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Chronic pain is pain that has lasted for longer than six months (B.H. Smith, Elliott, & Hannaford, 2004) and has a wide ranging impact on individuals’ lives, affecting physical, social and psychological functioning (B. H. Smith et al., 2001). Despite the impact of chronic pain and the significantly increased use of healthcare (Von Korff, Wagner, Dworkin, & Saunders, 1991), the effectiveness of treatments for chronic pain are limited to a minority of individuals, whether of a medical or psychological orientation (Turk, 2005). One approach to chronic pain is through pain management programmes, which aim to increase individuals’ quality of life, psychological functioning and levels of activity (British Pain Society, 2007). Although previous reviews of the effectiveness of pain management programmes have concluded that such programmes are effective (Eccleston, Williams, & Morley, 2012; Flor, Fydrich, & Turk, 1992; Scascighini, Toma, Dober-Spielmann, & Sprott, 2008), these reviews have focussed on the short-term (less than 12 months) outcomes. Considering that such programmes do not ameliorate pain and that individuals will often experience pain for the rest of their lives there is a need for review of the long-term outcomes of these programmes. Paper one of this thesis is a review of the quantitative literature concerning long-term (greater than 12 months) psychological and quality of life outcomes of pain management programmes. Whilst quantitative research concerning chronic pain has focussed upon the shortterm effectiveness of psychological treatments, qualitative research has focused upon the experience of chronic pain prior to interventions (Hellström, 2001; J. A. Smith & Osborn, 2007; Toye et al., 2013). In particular, this research has highlighted themes relating to a changing understanding of individuals’ bodies and a threat to their identity (Hellström, 2001; Osborn & Smith, 2006; J. A. Smith & Osborn, 2007; Toye et al., 2013). As there is now greater certainty of the effectiveness of psychological approaches to chronic pain (Eccleston, Williams, & Morley, 2012) there is currently a shift away from studies of the effectiveness of interventions to a greater focus upon the mechanisms of change (McCracken & Marin, 2014; Morley, Williams, & Eccleston, 2013). Qualitative research of living with chronic pain following pain management programmes would inform both clinicians’ and researchers’ understanding of the experience of living with chronic pain after an intervention and therefore contribute to the development of this area of research. It would also help to contextualise psychological models of chronic pain (Hayes, Strosahl, & Wilson, 2004; Vlaeyen & Linton, 2000) within a phenomenological understanding (J. A. Smith, Flowers, & Larkin, 2009). The second paper of this thesis aims to provide a phenomenological account of the experiences of participants who have completed a pain management programme 12-36 months prior to participating in the research.

Background: Chronic fatigue syndrome (CFS) known interchangeably as myalgic encephalomyelitis or encephalomyelopathy (ME) is a contentious and often misunderstood condition of unknown cause. Associated symptoms may fluctuate and include post exertional mental and physical fatigue, sleep disturbance, generalised aches and pains and for some, hypersensitivities to alcohol, light and noise. The impact of having CFS/ME can result in disruption to all aspects of day to day life for children and adults regardless of ethnicity or socioeconomic factors. In adults, it is estimated that population prevalence is 0.2 – 0.4% which is higher than in children and that women are affected by the condition more than men by a ratio of 3:1. The vast majority of the literature linked to living with CFS/ME focuses on the experiences of women with the condition and as a consequence, there is a dearth of literature reporting on the experiences of men. Additionally, men with CFS/ME are considered as difficult to recruit in terms of research participation. Objective: The focus of this study was to explore the experiences of men living with CFS/ME and its impact on their day to day lives and occupations. Design: A qualitative design was employed underpinned by interpretive phenomenology. Eight men aged between 21 and 68 years old were recruited with a clinically confirmed diagnosis of CFS/ME and interviewed up to four times. Rich data were generated through dialogue, poetry and artworks. Interpretations were made using the hermeneutic work of Gadamer (2004) as a philosophical framework. Analysis: Thematic analysis was employed. Unique and shared experiences were identified from the data. Shared findings were synthesised into three themes to reflect the temporally situated nature of the men’s experiences. Findings: The findings illustrate that existentialist notions of ‘being-in-the-world’ were significantly disrupted by the presence of CFS/ME. Additionally, the occupational dimension of ‘being-in-the-world’ referred to as ‘doing’ and notions of ‘belonging’ and ‘becoming’ were also disrupted. How CFS/ME impacted upon individual risks to survival and health was also elicited. Conclusions: New knowledge was generated to add to the body of work linked to the impact of CFS/ME on the lives and occupations of men with the condition. A unique way of knowing about the meaning of occupation was also gained through fusing philosophical and occupational orientations/frameworks to inform occupational therapy practice and the occupational science literature. The importance of considering the men’s ‘being-in-the-world’ was emphasised in order to understand their ‘doing’ as a dimension of ’being’ and their subsequent ‘belonging’ and ‘becoming’. Uniquely, notions of ‘traumatised being’, associated with potentially life threatening causes of fatigue, and ‘emasculated being’ were experienced by some of the men and the importance of an awareness of these concepts is addressed in terms of occupational therapists facilitating survival, well-being and ‘harmonious health’ for men with CFS/ME.

Hunger and pain are powerful homeostatic drives, which compete for a behavioural response when experienced simultaneously. This thesis set out to explore neural mechanisms underpinning this competition, and how appetitive visual and olfactory stimuli may modulate the effect of homeostatic energy manipulations on pain. Using well-established techniques including EEG source analysis and resting state fMRI, we consistently employed a within-subjects fasting vs. satiation paradigm to investigate the effects of appetite on subjective pain perception and neural pain processing. Pain stimuli which selectively activated nociceptive Aδ fibres were presented concurrently with appetitive stimuli, and the neural nociceptive responses were mapped with high-density (128-channel) EEG recordings and fMRI functional connectivity. Based on the results of previous research, we hypothesised that fasting would suppress subjective and neural pain processing, and that visual and olfactory appetitive stimuli may augment this effect. We first found that a relatively short overnight fast was sufficient to induce significant changes in resting state functional connectivity in areas that underlie both hunger/satiety and pain: insula cortex, hypothalamus, and regions of prefrontal cortex. Source analysis of EEG data revealed a small group of brain regions whose pain-related activation was suppressed by hunger and/or appetitive stimuli: anterior cingulate cortex, operculo-insular cortex, parahippocampal cortex, and cerebellum. Functional connectivity analysis of fMRI data further uncovered a widely-distributed network of brain areas whose pain-induced connectivity was enhanced by fasting or satiety. Of particular interest was a small network of areas involved in stimulus saliency processing (anterior insula, anterior cingulate cortex, and prefrontal cortex), which was stronger during fasting; presumably advantageous when searching for food. Lastly, in an experiment using a bread odour, we found that the suppressive effect of appetitive stimuli on nociception is not just confined to the visual modality. Brief, strong pain can also be suppressed by an appetitive odour during fasting. We conclude that fasting reliably interferes with pain processing, and that ambient appetitive stimuli might be of use in situations where short-lasting pain is likely to occur.

Clostridium difficile is a spore-forming, gram positive bacteria responsible for causing Clostridium difficile infection (CDI), the main symptom of which is diarrhoea. It can also cause serious symptoms, for example, pseudomembranous colitis, toxic megacolon and death. CDI spreads through the ingestion of C. difficile spores, which are very resistant to cleaning products and can survive on surfaces for many months. Little is known about the germination of C. difficile spores; taurocholic acid, a bile acid found naturally in the gut is one of the known germinants, but the exact mechanism of germination is unknown. Other bile acids, such as cholic acid have shown germinating ability, but to a lesser extent. The aim of this PhD was to create a polymer surface that forced the germination of the C. difficile spores upon contact, then to kill the resulting more susceptible vegetative cell. A known germinant of C. difficile spores, cholic acid, was derivatised at the carboxyl group in a flexible synthesis to give a range of carboxamide analogues terminating in a quaternised amino function, with or without a polymerisable function. The attachment of polymerisable groups at the hydroxyl functions was also explored. The cholic acid monomers proved to be resistant to polymerisation. Of the monomeric compounds, however, nine exhibited C. difficile spore-germinating activity, two had either sporicidal or germinating and antimicrobial abilities and two other compounds had germinating and sporicidal and/or antimicrobial activity. The results for this series of compounds indicate that germination of C. difficile spores is favoured by the presence of a quaternary ammonium function and a two- to four-carbon chain between the cholamide carbonyl and the quaternary centre. Overall, eleven new compounds exhibited activity against C. difficile spores. The incorporation of these compounds into a polymer surface or disinfectant spray has the potential to reduce the risk of infection of CDI by eliminating C. difficile from surfaces, in both healthcare and community based settings.

Chronic neuropathic pain results from nerve dysfunction/lesion and affects approximately 20% of European adults. Due to its complexity neuropathic pain is often misdiagnosed and inadequately treated. Nerve injury induces several changes such as synthesis of neurotoxic mediators and prolonged transcription of inducible nitric oxide synthase (iNOS) leading to increased production of nitric oxide (NO). These mediators are believed to contribute to peripheral and central neuronal sensitisation and their activity correlates with pain severity, signifying their importance in nociception. The central aim of this thesis was to investigate the role of iNOS and cytokine signalling in models of chronic pain, and then identify underlying changes in ion channel transcription that may contribute to DRG neuron hyperexcitability. Using the in vivo L5- spinal nerve axotomy (L5-SNA) model of neuropathic pain, behavioural data showed that pain can be alleviated with the highly specific iNOS inhibitor, 1400W. This data showed that iNOS and NO are involved in causing neuronal hyperexcitability and in turn mechanical and heat hyperalgesia; two hallmarks of chronic pain. Immunohistochemical staining data showed that elevations in IL-1β, TNF-α and MCP1 expression in small-sized DRG neurons can be modified with 1400W, outlining its role as a potential neuroprotective agent. This was further investigated by examining the effect of iNOS modulation of the circulating cytokine content in blood plasma following surgery-induced neuropathic pain. In these studies the role of 1400W was more complex. 1400W up-regulated anti-nociceptive mediators, including IL-1α and IL-10, but also significantly increased levels of the pro-nociceptive mediators, IL-1β, TNFα and RANTES. DRG neuron action potential frequency responses to thermal stimuli were investigated in vitro in a further novel model of chronic pain. Whole-cell patch-clamp was also used to investigate changes in voltage-sensitivity of DRG neurones post-TNFα treatment. Under control conditions, elevated temperatures decreased reversal potential; however, whole cell conductance remained stable. In contrast, the TNFα treatment showed that the hyperpolarisation in response to noxious heat (45oC), measured in the control cells, was sensed at lower temperatures (30oC). This was consistent with thermal hyperalgesia. Using qPCR, TNF-α treatment significantly altered 17 neuronal ion channel transcripts were and this could underlie the neuronal hyperexcitability observed in pain states. This approach highlighted how cytokines may act on multiple DRG neuronal ion channels, which was also demonstrated in action current studies. In conclusion, this thesis emphasises the key role of the neuroimmune functions in nociception and identified 1400W as a promising analgesic agent with neuromodulatory effects. This study also identified some electrophysiological parameters that are affected as well as discovering key ion channels that are dysregulated in pain states and could be targeted for future disease-modifying drugs for the chronic pain.

Individuals with chronic pain commonly report significant functional impairment and reduced quality of life. Emerging evidence demonstrates the relevance of capturing clinical outcomes in relation to improved psychological well-being (PWB), though little is known about the psychological processes or mechanisms underpinning enhancements in PWB within this population. The study aimed to investigate whether 1) increased levels of pain intensity and interference predicted lower levels of PWB, 2) increased goal-focused hope and solution-focused thinking predicted higher levels of PWB, and 3) whether the relationships between pain characteristics and PWP were mediated by increased goal-focused hope and solution-focused thinking. A total of 586 individuals with chronic pain participated in the online, cross-sectional study. Structural equational modelling was used to test a hypothesised model whereby self-report measures of solution-focused thinking and goal-focused hope comprised the latent variable positive goal engagement (PGE). Self-report measures of pain characteristics and PWB were also completed. Results showed that both pain characteristics and PGE predicted PWB. Moreover, relationships between pain intensity and interference and PWB were partially mediated by PGE. The results provide tentative evidence for the protective role of PGE in enabling individuals with chronic pain to maintain a sense of PWB.

No description available.

We do not know what it means to live with Russell-Silver syndrome (RSS), as currently there is a dearth of literature exploring the lived experience of this rare genetic condition characterised by pre and postnatal growth retardation. Discovering how this syndrome affects the lived experience will provide valuable information for better healthcare provision and aid families in making difficult treatment decisions. In this qualitative study, in-depth semi-structured interviews were used with 15 participants (6 female). Using thematic analysis, three themes were identified: “It’s not just all about height”, ‘everyone’s comparing, everyone’s judging’, and “mayor of the friend zone”. These themes describe participants’ struggles with varied psychosocial, appearance and body image related concerns. The key findings were: participants experienced appearance-related concerns that surpassed a concern about height; adolescence was a particularly difficult time; and there was a mismatch between patient need and existing healthcare provision. Two main recommendations were made: Firstly, psychosocial evaluation and interventions to improve self-esteem, self-confidence, negative body image, and social interactions during early adolescence could ameliorate psychological distress. And secondly, a conflation of the 2016 expert consensus statement, which summarised recommendations for the management of patients with RSS as well as for diagnosis and investigation, and the results from the present study is needed to inform a care pathway recommending psychosocial assessment and that continues into adulthood.

The presence of DNA damage in mature sperm may be associated with poor chromatin structure due to abnormal protamination. Interestingly, however, approximately 5-15% of the DNA in the human sperm nucleus remains bound to histones. In this study, oxidative stress was used to induce DNA damage in mature sperm aimed at investigating the integrity of sperm chromatin structure. The extent of the damage was assessed by acridine orange, alkaline comet and halo assay (HalospermTM). Experiments were designed to probe the relationship between sperm DNA fragmentation as revealed by halo dynamics and the DNA sequences that constitute the nuclear halo structure, and so provide a more robust link between the halo assay as a discriminator of high-quality sperm and paternal genes that may be disrupted in damaged sperm. Differential Density Gradient Centrifugation (DDGC) was used to resolve human spermatozoa into 90% percoll solution (high density) and 45% percoll solution (low- density) fractions. DNA damage was induced by exposure to H2O2 at two different concentrations (100 and 300 μM) for fixed times. Acridine orange, alkaline comet and halo assay were used conventionally to measure the extent of DNA fragmentation in peroxide-treated cells. In a variant of the halo assay aimed at investigating the differences between protamine and histone-bound DNA, human sperm nuclei were treated with either low or high ionic strength salt solutions to generate nuclear halos. Halos produced from control (undamaged) sperm by HalospermTM or by salt extraction were treated in suspension with restriction enzymes to release halo-DNA, which was analysed by Next Generation Sequencing (NGS). Results of acridine orange, alkaline comet and halo assay revealed that pellets of DDGC processed sperm were far more resistant to H2O2 treatment compared with interface sperm. The efficacy of halo formation as an indicator of DNA damage was shown by the high percentage of strong halos generated by HalospermTM and salt extraction methods from sperm isolated from the pelleted sperm compared with interface sperm. Analysis of NGS data of halos generated by HalospermTM and by low or high salt extraction of nuclear proteins suggests that approximately 2000 genes, many of developmental significance are significantly ‘over-represented’ in nuclear halos compared with residual (nucleoid) DNA. Moreover, the data suggests that halo-DNA was originally associated with the histone compartment of sperm chromatin. The nuclear halo can indicate the level of DNA fragmentation in sperm, and the sequence composition of halos suggest that such fragmentation could compromise important paternally-derived DNA sequences that the oocyte may be unable to repair.