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Mitochondrial diseases are one of the most common forms of inherited neuromuscular disease. The presentations of these diseases are highly variable with both neurological and systemic involvement . Despite progress in identifying mitochondrial DNA mutations that result in disease, the natural history of mitochondrial diseases still remains unclear and no effective treatments are currently available (Pfeffer et al., 2012). The use of numerous primary outcomes in studies has made comparisons between studies difficult. A recent Cochrane review recommended the use of measures that were more relevant to patients in studies. This thesis aims to explore the use physiological measures alongside functional measures and gait in mitochondrial disease. The studies demonstrated that all functional outcome measures were able to discriminate between participants with mitochondrial disease and control subjects. However, gait characteristics were also able to discriminate between the two different mitochondrial genotypes. An aerobic exercise intervention resulted in an improvement in exercise capacity. However, disease severity, functional ability and gait measures remained unchanged. The main findings from this thesis are that: Clinical functional measures and gait are relevant for use in the research and clinical management of mitochondrial disease to monitor disease burden. The improvement in exercise capacity following a cycling intervention was unable to be translated into an improvement in function or gait. Therefore further research into other types of interventions, which may improve activities relevant to patients, is required.

This review explores how the experience of chronic pain impacts upon a person's identity. Firstly, drawing on an established body of literature, an outline of chronic pain research is provided. This includes an introduction to theories on cause and treatment, followed by an overview of the physical, psychological and social impact of chronic pain. Secondly, a detailed literature review is conducted on the impact of chronic illness on identity, followed by the impact of chronic pain on identity. Thirdly, factors relating to adjustment in chronic pain are reviewed along with their usefulness in helping us understand what may lead to identity change. Finally, the limitations of studies are discussed along with gaps and directions for future research.

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The phosphodiesterase 4 (PDE4) family are cAMP specific phosphodiesterases that play an important role in the inflammatory response and is the major PDE type found in inflammatory cells. A significant number of PDE4 specific inhibitors have been developed and are currently being investigated for use as therapeutic agents. Apremilast, a small molecule inhibitor of PDE 4 is in development for chronic inflammatory disorders and has shown promise for the treatment of psoriasis, psoriatic arthritis as well as other inflammatory diseases. It has been found to be safe and well tolerated in humans and in March 2014 it was approved by the US food and drug administration for the treatment of adult patients with active psoriatic arthritis. The only other PDE4 inhibitor on the market is Roflumilast and it is used for treatment of respiratory disease. Roflumilast is approved in the EU for the treatment of COPD and was recently approved in the US for treatment to reduce the risk of COPD exacerbations. Roflumilast is also a selective PDE4 inhibitor, administered as an oral tablet once daily, and is thought to act by increasing cAMP within lung cells. As both (Apremilast and Roflumilast) compounds selectively inhibit PDE4 but are targeted at different diseases, there is a need for a clear understanding of their mechanism of action (MOA). Differences and similarity of MOA should be defined for the purposes of labelling, for communication to the scientific community, physicians, and patients, and for an extension of utility to other diseases and therapeutic areas. In order to obtain a complete comparative picture of the MOA of both inhibitors, additional molecular and cellular biology studies are required to more fully elucidate the signalling mediators downstream of PDE4 inhibition which result in alterations in pro- and anti-inflammatory gene expression. My studies were conducted to directly compare Apremilast with Roflumilast, in order to substantiate the differences observed in the molecular and cellular effects of these compounds, and to search for other possible differentiating effects. Therefore the main aim of this thesis was to utilise cutting-edge biochemical techniques to discover whether Apremilast and Roflumilast work with different modes of action. In the first part of my thesis I used novel genetically encoded FRET based cAMP sensors targeted to different intracellular compartments, in order to monitor cAMP levels within specific microdomains of cells as a consequence of challenge with Apremilast and Roflumilast, which revealed that Apremilast and Roflumilast do regulate different pools of cAMP in cells. In the second part of my thesis I focussed on assessing whether Apremilast and Roflumilast cause differential effects on the PKA phosphorylation state of proteins in cells. I used various biochemical techniques (Western blotting, Substrate kinase arrays and Reverse Phase Protein array) and found that Apremilast and Roflumilast do lead to differential PKA substrate phosphorylation. For example I found that Apremilast increases the phosphorylation of Ribosomal Protein S6 at Ser240/244 and Fyn Y530 in the S6 Ribosomal pathway of Rheumatoid Arthritis Synovial fibroblast and HEK293 cells, whereas Roflumilast does not. This data suggests that Apremilast has distinct biological effects from that of Roflumilast and could represent a new therapeutic role for Apremilast in other diseases. In the final part of my thesis, Phage display technology was employed in order to identify any novel binding motifs that associate with PDE4 and to identify sequences that were differentially regulated by the inhibitors in an attempt to find binding motifs that may exist in previously characterised signalling proteins. Petide array technology was then used to confirm binding of specific peptide sequences or motifs. Results showed that Apremilast and Roflumilast can either enhance or decrease the binding of PDE4A4 to specific peptide sequences or motifs that are found in a variety of proteins in the human proteome, most interestingly Ubiquitin-related proteins. The data from this chapter is preliminary but may be used in the discovery of novel binding partners for PDE4 or to provide a new role for PDE inhibition in disease. Therefore the work in this thesis provides a unique snapshot of the complexity of the cAMP signalling system and is the first to directly compare action of the two approved PDE4 inhibitors in a detailed way.

OBJECTIVES The objective of this study was to explore the factors that are perceived to influence fathers' decisions of whether to attend an initial appointment with a Child Clinical Psychologist when their child is referred. DESIGN The research explores the perspectives of fathers who are potential service users (n=5), and also those of the service providers: Clinical Psychologists working with children and their families (n=9). A mixture of focus group and individual interview procedures were used to collect data. All interviews were audio recorded and subsequently transcribed. The research employs the method of Grounded Theory to analyse the data. This involved developing codes, categories, and themes from the data and linking them together to form a conceptual understanding of the participants' accounts. RESULTS The participating fathers and psychologists gave very similar accounts, often using the same language and constructs to explain why fathers might or might not attend appointments. A theoretical model describing the key factors that are perceived to influence fathers' decisions is presented. Family involvement and commitment was described as a pivotal factor. Whilst it was suggested that uninvolved or uncommitted fathers would not even consider attendance, it was felt that more involved fathers would be affected by a host of other factors that would either inhibit or drive their motivation to attend. Fathers' perceptions of psychology services, sociocultural barriers to help-seeking, and organisational barriers to help-seeking were perceived to be particularly important. CONCLUSIONS Difficulties in engaging fathers in child psychology services appear to arise for a number of reasons. First, the engagement of fathers in therapeutic work might mirror their engagement with their family and child outside of the clinic setting. Second, attending child mental health appointments may be perceived by fathers to be at odds with their gender identity. Prevailing societal conceptualisations of masculinity suggest help-seeking, problem sharing, and emotional expression is not `manly' behaviour. Third, uncertainty about the role of Child Clinical Psychologists and what the appointment might entail, and negative or fearful expectations, may reduce fathers' willingness to engage. It is felt that services need to consider how they might promote father engagement. Improvements in terms of the information fathers receive when their child is referred, and efforts towards portraying a more `father-friendly' image, might help to encourage some fathers, particularly those who are already involved in childcare.