Astronauts experience low back pain (LBP) and heightened spinal injury risk due to lumbopelvic deconditioning following spaceflight. Atrophy and reduced control of the lumbar multifidus (LM) and transversus abdominis (TrA) muscles have been linked with LBP, and are commonly found in astronauts, as well as individuals with LBP in the general population. Many people have difficulty voluntarily recruiting LM and TrA, presenting a rehabilitation challenge. Previously, it was found that LM and TrA are recruited automatically during Functional Readaptive Exercise Device (FRED) exercise, and that the recruitment is tonic, which is the most effective way to train these muscles, suggesting it could be suitable for use post spaceflight and in LBP populations. However, the mechanisms underpinning the effect that FRED exercise has on LM and TrA needed to be investigated before clinical trialling the device to determine: 1. What current interventions are used to prevent or rehabilitate lumbopelvic deconditioning and what are their effects? 2. Do the underlying mechanisms of FRED exercise indicate that it may be a useful intervention to trial in the rehabilitation of lumbopelvic deconditioning resulting from microgravity exposure in astronauts and a sedentary lifestyle in the general population? 3. What are the requirements for a standard and progressive training protocol using the FRED? Interventions preventing lumbopelvic deconditioning in human spaceflight simulation studies were systematically reviewed regarding effectiveness and future needs. Countermeasures during microgravity exposure were found ineffective for maintaining lumbopelvic health, presenting an immediate rehabilitation need, and future countermeasure refinement within the human spaceflight community. Rehabilitation to recover lumbar lordosis and train LM and TrA was suggested as beneficial. Recruitment of the LM and TrA muscles and movement variability was measured during FRED exercise using all available foot movement amplitudes on the device. Both muscles were recruited in all settings, and the challenge to the muscle and movement control was increased in larger amplitudes. Four chapters measured lumbopelvic kinematics and movement variability. Assessment was made of kinematic effects, the usefulness of FRED generated visual exercise feedback, the exercise familiarisation time and the effect of using the device handle bars in people with and without LBP. The FRED promotes increased lumbar extension and anterior pelvic tilt compared to over ground walking. Increasing crank amplitude increased movement variability, ΔTrAmax, ΔLMmax and TrA muscle recruitment. There was more variation away from the target exercise frequency when visual feedback was not provided. It took 170 seconds for asymptomatic individuals to familiarise to FRED exercise and155 for those with LBP. Spinal positioning became more flexed with reduced movement variability when the handles were used during exercise. There is now sufficient evidence that FRED exercise promotes beneficial lumbopelvic posture and deep muscle activity to justify a clinical trial of the device in astronaut and general deconditioned LBP populations. Following an eighty second familiarisation period, training should begin in the smallest exercise amplitude and increase in one amplitude setting intervals once FRED users can maintain a consistent movement speed, using visual feedback, but without using the handle bars.

Introduction: This study aimed to work with older people attending a regional falls and syncope service, older people with the falls-associated chronic liver disease primary biliary cirrhosis, relatives and local physiotherapy practitioners to develop a framework for physiotherapy practice to promote self-management and adherence with an exercise based falls prevention programme for older people with a long-term condition. Methods: Focus groups were conducted with older people attending a regional falls and syncope service (3 groups, total 12 participants), relatives (1 group, total 4 participants) and local physiotherapists (4 groups, total 18 participants). Participants were asked to propose strategies to promote self-management and adherence with an exercise-based falls prevention programme. These strategies were tested and refined in an experimental case-series for 10 older people with primary biliary cirrhosis. Findings: The older people participating in the focus group research expressed a long-term commitment to exercise-based falls prevention programmes. They valued approaches that promoted self-efficacy and self-management. The physiotherapists indicated that the older people they came into contact with were poorly motivated to participate in an exercise-based falls prevention programme. They demonstrated a limited awareness of strategies to promote self-efficacy and self-management. Visual analysis of the experimental case-series data revealed unstable baselines and fluctuations throughout the treatment and follow up phases in keeping with variations in disease-specific quality of life measures, suggesting that long-term conditions interact with measures that predict and monitor falls-risk and self-efficacy. The exercise-based falls prevention programmes had perceived benefit for older people with primary biliary cirrhosis. However, this was not evident in the measures selected, many of which demonstrated a ceiling effect in the population group under investigation. The self-management strategies had low levels of perceived acceptability. Participants indicated that they lacked the necessary skills to monitor their progress with an exercise-based falls prevention programme on completion of the experimental case-series. Conclusion: This study demonstrated that self-management does not sit comfortably within the philosophy of routine clinical practice. The framework for physiotherapy practice developed during the course of the current study has the potential to empower physiotherapists and older people with long-term conditions identified as being at increased risk of falling to work in partnership to challenge existing approaches to clinical service delivery.

BACKGROUND: Each year approximately 350,000 women in the United Kingdom (UK) experience perineal suturing following childbirth. For those women whose perineal wound dehisces, the management will vary according to individual practitioner's preferences. For most women the wound will be managed expectantly (healing by secondary intention) whereas others may be offered re-suturing. However, there is limited scientific evidence and no clear guidelines to inform best practice. DESIGN: PREVIEW was a four-phase study, using a sequential range of quantitative and qualitative paradigms including: • A Cochrane systematic review (phase 1) • A comparative retrospective case note audit (phase 2) • A national electronic survey (phase 3) • A multi-centre pilot and feasibility randomised controlled trial (RCT) (phase 4, part 1) and semi-structured interviews with women who participated in the RCT (phase 4, part 2). Phase four was the main component of the study. AIMS AND OBJECTIVES: Phase 1: • Evidence synthesis for the therapeutic effectiveness of secondary suturing of dehisced perineal wounds following childbirth compared to non-suturing. Phase 2: • Explore risk factors associated with perineal wound dehiscence, with the use of a logistic regression model. Phase 3: • Survey current practice relating to the current management of dehisced perineal wounds from a representative cohort of RCOG members. Phase 4: • Establish the feasibility of conducting a definitive RCT comparing re-suturing of dehisced perineal wounds versus expectant management. • Provide preliminary evidence of the effectiveness of re-suturing versus expectant management for dehisced perineal wounds following childbirth. • Explore women's experiences of living with a dehisced perineal wound. METHODS: Phase 1: A systematic review of RCTs investigating re-suturing versus expectancy for dehisced perineal wounds following childbirth. This was conducted in accordance with Cochrane guidance. Phase 2: Case notes from women with perineal wound dehiscence (n=100) were compared with case notes from women with no dehiscence (n=100) using an audit tool developed in accordance with NHS Litigation Authority guidance. Phase 3: National electronic survey of members of the Royal College of Obstetricians and Gynaecologists. Phase 4: A mixed methods study where participants with a dehisced perineal wound were recruited to one of ten participating centres and randomised to either re-suturing or expectant management. The primary outcome for the RCT was time taken to heal. The secondary outcomes were: pain, dyspareunia, women's satisfaction with the aesthetic results of healing and breast feeding. A purposive sample of women who participated in the RCT were interviewed for the qualitative study. RESULTS: Phase 1: The Cochrane systematic review (2 studies n=52 women) recommended that there was an urgent need for a robust randomised trial to fully evaluate the comparative effects of both treatment options. Phase 2: The audit (n=200 case notes) revealed that episiotomy was an increased risk factor for perineal wound dehiscence. Phase 3: The national survey (n=53 respondents) confirmed the lack of evidence based guidelines to support clinical practice. Phase 4: The mixed methods study revealed a number of feasibility issues, particularly relating to a strong patient preference for a treatment option and researcher/clinician engagement at recruiting centres which would need careful consideration before proceeding to a definitive study. Thirty four women were randomised in the pilot RCT (17 in each arm). A further 95 women were eligible but not randomised. Data from 33 women were analysed on an intention to treat analysis. There was a trend for increased wound healing at 2 weeks following randomisation, Odds Ratio (OR) 20.00 95% Confidence Interval (CI) (2.04, 196.37) P = 0.004 but no difference at 6 weeks. Findings from the interviews (n=6) revealed 4 emerging themes: physical impact, psychosocial impact, sexual impact, satisfaction with healing and an 'a priori' theme participating in the RCT. CONCLUSIONS: This study has contributed to the paucity of literature surrounding perineal wound dehiscence. The results of the RCT should be interpreted with some caution due to the relatively small numbers included in the final analysis, mostly due to patient preference for a treatment option. However, there was a significant trend to favour re-suturing for the primary outcome measure of wound healing and the overall findings of phase four show that a further study is feasible. Furthermore, data from this study will be included in future updates of the Cochrane review published in 2013 and presented in chapter three of this thesis.

The prevailing lifestyle pattern in western society results in humans spending the majority of non-sleeping hours in the postprandial state. Given that impaired postprandial metabolism may have adverse consequences for health, interventions that positively influence the postprandial milieu are pertinent considering the global rise in prevalence of chronic metabolic disorders. The aim of this thesis was to investigate whether consumption of whey protein, which has reported beneficial properties relevant to metabolic health, could impact favourably upon acute and second-meal postprandial metabolic and appetite responses. More specifically, a series of studies was designed to establish the conditions under which a rationale for whey protein supplementation may be strongest, through investigation of co-ingestion with other macronutrients, timing of supplementation and interactions with low-moderate intensity exercise. Study one revealed that consuming whey (20 g) alongside a high-carbohydrate or high-fat breakfast significantly augmented the plasma insulin response to that meal in physically active, normal-weight males, without significantly affecting postprandial glycaemia, lipaemia or subjective appetite. Whey protein consumption at breakfast did not affect second meal responses or 24-hour glycaemia when co-ingested with either macronutrient. Study two compared the effects of the same dose of protein administered before, during or after a mixed-macronutrient breakfast in centrally-obese males. Consuming whey as a preload 15 minutes prior to breakfast significantly reduced postprandial glycaemia compared to consuming it afterwards or not at all, with evidence indicating that insulin-independent mechanisms may be responsible. Again, prior whey consumption, irrespective of timing, did not influence glycaemic, insulinaemic or appetite profiles following a standard lunch meal. The final study investigated the effects of a post-exercise whey protein preload on postprandial metabolism and appetite in physically inactive, centrally-obese males. Postprandial glycaemia was moderately impaired following brisk walking exercise without supplemental protein, however this effect was negated when exercise was followed by a whey preload, with a reduced peak glycaemic excursion observed compared to other conditions. Ad libitum energy intake, assessed at lunch, did not differ between conditions. This thesis has shown that whey protein supplementation at breakfast may acutely influence postprandial glycaemia in centrally-obese individuals, however this beneficial effect is not carried over to subsequent meal occasions. Timing of protein intake appears to be important, and this effect is not diminished by prior walking exercise in previously sedentary individuals. Further studies to investigate the effects of whey protein supplementation at multiple meals are required to determine whether this may be a worthwhile strategy to prevent day-long elevated glycaemic exposure.

The aim of this research was to undertake an evaluation of domiciliary physiotherapy, by assessing the cost effectiveness of a new Domiciliary Physiotherapy Service (DPS) and by analysing the process of domiciliary physiotherapy practice. The main element of the work was a randomised controlled trial of the DPS, in which an experimental group receiving domiciliary physiotherapy assessment and intervention was compared with a control group receiving conventional care. Hypotheses that domiciliary physiotherapy would improve clients' independence in activities of daily living (ADL) and health status, and reduce clients' use of other services, were tested. The null hypotheses related to ADL and health status could not be rejected, possibly because of a smaller than intended sample size, and/or the masking of real effects by sample attrition, or lack of sensitivity of the outcome measures. There was evidence to suggest that the DPS may have significantly increased, rather than decreased, the proportion of clients with at least one contact with another health or social service. The analysis of the process of domiciliary physiotherapy developed as the RCT progressed. An interpretive account of domiciliary physiotherapy practice, framed within the author's own experiential knowledge, was constructed using quantitative and qualitative data from DPS treatment records, GP referral forms, and interviews with clients, carers and experienced community-based therapists. The interpretive analysis has underpinned a new `reciprocal learning' model of domiciliary physiotherapy, which may assist practitioners working in the field. The way forward for domiciliary physiotherapy practice may be to acknowledge that measurable clinical outcomes cannot easily be determined, and that criteria for assessing the value of domiciliary physiotherapy should be based on client and carer perspectives.

It is well-documented that strenuous physical activity has the potential to elicit exercise-induced muscle damage (EIMD), particularly when the exercise is novel and has an eccentric component. Given that the symptoms of EIMD can compromise subsequent performance, there has been substantial investigation into potential strategies that might reduce these detrimental effects in athletic populations. However, while significant advances have been made in this field, few investigations address the diversity of exercising populations who might experience EIMD following the activities they engage in, and the strategies that could facilitate their recovery. Globally, dance and dance-based exercise are popular forms of recreational physical activity, and the intensity and volume of exercise previously reported in highly trained and professional dancers can often be comparable to that of many other elite athletes. The overall purpose of this thesis was to understand the nutritional challenges facing female dancers, increase knowledge of the EIMD response, and examine potential nutritional interventions to reduce the negative issues associated with damaging exercise in this understudied population. The first study characterised the typical energy intake (estimated by combined 24 h recall and weighed food diary) and energy expenditure (estimated by the sum of basal metabolic rate, the thermic effect of food, and physical activity energy expenditure) of pre-professional contemporary dancers during 7 days of full-time training. This study determined that there is a prevalence of energy deficiency in this population (with an average daily deficit of -356 ± 668 kcal or -1.5 ± 2.8 MJ). Additionally, the second study demonstrated that female dancers experience EIMD, both from dance-specific and repeated-sprint exercise; with observed increases in muscle soreness, limb girth, plasma creatine kinase, and reductions in muscle function (all p < 0.05). These data served to inform the final two experimental chapters, which sought to investigate the role of nutritional interventions in alleviating the various symptoms of damage following repeated-sprint exercise in female dancers. Montmorency tart cherry supplementation accelerated recovery of countermovement jump height compared to placebo (p = 0.016). There was an improved recovery of reactive strength index (p = 0.016), flexibility (p = 0.050) and reduced CK (p = 0.002) following supplementation with whey protein hydrolysate. Consequently, this research provides justification for the use of these supplements as practical interventions, which could be implemented to benefit the day-to-day life of a dancer; not least for promoting recovery, but also contributing to maintaining energy balance.

Probiotics are bacteria which have the capacity to exert a beneficial effect upon the host when consumed in sufficient numbers. However, in order for these bacteria to colonise the gut, they need to survive the harsh conditions of the upper gastrointestinal tract (GIT). In this project, the probiotic spore former Bacillus subtilis has been investigated upon exposure to simulated pig gastric conditions. The main aim of this work was to elucidate what phenomena influence the perceived decline in viable count observed in gastric conditions by exploring the impact of acidified medium on the physiological state and viability of spores. It was anticipated that the main cause of spore death would either be a germination-induced death, or a direct sporicidal effect. The findings of this work highlight the need to find better methods to assess bacterial numbers, as current methods may give misleading data into probiotic survival in the host. The advantage of using a method such as FCM is also highlighted, given its ability to assess sub-populations of bacteria, rather than being limited to assessing culturability. Furthermore, the need for precise dosing instructions with regards to probiotics should also be considered.

Breast cancer is the most common type of cancer in women worldwide. Approximately two-thirds of breast cancers are oestrogen receptor positive (ER+), which are activated via oestrogen dependent and independent mechanisms. The pathogenic role of oestrogen in breast cancer is well established, thus, targeting ER becomes an essential target in breast cancer anti-hormonal therapy. Tamoxifen is the most important anti-hormonal therapeutic agent which has been used as the gold standard in the treatment of ER+ breast cancer patients. Tamoxifen acts by competing with oestrogen for binding to the ER and reduces the transcription of oestrogen dependent genes. However, approximately 30-50% of patients either fail to respond or eventually become resistant to tamoxifen via not fully elucidated mechanisms, resulting in a serious clinical challenge in breast cancer management. Also there is increasing evidence that cancers are driven by cancer stem cells which are characterised by their ability for self renewal and resistance to drug therapies. Therefore the aim of this study was to evaluate the role of oestrogen receptors in both de novo and acquired tamoxifen resistant breast cancer. Study the influence of stem cell factors and the embryonic stemness gene in both MDA-MB-231 and MCF7/Tmx breast cancer cell lines with respect to the hypothesis that anti-stem cell factor and silencing of the Nanog may restore sensitivity to tamoxifen and enhance cell apoptosis. Qualitative and quantitative assays showed significant expression of CD44, PgP, MRP1 and embryonic markers (Nanog, Oct3/4 and Sox2) in MDA-MB-231 and MCF7/Tmx cells. Independently, MDA-MB-231, MCF7/Tmx and parental MCF7/WT cells were treated with monoclonal anti-stem cell factor (ACSF) and interfered with Nanog short interference RNA (siRNA), then growth rate, drug accumulation and apoptosis were assessed in response to 4-hydroxtamoxifen (4-OHT). Quantitative analysis of the influx and efflux rate was performed using the Technetium (99mTc) sestamibi assay in response to blocking SCF. iv Results show a significant apoptosis enhancement after treatment with ASCF in both MDA-MB-231 and MCF/Tmx cells (P<0.005) and a significant increase in the influx rate of 99mTc-MIBI in MDA-MB-231 cells. Growth rate and apoptosis markers were assessed prior to and after the silencing of Nanog gene. Results show a significant increase in apoptosis and reduction in the growth rate in both MDA-MB-231 and MCF/Tmx cells (P<0.005). This study demonstrates that multi drug resistance is mainly a phenomenon of acquired tamoxifen resistance, but not de novo resistance. The inhibition of SCF could inhibit cell proliferation and significantly increases cell sensitivity to tamoxifen in MDA-MB-231 and acquired tamoxifen resistant cells MCF7/Tmx. This study identified a high expression of embryonic markers Nanog, Oct3/4 and Sox2 in both MDA-MB-231 and MCF7/Tmx cells and that the silencing of the Nanog gene reduces cell proliferation and increases apoptosis in MDA-MB-231 and MCF7/Tmx cells. In conclusion, the results suggest that the neutralisation of stem cell factor may play an important role in enhancing tamoxifen response in ER- cells and less in acquired tamoxifen resistant breast cancer cells, via enhancing drug accumulation. The positive association of the embryonic markers with negative (ER-) and acquired tamoxifen resistant breast cancer cells could be used as prognostic markers and the knockdown of these transcription markers could enhance the response to tamoxifen and could be used in the management of breast cancer.

Introduction: Pigeon fanciers’ lung (PFL) is one of the most common forms of hypersensitivity pneumonitis (HP) in the UK. Generally it is considered that PFL is caused by immune complexes, however, this does not explain why some fanciers are asymptomatic despite the presence of high levels of anti-avian antigen antibodies in their serum. Pigeon intestinal mucin (PIM) is considered to be an important antigen in PFL. Thus this study was designed in order to understand the role of specific antibodies and T cells in the pathogenesis of PFL. Methods: Anti-avian IgG and IgG subclass responses among 50 symptomatic and 50 asymptomatic pigeon fanciers were determined by ELISA and the functional affinity of IgG1 and IgG2 against a range of pigeon antigens was determined by inhibition ELISA and microcalimetry. Mucin-specific T cell clones were also generated from pigeon fanciers and T cell phenotypes and cytokine profile of these cells were identified. Results: The median titres of IgG1 and IgG2 against all the pigeon antigens tested was always higher in asymptomatic than symptomatic fanciers and these differences were significant for anti-PS IgG1 (P=0.04), anti-PDF IgG2 (P=0.028), anti-PDO IgG2 (P=0.04) and anti-PIS IgG2 (P=0.03). The functional affinity of IgG1 and IgG2 against PDO was higher in symptomatic individuals as compared to asymptomatic fanciers (P=0.006 and P=0.002, respectively) whilst the functional affinity of anti-PDF IgG2 was also significantly higher in these patients (P≤0.001). Symptomatic fanciers were also significantly more likely to have high ΔH and thus had higher avidity antibodies against PDO (P=0.044). 12 T cell clones specific for t mucin also were generated from an asymptomatic fancier and 90-96% of clone 04, 22, 23 were CD4-CD8- double negative (DN). Conclusion: The data suggests that the magnitude of the serum antibody response cannot determine the development of the disease and as symptomatic fanciers had higher IgG antibody avidities and therefore immune complexes in individuals with PFL may have a stronger composition and bonds. In addition, this is the first demonstration of the use of ITC to measure antibody avidity in a clinical situation. This is a rapid and simple method of measuring antibody avidity and has a diagnostic potential in PFL. Finally t mucin-specific T cell clones with double negative phenotype may have a crucial role in immune regulation in asymptomatic fanciers and can be one of the reasons why these individuals do not have any symptoms in spite of having high antibody responses.

This thesis investigates the lives of seven disabled people who were sexually abused in childhood by utilising narrative methodology and the application of the social model of disability. Flexible methods of participation were offered to participants and continuous ethical evaluation formed the backbone of the research relationship. Thematic analysis generated three interlocking and overarching "grand" themes that constituted the substantive chapters of the thesis (power, identity and narrative) and provided a structure within which the findings were embedded. Narratives of power illustrate how the sexually abused disabled child is potentially located at the collision point of a number of oppressive societal beliefs and practices related to the treatment of both children and disabled individuals. These debilitating attitudes become apparent in the workings of certain organisational structures and the general functioning of some family environments. Narratives of identity deals with the issue of how a, sometimes, fragile identity created by disability oppression becomes fragmented by the sexual abuse experience. It also illustrates that from this compromised starting position, participants have been able to forge a series of self-affirming collective identities. The chapter entitled narratives of the narrative concerns itself, ostensibly, with the reconstruction of the abuse narrative. Within this chapter it can be seen that when the usual defence mechanisms (dissociation) become less necessary for survival, and when the external triggers are prevalent, the sexual abuse narrative emerges creating narrative chaos (Frank, 1995) and emotional destabilisation. The personal healing process has involved the reconstruction of a more reflective, self-absolving and coherent version of events, which contains narrative truth (Spence, 1994). In concluding this thesis, several tasks were undertaken including the weaving together of the complex relationship between disability and child sexual abuse, and a highlighting of the key pressure points where difficulties were exaggerated. It also involved: consideration of whether narrative methodology fulfilled its purpose, a reflection on the work's theoretical positioning and the implications of the thesis for policy and practice.