One new treatment strategy for children with hemiplegic cerebral palsy (CP) is constraint-induced movement therapy (CIMT). CIMT combines restraint of the less affected upper extremity and intensive exercise with the affected limb. CIMT has been shown to be effective in adults following stroke but it is not clear whether or not CIMT can readily be incorporated into clinical practice either with adults or children. An intervention that may be more practical involves the restraint element of CIMT without additional exercise (Forced use therapy-FUT). FUT has been only sparsely investigated, especially in children with CP. Different versions of CIMT protocols have been suggested as being „child-friendly‟ but identifying a practical and effective protocol remains challenging. Part of a child-friendly protocol includes identification of the most appropriate type of constraint, as different splints have been used for different populations without justification of their selection. In this project, the aim was to identify the most appropriate splint from children‟s and parents‟ perspective as reflected by effectiveness and adherence to home-based FUT (feasibility study) and to investigate the functional effects of a modified version of CIMT (mCIMT) (effectiveness study) that was designed based on the findings of the feasibility study. A further aim of the study was to compare the effect of additional functional activities and feedback with constraint alone. Two questions emerged as being important during the course of the project; the first addressed poor recruitment to the effectiveness study and explored parents and therapist‟ views on the practicality and effectiveness of both the classic paediatric protocol and the one suggested by the present study. The second was to provide insight into the physiological effects of CIMT or other treatments that might explain variations in response. In this study a test using the lateralised readiness potential (LRP) component of the EEG that was appropriate for young children was developed and evaluated with a small sample of unimpaired children and children with CP.

The recent introduction of open formulary non-medical prescribing has created opportunities to radically change health care delivery. This thesis is the first of its kind to document the process of undertaking an examination of NMP in a chemotherapy setting. A purposeful sample of 23 stakeholders connected with the chemotherapy service in a local cancer setting was used including 12 doctors, 5 nurses, 4 pharmacists and 4 managers. A serial data collection technique with individual interviews followed by uni professional focus groups was adopted. Finally a multi professional focus group was held to determine the strategic way forward. A systematic qualitative data management package -NUDIST was used to code and theme data and this data was used as the basis for discussion. This thesis offers an insight into the working of the multidisciplinary team in relation to NMP. It establishes the concerns and issues of the professional stakeholders as well as areas of concurrence. It charts the complexities and difficulties faced when shifting responsibilities of professionals. It has used a novel approach to engage with stakeholders from within the day to day practices of the clinic and developed a framework for monitoring agreed progress. An action oriented approach was inherent to the study and dovetailed to understand the service and concurrently create an opportunity for development. Through its insider perspective it has highlighted the complexes of changing practice and attempted to move forward using a negotiation process. The study illuminated the key features necessary to maximise success of NMP in chemotherapy clinics and captures the importance of good working relationships. Whilst different models of nurse-led practice will emerge, fundamental and core to services is the need for good team working, established and effective communication strategies and perhaps most importantly avoiding isolation in practice. This study additionally reinforced that any evaluation takes place within pre- existing political contexts and in particular medical dominance. Not all medical colleagues agreed with or wanted NMP for their patients highlighting difficulties of developing new models of working within a resisting culture. Medical dominance should be acknowledged and strategies developed to work within this dominance to ensure the unique contribution of nursing is valued and seen. Insights from this study raise the need for further research and exploration of the usefulness and acceptability of NMP in chemotherapy.

Coccydynia is a form of back pain and occurs more commonly in women than in men, and is a particular clinical problem seen in Taiwan. Understanding of the condition is limited and it cannot be isolated from other dysfunctions in the lumbopelvic region. It is proposed that neuromuscular alterations that occur in low back pain (LBP) could also occur in coccydynia and forms the topic of this thesis. The aims of this study were to explore neuromuscular and musculoskeletal changes in Taiwanese women with coccydynia. A total of 55 Taiwanese women, aged 23-65 years were studied in three groups: healthy young participants in Southampton (n=18, aged 23-35 years); patients with coccydynia in Taiwan (n=20 aged 23-65 years) and healthy older women in Taiwan (n=17, aged 35-65 years). Three techniques were used to investigate musculoskeletal changes in coccydynia: rehabilitative ultrasound imaging (RUSI), 3-dimensional motion analysis (using the VICON system) and surface electromyography (sEMG).The reliability of the developed experimental protocols was first established at the University of Southampton and then the protocols were replicated for he main study in Taiwan. Patients had thicker resting transversus abdominis (TrA) muscles than healthy participants but showed less thickness change during a functional task, indicating reduced ability to contract the muscle. Differences between patients and healthy groups from motion analysis and EMG studies were found and indicate that neuromuscular alterations occur in coccydynia. In six case studies, a six week intervention using a pelvic belt, patients reported improvements in symptoms and function but there were no changes in the objective tests of musculoskeletal function. The contributions of this preliminary work to knowledge include: (1) provision of normal reference data of muscle morphology in Taiwanese women of different ages; (2) a possible effect of age on muscle contractile ability; (3) objective evidence of changes in musculoskeletal function in patients with coccydynia, specifically muscle morphology, motor control and biomechanical changes; (4) evidence of the feasibility of using RUSI as an appropriate tool to detect differences in the lumbopelvic muscles between patients with coccydynia and healthy participants; (5) Reliability of inter-recti distance measurement on RUSI at rest and during contractions in patients with coccydynia and healthy participants; (6) the pelvic belt may be a potentially effective intervention in the management of pain in coccydynia.

Cancer is a major medical problem and a leading cause of mortality in the UK. The experience of diagnosis and treatment can be a traumatic one for many people, with symptoms of anxiety, depression, and posttraumatic stress disorder (PTSD) common for many patients. Despite this, many survivors also report benefits and a sense of personal growth from their experience. Understanding this process and the influence of posttraumatic growth (PTG) on mental health outcomes for cancer patients may have far reaching implications for the promotion of psychological adjustment to this chronic illness. The literature review in this paper explores the predominant theories of PTG and the research on cancer-related PTG. The literature review explores links between the predictions of these general theories and research findings for cancer patients specifically. Establishing factors that predict PTG and its relationship with a range of mental health outcomes would help to build our understanding of emotional adjustment to chronic illness and inform the development of psychological interventions. The empirical paper investigates the role of trauma-related cognitive appraisals in the perception of PTG for breast cancer patients. More negative appraisals in relation to the event were associated with benefit finding.

The Assert programme (Gardner 2006) is A Semi-Structured Empowering Reflective Therapy for unpaid carers. It is based on Butler’s (1963; 1974) life review therapy and incorporates Pennebaker’s (1990) narrative writing paradigm. This single-subject study (Sinclair 1962; MacIntyre 1985; Erben 2000) sought to determine whether Assert was safe and effective in an individual setting and whether mirroring (Winnicott 1971) was effective as an educative and therapeutic strategy for a carer on a one-to-one basis. Underpinned by humanistic, person-centred principles (Rogers 1951; 1961), fortnightly life review sessions alternated with opportunities for narrative writing during the sixmonth programme. ‘John’, the participant, aimed to reduce his stress and ‘put the past in the past’. An additional aim of the study was to ascertain whether engaging in the Assert life review process improved John’s childhood autobiographical memory recall. Qualitative data analysis employed verstehen hermeneutics (Dilthey 1976) with grounded theory (Glaser and Strauss 1967; Patton 2002) and biographical research methods (Erben 1998). The most noticeable outcome was a positive shift in John’s biographical reflective focus indicating increased psychological congruence together with some startling improvements in his sense of selfhood. Conversation analysis (Sacks, et al. 1974) also revealed a change in John’s interaction style. John achieved his personal aims but retrieved no ‘new’ memories; however his narrative assumed greater coherence. It was concluded that the Assert programme was safe and effective and that mirroring was effective as an educative and therapeutic strategy on a one-to-one basis with a carer. To compare the programme’s long-term effectiveness with other conventional therapies a randomised control trial is recommended with pre- and post-programme brainscanning of participants to detect any change in neural activity. Potential applications for the Assert programme are more wide-ranging than originally envisaged, including the amelioration of burnout in what is termed in this study as the ‘unpaid carer’s syndrome’.

An inability to perform tasks involving reaching is a common problem following stroke. Evidence supports the use of robotic therapy and electrical stimulation (ES) to reduce upper limb impairments following stroke, but current systems may not encourage maximal voluntary contribution from the participant. This study developed and tested iterative learning control (ILC) algorithms mediated by ES, using a purpose designed robotic workstation, for upper limb rehabilitation post stroke. Surface electromyography (EMG) which may be related to impaired performance and function was used to investigate seven shoulder and elbow muscle activation patterns in eight neurologically intact and five chronic stroke participants during nine tracking tasks. The participants’ forearm was supported using a hinged arm-holder, which constrained their hand to move in a two dimensional horizontal plane. Outcome measures taken prior to and after an intervention consisted of the Fugl- Meyer Assessment (FMA) and the Action Research Arm Test (ARAT), isometric force and error tracking. The intervention for stroke participants consisted of eighteen sessions in which a similar range of tracking tasks were performed with the addition of responsive electrical stimulation to their triceps muscle. A question set was developed to understand participants’ perceptions of the ILC system. Statistically significant improvements were measured (p≤0.05) in: FMA motor score, unassisted tracking, and in isometric force. Statistically significant differences in muscle activation patterns were observed between stroke and neurologically intact participants for timing, amplitude and coactivation patterns. After the intervention significant changes were observed in many of these towards neurologically intact ranges. The robot–assisted therapy was well accepted and tolerated by the stroke participants. This study has demonstrated the feasibility of using ILC mediated by ES for upper limb stroke rehabilitation in the treatment of stroke patients with upper limb hemiplegia.

Recent improvements in molecular sub typing of Non Hodgkin’s lymphomas have resulted in targeted therapies becoming incorporated into treatment paradigms. The anti-CD20 monoclonal antibody, Rituximab, has resulted in dramatic improvements in survival for patients with B cell Non Hodgkin’s lymphoma. Histone deacetylase inhibitors are a novel class of anti cancer agents targeting epigenetic regulation. This thesis addresses the interaction between histone deacetylase inhibitors and anti-CD20 monoclonal antibodies, including Rituximab, both in vitro and in vivo. The initial approach identified synergistic induction of apoptosis in a number of B cell lines. In a Ramos xenograft model, combination treatment with suberoylanilide hydroxamic acid (SAHA) and Rituximab reduced tumour growth compared to either agent alone, without discernable toxicity. This effect appears specific to CD20 since monoclonal antibodies directed to other surface molecules (CD32b, CD22, CD37) did not exhibit cooperative effect. Analysis of apoptotic pathways demonstrated that PARP cleavage and caspase processing is significantly higher in cells receiving both treatments. Co-treatment of Ramos cells with the pan caspase inhibitor QVD-OPH abolished the synergy observed with CD20 monoclonal antibodies, suggesting that caspase processing is necessary for synergy. Treatment of Ramos cells stably transfected to overexpress Bcl-2 resulted in loss of synergy with Rituximab, but not with the type II CD20 mAb B1 (Tositumomab). Gene expression array analysis of Ramos cells was performed. Geneset enrichment analysis identified significant regulation of NFқB target genes in some genesets (Rituximab Vs control, p<0.001) with a number associated with apoptosis and B cell activation (Bcl2A1, LTA, CD69) which were confirmed using RT-Q-PCR. This novel combination elicits the induction of apoptosis in vitro, potentially through regulation of Bcl-2 family proteins and should be tested in a phase I/II clinical trial.

Introduction: Kidney Cancer accounts for approximately 2% of all new cancer diagnoses in the UK each year. Patient survival has improved over the past few decades; however the mechanisms of this are yet to be fully elucidated. Hypoxia inducible factor isoforms, HIF-1 and HIF-2, are constitutively expressed in many clear-cell RCCs due to loss of pVHL tumour suppressor function within the tumour. In vitro, HIF-1 and HIF-2 regulate a differential set of target genes, although their expression in primary ccRCC clinical samples and their effects on patient prognosis has yet to be fully understood. Methods: In this thesis analysis has been performed on all Nephrectomies performed at Oxford Radcliffe Hospitals for Renal Cell Carcinoma (RCC) from 1983 to 2007. Data extracted from Charlesworth Research Uro-Oncology Database, CRUD©, provided long-term survival data, maximal tumour diameter, Fuhrman grade, T-Staging and patient age. A subset of RCCs from this series (170 consecutive clear cell renal tumours from 1983 to 1999) were analysed within a tissue microarray and expression of HIF-1 and HIF-2, together with seven primary target genes (BNIP3, CAIX, CyclinD1, GLUT1, LDH5, Oct-4 and VEGF) was assessed. Comparison was made with tumour angiogenesis (CD31), tumour stage, Fuhrman grade, maximum tumour diameter and patient survival. Further work in this thesis analysed a series of paired VHL (functional and non-functional) ccRCC cell lines, assessing for hypoxic differential MicroRNA expression. Results: Analysis of 664 RCCs demonstrated a clear change in kidney cancer specific survival over the past 24 years, with 5-year survival improving from 42% (1983-1986) to 73% (1999- 2002). The incidence of RCC has increased 10 fold and has a significant association with 4-year survival. There was no significant change in operative mortality, patient age, Fuhrman grade, Pathological T-Stage or mean tumour size. However, there was a 5-fold increase in tumours <6cm, corresponding to an equal fold decrease in tumours 6-8cm, and no change in tumours >8cm. Tumour size >8cm was a significant prognostic marker. HIF-1 and HIF-2 showed no correlation and individually, neither HIF-1 nor HIF-2 expression had any prognostic utility; however a significant time-dependent deterioration of HIF-1 and HIF-2 antigenicity within paraffin blocks was identified. Angiogenesis (VVI CD31) had a strong negative correlation with Fuhrman grade and maximal tumour diameter and had prognostic significance, with high levels associated with good overall survival. Results from microRNA expression arrays found a specific microRNA (MiR-23a) that was differentially expressed depending upon VHL functionality and hypoxic conditions. Furthermore microRNA-23a was up-regulated in cells that expressed both HIF isoforms, and down-regulated in cells that only expressed HIF-2. Conclusions: Outcome following Nephrectomy for Renal Cell Carcinoma has dramatically improved over the past 24 years. Increasing incidence and decreasing tumour size at operation combined with the lack of statistical variation in Fuhrman grade, suggests that earlier detection of tumours offers subsequent curative treatment by Nephrectomy. Furthermore, stable incidence rates of tumours >8cm potentially represent alternative tumour biology, which grow rapidly, avoiding early detection and curative treatment. Although neither HIF isoform nor the seven HIF target genes was found to influence disease prognosis, the discovery of HIF antigenicity deterioration with time, is a very important finding and casts into doubt previous literature about HIF-1 immunostaining in human cancers. The prognostic significance of CD31+ angiogenesis appears initially counterintuitive, however, CD31+ endothelial cells may represent functional vessels which protect the tumour from sustained periods of ischaemia, unlike the low VVI group, from which hypoxia death-resistant clones could arise facilitating tumour metastasis. This could be very important when considering the effects of biologically targeted antiangiogenic therapies. Furthermore, the negative correlation with angiogenesis (CD31+) and Fuhrman grade suggests that vessel functionality and tumour aggressiveness may change with tumour size. The finding of a specific microRNA that appears to have VHL and HIF dependent expression extends our understanding of the hypoxic pathway and opens the possibility of further development of novel targeted therapies.

Epidemiological studies indicate that there is an inverse relationship between consumption of cruciferous vegetables and risk of cancer. As a result there is much interest in understanding the anticancer potential not only of cruciferous vegetables themselves but also of the key phytochemicals contained in them. This project focuses on the potential anticancer properties of watercress, a cruciferous vegetable which is cultivated around the world and eaten raw as a salad vegetable as well as in cooked dishes. Watercress is the most abundant source of gluconasturtiin, a precursor to the phytochemical phenethyl isothiocyanate (PEITC), and is also a rich source of indole-3- carbinol (13C) and quercetin. This project addressed the hypothesis that the in vitro anticancer activity of watercress can be enhanced by altering the growth environment. To investigate this it was necessary to develop assays that can be used to assess the in vitro anticancer activity of watercress-derived compounds, to explore the mechanisms by which PEITC exhibits its anticancer effects, and to determine potential effects of altered growth conditions on in vitro anticancer properties. The activity of watercress-derived phytochemicals was analysed in a series of in vitro assays. Based on these results, inhibition of MCF7 cell growth and activation of Nrf2-dependent transcription were selected as potential assays for subsequent analysis of watercress extracts. Mechanistic studies demonstrated that PEITC inhibited the transcriptional activity of hypoxia inducible factor (HIF), a key positive regulator of angiogenesis in malignant cells. Inhibition of HIF function was associated with inhibition of mammalian target of rapamycin complex 1 (mTORC1) activity and decreased HIF1 a mRNA translation, and was dependent on the presence of the mTORC1 regulator, tuberous sclerosis complex 2 (TSC2). I also demonstrated that, in addition to effects on HIF1 a mRNA translation, PEITC inhibited general protein synthesis and modulated two other key regulators of translation, eukaryotic initiation factor 2 (eIF2) and eukaryotic elongation factor 2 (eEF2). In proof-of-principle experiments, I demonstrated that growth inhibition and Nrf2 activation assays were suitable for the analysis of crude watercress extracts and that a natural variety of "red" watercress displayed approximately 10-fold more potent in vitro anticancer activity than standard, commercial "green" watercress. However, in a series of field trials, modulation of time of harvest, water availability or sulfur fertilisation did not alter the in vitro effects of watercress extracts in growth inhibition/Nrf2 activation assays. In conclusion, this study suggests that, rather than altering environmental factors, selective breeding might be a better approach to increase the in vitro anticancer activity of watercress. Moreover, my findings have increased our understanding of the mechanisms underlying the anticancer activity of PEITC, uncovering a novel role for PEITC in inhibiting HIF1 a and total protein synthesis, and identifying several key regulators of these processes that are modulated by PEITC

This thesis describes the research carried out by the author on the exploitation of acoustic emissions detected during extracorporeal shockwave lithotripsy (a non-invasive procedure for the treatment of urinary stones) to develop a new diagnostic system. The work formed part of a research project on lithotripsy undertaken by the University of Southampton in collaboration with Guy's and St Thomas' NHS Foundation Trust (London) and a UK based company, Precision Acoustics Ltd (Dorchester). It takes to a clinical conclusion the proposition made by Leighton and Coleman in 1992 that it might be possible to build a sensor which would automatically exploit these passive acoustic emissions to monitor the efficacy of a lithotripsy treatment. The work, predominantly experimental, involved both in vitro and in vivo investigations. In particular, a first prototype diagnostic system (i.e. sensor plus analysis software) was developed and tested in vitro during trials which included the use of a novel cavitation sensor (on loan from the National Physical Laboratory, Teddington) and stone phantoms designed by the author. This initial system was, then, refined and tested during clinical trials that involved 130 patients. A preliminary trial on 51 patients aimed at refining the system and gathering knowledge on the features of emissions recorded in vivo to produce an on-line monitoring system. This trial was followed by other two trials that compared the output of the on-line acoustic system against the ‘gold standard’ X-Ray assessment of treatments outcomes. The former of these two trials involved 30 patients, and empirically defined the values of the key parameters (identified during the in vitro tests) that would be used as the basis of the diagnosis. In particular, a classification rule of treatments as being successful or unsuccessful was identified, and shown to agree significantly (kappa=0.95) with the ‘gold standard’ follow-up assessment. The latter trial tested the final system on 49 patients and confirmed an accurate treatment classification (kappa=0.94) in terms of the successful/unsuccessful criterion.