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Psoriasis is an immune-mediated chronic dermatological condition associated with a range of physical and psychological comorbidities, and a significant disease burden. Healthy sleep plays a key role in maintaining health and wellbeing. Conversely, chronic sleep disturbance significantly increases the risk of developing a range of physical and mental health conditions if left untreated. Sleep disturbance is a known feature of other chronic conditions and is associated with disease-specific influences and consequences. Therefore, given the links between sleep, health and functioning, the experience of sleep disturbance in psoriasis was investigated using a multi-method approach. Chapter One provides an overview of psoriasis and sleep and the potential impact psoriasis and sleep disturbance can have on health and wellbeing. Chapter Two identifies what is known from the existing literature and the limitations of the studies reviewed. From here a prospective research agenda was formulated. A cross-sectional survey (Chapter Three) sought to address the gaps in the literature by examining the extent, characteristics and correlates of sleep disturbance using validated measures. Chapter Four then describes the first in-depth qualitative study exploring the experience of sleep disturbance in people with psoriasis. The Common-Sense Model of Self-Regulation was used as a guiding framework and facilitated exploration of beliefs, emotions and behaviours associated with sleep disturbance. This study provided insights into the role of psoriasis specific factors, the impact of sleep disturbance on daily life and the limited coping options available. Using Experience Sampling Methodology, Chapter Five examined the bi-directional and sequential relationships between sleep disturbance and daytime variables in psoriasis. Multiple daily assessments of psoriasis, mood, night-time experiences and functioning were combined with actigraphy and sleep dairies. This study revealed possible treatment targets to improve sleep and daytime functioning. However, findings related to psoriasis were contrary to previous chapters. The findings from the preceding chapters were synthesised in Chapter Six. The methodologies used were also critically appraised. Clinical implications were discussed in addition to a brief overview of potential avenues for future research.

The pulmonary veins are widely recognised as a source of ectopic electrical activity that can cause atrial fibrillation. While the ectopic activity likely originates in the cardiomyocytes that form an external sleeve around the veins, the underlying mechanisms are unknown. Changes in intracellular Ca2+ signalling have been proposed to play an important role in the arrhythmogenic properties of the pulmonary vein. Therefore, the aim of this thesis was to study factors that might influence Ca2+ signalling in the cardiomyocytes. This involved determining the localisation of Ca2+ handling proteins in the cardiomyocytes, examining interventions that might alter the characteristics of intracellular Ca2+ signalling, as well as looking at the arrhythmogenic effect of adrenergic stimulation. In the rat pulmonary vein, the cardiomyocytes displayed spontaneous Ca2+ transients that were usually manifest as waves, and were asynchronous in neighbouring cardiomyocytes. The frequency of spontaneous Ca2+ transients was increased following a brief period of electrical stimulation at 3 Hz or greater, and this effect was enhanced in the presence of isoprenaline, or when the external Ca2+ concentration was raised. Noradrenaline also increased the frequency of the spontaneous Ca2+ transients; however, synchronous Ca2+ transients, like those that could be evoked by electrical field stimulation, were not observed. As spontaneous Ca2+ transients are due to Ca2+ released from the sarcoplasmic reticulum through the ryanodine receptors, immunocytochemistry was used to determine their distribution. The ryanodine receptors were arranged in a striated pattern with some distribution at the periphery of the cells, which was similar to myocytes from the atria. When the sarcolemma of the pulmonary vein cardiomyocytes was labelled with Di-4 ANEPPS, they were shown to possess transverse (T)-tubules, which are involved in co-ordinating the intracellular Ca2+ transient in response to depolarisation. This differed from atrial myocytes where a T-tubule system was not observed. Furthermore, the L-type Ca2+ channels and Na+/Ca2+ exchanger (NCX), which are involved in Ca2+ influx and removal during excitation-contraction coupling, were arranged in a more striated manner in the pulmonary vein cardiomyocytes, compared to those of the atria. This could have important consequences for the contractile activity of the cardiomyocytes, as well as their ability to generate abnormal electrical activity, as the NCX is known to cause depolarisation in response to an increase in intracellular Ca2+. The contractile properties of the pulmonary vein were studied in vitro using myography techniques, where it was shown to display a negative force-frequency relationship, whereby increasing the frequency of electrical stimulation reduced the contractile amplitude. In the presence of noradrenaline, the amplitude of the electrically evoked contractions was increased and the negative force-frequency relationship was only evident at the higher stimulation frequencies (5 to 7 Hz). Noradrenaline also induced periodic bursts of contractions that occurred independently of electrical stimulation, suggesting that it had an arrhythmogenic effect. Such activity was partially inhibited by blocking the NCX with ORM-10103. This suggests a potential target for future research into selective pharmacological intervention for catecholamine based arrhythmias.