The immunopathology of multiple sclerosis (MS), a disease of the central nervous system (CNS), is characterised by widespread inflammation, focal demyelination and axonal degeneration. As a result of early disturbances in the blood brain barrier (BBB), serum proteins, including fibrin(ogen) enter into the CNS. Up-regulation of components of the plasminogen activator (fibrinolytic) system correlates with onset of inflammation and migration of leucocytes into the brain parenchyma. Significant upregulation of plasminogen and plasminogen activator inhibitor-1 (PAI-1), and an accumulation of fibrin D-dimer was found during neuroinflammation, in the established mouse model of MS, chronic relapsing experimental allergic encephalomyelitis (CREAE) induced with spinal cord homogenate (SCH). Onset and progression of disease correlated with a reduction in dendritic markers, supporting evidence of early neuronal/axonal dysfunction. Furthermore an impairment of fibrinolysis in these mice ensured that fibrin entering the CNS was not effectively removed, suggesting a role for the PA system in the pathogenesis of CREAE. Initially, using mice deficient in tissue-type plasminogen activator (tPA"/") and myelin oligodendrocyte glycoprotein (MOG)-induced EAE, animals displayed an early and a more severe acute disease characterised by incomplete recovery when compared to wild-type controls, with significantly higher CNS levels of PAI-1. This correlated with fibrin accumulation, which co-localised with non-phosphorylated neurofilament on thickened axons in EAE tissue. In contrast, urokinase plasminogen activator receptor knockout mice (uPAR"A) had a delayed, less acute disease reflected in delayed infiltration of inflammatory cells. However, these animals developed chronic disease as a result of steadily increasing inflammation, high levels of urokinase-type plasminogen activator (uPA) and greater degree of demyelination. Due to low rates of EAE susceptibility, mice deficient for PAI-1 were backcrossed onto the ABH strain for 4 generations. Induction of SCH-CREAE in PAI-1"7" mice resulted in a lower incidence of disease, with mice developing clinical signs of EAE significantly later than WT littermates. A delay in cellular entry into the CNS accompanied by a higher capacity for fibrinolysis resulted in a milder disease in PAI-1"7" mice with no clinical relapses and less axonal damage. Thus, the plasminogen activator system can modulate both inflammatory and degenerative events in the CNS through the respective effects of tPA, PAI-1 and uPAR on fibrinolysis and cell adhesion/migration, manipulation of which may be of therapeutic importance in multiple sclerosis.

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The aim of the research was to investigate the relationship between early maladaptive schemas, as described by Young, Klosko and Weishaar (2003), and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Despite the recognition of characteristics associated with these schemas in people with ME/CFS by clinicians, a review of the literature suggests that systematic research into this relationship has not previously been conducted. This thesis progresses knowledge in this area by providing a schema-level understanding of ME/CFS and offering insights into the behavioural process involved in the progression from schema to illness. The research employed mixed methods enabling a consideration of the relationship from different perspectives, and is grounded in a critical realist perspective. The quantitative study involved 40 people with ME/CFS and 40 people from a non- clinical population who completed Young's Schema Questionnaire (YSQ-S3), a questionnaire designed to elicit 18 early maladaptive schemas. The schemas Unrelenting Standards and Self-Sacrifice were the most prevalent in both groups. Unrelenting Standards was endorsed by 47.5% of the ME/CFS group and by 25% of the non-clinical group at a level of' clinical caseness', whilst the percentage of people that endorsed the Self-Sacrifice schema was similar in each group; 27.5% of the ME/CFS group endorsed this schema and 25% of the non-clinical group. There were significant correlations between the schemas Unrelenting Standards and Self- Sacrifice; age and the schema Social Isolation; qualifications and the schema Self- Sacrifice also current employment and the schema Unrelenting Standards. The qualitative study, which involved 13 people with ME/CFS, adopted a Grounded Theory approach influenced mainly by the works of Glaser, (1978, 1998, 2011) and Charmaz (1995, 2007). The core category generated from the data was termed 'obscuring', and conceptualised the manner in which early maladaptive schemas and the coping style 'surrender to the schema' obscured the needs of individuals with throughout the therapeutic process. The number of early maladaptive schemas reduced once depression had been treated, whilst the schemas Unrelenting Standards and Self-sacrifice remained at a level of 'clinical caseness' at the end of therapy, although their scores on Young et al. 's Schema Questionnaire (YSQ S-3) had decreased. The qualitative study and case study gave an insight into the complexity of early maladaptive schemas in relation to the illness, giving real life meaning to the quantitative findings and together the three studies increased the credibility of the theory that emerged from the qualitative analysis. Taken together the studies have implications for the Cognitive Behavioural model of ME/CFS (Surawy et al. 1995). It is proposed that early maladaptive schemas have relevance for the model at the predisposing and perpetuating levels; that the theoretical codes 'compelling', 'curtailing' and 'compassionating', derived from the grounded theory analysis, are evident at these levels; and that the model might benefit from the inclusion of the terms 'unhelpful emotional responses' and 'psychological rewards'. The research not only supports clinical observations, but also contributes to cognitive and behavioural theory and therapeutic interventions for ME/CFS, helping to deepen understanding of the role that early maladaptive schemas have in this disabling and unpredictable illness. Recommendations are made for clinical practice and future research.

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