People with psoriasis are known to engage in high levels of unhealthy lifestyle behaviours which may lead to poorer psoriasis outcomes and increase the risk of cardiovascular disease (CVD). Thus, helping individuals with psoriasis understand the link between behaviours and health risks, that is health risk communication, and direct support for lifestyle behaviour change (LBC) are important aspects in optimal management of psoriasis, a long-term inflammatory skin condition. There are two aspects of the literature that remain unclear. First, whether adequate support is given to patients to enable them to understand the links between lifestyle behaviours and health outcomes is part of psoriasis patient management strategies. Second, whether there is agreement around effective health risk communication techniques. This programme of research aimed to examine these gaps in the literature using four related studies. The first study used content analysis to examine general and dermatology-specific healthcare professionals’ core training competencies for evidence of skills relating to LBC. An important finding was the lack of explicit skills relating to LBC and changing understanding of health risks. There was little or no reference to recognised LBC techniques that could be used to support and facilitate LBC with patients. The second study used observational techniques to examine messages about the links between behaviour and health outcomes and LBC signposting (such as leaflets or posters about healthy living) for patients with psoriasis in primary and secondary care patient waiting areas. There was little evidence of psoriasis-specific information about healthy living. Generic information (not specifically about psoriasis) was often of poor quality and was poorly displayed, and did not conform to evidence-based recommendations for effective LBC signposting. The third study combined observational and qualitative techniques to examine how healthcare professionals communicate information about CVD risk to patients and the role of LBC in reducing risk in the context of primary care risk assessments with people with psoriasis. A key finding was that interpretation of risk information was not always linked to specific advice about how to modify each risk factor. Discussion was mostly instructional rather than a shared collaborative discussion about behaviour change and risk reductionThe fourth study used experimental methods to examine the effects of message framing theory as a health risk communication strategy on reported behavioural intentions (BIs) in people with psoriasis. An important finding was that for messages about psoriasis symptom reduction, gain-framed (positively-framed) messages were more effective in increasing BIs for alcohol reduction. Conversely, for messages about CVD risk reduction, loss-framed (negatively-framed) messages were more effective for increasing BIs to reduce alcohol consumption. The body of work presented in this thesis demonstrated that much needs to be done to increase the skill sets of healthcare professionals in order to help people with psoriasis recognise the specific links between their own health behaviours and health outcomes. In addition specific recommendations have been suggested as a way of improving risk communication strategies, such as using theory-based personally-relevant health information for people with psoriasis.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22150号 / 医博第4541号 / 新制||医||1039(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 竹内 理, 教授 稲垣 暢也, 教授 杉田 昌彦 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Psoriasis is a chronic recurrent inflammatory disease. Genetic and immunological factors are involved in development of psoriasis. Psoriasis is associated with numerous comorbidities including metabolic syndrome (MetS). Adipocytokines produced by white adipose tissue may be involved in the pathogenesis of psoriasis. Adipocytokines could serve as a missing link in the association between psoriasis and obesity/MetS. The most important adipokines include adiponectin, leptin and resistin. Adiponectin is expressed by adipocytes and has a high anti- inflammatory potential. Leptin is a protein produced in adipose tissue and is an important part in regulating energy metabolism. It has a pro-inflammatory effect. Polypeptide resistin is produced by macrophages and monocytes of the visceral adipose tissue. It was named for its ability to induce insulin resistence. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is also product of macrophages, that can be served as a marker for cardiovascular risk. Increased smoking rates in patients with psoriasis is associated with their reduced quality of life. In addition, smoking of tobacco cigarettes is closely associated with MetS: smokers have an increased risk of MetS. Between psoriasis and smoking has also been demonstrated a direct link. Smoking is a well-recognized cause...

Background: Metronidazole (MTZ) is an anti-oxidant and anti-inflammatory agent with beneficial therapeutic properties. The hydrophilic nature of the molecule limits its penetration across the skin. Existing commercial formulations have limitations of inadequate drug concentration present at the target site, which requires frequent administration and poor patient compliance. Objective: The aim of the current study was to develop and evaluate water in oil microemulsion of Metronidazole with higher skin retention for the treatment of inflammatory skin disorders. Methods: Pseudo ternary phase diagrams were used in order to select the appropriate ratio of sur-factant and co-surfactant and identify the microemulsion area. The selected formulation consisted of Capmul MCM as oil, Tween 20 and Span 20 as surfactant and co-surfactant, respectively, and water. The formulation was characterized and evaluated for stability, Ex vivo permeation studies and in vivo anti-inflammatory effect (carrageenan induced rat paw edema, air pouch model), anti-p-soriatic activity (mouse-tail test). Results: The particle size analyses revealed the average diameter and polydispersity index of the selected formulation to be 16 nm and 0.373, respectively. The results of ex vivo permeation studies showed statistically higher mean cumulative amount of MTZ retained in rat skin from microemul-sion, i.e., 21.90 ± 1.92 µg/cm2, which was 6.65 times higher as compared to Marketed gel (Metro-gyl gel®) with 3.29 ± 0.11 µg/cm2 (p<0.05). The results of in vivo studies suggested the microemul-sion based formulation of MTZ to be similar in efficacy to Metrogyl gel®. Conclusion: Research suggests the efficacy of the developed MTZ loaded microemulsion in the treatment of chronic skin inflammatory disorders.

Publicación a texto completo no autorizada por el autor / Determina la frecuencia, y las características epidemiológicas y clínicas de la enfermedad cardiovascular (hipertensión arterial, enfermedad coronaria y enfermedad cerebrovascular) en pacientes con psoriasis del Hospital PNP Central Luis N. Sáenz durante el período 2006-2011. El estudio es descriptivo de tipo serie de casos retrospectivo. La población estuvo constituida por los pacientes que presentaron simultáneamente enfermedad cardiovascular y psoriasis atendidos en el Hospital Luis N. Sáenz en el período 2006-2011. No se realizó muestreo, se trabajó con la totalidad de la población por ser pequeña y accesible. Se incluyó en las enfermedades cardiovasculares a la hipertensión arterial, enfermedad coronaria isquémica y enfermedad cerebrovascular. Se obtuvo datos relacionados a la presencia de enfermedad cardiovascular así como la frecuencia, características clínicas y epidemiológicas. Se elaboró un instrumento de recolección de datos (Anexo 1) que incluyó datos de filiación, datos epidemiológicos, clínicos, de laboratorio. El instrumento fue validado mediante una prueba piloto. De un total de 8766 pacientes con psoriasis atendidos en el período 2006-2011, se documentó enfermedad cardiovascular en 69 (0.8%) los cuales fueron incluidos en el estudio; de ellos, el 81.2% correspondió al sexo masculino y el 18.8% al sexo femenino. La edad promedio de los pacientes con psoriasis y enfermedad cardiovascular fue de 65.2 ± 12.4 años (mediana 64 años), el grupo de edad más afectado se situó entre los 50 y 79 años que agrupó al 79.7%. La ocupación más frecuente fue la de policía en retiro (50.7%). El tiempo de enfermedad promedio para psoriasis fue de 13.9 ± 10.7 años (mediana 12 años). Las lesiones se presentaron con mayor frecuencia en el cuero cabelludo (37.7%), extremidades superiores (34.8%), extremidades inferiores (30.4%) y el 8.7% de los pacientes presentó artritis psoriática. El PASI promedio fue de 6.0 ± 5.5 (mediana 4.8). Al correlacionarse el PASI con otras variables se encontró que existió leve correlación con el tiempo de enfermedad de la psoriasis (r=0.339; p=0.008) y con el tiempo de enfermedad cardiovascular (r=0.298; p=0.026). / Trabajo académico

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21634号 / 医博第4440号 / 新制||医||1034(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 生田 宏一, 教授 三森 経世, 教授 濵﨑 洋子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

This study explores processes of identity construction among women who have skin conditions and body modifications. Analyzing seven semi-structured qualitative interviews, the author examines how individuals affected by skin conditions employ body modification practices to organize their identities and promote feelings of agency across both personal and social domains. Engaging a Bakhtinian dialogic lens, the author argues that body modification may operate as a de-stigmatization strategy that supports individuals with skin conditions in cultivating a sense of self-determination and bodily sovereignty. Shaped by grounded theory, this study’s findings trace relationships between body modification and the development of agentic identities among women with skin conditions. Confronted by medical, physical, and social disenfranchisement, women affected by skin conditions may implement body modification practices to navigate treatment, incorporate their conditions, and negotiate their relationships. The author additionally suggests implications for the application of body modification practices as somatic therapeutic modalities.

Le psoriasis se caractérise par la présence d’infiltrats leucocytaires inflammatoires au niveau du derme et de l’épiderme cutané humain, menant à des désordres cutanés considérables : hyperprolifération des cellules épidermiques basales, différenciation altérée des kératinocytes et sécrétion accrue de médiateurs pro-inflammatoires dans le microenvironnement local. Cette dysfonction immuno-épithéliale menant au développement de lésions blanchâtres, agit tel un cercle vicieux incontrôlable, stimulant réciproquement les kératinocytes et les cellules immunitaires. Dans cette optique, mes travaux de doctorat ont visé à : (1) générer un microenvironnement immunocompétent par l’intégration de cellules T pré-activées dans un modèle de peau saine, non-lésionnelle et lésionnelle, produit selon la méthode d’auto-assemblage afin (2) d’étudier le rôle de cette composante importante sur les caractéristiques-clés associées au psoriasis. De surcroit, nous avions pour autre objectif (3) d’analyser l’impact de macrophages dérivés de monocytes dans un modèle tridimensionnel de peau saine afin (4) de déterminer l’influence de ces cellules sur le remodelage matriciel et la différenciation épidermique à l’état d’équilibre pour, finalement, (5) analyser l’empreinte du microenvironnement sur leur polarisation in vitro. Nos données mettent en lumière le caractère déterminant de la composante immunitaire, lorsqu’associée aux cellules cutanées pathologiques, dans le développement des lésions psoriasiques, puisque la présence de cellules T, dans un modèle de peau saine, n’induit pas l’ensemble des caractéristiques histopathologiques associées à cette dermatose. D’autre part, ces modèles de peau immunocompétente répondent à un traitement de choix pour le psoriasis, le méthotrexate, qui inhibe la prolifération cellulaire et atténue l’inflammation. Ces nouveaux modèles organotypiques serviront d’outils précliniques performants pour le criblage d’actifs visant à traiter certaines pathologies d’origine auto-immune inflammatoire chronique, dans lesquelles le système immunitaire joue un rôle crucial, à l’exemple du psoriasis. Par ailleurs, l’intégration de macrophages dérivés de monocytes dans un modèle de peau normale, affecte l’état de différenciation des kératinocytes épidermiques tout en réduisant l’état inflammatoire basal. Ces macrophages induisent, en outre, un remodelage matriciel tissulaire important modifiant de ce fait le microenvironnement avoisinant. Finalement, ce nouveau modèle tridimensionnel nous a permis, d’une part, de mimer davantage la structure cutanée physiologique et, d’autre part, de mieux comprendre l’influence de ces cellules sur le phénotype cutané à l’état d’équilibre. Bien que d’autres études soient nécessaires avant l’utilisation de ces modèles en phase préclinique, ces travaux constituent une avancée majeure dans le développement de modèles produits par génie tissulaire, plus complexes et plus pertinents d’un point de vue physiologique. / Psoriasis is characterized by the presence of inflammatory leukocyte infiltrates in the human skin dermis and epidermis, leading to important skin disorders: hyperproliferation of basal epidermal cells, altered differentiation of keratinocytes, and increased secretion of proinflammatory mediators in the local microenvironment. This immuno-epithelial dysfunction leading to the development of whitish lesions acts as an uncontrollable vicious circle, stimulating the keratinocytes and the immune cells. With this in mind, my thesis work aimed to: (1) generate an immunocompetent microenvironment by integrating pre-activated T cells into a healthy, non-lesional and lesional skin model, produced using the self-assembly method (2) to study the role of this essential component on key features associated with psoriasis. In addition, our other objective was (3) to analyze the impact of monocyte-derived macrophages in a three-dimensional model of healthy skin (4) to determine the influence of these cells on tissue remodeling and epidermal differentiation at steady state, (5) in order to finally analyze the microenvironment effect on their in vitro polarization. Our data highlight the essential feature of the immune component, when associated with pathological skin cells, in the development of psoriatic lesions, since the presence of T cells, in a healthy skin model, does not induce all of the histopathological key features, associated with the dermatosis. On the other hand, these models of immunocompetent skin respond to a treatment of choice for psoriasis, methotrexate, which inhibits cell proliferation and reduces inflammation. These new organotypic models will serve as powerful preclinical tools for the screening of active agents to treat some chronic inflammatory pathologies of autoimmune origin, in which the immune system plays a crucial role, like psoriasis. Moreover, the integration of monocytederived macrophages into a normal skin model affects the differentiation state of epidermal keratinocytes while reducing the basal inflammatory state. These macrophages induce, in addition, a significant matrix remodeling thereby modifying the surrounding microenvironment. Finally, this new three-dimensional model allowed us, on the one hand, to further mimic the physiological cutaneous structure and, on the other hand, to better understand the influence of these cells on the skin phenotype at steady state. Although further studies are needed prior to the use of these preclinical models, this work represents a major breakthrough in the development of more complex tissue-engineered models that are physiologically relevant.

Le psoriasis est une maladie cutanée grave pour laquelle il n’existe encore aucun traitement curatif. Des modèles de peau psoriasique in vitro sont alors nécessaires afin de tester de nouveaux traitements. Cette étude visait, en premier lieu, à optimiser la production de substituts cutanés psoriasiques par la méthode d’auto-assemblage, pour ensuite les utiliser afin d’évaluer l’efficacité d’une nouvelle molécule potentiellement antipsoriasique, la tBEU. Dans un premier temps, des substituts sains et psoriasiques ont été produits par la méthode d’auto-assemblage partiellement modifiée en utilisant des plaques 6 puits et 12 puits. Ces expériences ont permis de démontrer que les plaques 6 puits étaient plus efficaces pour la production de substituts reproductibles et représentatifs d’une peau psoriasique in vivo. Ensuite, ces substituts ont été traités avec la tBEU, démontrant que cette molécule diminue la prolifération des kératinocytes et améliore leur différenciation. Ainsi, la tBEU pourrait éventuellement être utilisée comme un traitement efficace du psoriasis. / Psoriasis is a serious cutaneous disease for which there is currently no cure. In vitro psoriatic skin models could become new tools to assess the potency of new drugs during the development of new therapies. First, this study aimed to optimize the production of psoriatic skin substitutes by the self-assembly method, and then use them to assess the effectiveness of a new potentially antipsoriatic molecule, tBEU. Initially, healthy and psoriatic substitutes have been produced by the self-assembly method partially modified, using 6-well and 12-well plates. These experiments demonstrated that the 6-well plates were more effective for the production of reproducible substitutes and representative of psoriatic skin in vivo than the 12-well plates. Then, these substitutes were treated with tBEU, showing that this molecule decreases significantly keratinocytes proliferation and improves their differentiation. Thus, tBEU may eventually be used as an effective topical treatment for psoriasis.

Psoriasis is an immune mediated inflammatory disease which affects 2-3% of the world’s population. Over the last decade, psoriasis has been acknowledged as an independent risk factor for atherosclerosis. The precise mechanism or mechanisms of the heightened risk is widely speculated. Endothelial cells and macrophages are central players in the immunopathological development of both diseases. Interleukin-36 cytokines (IL-36) have been heavily implicated in psoriasis immunopathology. Significant upregulation of epidermal IL-36 is a recognised characteristic of psoriatic skin inflammation. IL-36 induces inflammatory responses in dendritic cells, fibroblasts and epithelial cells. While vascular alterations are a hallmark of psoriatic lesions and dermal endothelial cells are well known to play a critical role in dermal inflammation, the effects of IL-36 on endothelial cells have not been defined. We report that endothelial cells including dermal microvascular cells express a functionally active IL-36 receptor. Adhesion molecules VCAM-1 and ICAM-1 are upregulated following IL-36γ stimulation, and this is reversed in the presence of the endogenous IL-36 receptor antagonist. IL-36γ-stimulated endothelial cells secrete the proinflammatory chemokines IL-8, CCL2 and CCL20. Chemotaxis assays showed increased migration of T-cells following IL-36γ stimulation of endothelial cells. Both resident and infiltrating inflammatory myeloid cells contribute to the immunopathology of psoriasis by promoting the IL-23/IL-17 axis. We show that IL-36γ induces the production of psoriasis-associated cytokines from macrophages (IL-23, TNFα) and that this response is enhanced in macrophages from psoriasis patients. This effect is specific for IL-36γ and could not be mimicked by other IL-1 family cytokines such as IL-1α. Furthermore, IL-36γ stimulated macrophages potently activated endothelial cells as illustrated by ICAM-1(CD54) upregulation, and led to increased adherence of monocytes, effects that were markedly more pronounced for psoriatic macrophages. Interestingly, regardless of stimulus, monocytes isolated from psoriasis patients showed increased adherence to both the stimulated and unstimulated endothelium when compared to monocytes from healthy individuals. Collectively, these findings add to the growing evidence for IL-36γ having roles in psoriatic responses, by enhancing endothelium directed leukocyte infiltration into the skin and strengthening the IL-23/IL-17 pathway. Our findings also point to a cellular response which could potentially support cardiovascular comorbidities in psoriasis.