The molecular mechanism that leads to ischemic preconditioning and hence to ischemic tolerance, are not completely understood although it is clear that multiple effectors and pathways contribute to the instauration of this neuroprotective profile. To study the mechanism/pathway involved in the ischemic tolerance, brain proteins, plasma proteins and plasma metabolites were analyzed in preconditioning stimulus, in severe stroke and in preconditioned mouse model. A conventional 2-DE approach was used to study technical replicates of pooled brain proteins revealing an involvement of energy metabolism, mitochondrial electron transport, synaptic vesicle transport and antioxidant processes; moreover network analysis suggested an involvement of the androgen receptor that was validated on technical replicates of pooled brain proteins by western blot analysis revealing an increased expression in preconditioned stimulus animals. Plasma proteins were analyzed using a i-DE Le-MS/MS approach on technical replicates of pooled plasma proteins revealing decreased levels of epidermal growth factor receptor (EGFR) and increased levels of insuline like growth factor acid labile subunit (IGFALS), which expression was paralleled by increased insulin like growth factor 1 (IGFi) plasma concentration, as validated by ELlSA on biological replicates, in preconditioning stimulus animals. Finally an untarget metabolomics analysis was applied to technical replicates of pooled plasma proteins revealing fatty acid oxidation and branched-chain aminoacid metabolism as the main biological processes modulated in ischemic tolerance and highlighted an involvement of the aminoacid leucine, carnitine esters and adenosine. The results described in this thesis represents the first application of both' proteomic and metabolomic approaches in cerebral ischemic sets, highlighting the androgen receptor as an important mediator between proteins and metabolites and adding new evidence to the current knowledge on ischemic preconditioning that may represent a starting point for future experiments on investigating candidate pathways that relate to the androgen receptor.

Introduction: Executive function (EF) is impaired In up to 75% of patients following stroke and can hinder recovery. Despite this high incidence of executive dysfunction (EO), interventions to improve task performance focus on repetitive practice which does not address EF development. To explore further options for addressing ED following stroke, the work in this thesis includes three key studies: 1. Review of executive function research and development of the e){executive function task application model (EFTAM): An exploration of components within established definitions of EF suggested that EF can be explained by five core components: concept formation, planning, initiation, inhibition and flexibility. However, within existing EF models the task process was limited to one stage, while, in contrast, occupational performance models conceptualize tasks as multifactorial. This suggested the need for a new model which integrated models of EF and occupational performance. Hence the EFTAM was constructed with the key aim of providing a model to demonstrate how EF is applied at the various stages of task performance. 2. Cochrane systematic review of cognitive rehabilitation: This review found insufficient evidence to support the effectiveness of cognitive rehabilitation for improving EF after stroke and acquired brain injury. The review also identified limitations relating to assessment of EF leading to the hypothesis that instructing patients to verbalise their thoughts may be a method of determining how patients apply EF during tasks. Thus, a qualitative study to explore how participants expressed EF through their actions and talking was indicated. 3. Ethnomethodological study to explore how individuals express EF through talking and actions: 20 participants with stroke, upper limb injury and a healthy individual were Video-recorded during a semi-structured interview including an upper body dressing task. Data analysis, using a narrative analysis framework, and based around the EF core components and the EFTAM, explored how EF was expressed during application to the task. The participants demonstrated several patterns of EF expression and dressing ability from their combined actions and talking. Conclusion: This thesis provides a comprehensive synthesis of current evidence relating to interventions for EF and identifies the clear limitation within current literature as the lack of suitable assessment tools. A new model integrating EF and task performance theories has been generated with the potential to provide a useful tool for profiling EF during task performance. Innovative methods have been used to explore storytelling during task performance, providing new insights in relation to how EF is applied to the different stages of a task. Future research should include further exploration of the application of these methods to a range of different tasks to unlock the potential of storytelling during task performance. This could enhance our understanding of EF and lead to the development of a new standardised EF assessment and effective interventions to treat ED.

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Stroke is the third most common cause of death in the United Kingdom and the single greatest cause of severe disability. The effects of stroke are complex but the impact on emotional wellbeing is arguably one of the most problematic aspects of stroke rehabilitation to address. Nurses play a key role in stroke rehabilitation and the ways in which they interact with and respond to the emotional experience of stroke, may be crucial to the well-being of the patient and their relatives. Informed by an interactionist theory of emotion, the aims of this interpretive ethnographic study were to explore the emotional experiences of persons affected by a stroke (patients and relatives), nurses’ interpretations of these experiences and how they used them to inform and influence person-to-person interactions during the period of hospital-based rehabilitation. Taking a case study approach, a purposive sample of 10 cases was selected, with each ‘case’ comprising a patient, their closest relative and the nurses who provide their care. Data were constructed through participant observation, interviews and documentary review. Data analysis revealed that through a complex interplay of core beliefs, personal and professional attributes and interpersonal skills, nurses enabled patients and relatives to access and utilise their own personal attributes in order to recover from stroke. An emergent relationship model explains how the relationships built and sustained between nurses, patients and relatives during their encounters with each other on a stroke rehabilitation unit are central to creating a positive culture of caring which promotes emotional wellbeing and aids recovery. The findings have implications for policy, clinical practice, health care education and research.

Stroke is the single largest cause of disability and second highest cause of death globally. It is estimated that 10 million people a year are affected by stroke in the United Kingdom (UK). Of the 130,000 annual new stroke occurrences in the UK, one third will go on to have a further stroke. Recurrent stroke is more likely to be fatal than first stroke and survivors are more likely to be left with major disability. Many stroke patients do not adhere to secondary prevention strategies due to complex reasons, including lack of appreciation of their high risk of a secondary cardiovascular event. Long-term secondary prevention remains a desired goal in the management of stroke survivors, however, studies have shown that current strategies are not routinely and universally working. Hypothesis: Raising awareness of secondary stroke risk may improve stroke survivor’s adherence to secondary prevention strategies after stroke. Results: A survey of the general public (n=1019) and a population-based study of over 600 stroke survivors found that knowledge about Blood Pressure (BP) and stroke risk factors was poor in high risk populations. Only 55% of stroke survivors were able to cite any well-known vascular risk factors. However, those who were appropriately risk-aware significantly improved their health behaviour post-stroke by consuming less alcohol (P<0.001), less salt (P=0.05) and eating a healthy diet (P=0.02). Further, In a Randomised Controlled Trial setting an intervention to increase risk awareness was successful in increasing awareness (P=0.04) and resulted in a significant increase in knowledge of stroke sub-type (95% CI 0.72-0.677, P<0.001), risk factor control of systolic BP (95% CI 12.1-10.4, P=0.01) and increased the number of healthy lifestyle behaviour changes made at follow-up (P<0.001). Conclusions: Increasing risk awareness is potentially an important mechanism to improve health behaviour following stroke and may improve risk factor control as part of secondary stroke prevention.

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