclear families of the Silesian Hypertension Study. Two-point and multipoint analyses showed linkage of a 7 cM region to both hypertensive status and blood pressure phenotypes. A maximal multipoint Z-score of 2.2 for systolic blood pressure (SBP) was obtained proximal to the marker D5s1480. In light of the debate regarding significance in linkage studies, this quantitative trait locus (QTL) was confirmed in a second sample derived from the Scottish population. Genotyping of the same markers was done for 1,469 individuals from sibships of the MIDSPAN Family Study. Two-point and multipoint analyses confirmed a reproducible 7 cM QTL with a maximum multipoint logarithm of odds (LOD) score of 1.8 obtained for mean arterial pressure. Several putative candidate genes were located within the QTL including the b2-adrenergic receptor gene, ADRB2, which is known to have a major role in cardiovascular physiology. Three functional loci, Arg16Gly, Gln27Glu and Thr164Ile, were genotyped within the ADRB2 gene using the Silesian sample. Single locus and haplotype analyses using transmission disequilibrium tests and family-based association methods showed no association to hypertension status (P>0.05), effectively excluding this gene in the Silesian sample. The fibroblast growth factor 1 gene, FGF1, is located at the centre of the QTL. This gene had previously been cited as a putative blood pressure candidate gene in the 5q region but not studied in humans. With roles in endothelial cell proliferation, possible oxidative stress defence and proven direct effects on blood pressure in rodent models, we considered it a possible novel candidate. Coding regions and 3’ UTR were sequenced and family-based association analyses performed for three polymorphisms which were discovered in the 3’ UTR. Association of SBP (P=0.045), pulse pressure (P=0.019) and hypertension status (P=0.038) was demonstrated to the most proximal locus. Association of hypertension to a three-locus haplotype was also shown (P=0.020). The work on essential hypertension demonstrated the merit of confirming linkage in independent populations, implicating a 7 cM region of 5q31.1-q33 linked to blood pressure. Subsequent candidate gene studies utilised the added value of haplotype analyses, excluding the ADRB2 locus but showing interesting data to implicate the novel FGF1 locus as a putative positional candidate. Further fine mapping strategies are now underway to define, more clearly, the haplotype tag across the FGF1 locus.

Loss of upper-limb function is a problem following stroke. Recent research has led to the emergence of new treatments but progress is hampered by lack of reliable objective measures of impairment, and understanding of the underlying impairment mechanisms associated with loss and recovery of functional activity. The aim of this research was to identify, using neuromechanical measurement methods, inter-relationships between motor impairments, and correlates of motor impairments with functional activity limitation in the upper limb of acute and chronic stroke survivors. An instrumented rig has been developed to measure impairments: muscle weakness, active range of movement, motor control accuracy in rhythmic and discrete tracking tasks, spasticity, coactivation, contracture and non-neural stiffness. In pilot studies, signal processing and data analysis techniques have been used to generate novel, clinically and physiologically relevant indices to quantify impairments. In a Main Study, 13 older impaired participants in the acute phase post-stroke, 13 in the chronic phase 14 age-matched unimpaired participants underwent rig assessments and performed a test of upper limb activity. A sub-group of impaired participants were tested on two days for test-retest reliability evaluation. Statistical tests have confirmed the validity of the impairments to distinguish between acute and chronic patients and unimpaired individuals, except coactivation during discrete movements and non-neural stiffness. Repeatability coefficients for the active test indices have been presented as benchmark values for use in future trials. The muscle activation indices showed lower repeatability which highlights the challenge of using these to measure change over time. The impairments that contributed to lower motor control accuracy were reduced extensor weakness, delayed extensor onset timing, coactivation and smaller extension AROM and PROM; coactivation was more strongly associated with motor control accuracy than with spasticity or stiffness. The most important contributors to functional activity in the acute group was extensor weakness, and in the chronic group was motor control accuracy and coactivation (rhythmic task). Contracture was important contributor in both groups, and was associated with weakness and loss of active range of movement rather than spasticity. The findings support the notion that rehabilitation strategies should focus on increasing muscle strength and prevention of contracture. However, assessment of more complex impairments like motor control accuracy and coactivation may be crucial to better target therapy, especially in the later phases post-stroke.

Recent studies have established that adults with post-stroke aphasia can learn to establish connections between familiar words and abstract images, and nonwords with familiar objects. What has not been investigated was whether adults with aphasia could learn non-words with abstract images/ novel meanings i.e. new vocabulary. The main objective of this study was to investigate whether adults with post-stroke aphasia could learn ‘novel’ word forms with ‘novel’ word meanings, despite phonological and/or semantic impairment. Specific research questions included: Can post-stroke adults with aphasia learn new vocabulary? If so, what factors affect their capacity to learn? Is it possible to predict which individuals will learn most successfully? The methodology was developed using preliminary studies both with adults of normal language and cognitive functioning and post-stroke non-aphasic and aphasic adults. It incorporated learning theory and a cognitive neuropsychological model of language. A range of assessments was used to facilitate the capture of new learning. ‘New learning’ was measured not only in terms of the accurate production of the new stimuli but also the recognition and knowledge of the word forms and meanings of this new vocabulary. In the main investigation twenty novel word forms with 20 novel meanings were taught to 12 aphasic adults (< 65 years), over a four day period, using an errorless learning paradigm. Immediate recall of these newly learnt representations was investigated as well as delayed recall. Quantitative and qualitative results from a case series of 12 participants are presented and discussed. Despite semantic and phonological difficulties, all but three participants demonstrated substantial learning of the new vocabulary. The participants’ range of learning ability (from both immediate and delayed recall data) was analysed in relation to severity of aphasia, cognitive factors (including attention, memory and executive function), as well as variables such as age, months post-stroke and number of years in education. With an intensive training period, these participants with aphasia demonstrate varying degrees of ability for new learning. Possible influencing factors and implications for speech and language therapy rehabilitation are discussed.

Introduction: Sub-arachnoid haemorrhage (SAH) occurs when cerebral artery ruptures and blood leaks out into the sub-arachnoid space. This is often a catastrophic event for the individual and morbidity and mortality rates are significantly influenced by early intervention. This makes the role of the clinical biochemistry laboratory in early diagnosis vitally important, as delays in diagnosis can have a major clinical impact. The cerebrospinal fluid (CSF) of healthy individuals is optically clear. It has, however, been recognised for over a century that it can become coloured (xanthochromia) following a cerebrovascular incident such as a SAH. This has made the main role of the clinical biochemistry laboratory in SAH diagnosis that of detecting xanthochromia in the CSF. The majority of laboratories which offer a xanthochromia screening service use the national guidelines that are based upon ultra-violet scanning spectrophotometry (350 nm to 600 nm). This analytical technique is not without its problems: it is subjective, has a possibility of inter-operator variability and due to the specialised nature of the test can take many hours or even days for a result to be issued. This project aimed to improve the current laboratory service by investigating: turnaround times, users opinions of the current service and potential alternative analytical methods. Methods: An audit of the current analytical provision was used to assess its effectiveness and in order to elucidate the service users’ perception. This was effected by a questionnaire that was distributed to service users across three different NHS Trusts in England and Wales. In an attempt to improve the laboratory service, alternatives to scanning spectrophotometry were investigated. These were selected through consideration of the nature of SAH i.e. blood is released into the subarachnoid space and the brain is damaged. Laboratory analysis therefore needed to focus on detecting the presence of blood and/or its breakdown products, any change in CSF constituents that arise as a direct consequence of blood being introduced in to the subarachnoid space or a specific analyte which would only be present if brain damage occurred. Investigation of current research into subarachnoid haemorrhage identified the following analytes as potential alternatives: CSF diazo bilirubin, CSF Ferritin, CSF protein S100 and serum protein S100. Results: The audit revealed the average turnaround time for reporting xanthochromia results to be 26 hours, with almost 20% of samples being reported as equivocal. The service user’s questionnaire revealed a general lack of awareness of current United Kingdom National External Quality Assurance Scheme (UKNEQAS) guidelines for the ‘Analysis of cerebrospinal fluid for bilirubin in suspected Subarachnoid haemorrhage’ and a lack of understanding regarding the timing of lumbar punctures. Additionally, one third of users felt that the turnaround time for results was inadequate. CSF protein S100 was found to be unsuitable due to the difficulty in achieving a suitable balance between sensitivity and specificity; at a cut-off of 0.40 μg/l sensitivity is 80% and specificity is 4%, at a cut-off of 1.60 μg/l sensitivity is 40% and specificity is 94%. Serum protein S100 was found to be unsuitable due to the difficulty in achieving a suitable balance between sensitivity and specificity at appropriate cut-offs (66 % and 73%, respectively, at a cut-off of 0.09 μg/l). When the CSF diazo bilirubin and CSF ferritin were compared to current laboratory practises using pre-defined criteria then CSF diazo bilirubin was found to be the analyte of choice to base new guidelines upon. CSF diazo bilirubin was then used as an initial ‘rule-out’ step in a new set of guidelines for the determination of SAH utilising CSF analysis. Conclusion: The new guidelines employ CSF diazo bilirubin analysis as a ‘rule-out’ step with all samples that are above the cut-off (300 nmol/l) being processed through the UKNEQAS guidelines. In order for the guidelines to be introduced and accepted, local training and education programmes for laboratory and clinical staff will need to be developed and implemented and they will need to be disseminated through publication of articles in journals relevant to both the clinical biochemistry community and requesting clinicians.

This research portfolio is divided into three parts:Part one is a systematic literature review of the literature titled ‘Expressed Emotion (EE) in long term health conditions including those with a neurological basis’. A great deal of research has been carried out looking at the role of EE in psychiatric conditions where EE is now seen as a well established strong predictor of relapse in schizophrenia. More recently, research has turned its focus onto the effects of EE within the domain of chronic health conditions, however, whether this maintains the same significance as shown in psychiatric illnesses remains unclear. This review examines the concept of EE in relation to adjustment, course of illness and functional outcomes in long term health conditions. Broadly it explores the individual components of EE (criticism, emotional over-involvement, hostility, warmth and positive remarks) to identify which have been most associated with outcome. Furthermore, this review has also focused upon how EE has been operationalized and measured in to relation long term health conditions. Clinical and research implications are discussed further in this review. Part two is an empirical research study titled ‘Post stroke depression and expressed emotion’. The causes of PSD remain controversial, particularly regarding the location of lesion that could be linked to depression. What remains clear, however, is that depression after a stroke injury is commonly experienced and has been evidenced as one of the key factors influencing adjustment and rehabilitation outcomes. Given the potential of the impact of EE in long term health conditions, particularly on psychological distress, understanding the causes of PSD in terms of how organic and psycho-social factors might relate to each other is vital for recovery. A cross-sectional design was used to investigate the extent to which EE might interact with lesion laterality to determine levels of post stroke depression (PSD) in stroke survivors. It was hypothesised that stroke survivors with a left lesion stroke injury living in a high EE climate would experience higher levels of PSD compared to those with a right lesion stroke injury living in a low EE climate. Secondary aims of this research explored the relationship between lesion laterality and levels of PSD; and levels of EE and PSD. Additional exploratory research was also carried out to examine the extent to which stroke survivors’ perceptions of EE may interact with lesion laterality to determine levels of PSD. Clinical implications and scope for further research are discussed further. Part three contains the appendices which provide further information in relation to the systematic literature review, empirical paper and a reflective statement of the process on this research.

The literature on stroke reveals an increasing interest in the role played by social and emotional factors in rehabilitation after stroke. A comprehensive literature survey shows profiles of spontaneous recovery, the significance of a team approach to rehabilitation, patterns of prognostic significance for long-term recovery and adaptation and formulations of rehabilitation models for the Western world. The importance of depression as a major factor in demotivation to participate in rehabilitation and achieve long-term quality of life post-stroke emerges. From the literature survey a research design was formulated for the ecological study of a sample of 51 stroke patients at Ga-Rankuwa Hospital near Pretoria. The questionnaire was structured according to the Synchronous Systems Model, and data gathered from the biological, personal and environmental spheres of patients. Data was collected by a multidisciplinary team at three assessment times, three days, two weeks and three months post-stroke. These corresponded to the acute physical phase of stroke, the end of the hospitalisation period, and an assessment of patients once they had been discharged back into the community. Descriptive statistics were obtained on all variables and principle axis factor analysis was performed to verify the factorial structure of the tests. In order to establish whether group scores changed between assessments, t-tests for dependent measures were applied. Pearson Product Moment correlations were computed for the purpose of establishing relationships between variables. The results revealed dramatically differing biographical characteristics of the sample of stroke patients both premorbidly and at three months after the stroke. Significant recovery profiles emerged in both the physical and neuropsychological spheres at both the 14 day and 3 month assessments. Depression and the functioning at home and at work social sphere of role emerged as profiles of deterioration. At 14 days, depression was related to physical and cerebral functioning. This changed at three months, with depression also being significantly related to aspects of social functioning. On the basis of these results, depression after stroke was conceptualised as a severance of relational connectedness in the social ecological functioning of stroke patients. An ecological approach to rehabilitation is proposed that would seek to reframe the identity of stroke patients and establish relational connectedness post-stroke. / Psychology / D. Litt. et Phil. (Psychology)

Timing is a crucial aspect of dynamic tasks, and understanding of timing effects in balance control may contribute to refine balance retraining paradigms for hemiparetic stroke. This thesis opens with a review on predictive and reactive modes of balance control. The initial review concludes there is unexplored potential in predictive setting of timing in imposed balance and in reactive adjustment of timing in self-perturbed balance. This leads to introduction and development of two paradigms by group studies. The first paradigm increases timing certainty of imposed force perturbations by using a regular metronome. Experiments indicate the effect of predictive control on reducing prolonged response time of hemiparetic stroke. The second paradigm introduces temporal metronome error to self-produced postural perturbations that are made in synchrony with the metronome. Experiments show deteriorated reactive control of timing due to increased biomechanical constraint in maintaining balance, but the potential of hemiparetic patients to adjust movement timing is also noted. Effects of these two paradigms in retraining hemiparetic balance are tested by single case studies. The first evidences training potential of predictive control to speed up responses. The second demonstrates training effect of timing cues in re-adjusting the asymmetric pattern between motions of two sides of the body. In conclusion, the paradigms of this thesis provide new means for examining timing effects of predictive and reactive postural responses. Empirical results encourage further development of balance retraining paradigms for hemiparetic stroke with an emphasis on timing, and so potential RCT designs are outlined.

Having a stroke at a younger age has been described as a complex experience that raises specific issues and related serice needs, mainly to do with child care, employment and social life. However, there has been little research into how younger people define what a stroke means for them personally and socially and how they live with it in the long term. This study aims to capture the experience of having had a stroke in people under fifty-five during the first year of their stroke. The purpose is to develop an understanding of the experience and to make this knowledge useful- for other people with this illness, for health care in general- and nursing in particular.

This overview reviews seventeen publications between 1995 and 2005. CHE Imray was the first author of eleven of the papers, the senior author of four and a major contributor to two of the publications. The overview should be read in conjunction with the full copies of the seventeen publications (Appendix 2). The brain is exquisitely sensitive to oxygen requiring a constant supply of adequately oxygenated blood to function normally. Cerebral oxygen delivery is dynamic, and alters rapidly in response to changes in physiological and pathological stimuli. Interference with cerebral oxygen delivery, either as a result of decreased cerebral blood flow, decreased arterial oxygenation or particulate matter (cerebral microemboli) within the blood can all rapidly result in temporary or permanent loss of function within minutes. The author has used non-invasive cerebral perfusion imaging techniques, initially in the clinical setting (in clinic, at the bedside and in the operating theatre) and later transferring these methods to the field setting at high altitude. As a result of these studies, new insights into cerebral perfusion have been gained. Novel concepts such as 'virtual altitude' and 'partitioning of arterial and venous volumes' have been developed. New equipment has been designed and developed, such as the recumbent, collapsible, portable exercise bike. Finally new clinical treatments have been developed, including an apparently safe way to treat the high-risk group of patients with crescendo transient ischaemic attacks or mini-strokes, greatly reducing the risk of developing a subsequent major stroke. The work submitted for consideration for a PhD by publication represents ten years of investigation in two closely inter-related fields. The aim of the submission is to provide a background to the seventeen publications (Appendix 2) allowing them to be seen in context to existing knowledge. Appendix 3 contains twelve additional communications that have either been published, or accepted for publication after the original list of seventeen publications was submitted to the University of Glamorgan. They confirm the author's ongoing interest and contributions to this field of research.