Systemic sclerosis (SSc) represents a spectrum of fibrotic connective tissue disorders. Endothelial cell damage preceding fibrosis is thought to be a key component of the pathological cascade that ultimately results in fibrosis. However, the cell and molecular mechanism(s) linking microvascular damage to the subsequent fibrogenic response are poorly understood. Microvessels consist of two cell types, endothelial cells and pericytes and while recent studies have demonstrated that pericytes play a critical role in the progression of a number of fibrotic conditions, hitherto, nothing is known about their role in SSc. The aim of my thesis was to determine whether microvasuclar pericytes can be implicated in the pathogenesis of SSc. Pericyte activation and proliferation was found to be an early and prevalent feature in SSc and was accompanied by an upregulation of PDGF-p receptor expression by pericytes (p < 0.01). Pericytes in SSc lesions phenotypically resembled myofibroblasts with regards to the expression of a-SMA, ED-A FN and Thy-1. When cultured in vitro, microvascular pericytes spontaneously changed to a myofibroblastic phenotype maintaining expression of a-SMA and increasing their expression of ED-A FN and vinculin within fibronexus adhesion junctions. The use of the PDGF-p receptor inhibitor imatinib mesylate inhibited fibroblast and pericyte migration and proliferation in vitro (p < 0.01), but did not block TGF-p-mediated differentiation of fibroblasts into myofibroblasts. In vivo, PDGF-p receptor inhibition during tissue repair severely disrupted microvascular architecture, delayed wound healing and reduced collagen deposition in healing wounds. The data presented in this thesis provide the first evidence that pericytes may play an important role in the pathogenesis of SSc as precursors for myofibroblasts. Pericytes are also demonstrated to be a target of endogenous PDGF-p receptor blockade during cutaneous tissue repair and should thus be considered a candidate cell when considering therapeutic targets in SSc and fibrosis.

When skin is occluded by continuous wearing of incontinence pads, it becomes over-hydrated, making the skin more susceptible to mechanical damage and bacterial attack than normal skin. This project focused on understanding the impact of skin occlusion on (i) the hydration of the stratum comeum (SC) - the outermost layer of the skin, and (ii) friction between the skin and nonwoven materials. A methodology for measuring the excess water in over-hydrated skin using evaporimetry was developed, validated and used to compare the performances of five commonly used evaporimetry devices, and to investigate their strengths and limitations. All measurements were made on the volar forearm skin of one young female subject. Good reproducibility was found for each of the five devices, but some significant differences were found between measurements made with different devices. Some possible causes for these discrepancies were investigated with partial success: correction factors obtained from various calibration procedures were applied and reduced differences to some extent, but significant difference still remained. It was concluded that the methodology developed could be used with confidence to compare readings made with the same device, but it would be unwise to trust the absolute values obtained until the reasons for differences between devices have been more fully explained. A new approach for measuring the water distribution within the SC - Opto-Thermal Transient Emission Radiometry (OTTER) - was adopted in this work and a methodology was developed for measuring the saturation profile within over-hydrated SC. The relationship between the SC saturation at the surface (measured using OTTER) and the water vapour flux from over-hydrated SC (measured using evaporimetry) was investigated using the volar forearms of three young female subjects. As expected, strong correlation was found during desorption, with a dog-leg in the plot at about 36% saturation from two subjects, which was consistent with the transition between loosely and tightly bound water reported by Berardesca (1997). Two methods for measuring friction between nonwoven materials and the over-hydrated or normal skin were developed and validated, on the volar forearms of five young female subjects. Coefficients of friction were measured with the two methods and compared. Good reproducibility and remarkably good agreement was found between the two methods, even though one of the methods (curved friction) assumed the arm to be a rigid cylinder and the nonwoven material to be inextensible. Additional theoretical work (by Cottenden (2007)) and experimental work (by Karavokiros (2007)) was conducted to explain and extend the findings. The theoretical analysis showed that the equation describing friction around a cylinder is valid for any convex prism, and the experimental work supported the solution very well. It was concluded that the curved method developed was simple to run and produced results with good reproducibility.

Pressure ulcers represent a debilitating condition for patients and present a significant challenge for healthcare professionals. To determine the risk of pressure ulcer development, patients are typically assessed with pressure ulcer risk assessment scales. Bed-bound patients deemed at risk of pressure ulcers may receive a range of interventions, including regular repositioning by nursing staff. However, this is resource intensive and could be augmented by mechanical lateral rotation systems, although there is a paucity of research examining these systems. Several experimental studies were conducted, utilising physical output parameters and comfort assessments to examine the efficacy and acceptability of two lateral rotation systems, when compared to traditional repositioning, in cohorts of healthy participants. In addition, a study sought to determine the inter-practitioner variability of traditional repositioning. An integrative review of pressure ulcer risk assessments scales was further undertaken, to update and extend previous reviews. A number of differences were observed in the physical and comfort data, some of which were device dependent. A trend towards fewer instances of compromised tissue viability was observed during traditional repositioning, although some participants preferred turning by means of a lateral rotation system. Considerable variation was noted in the repositioning technique employed by practitioners, even after written guidance, and offloading of vulnerable areas was not always achieved. Ninety-four risk assessment scales were identified, but only 15% of these scales were assessed for inter-rater reliability. The methodological quality of such studies was often poor. Lateral rotation systems may provide an adjunct to repositioning by traditional methods, but the design is important, both in terms of efficacy and acceptability. Practitioners should be provided with practical training, focusing on the procedural aspects of repositioning. Further high-quality primary research is required to evaluate existing risk assessment scales.

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Psoriasis is a common complex inflammatory disorder of the skin. It affects on average 2% of the UK population, but can vary in other populations. The disease is characterised by hyperproliteration and abnormal differentiation of keratinocytes, and infiltration of immune cells into the skin, including activated CD4+ T-cells in the epidermis and activated CD8+ T-cells in the dermis. This disorder is seen clinically as well-demarcated thickened, erythematous, areas of skin covered by a silvery scale predominantly on extensor surfaces. The disease can have serious implications on the social and mental wellbeing of a patient and recent studies have demonstrated serious social stigmatism attached with the disease. Previous studies have implied complex genetic factors are involved in the pathogenesis of psoriasis along with environment triggers. In attempt to identify novel psoriasis loci and confirm previously reported loci a genome wide scan was performed in a cohort of 158 psoriasis families. Genome wide levels of significance were observed for microsatellite markers on chromosome 6p, spanning the MHC, and a novel locus on chromosome lp. Three further regions provided evidence of linkage on chromosomes 7p, 18p and 19p. All of which had been observed in previous studies of psoriasis or immune related diseases. In parallel to the genome wide scan, a collaboration of a larger collection of families was used to assess fourteen previously reported loci. Only microsatellites within the MHC on chromosome 6 provided highly significant evidence for linkage to psoriasis, confirming that this locus is the major psoriasis susceptibility locus. Support was seen for two other loci on chromosome 16q and 17q. As the PSORS1 locus within the MHC is the major susceptibility locus identified for psoriasis it was subject to in depth investigation. Candidate genes HCR and CDSN were assessed for association with psoriasis and compared to the HLA-Cw6 allele. Significant association was observed at both genes, however their relationship could not be distinguished from the association observed at HLA-Cw6. Further dissection of PSORS1 was attempted through the genotyping of 59 SNPs across the interval. Analysis revealed the entire interval to demonstrate significant association with psoriasis, though a distinct peak of association centromeric of HLA-C was observed. Haplotype analysis revealed a single set of similar haplotypes to be associated with the disease. This also identified a putative recombinant psoriasis associated haplotype raising the possibility of further refinement of the PSORS1 interval.

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