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No description available.

Expressive writing has been shown to improve health outcomes in a variety of populations, from healthy college students to people with rheumatoid arthritis. A number of hypotheses have been suggested to account for these beneficial effects, but the precise mechanism of action underlying expressive writing has yet to be established. Positive outcomes obtained in studies with clinical populations, have led to the question of whether expressive writing could be helpful for people with Chronic Fatigue Syndrome (CFS). This study aimed to pilot an expressive writing intervention for people with CFS and to explore their experience of the intervention. It aimed to investigate the feasibility, acceptability and perceived helpfulness of the intervention, and attempted to shed light on its possible mechanism of action. Nine patients were recruited from a specialist CFS clinic. They were asked to write about an emotionally upsetting or traumatic experience, for twenty minutes, once a week, for four consecutive weeks. Following the expressive writing intervention, they participated in a semi-structured interview to explore their experience. Interpretative Phenomenological Analysis (IPA) was used to analyse the transcribed interviews. Expressive writing was found to be both feasible and acceptable to the people with CFS in this study. Participants reported that overall the home-based writing intervention had been helpful and had provided them with a possible coping strategy for the future. They articulated how they thought the writing had made a difference and from this three possible mechanisms of action were proposed, including emotional expression, behavioural activation and cognitive organisation. These findings lend support to the notion that there may be more than one mechanism of action underlying the beneficial effects of writing.

Tumours have been shown to have a number of mechanisms to suppress immunosurveillance allowing them to survive and grow. One of these mechanisms involves expression of molecules which inhibit T cells such as the molecules involved in the PD-1 pathway. PD-1 is expressed on activated T cells and one of its ligands, PD-L1 has been shown to be expressed on a wide range of cell types including antigen presenting cells (APCs), endothelial cells as well as tumour cells. This pathway is important in maintaining T cell tolerance and homeostasis and as a result we hypothesised that this pathway may be an important target for immunotherapy in ovarian cancer. Ascites and blood from patients with ovarian cancer were collected over a two year period and analysis into the phenotype of immune cells and the cytokine content of the ascites was carried out. The major finding during this analysis was that APCs from ascites and blood of patients with malignant cancer showed a significantly higher level of PD-L1 than on APCs from patients with benign/borderline cancer. Furthermore the monocytes from ascites could suppress T cell proliferation in a co-culture which could be partially reversed when blocking PD-1. The cytokine content of the tumour revealed high levels of immunosuppressive (TGF-β and IL-10 correlated with malignancy) and pro-angiogenic cytokines which may contribute to the suppression of T cell proliferation observed when stimulated T cells were cultured in the ascites supernatant. These cytokines may also be responsible for the upregulation of PD-L1 observed on normal blood monocytes following culture in the ascites supernatant. Real time PCR analysis of tumour mass mRNA revealed higher levels of PD-L1 in borderline and malignant mRNA compared to normal ovary and flow cytometry showed that PD-L1 is expressed on ovarian cancer cell lines of serous histology. The second part of this project concentrated on the cloning of a PD-1 KDEL construct. PD-1 KDEL was to be used as a novel mechanism to down regulate PD-1 ligands on ovarian cancer cell lines. The construct was not successful in knocking down expression of PD-L1 on cancer cell lines and reasons were put forward for this lack of functionality. Each reason was tested experimentally and a hypothesis is put forward as to the reason of its lack of function. Alternatives to PD-1 KDEL were also tested.

The existing social sciences literature has placed considerable emphasis on the experiences of people living with singular illnesses or disabilities (Clarke and Griffin 2008). In this thesis it will be argued that it is also important to explore people’s experiences of negotiating multiple illnesses and/or disabilities. The number of people living with three or more long- term conditions in England is expected to rise from 1.9 million in 2008 to 2.9 million in 2018 (Department of Health 2012). Despite this significant increase, the voices of people negotiating multiple illnesses and/or disabilities are rarely heard in academia, politics, activism, medicine, education, employment and civic society. Using data generated during semi-structured interviews conducted in the North-East of England, this piece of research explores the extent to which people negotiating multiple illnesses and/or disabilities present a challenge to dominant expectations about the functions, capacities and conduct of bodies across time and space. I will specifically examine the ways in which participants in this research do not ‘fit into’ three important settings/contexts: (i) clinical encounters, (ii) spaces of mobility and (iii) imaginations of (hopeful) futures. Predominantly shaped by epistemological, methodological and empirical insights from existing feminist social sciences literature, this research focuses on the individual and collective (emotional, relational, material) implications of negotiating the (often) uncertain, confusing and incomprehensible bodily experiences associated with ‘managing’ multiple illnesses and/or disabilities. As well as providing a space in which the voices of this previously silenced group of people are heard, this thesis prompts consideration of the structures, processes and practices that shape and constrain people negotiating multiple illnesses and/or disabilities. Addressing such problems necessarily involves destabilising accepted norms about how bodies ‘should’ operate in particular spaces, at particular times and, thus, presents a critique to dominant and standardised ideas about how our society ‘should’ be organised. One important consequence of the contravention of such societal expectations by people negotiating multiple illnesses and/or disabilities is the sense that multiply ill and/or disabled bodies are less valuable than other bodies: an idea that this research seeks to challenge. In doing so, this thesis not only contributes to the development of the existing social sciences literature that currently focuses on experiences of people with singular illnesses and/ or disabilities, but also provides discussion that medics, activists and policy makers (amongst others) may find interesting.

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Next generation sequencing generates a large quantity of sequence data which has the potential to be highly informative when evaluated using appropriate analytical methods. One of the key aims of human genetic disease studies is to use such methods to help identify sequence variants having some phenotypic effect. In the past few years, whole exome sequencing in particular has been used to identify single variants that cause many monogenic diseases. However, monogenic diseases in which genetic heterogeneity plays a role present a more difficult problem because different affected individuals in a study may not carry disease-causing mutations in the same gene. A major focus of my work is to develop and implement algorithms to identify disease-causing variants in such diseases. In particular I make use of functional information, such as that encoded by interaction networks, to prioritise genes for follow-up analysis. In this thesis I present two different analysis tools designed for this purpose. Simulated datasets are constructed to demonstrate the utility of these tools and test their performance under varying conditions. The tools are applied to a whole exome sequencing study for a genetically-heterogeneous monogenic disease (Adams-Oliver syndrome) with the aim of generating novel hypotheses regarding disease aetiology. This work also allows comparison and exploration of the challenges facing network-based methods in practice. The tools are also applied to a study of families exhibiting atypically strong recurrence of a complex disorder (Crohn’s disease), testing the hypothesis that one or a small number of rare highly-penetrant variants might be implicated in each family. In this way it is proposed that the application of network-based methods to next generation sequencing data can help to describe disease mechanisms that move beyond monogenic diseases and towards more complex genetic architectures.

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No description available.

Chronic musculoskeletal pain (CMP) is a major cause of morbidity, and one of the most common reasons for individuals to seek treatment in both the primary and secondary care settings. Physical activity interventions are a central component of the non-pharmacological management of such conditions. However, encouraging patients to exercise or increase their overall physical activity can be problematic. This can be due to a number of potential barriers, including a belief that some activities may cause pain or injury. Walking is a form of exercise or physical activity that may potentially be effective at improving adherence to treatment recommendations; due in part to its relatively low impact, ease of accessibility and general acceptability. However, there is limited evidence which has sought to investigate the effectiveness of such interventions in patients with chronic musculoskeletal complaints. The central aim of this thesis was therefore to examine the role of walking-based physical activity interventions in this population. A number of different methodological approaches were used to address this aim. This included: (1) a systematic review of randomised and quasirandomised studies examining walking-based interventions in participants with osteoarthritis (OA), fibromyalgia (FM) and chronic lower back pain (CLBP) (chapter two and chapter three); (2) a laboratory based pilot study examining the effects of a single bout of moderate intensity treadmill walking on experimentally induced lower-limb muscle pain (chapter four); (3) a randomised controlled trial (RCT) to determine the feasibility of using a structured, pedometer walking programme as an adjunct to a standard education and advice session in participants with CLBP (chapter five and chapter six).