Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-06-29T13:21:09Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação Pablo Cardoso 2014.pdf: 3350391 bytes, checksum: 407ec26dd181ec31e5ed50bee8e4f25a (MD5) / Made available in DSpace on 2016-06-29T13:21:09Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação Pablo Cardoso 2014.pdf: 3350391 bytes, checksum: 407ec26dd181ec31e5ed50bee8e4f25a (MD5) Previous issue date: 2014-04-15 / FACEPE / Introdução: A psoríase afeta cerca de 2-3% da população. Esta doença é uma dermatite crônica, recorrente e tem envolvimento inflamatório mediado por células T. A apresentação mais comum da psoríase é o envolvimento da pele com placas eritematosas bem definidas, escamosas, de posição e tamanhos variados. Na placa psoriásica há uma disfunção imunológica que envolve vários tipos celulares e mediadores inflamatórios, como citocinas, tal qual IL -17A. Estuda-se uma atividade imunomoduladora dos derivados tiazolidinadionas (TZD). Esta classe de medicamentos tem uma possível ação anti-inflamatória, e pode ser capaz de reduzir as lesões de psoriásicas. Materiais e Métodos: Portanto, decidiu-se estudar três novos derivados TZD em células mononucleadas do sangue periférico (PBMC) de pacientes com psoríase. Depois da confirmação da estrutura química, os compostos LPSF-SF-33, LPSF-SF-34 e LPSF-SF-35 foram adicionados em cultura de PBMC estimuladas ou não com PMA/Iono. Após 48h os sobrenadantes destas culturas foram utilizados para a avaliação da IL-17A, IL-22 e IL-6. Resultados: O LPSF-SF-33 mostrou uma boa atividade imunomoduladora, reduzindo os níveis de IL - 17A e IL - 22 no sobrenadante de cultura em comparação com a estimulação por PMA/Iono. O LPSF-SF-34 mostrou bons resultados de inibição de IL-17A e IL-22 e ainda em todas as doses foi mais eficaz do que a metilprednisolona, droga padrão, na redução da IL-22. O composto do LPSF-SF-35 diminuiu a produção de IL-17A e IL-22 e também foi capaz de diminuir a produção de IL-6 quando comparado com PMA/Iono. Conclusão: Estes novos derivados tiazolidínicos LPSF-SF-33, LPSF-SF-34 and LPSF-SF-3 são capazes de inibir a produção de IL-17A, IL-22 e IL-6 em doses diferentes e o efeito pode indicar melhoria da inflamação. / Introduction: Psoriasis affects about 2-3% of the population. This is a chronic dermatitis, recurrent and inflammatory disease mediated by T cells. The most common presentation of psoriasis is skin involvement with well-defined and demarcated erythematous plaque, scaly, and random position in the patient's body. In psoriatic plaque, there is an immune dysfunction involving many cell types and inflammatory mediators such as cytokines like IL-17A. There is an immunomodulatory activity of thiazolidinedione derivatives. This class of drugs has a possible anti-inflammatory action, may be able to mitigate the psoriatic lesions. Objectives and Methods: Therefore, we decided to study three new TZD derivatives in PBMC of patients with Pso. After chemical structure confirmation, the thiazolidinedione derivatives LPSF-33, LPSF-34 and LPSF-35 were prepared in culture of PBMC, stimulated or not with PMA / Iono. After that, the supernatant of these cultures were used for IL-17A, IL-22 and IL-6 evaluation. Discussion: The three new TZDs tested were able to reduce the expression of IL-17A and IL-22 at different doses compared to PMA/Iono, but only LPSF-SF-35 was able to reduce a significant IL-6 levels. The compounds differ in their molecular structure that is added by the radical and perhaps the LPSF-SF-35 has been better because in its final structure it features a pyridine. Conclusion: The new thiazolidinedione derivatives LPSF-SF-33, LPSF-SF-34 and LPSF-SF-35 are capable of inhibiting the production of IL-17A, IL-22 and IL-6 at different doses and the effect may indicate improvement in inflammation.

Made available in DSpace on 2014-10-09T12:54:18Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:09:21Z (GMT). No. of bitstreams: 1 12722.pdf: 558008 bytes, checksum: 01284590d84b5a596a55c0b0b7177695 (MD5) / Dissertacao (Mestrado Profissionalizante em Lasers em Odontologia) / IPEN/D-MPLO / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP; Faculdade de Odontologia, Universidade de Sao Paulo, Sao Paulo

Orientador: Maria Heloísa de Souza Lima Blotta / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-26T03:20:18Z (GMT). No. of bitstreams: 1 Lima_XinaidaTaligareVasconcelos_D.pdf: 3727963 bytes, checksum: a0555708c2d46609c2d9c883c494c6dc (MD5) Previous issue date: 2014 / Resumo: A psoríase é uma doença inflamatória crônica que afeta a pele e pode estar associada à maior frequência de eventos cardiovasculares, decorrentes de aterosclerose. A frequência de um subtipo de linfócitos T CD4, que não expressa a molécula de superfície CD28 (CD4+CD28null) e possui potencial citotóxico, está aumentada no sangue periférico de pacientes com síndrome coronariana aguda, bem como outras doenças inflamatórias crônicas. O objetivo do estudo foi a avaliação da frequência e características de células T CD4+CD28null no sangue periférico de pacientes com psoríase e indivíduos controle, além de correlacionar estes achados com a espessura da camada íntima-média (EIM) da artéria carótida comum. Foram incluídos 42 pacientes com psoríase e 42 indivíduos controle. As células mononucleares do sangue periférico (CMSP) dos participantes foram analisadas, por meio de citometria de fluxo, quanto à frequência de células T CD4+CD28null e sua expressão de grânulos citotóxicos, receptores relacionados à migração celular e citocinas inflamatórias. Além disso, as características destas células foram avaliadas em um subgrupo de pacientes em remissão clínica, após tratamento da psoríase. Na análise primária, não houve diferença na frequência de células CD4+CD28null entre os grupos. Entretanto, houve maior número de células expressando grânulos citotóxicos e menor número expressando o receptor de quimiocina CXCR3 no grupo psoríase. Estes resultados se mantiveram em análise multivariada. Detectou-se ainda correlação negativa entre a frequência de células CD4+CD28null e a gravidade da psoríase. Conforme esperado, alguns marcadores inflamatórios e moléculas de adesão, como proteína C reativa, VCAM e E-selectina, estavam aumentados em pacientes com psoríase. Por outro lado, não houve diferença na EIM entre os grupos ou correlação desta com a frequência de células T CD4+CD28null no sangue periférico. Na avaliação de nove pacientes em remissão clínica da psoríase, não houve diferença na frequência de células T CD4+CD28null, mas houve diminuição significativa no número de células expressando os grânulos perforina, granzima A e granzima B, após o tratamento. Estes resultados sugerem que além do ambiente inflamatório, a presença de células com potencial citotóxico poderia contribuir para imunopatogênese da psoríase, independente da presença de fatores de risco para aterosclerose. É possível ainda que, mesmo não sendo significativo, um menor número destas células no sangue periférico de pacientes com psoríase, além de correlação negativa desta frequência com a gravidade do quadro cutâneo, esteja refletindo o recrutamento destas células para locais de inflamação, como pele e articulações / Abstract: Psoriasis is a chronic inflammatory disease that affects the skin and could be associated with increased frequency of cardiovascular events related to atherosclerosis. A subtype of CD4+ T lymphocytes, which does not express the surface molecule CD28 (CD4+CD28null) and is potentially cytotoxic, has increased frequency in peripheral blood of patients with acute coronary syndromes as well as other chronic inflammatory diseases. The objective of this study was to evaluate the frequency and characteristics of circulating CD4+CD28null T cells in patients with psoriasis and control subjects, attempting to correlate these findings with the carotid intima-media thickness (IMT). A total of 42 patients with psoriasis and 42 controls were included. Peripheral blood mononucleated cells (PBMC) from participants were analyzed through flow cytometry for the frequency of CD4+CD28null T lymphocytes and their expression of cytotoxic granules, homing receptors and inflammatory cytokines. Furthermore, these cells were reevaluated in a subgroup of patients that achieved clinical remission of psoriasis after therapy. The main analysis revealed no difference in the frequency of CD4+CD28null T cells between the two groups. However, there were increased numbers of these cells expressing cytotoxic granules and decreased number expressing the chemokine receptor CXCR3 in ex vivo samples of psoriasis patients. These results were sustained in multivariable analysis. Negative correlation was also observed between number of these cells and psoriasis severity. As expected, certain inflammatory markers, such as C-reactive protein, vascular cell adhesion molecule and E-selectin, were increased in patients with psoriasis. On the other hand, there were no differences in IMT between the groups or correlation with number of circulating CD4+CD28null T cells. Although, in the analyses of nine patients after clinical remission of psoriasis, there was no change in the frequency of CD4+CD28null T lymphocytes, numbers of these cells expressing cytotoxic granules were decreased after treatment. These data suggest that, in addition to the inflammatory environment, presence of cells with cytotoxic capabilities may have a role in the pathogenesis of psoriasis, aside from cardiovascular risk factors. Moreover, it is possible that, albeit not significant, decreased number of circulating CD4+CD28null T cells in psoriasis, in addition to a negative correlation with disease severity, could reflect their recruitment to inflammatory sites, such as skin and joints / Doutorado / Patologia Clinica / Doutora em Ciências Médicas

Background: Psoriasis is a complex disease with a genetic component contributing to disease pathogenesis. Chronic plaque psoriasis can be dichotomised into two subtypes according to age of onset; type 1 (early-onset; <40 years) and type 2 (late-onset; ≥40 years). Despite clinical and biological differences between the two subtypes, the genetics underpinning late-onset psoriasis remains poorly characterised compared to early-onset psoriasis. Aims: The aim of this project was to identify genetic loci associated with late-onset psoriasis, to assess the overlap of loci with early-onset psoriasis and to elucidate the functional role of the identified variants. Methods: The study had three parts; the first was a candidate-gene association study of the IL1B gene. A total of 16 SNPs from the region were genotyped in 595 late-onset and 1,137 early-onset psoriasis samples and compared to 4,770 controls from the European population. The second was a large-scale study conducted in 543 late-onset psoriasis and 4,373 controls using the Immunochip array. The third was a functional study using bioinformatics data mining, chromatin immunoprecipitation and electrophoretic mobility shift assay techniques to analyse the role of a disease-associated variant at the biological level. Results: The candidate-gene study replicated a previously reported association at a promoter polymorphism, rs16944 (P<0.05), within the IL1B gene and discovered a novel association at a second variant, rs11687624 (P<3.12x10-3), in late-onset psoriasis. None of the variants analysed were significantly associated with early-onset psoriasis. Bioinformatic eQTL data suggests the two variants and their proxies are associated with the expression of IL1A, IL1B, IL38 and PAX8. The Immunochip study identified 6 non-HLA loci (P<2.3x10-5) previously associated with early-onset psoriasis to also be associated with late-onset psoriasis (IFIH1, IL12B, IL23A, IL23R, TRAF3IP2 and ZNF313). Conditional analysis of the MHC region also identified two loci (HLA-C and HLA-A). A novel locus, IL1R1, was associated with late-onset psoriasis, but not early-onset psoriasis. Bioinformatic data mining found no role for the IL1R1 variants as eQTLs and prioritised the IL1B variant rs2708914 for functional analysis. The transcription factor STAT3 was found to be enriched at rs2708914 in keratinocyte and CD8+ T-lymphocyte cell lines. Allele-specific binding could not be established. Conclusions: This project is the largest genetic study of late-onset psoriasis to date and provides evidence that it shares susceptibility loci with early-onset psoriasis as well as having specific susceptibility loci. These findings provide further evidence for the dichotomisation of chronic plaque psoriasis, firstly to facilitate better understanding of the pathogenesis of the two subtypes and secondly to enable tailored therapy to be developed. Both have potential benefits for patients in the future. The genetic and functional studies conducted have provided a platform from which further studies can be carried out.

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