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Streptococcus pyogenes (group A streptococcus, GAS) is an obligate human pathogen that causes a spectrum of pathologies ranging from superficial infections of the skin and oropharynx to severe invasive infections of the soft tissues. Despite a steady rise in the global rate of severe GAS disease over the past 30 years, there is currently no licenced vaccine available for the prevention of GAS infection. The initial stages of GAS pathogenesis are mediated by a repertoire of proteinaceous virulence factors expressed on the bacterial cell surface that facilitate colonisation and infection through specific interactions with the host extracellular matrix. These proteins are therefore predisposed to recognition by the host immune system, which in turn makes them important targets for the development of a novel subunit vaccine. The thesis describes the development of a novel approach to the isolation and identification of the major surface antigens of GAS using twenty GAS isolates representing four serotypes actively circulating within the United Kingdom (M1, M3, M12 and M89). Antigens were purified by immunoprecipitation using an antibody formulation derived from the human clinical blood product IVIG which has been shown to protect against severe GAS infection both clinically and in vivo. This 'enriched' (E-)IVIG was produced by affinity purification using a concentrated GAS cell wall protein fraction and was shown to promote neutrophil uptake in an ex vivo opsonophagocytosis assay, and impair dissemination of GAS from the nidus of infection in a murine model. A total of eight pan-serotype vaccine candidate antigens were identified by E-IVIG immunoprecipitation, seven of which were produced recombinantly for use in murine vaccination experiments. This novel approach to vaccine candidate identification could be applied to other gram positive pathogens including Staphylococcus aureus, and may have wider implications for the field of bacterial vaccinology as a whole.

Pressure ulcer (PU, bedsore, ischemia, decubitus ulcer) has become a global healthcare problem. In United Kingdom 412,000 people develop pressure ulcer annually and it costs the National Health Service (NHS) £1.4-£2.1 billion pounds (4% of total NHS budget). Pressure ulcers are a combined result of multiple factors such as prolonged external load applied to the skin, reduced blood flow in tissues, the patient’s physiological parameters (body mass index, age, mobility) and body support surface properties. The aetiology of pressure ulcer formation includes both mechanical and biological properties of skin and soft tissues. In order to prevent PU formation in the human body, a new type of risk predicting tool is required where identification of PU risk is based on combined effect of patient’s physiological parameters and support surface properties. Previous research suggests that interface pressure (IP) of 32 mmHg (4.2kPa) can cause PU but there is no strong evidence to show when that pressure is reached. Also IP varies from person to person due to their physiology. There are three risk assessment scales available to predict the occurrence of PU formation; however, none of these scales take interaction of body support surface material into account. Also they do not provide any information at which area a person is at risk of ulceration. In order to identify the harmful IP, biomechanical behaviour of skin and soft tissue is modelled and interaction of body support surface is studied. A mathematical model has been developed to characterise a new type of body support surface material (viscoelastic) and validated by conducting experiments. The relationship between patient’s physiological parameters and surface material are identified along with risk assessment scales for pressure ulcer prediction by conducting experiments. External load at different bony areas are measured using eleven volunteers. By measuring the external load for eleven subjects (age =33±7) and (BMI =25.0±3.01 kg/m2) at different bony areas, the relationship between IP with the total body weight and BMI was developed. A mathematical model is proposed to predict the risk of PU formation combining the Waterlow risk assessment scale and risk prediction algorithms on a user friendly interface.

Pressure ulcers are known to be costly for the healthcare system and delay recovery in many patients. As research continues to highlight the cost of pressure ulcers in humanitarian and financial terms, they are increasingly being used as a key quality indicator. Healthcare professionals and patients may make assumptions about what it must be like to experience a pressure ulcer. Understanding the phenomenon of living with a pressure ulcer is crucial to providing and planning care for the pressure ulcer patient and to enhancing the overall quality of life for these individuals. Pressure ulceration continues to be reported and discussed in the nursing literature whilst the methodological quality of some studies has been poor, there is no doubt that patients continue to suffer harm. One commonly implicated effect of pressure ulcers is a reduction in quality of life. This is believed to be due to factors such as increased pain, social exclusion, malodour and growing limitations on activity and mobility. This study aimed to explore how developing a pressure ulcer affected patients' quality of life. A qualitative approach in the style of phenomenology was used to explore and describe the, experiences of people who had endured an episode of an open pressure ulcer. A purposeful sample of fifteen participants (10 females and five males) were selected, age range: 45-89 years. All the fifteen patients recruited, had a new episode of either a sacral pressure ulcer, or heel ulceration, which was graded three to four using the European Pressure Ulcer Advisory Panel grading system. Although grade one and two pressure ulcers are more common, they are not usually referred to the Tissue Viability service as grade three and four are treated as clinical incidents which have to be referred to the Tissue Viability Service. Homogeneous sampling reduces variation and permits a more focused inquiry. For complete confidentiality pseudonym names were given to the participants. Pressure ulcers can result in great discomfort and pain for patients. Enabling respondents to talk freely about their experiences of developing a pressure ulcer, rich data were obtained that should be helpful in understanding the impact of developing a pressure ulcer on people's lives. As emerging themes were similar following data collection the researcher took the decision to stop interviewing at fifteen participants. Six major themes were identified in the study; all the participants had a very good understanding of how a pressure ulcer developed. Each patient could remember exactly when the ulcer developed even though in some cases this had been a long time ago. All the participants expressed feelings of anger and frustration at the impact of developing a pressure ulcer had on their lives.

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The process of wound healing is slow in diabetes, often resulting in infection or chronic wounds that can lead to amputation. Cell-cell communication through the gap junction protein connexin 43 (Cx43) and the dynamic regulation of Cx43 expression play pivotal roles in the wound healing process. Acute streptozotocin-induced diabetes in rats altered connexin expression in uninjured back skin, decreasing Cx26, Cx30 and Cx43 protein and gap junctional communication in the epidermis and increasing Cx43 protein and communication in the dermis. Diabetes was also found to alter the dynamic changes of connexins associated with the wound healing response. Within 24 hours, Cx43 was upregulated in a thickened bulb of keratinocytes at the wound edge (rather than downregulated, as in controls which formed a thin process of migratory cells). Cx43 protein reduction was delayed until 48 hours when re-epithelialisation then began. Although Cx26 protein was upregulated as usual in diabetes, its distribution at the wound edge was abnormal, being more widespread. Preventing the abnormal upregulation of Cx43 expression in wound edge keratinocytes with Cx43 specific antisense oligodeoxynucleotides doubled the rate of re-epithelialisation to control levels and above. Other subsequent events of wound healing including the inflammatory response and granulation tissue maturation were also greatly improved. These results imply that diabetes-induced changes in connexin expression dynamics contribute to delayed wound healing and that targeting Cx43 expression is of potential therapeutic value in diabetic wound healing. A pilot study showed that Cx43 plays a role in the early activation of endothelial cells during inflammation. The data in this thesis provide further evidence for the central roles of connexins in the homeostasis of skin and response to injury. In particular, its role in the coordination of inflammatory response can have a pivotal impact on the quality of cutaneous wound repair.

Telemedicine, or the practice of medicine at a distance, is a relatively recent medical development. The easy access of the skin, and an extensive visual knowledge of dermatological problems throughout the history of dermatology, lends the speciality to the practice of telemedicine. In Morecambe Bay, with a greater than average skin cancer incidence, we have examined the use of telemedicine to enhance dermatological management. A historical perspective examines the history of dermatological illustration, and also traces the development of photography and medical photography. Because art and medicine may link, art is a common theme, particularly since an artist derives knowledge and understanding from observation in the same way as dermatologists, when examining skin problems. Conventional and digital photographs are examined as a medium for examining dermatological problems, and studies described which support the use of teledermatology in patient management. The work concludes by examining the use of artificial intelligence for skin tumour diagnosis, and potential for automated telemedicine, forward looking to the next millennium.