A partir d'uns casos limítrofes vists al Departament de Dermatologia i d'alguns casos descrits a la literatura, vàrem observar que algunes formes d'histiocitosis de cèl·lules no de Langerhans (HCNL) no podien ser diagnosticades d'acord amb els criteris establerts pels autors quan inicialment les varen descriure. Provablement aquests casos limítrofes als quals ens referim no constitueixen pas els "primers casos" d'una nova entitat sinó que són formes mixtes o cavalcades de HCNL. Per tal de fer un estudi sistemàtic vàrem escollir el xantogranuloma juvenil, el xantoma papulós, la histiocitosi cefálica benigna i l'histiocitoma eruptiu generalitzat, com a formes més comuns i per tant representatives de HCNL. Ens hem decidit a iniciar aquesta recerca davant les dificultats que ofereixen aquests malalts tant des del punt de vista clínic com a nivell histopatològic. De fet, el diagnòstic purament histologie sense dades clíniques difícilment ens permet arribar a un diagnòstic de tipus de HCNL. Un dels motius cabdals d'aquesta Tesi fou intentar aconseguir de trobar algún marcador immunohistoquímic que permetés un aclariment diagnòstic que no s'havia aconseguit amb els mètodes analítics previs. En aquest estudi creiem que hem aconseguit demostrar que les quatre histiocitosis estudiades no tenen de fet cap caràcter propi que permeti diferenciar-les entre elles i que per tant, cal que siguin considerades una única entitat malgrat algunes diferències clíniques pròpies, causa de que al principi fossin considerades com entitats patològiques diferents.

Dado que en el periodo comprendido entre los años de 1968 a 1974 se observaron en la Cátedra de Dermatología de la Facultad de Medicina de Barcelona, dirigida por el Prof. Dr. D. J. Piñol Aguadé, 10 casos calificables de "Hydroa vacciniforme seu aestivalis", ello nos permitió realizar un estudio muy completo sobre esta entidad cuya casuística en la literatura dermatológica no es muy numerosa y cuya fotodependencia por otra parte, aunque evidente, no ha podido ser demostrada con resultados concluyentes.Gracias al equipo de que se dispone en el departamento de Fotobiología de la Cátedra se pudo realizar un estudio fotobiológico completo además de una investigación de los mecanismos de reparación del D.N.A. lesionado por las radiaciones ultravioleta.El trabajo que presentamos a continuación incluye las siguientes partes: Estudio clínico del Hydroa vacciniforme, Estudio histológico, Estudio fotobiológico, Estudio del estado de los mecanismos de reparación del DNA en los fibroblastos y linfocitos de nuestros enfermos, así como su posible implicación patogénica; posibilidades terapéuticas; y por último un ensayo de interpretación patogénica.

The decision whether or not to discharge an outpatient is vital in determining outpatient clinic attendance numbers, directly affecting overall patient care efficiency. A review of the factors influencing discharge decisions revealed that there was limited evidence of these factors and a lack of understanding how clinicians take discharge decisions. This project’s objectives were to describe the influential factors on discharge decisions from the clinicians’ and patients’ perspectives, to demonstrate the development and clinical evaluation of a novel "Traffic-light” design dermatology outpatient discharge information checklist to improve appropriateness and consistency in discharge decision-making. Semi-structured interviews were carried out with 40 consultant dermatologists across England. 148 influences were generated and thematically analysed manually and using NVivo10 software. A wide array of nonclinical factors, clinician-based, patient-based, practice-based and policy-based, influence discharge decision-making. Observations of 64 consultations and 56 semi-structured interviews with dermatology outpatients were carried out to understand their experience concerning the decision for their discharge. Twelve of 31 patients (39%) who were discharged considered their discharge inappropriate. A three-round Delphi exercise with 17 dermatology consultants (100% response) was carried out to reach agreement on what a high quality discharge information checklist should contain. There was strong inter-rater reliability (ICC=0.958) and fair inter-rater agreement (Fleiss Kappa=0.269). Thirteen items were identified that formed the "Trafficlight" design checklist. Twelve (67%) dermatology clinicians who evaluated the checklist found it useful. This study has demonstrated the importance of approaching discharge decision taking in an informed, structured manner. The checklist provide the basis for making discharge decisions more systematic, auditable and transparent, improving patient safety and optimising healthcare costs. These methods are potentially useful in other clinical disciplines.

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Currently, laser treatments for Port Wine Stain (PWS) lesions are considered the choice therapy, but response is poor or treatments are ineffective for around half of patients. It is proposed in this thesis that improvements to the effectiveness of laser treatment can be achieved through the acquisition of estimated PWS vessel number density, depths and diameters for each individual lesion. Information regarding PWS vessel architecture is found to be contained within the colour of the lesion. Presented in this thesis is a method of extracting this information through colour measurements and the inverse application of a skin model. Colour measurements are performed on 14 participants using a Konica-Minolta CM2600d spectrophotometer employing a xenon flashlamp illumination source and an integrating sphere. Light transport is simulated through an 8 layer mathematical skin model inclusive of horizontal, pseudo-cylindrical PWS blood vessels using a new Monte Carlo programme. Within the programme, model parameters were adjusted in an iterative process and skin colour was reproduced with a mean discrepancy of 1.9% reflection for clinically normal skin (24 datasets) and 2.4% for PWS skin (25 datasets). The programme estimated anatomical properties of the measured regions of skin, yielding epidermal melanin volume fractions from 0.4% to 3.3% and mean melanosome diameters from 41 nm to 384 nm across the participant group. The response to laser treatment was assessed for 10 participants through colour measurements taken immediately before and at least 6 weeks after treatment and through expert analysis of photographs for 9 participants taken at these times. Treatment response was not found to correlate directly with the pre-treatment melanin parameters estimated by the programme. Mean depths, diameters and number densities of PWS vessels were also estimated by the programme before and after treatment. These parameters were compared to data obtained from Optical Coherence Tomography (OCT) images for 5 participants. Number densities and diameters predicted by the simulation varied by no more than 10% from the values determined by OCT for 4 and 5 out of 7 regions respectively. Mean depths predicted by the simulation did not correspond with those determined by OCT however. This may be a result of the limited contribution of deeper vessels to the colour of PWS skin. Predicted PWS parameters were compared to treatment response assessed by colour measurement for 10 participants and by photographic analysis for 9 of these. Predicted vessel number densities were not found to correspond with treatment response. Vessel diameters predicted by the simulation correlated with treatment response when compared with the pulse lengths selected for treatment. Optical coefficients derived from the skin model were used to estimate appropriate laser treatment radiant exposures at the predicted mean vessel depths and these radiant exposures corresponded strongly with the treatment response. Suggestions for improvements in the predictions of melanosome diameters through changes in the adjacent skin minimisation procedure within the programme are discussed. The apparent underestimation of PWS blood vessel number densities and mean depths (compared to biopsy studies) may be a result of the reduced influence of deeper PWS vessels upon skin colour. Further investigation, including modifications to the PWS vessel minimisation procedure within the programme, would be necessary to determine whether improvements in these predictions may be achievable. The results of the study show that the new Monte Carlo programme is capable of extracting, from measurements of skin colour, realistic estimates of PWS skin characteristics which can be used to predict treatment response and therefore inform treatment parameters on an individual PWS.

This thesis is concerned with the psychosocial impact of psoriatic arthritis (PsA) - an inflammatory arthritis associated with psoriasis. Although an extensive literature exists on the nature and impact of psoriasis, little is known about the effect that psoriatic arthritis can have on an individual, and the bearing it may have on their quality of life. In order to address this gap in the literature, this study utilised a mixed methods research design, employing a qualitative study with semi-structured interviews, followed by a quantitative, cross-sectional postal survey. In the qualitative study, interviews were conducted with ten people living with psoriatic arthritis. Analysis of the data, using Interpretative Phenomenological Approach (JPA; Smith, 2003) resulted in five emerging themes; pain, functionality (including fatigue), emotions (including depression), coping and treatment experience/management. The quantitative study used a postal survey to measure the variables of interest and explore the associations between them. Survey respondents consisted of a sample (n = 313) drawn from The Psoriasis Association membership and also 44 from a hospital rheumatology clinic. AA participants completed a piloted questionnaire containing questions about their demographic characteristics and validated measures of quality of life. Analysis confirmed that the group with PsA fared less well on all measures of quality of life, than those with just psoriasis. Correlations identified highly significant relationships between most study variables, however of note were the relationships between fatigue and current pain (r = .547) and depression (r = .670). Within the Psoriasis Group correlations of interest included those between anxiety and social functioning (r = -.606) and DLQI and social functioning (r = -.546). Comparison of the correlations identified 18 that were significantly different between the groups. Of these, relationships between physical functioning, pain, fatigue and self efficacy were of particular interest, whilst in the psoriasis group the associations between self efficacy, social functioning and psychological health were noteworthy. This research provides some evidence that different psychosocial variables appear to be involved in the reductions in quality of life experienced by the two clinical populations in this study. The results suggest that in rheumatology and dermatology clinics, the routine measurement of fatigue, self efficacy and psychological health could be used to inform the prescribing of therapies, psychosocial interventions and drugs to improve emotional functioning, so impacting on health-related quality of life. Furthermore, these fmdings have highlighted the need to elucidate the symptom of fatigue in PsA and position it as an appropriate target not only for clinical management, but also psychological management. By advocating fatigue as a legitimate concern, this may offer patients the chance to discuss fatigue explicitly and obtain appropriate health advice.

Background: Pressure ulcers (PrUs) have a significant impact on health system expenditure and patient’s quality of life. It is a global problem. Many studies were undertaken in regard to PrU prevention and management. In Oman, no studies have been conducted to investigate nurses’ knowledge on prevention and management of PrUs. The purpose of this descriptive sequential explanatory mixed-method study was to explore the nurses’ level of knowledge in relation to prevention and management of PrUs in Oman. Methods: A mixed method design was used and the study was conducted over two Phases. In Phase I, a questionnaire was developed to explore nurses’ knowledge on PrU, policy, and resources. The main section of the questionnaire was the Pieper-Zulkowski Pressure Ulcer knowledge test (PZ-PUKT) which tests the knowledge on PrU. Another two sections were developed including questions about wound policy and resources available for PrU prevention and management in Oman. The questionnaire was distributed to nurses who were working in surgical, medical, orthopaedic, CCU, and ICU wards/units in seven hospitals. In Phase II study, semi-structured qualitative interviews were conducted with 16 of the questionnaire respondents. Interviews took approximately 30 minutes, were recorded and transcribed verbatim. Qualitative data were analysed using the Knowledge, Attitudes and Practice (KAP) model as the a priori framework. Results: In Phase I, 478 questionnaires were analysed. The knowledge test results showed the overall mean percent score for correctly answered questions was 51% suggesting a low level of knowledge. There was a significant relationship between nurses’ knowledge and age (P=0.001) and between knowledge and years of experience (P=0.001) with knowledge increasing with age and years of experience. In Phase II, four themes were identified from the interviews: knowledge, attitude, and practice (framework themes) and perception of role. Findings indicated positive and negative attitudes towards the care of PrUs. Some nurses stated feeling rewarded when they see wounds improving while others said they could not work with patients independently because they lacked the knowledge and the skills needed. There was variation in the management of PrU between hospitals. Both studies indicated that the wound management policy did not include enough information to guide nurses. Conclusion: Overall the nurses’ level of knowledge on PrU was relatively low. Most nurses were not familiar with wound management policy or different PrU prevention and management strategies. Nurses are aware of the risk of PrUs and try their best to manage them with the available resources however more training is required.

The complex process of wound repair becomes disrupted in the elderly with a profound effect on patient morbidity and huge financial implications for the NHS. While age itself is a risk factor for delayed healing recent work implicates estrogen decline, rather than intrinsic ageing per se, as the critical regulator of delayed healing in elderly subjects. In women estrogen levels fall dramatically post-menopause and with increasing life expectancy most women in the developed now world spend at least a third of their lives in a state of estrogen deprivation. Estrogen replacement can reverse this delay, but unfortunately long term estrogen treatment (HRT) increases breast cancer risk such that steroidal estrogen is now listed as a carcinogen. The aim of this study has been to functionally dissect the role of estrogen signalling during repair at the molecular, cellular and physiological levels. New data presented within this thesis reveal estrogen to be a global regulator of healing with pleiotropic effects on multiple wound cell types. By combining pharmacological manipulation and genetic ablation my data reveals novel diametrically opposed roles for the two estrogen receptor isoforms, ERalpha and ERbeta, during healing. I have further exploited this to demonstrate the in vivo therapeutic potential of compounds with receptor selective agonistic/antagonistic activity. Additionally, I have further investigated the mechanism of action of estrogen and these selective compounds implicating the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) in beneficial effects on healing. This research leads the way toward translation into human studies with the ultimate aim of developing targeted therapeutics for the treatment of delayed acute and chronic wounds, particularly in the elderly.

Exposure of the skin to ultraviolet radiation (UVR) results clinically in the formation of deep wrinkles and mottled pigmentation and histologically, in a vast remodelling of the dermal extracellular matrix (ECM), in particular the elastic fibre network. Fibrillin microfibrils and fibulin-5 are early biomarkers of photoageing, where a loss of these fibres from the dermal epidermal junction is apparent. A study by our group showed that isolated fibrillin microfibrils and fibronectin which are rich in amino acids which absorb energy from UVR (UV-chromophores) are susceptible to UVR-induced damage, whilst UV-chromophore poor collagen type I is not. This research, with other earlier studies, indicates that acellular mechanism may work in tandem with cell-mediated up-regulation of matrix metalloproteinases (MMPs) in the progression of photoageing. This thesis aims to: i) test whether acellular mechanisms of photoageing are a result of direct photon absorption and/or the photodynamic production of reactive oxygen species (ROS); ii) assess the functional consequences of UVB degradation on the susceptibility of fibrillin microfibrils to MMPs and; iii) assay whether ECM proteins are differentially susceptible to solar simulated radiation (SSR) or UVA (315-400nm) alone using physiologically relevant doses of irradiation. Isolated proteins were exposed to UVB (280-315nm) in depleted-O2 conditions and in the presence of deuterium oxide. Depleted-O2 conditions decreased and deuterium oxide conditions increased UVR-induced degradation. Isolated proteins also show a similar pattern of degradation when exposed to H2O2 as an exogenous source of ROS. These results indicate that ROS play an important role in the differential degradation of dermal proteins. MMPs-3 and -9 are both upregulated in the skin after exposure to UVR and have the ability to degrade elastic fibre components. After exposure to UVB, damaged fibrillin microfibrils become more susceptible to degradation by both MMPs-3 and -9. Chromophore-rich fibrillin microfibrils and fibronectin are susceptible to degradation by both SSR and UVA alone, whereas chromophore-poor collagens type I and VI and tropoelastin are not. These results support our previous findings that amino acid composition of proteins is a good indicator of their relative susceptibility to UV-induced damage with a physiologically relevant irradiation system. In conclusion this work shows that ROS are an important mediator of acellular mechanisms of photoageing and that amino acid composition is a good indication of relative susceptibility of proteins to both ROS and UVR. The ability to predict ROS-susceptible proteins also has wider implications for human ageing as a whole.

In this investigation a number of post-genomic technologies have be applied to study the dermatological disorders of psoriasis and keloid disease. In spite of considerable research focus on these diseases the pathogenesis remains unclear and currently no cure is available however, both diseases are manageable by drug intervention. It is common place that patients who are suffering from skin disorders are diagnosed and the extent of the disease assessed by a dermatologist which may be subjective due to human error. The availability and application of methods to screen patients and quantify the level of disease or response to treatment has obvious benefits in disease management. The work has incorporated a two-pronged approach combining the spectroscopic analysis of excised tissue samples and the phenotypic profiling of a rapidly proliferating cell line in response to drug intervention. The initial analysis of psoriatic skin samples by MALDI-MS provided poor results which remain relatively unexplained; however similar problems have been observed by other research groups. In a complementary approach the HaCaT cell line was exposed to increasing concentrations of three anti-psoriatic drugs namely dithranol, methotrexate and ciclosporin and the cells profiled using both metabolomic and proteomic methods. A number of metabolic pathways were highlighted including glycolysis and the TCA cycle. This has resulted in a selection of potential biomarkers which could be investigated in further work. In a small follow on study a collection of plasma samples from patients undergoing methotrexate treatment were analysed. The level of patient metadata and the number of samples was relatively limiting however, a subset of metabolites were significantly altered between responders and non-responders and with further validation could be potential biomarkers of successful treatment. The analysis of excised keloid samples was conducted using FT-IR microspectroscopy where it was possible to successfully discriminate between keloid and normal tissue. The use of imaging FTIR illustrated the complex cellular composition within a keloid scar, with increased lipid, amide and phosphate levels being observed. These measurable variations could, in the future, be incorporated into surgical procedures to allow targeted excision ensuring all keloid areas are removed. Finally a SERS-based analysis was conducted to investigate the possibility of probing dynamic enzymatic processes. This was successful and with the use of varying reporter molecules could be a beneficial tool for the analysis of metabolic processes.This project has successfully used a number of bio-analytical techniques to investigate dermatological problems. While the ultimate goal would be the application of a single analytical technique to provide answers to biological questions, it has been found that a number of complimentary techniques and statistical data handling approaches can provide a valuable insight into the problems posed.