Orientador: Maria Helena Stangler Kraemer / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-14T09:37:26Z (GMT). No. of bitstreams: 1 Magalhaes_RenataFerreira_D.pdf: 45600840 bytes, checksum: c3be46b9fbfab6e5433e2e91db336bb3 (MD5) Previous issue date: 2009 / Resumo: Psoríase é uma dermatose inflamatória crônica, determinada por desregulação do sistema imune e associada a várias comorbidades. O marcador genético mais associado à psoríase em todas as populações é o HLA-CW06. Polimorfismos na região promotora do TNF-a, especialmente a troca de uma guanina por uma adenina nas posições -238 e -308 estão relacionados à alta produção de TNF-a e risco aumentado para psoríase nas populações caucasóides e não em asiáticos. Com o objetivo de determinar se polimorfismos destes genes podem ser fatores de risco para susceptibilidade ou gravidade da doença em pacientes brasileiros, foi realizado um estudo caso-controle com 69 pacientes com psoríase de início até 40 anos, com acompanhamento por dez anos para caracterização de sua evolução clínica em doença leve (grupo I) e grave (grupo II), e 70 indivíduos sadios. Foi feita a identificação dos alelos HLA classe I e II e SNPs da região promotora do TNF-a -238 e -308. Coletaram-se 10 mL de sangue periférico dos indivíduos e se realizou a extração do DNA através do método salting out. O DNA foi amplificado pela reação em cadeia da polimerase (PCR), com primers sequência-específica. As freqüências alélicas e gênicas foram estimadas por contagem direta e a comparação entre as frequências dos grupos foi efetuada por Teste de Fisher (programa GraphPad InStat 3.05). Dois métodos computacionais foram usados para determinar os haplótipos dos indivíduo: (1) o algoritmo ELB implementado pelo software Arlequin 3.1 e (2) um método de base coalescente implementado pelo software PHASE v2, e as freqüências de cada haplótipo foram comparadas por Teste de Fisher. No grupo II, observou-se maior associação com fatores desencadeantes como estresse, início na adolescência e predominância do sexo masculino. Pode-se sugerir que os alelos HLA-B*37, -Cw*06, -Cw*12 e -DRB1*07 foram associados ao curso mais grave da doença, enquanto - B*57 à doença mais leve. O aielo DRBT04 teve tendência a associação negativa. Ao se comparar o grupo I com o grupo II, o alelo HLA-B*37 pode ser interpretado como fator de mau prognóstico. Não houve diferença estatística entre polimorfismos da região promotora do TNF-a entre pacientes e controles. Este estudo apontou uma alta frequência do genótipo TNF-a -238 G/G {OFt 3,21; Cl:1,06-9,71; p=0,04), assim como do alelo -238 G, no grupo com doença mais grave e, ao contrário, o genótipo -238 G/A com frequência maior no grupo de boa evolução. O haplótipo -238A-308G mostrou frequência reduzida conferindo um efeito protetor. Estes dados não correspondem ao reportado para as populações caucasianas, considerando que a população brasileira é miscigenada. Polimorfismos dos SNPs do TNF-a não parecem ser um fator de susceptibilidade genética mais importante do que o já conhecido HLA-Cw*06 em pacientes brasileiros, mas podem ter relação com as manifestações e evolução da doença. / Abstract: Psoriasis is an erythematous, scaly inflammatory dermatosis with a complex immunologic basis. The strongest genetic marker for psoriasis is HLA-Cw*06. Polymorphisms in the TNF-a promoter region, especially replacement of guanine with adenine in positions -238 and -308 are related to higher TNF-a production and higher risk for psoriasis in Caucasoid populations, not found in Asians. We did a case-control study of 69 patients with psoriasis type I and 70 controls, characterized clinical progression along 10-years of follow-up in mild or severe disease and determined HLA class I, II and TNF-a SNPs -238 and -308 polymorphisms to demonstrate whether these polymorphisms may be genetic risk for susceptibility to psoriasis or severity of the disease in Brazilians. Peripheral blood (10 ml) was collected. Genomic DNA from both psoriasis patients and controls was isolated using a salting out procedure. Polymorphisms were identified by PCR/SSP. Alleles and genotypes frequencies were compared by Fisher's test (GraphPad InStat 3.05 software). Two computational methods were used to determine the haplotypes of each subject, without taking into account any prior information: (1) the ELB algorithm implemented by the ARLEQUIN 3.1 software and (2) a coalescence based method as implemented by the PHASE v2 software. The haplotype frequencies were compared between group pairs by Fisher's test. Severe disease was found more frequently in male patients, associated with environmental factors and onset at adolescence. It may be suggested that alleles HLA- B*37, -Cw*06, -Cw*12 and -DRB1*07 were associated with severe disease course, while -B"57 with mild disease. No statistical difference was found between the patients and controls regarding polymorphisms frequencies in TNF SNPs. This study pointed to a higher TNF-238 G/G genotype frequency (OR 3,21; Cl:1,06-8,71; p=0,04) in the group with severe disease and -238A-308G haplotype was found in reduced frequencies revealing a protective effect. These data do not correspond to those reported for the Caucasian population, considering that Brazilian population is admixed, and this is the first consideration about TNF-a SNPs in psoriasis in this population. Polymorphisms in the TNF-a SNPs do not seem to be a more important genetic risk factor for psoriasis than the already known Cw*06 in Brazilian patients, but these markers may be related to clinical manifestations. / Doutorado / Clinica Medica / Doutor em Clínica Médica

Doenças crônicas sistêmicas, em especial o diabetes mellitus, favorecem o aparecimento e a continuidade de lesões dermo-epidérmicas, sendo o impacto econômico e social significativo. No âmbito da medicina regenerativa para o tratamento de lesões cutâneas crônicas, o emprego clínico da bioengenharia de tecidos associada à terapia celular tem sido considerado uma promissora alternativa terapêutica. Neste contexto, o estudo tem como objetivo avaliar a eficácia terapêutica no tratamento de úlceras cutâneas de pacientes diabéticos, empregando células-tronco mesenquimais do tecido adiposo (CT-TA) associadas a plasma rico em plaquetas (PRP) obtido de sangue autólogo. A pesquisa aplicada foi composta por seis pacientes diabéticos e portadores de úlceras cutâneas crônicas. A reepitelização total ocorreu em 5 das 9 lesões tratadas, sendo o índice de cicatrização médio superior a 70% após 3 meses da aplicação. Desta forma, é possível concluir que a terapia com CT-TA associadas a PRP proporciona uma redução na área ulcerosa de lesões cutâneas crônicas em pacientes diabéticos. / Systemic chronic diseases, especially diabetes mellitus, favor the emergency and continuity of dermal-epidermal lesions, being significant the economic and social impact. Within the regenerative medicine field for treatment of cutaneous chronic wounds, the clinical use of tissue bioengineering and cell therapy has been considered as a promising therapeutic alternative. In this context, the present study aims to evaluate the therapeutic efficiency, using adipose-derived mesenchymal stem cells (ADSC) associated with platelet-rich plasma (PRP) obtained from autologous blood, for the treatment of cutaneous ulcers from diabetic patients. The applied research was composed of six diabetic patients with chronic skin ulcers. The total re-epithelialization occurred in 5 of the 9 lesions treated, and the average wound healing index greater than 70% after 3 months of application. In this way, it can be concluded that ADSC therapy associated with PRP provides a reduction in ulcer area of chronic skin lesions in diabetic patients.

Vitiligo is an autoimmune disease in which CD8+ T cells selectively destroy melanocytes, leading to a patchy, disfiguring depigmentation of the skin. Our group and others have highlighted the central role of IFN-γ-dependent chemokines in the progression of disease; however, IFN-γ is also reported to have pleiotropic effects on melanocyte biology. We examined whether IFN-γ has a direct role in melanocyte killing. We tested the T-cell effector functions IFN-γ, Fas ligand and perforin by deleting them from autoreactive T cells used to induce vitiligo in mice. We found that disease incidence, disease severity and T cell accumulation in the skin was reduced in mice receiving adoptive transfer of either IFN-γ deficient or Fas ligand deficient gp100-specific T cells; however, perforin was dispensable and led to increased disease scores and T cell accumulation. To determine how melanocytes are affected by IFN-γ signaling during vitiligo, we performed single-cell RNA-sequencing on suction blister biopsies obtained from vitiligo and healthy subjects. We discovered that integrin expression and TGFb2 signaling was decreased only in lesional melanocyte transcriptomes. Moreover, melanocytes appear to participate in their own demise by increasing HLA expression and recruiting effector cells through the chemotactic ligand CCL18. The loss of melanocyte retention factors may explain their clean disappearance from the skin during keratinocyte turnover. Taken together, we believe IFN-γ production by autoreactive T cells in the skin leads to clean loss of melanocytes by downregulation of melanocyte retention factors and by increasing their potential to be detected by effector cells during vitiligo.

The content of this master thesis is design documentation of department of dermatology of hospital. The main point of the work is dispositional and functional designs of the building in accordance with all applicable standards and regulations for this type of building.

Background: Chronic plaque-type psoriasis is a major dermatosis, but a significant question is still unanswered: What defines severity in chronic plaque-type psoriasis? While objective assessments like the Psoriasis Area and Severity Index (PASI) have frequently been used in clinical trials, quality of life (QOL) questionnaires are currently becoming more and more popular. Objective: This article summarizes the most important objective and subjective measurements of severity in psoriasis. For every dermatologist it is critically important to distinguish between severe psoriasis and psoriasis that severely affects QOL. Even if the PASI also has disadvantages, it is the most adequate instrument available to evaluate severity in plaque-type psoriasis. Result: We provide reasons why PASI >12 defines severe, PASI 7–12 moderate and PASI <7 mild chronic plaque-type psoriasis. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Background: According to current guidelines the cost of productivity loss should be considered in pharmacoeconomic analyses. The cost of health-related productivity loss in psoriasis patients is unknown. Objective: To estimate the cost of productivity loss in psoriasis and its association with health-related quality of life and clinical disease severity. Methods: Cross-sectional study, recruitment of adult participants through Internet advertisements. 201 (72.3%) out of 278 eligible participants completed the study. Health-related work productivity loss, quality of life and clinical severity of psoriasis were assessed by standardized instruments. Results: Indirect costs of productivity loss clearly exceed the total direct cost. In contrast to objective clinical disease severity, health-related quality of life (measured by the Dermatology Life Quality Index) is an independent predictor of work productivity. Conclusions: There is good reason to believe that intervention can reduce health-related productivity loss by improving patients’ quality of life. Savings from increased work productivity might offset comparatively high acquisition costs of biological agents. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Despite the central role of IFNγ in vitiligo pathogenesis, systemic IFNγ neutralization is an impractical treatment option due to strong immunosuppression. However, most vitiligo patients present with less than 20% affected body surface area, which provides an opportunity for localized treatments that avoid systemic side effects. After identifying keratinocytes as key cells that amplify IFNγ signaling during vitiligo, I hypothesized that tethering an IFNγ neutralizing antibody to keratinocytes would limit anti-IFNγ effects to the treated skin for the localized treatment. To that end, I developed a bispecific antibody (BsAb) capable of blocking IFNγ signaling while binding to desmoglein expressed by keratinocytes. I characterized the effect of the BsAb in vitro, ex vivo, and in a mouse model of vitiligo. SPECT/CT biodistribution and serum assays after local footpad injection revealed that the BsAb had improved skin retention, faster elimination from the blood, and less systemic IFNγ inhibition than the non-tethered version. Furthermore, the BsAb conferred localized protection almost exclusively to the treated footpad during vitiligo that was not possible by local injection of the non-tethered anti-IFNγ antibody. Thus, keratinocyte-tethering proved effective while significantly diminishing off-tissue effects of IFNγ blockade, offering a new treatment strategy for localized skin diseases, including vitiligo.

Background Indoor tanning (IT) before the age of 35 increases melanoma risk by 75%. Nevertheless, IT and sunless tanning product (STP) use have gained popularity among youth. However, there are limited data on the prevalence and sociodemographic correlates of both IT and STP use in a representative sample of American teens. Methods Teenage females (N = 778) aged 12–18 years were recruited as part of an on-going longitudinal study conducted between May 2011 and May 2013. Descriptive statistics explored IT and STP usage in teen females at baseline. Logistic regression was used to determine sociodemographic correlates of IT and STP use. Results Approximately 16% of female teens engaged in IT behavior and 25% engaged in using STPs. Female teens living in non-metropolitan areas were 82% more likely to indoor tan compared to those in metropolitan areas (OR = 1.82, 95% CI: 1.07–3.10). Age, geographic regions, and race increased the likelihood of IT and STP use. Conclusions Results indicate a significant proportion of teen females engage in IT and STP use. There was evidence that in teens that have never used IT before, STP use precedes IT initiation. Given the evidence for increased IT in rural populations, research focused on rural tanning bed use is needed.

[ES] La Fotogrametría es una ciencia y tecnología que tiene utilidad médica creciente. Una aplicación médica destacable de la Fotogrametría es la medición de las úlceras de la piel. Las úlceras de la piel constituyen un problema médico y social importante: por su elevado coste económico, afectación de la salud y calidad de vida, frecuente cronicidad y complicaciones. La medición de la úlcera es necesaria y útil para el seguimiento clínico. La disminución de variables de tamaño de la úlcera indica su progresión hacia la cicatrización. Los procedimientos tradicionales de medición unidimensional y bidimensional, como la regla graduada y la planimetría con acetato, se siguen utilizando por su sencillez y comodidad de uso. Sin embargo, son invasivos y tienen inconvenientes técnicos, como inexactitud e imprecisión. Otros procedimientos de medición tridimensional (3D), como la inyección de líquido y los moldes de pasta, pueden tener, además, efectos adversos, como dolor, irritación o reacción alérgica. Algunos procedimientos sin contacto que utilizan técnicas de escaneo con luz estructurada o láser: 1/ necesitan dispositivos de escaneo específicos; 2/ no se ha demostrado su utilidad en la práctica clínica; 3/ tienen un coste elevado. Por otra parte, no hay un procedimiento de referencia (patrón oro) para la medición del volumen de las úlceras cutáneas. Una optimización de las técnicas utilizadas para la valoración objetiva de la evolución de las úlceras de la piel ayudaría a comparar la eficacia de los distintos tratamientos y seleccionar los más adecuados, así como predecir el tiempo de curación. Por todo lo anterior, se justifica el desarrollo de un procedimiento de medición de úlceras basado en una técnica fotogramétrica sin contacto, como la estereofotogrametría. El objetivo general de esta tesis es desarrollar un procedimiento fotogramétrico para el escaneo, medición, clasificación tisular y seguimiento clínico de úlceras cutáneas; y validar dicho procedimiento en un estudio clínico con pacientes, evaluando su fiabilidad y exactitud. El procedimiento SfM-3DULC está basado en las técnicas estereofotogramétricas SfM (Structure from Motion) y MVS (Multi View Stereo) y utiliza como software de escaneo Agisoft PhotoScan y como software de medición del modelo 3D el programa 3DULC, creado por los autores. Este procedimiento escanea y reconstruye un modelo digital 3D de la úlcera utilizando una cámara digital, con la que se adquieren una serie de fotografías desde varias localizaciones y orientaciones. Para la validación del procedimiento SfM-3DULC, se realizó un estudio piloto en el que se evaluó su fiabilidad y exactitud. También se propuso una nueva variante del procedimiento ImageJ, en la que se utiliza una ortofotografía (Ortho-ImageJ), para medir el área proyectada. Por último, se compararon las mediciones realizadas por un grupo de dermatólogos y otro grupo de no expertos. Todas las variables medidas por dermatólogos usando SfM-3DULC mostraron excelentes puntuaciones de fiabilidad intra-evaluador (ICC > 0.99) e inter-evaluador (ICC > 0.98). En conclusión, el software 3DULC desarrollado, en su versión 1.0: 1/ Interviene en la fase de medición de la úlcera cutánea, tras su escaneo. 2/ Es autónomo respecto al procedimiento de escaneo, y podría utilizarse junto a cualquier otra técnica que obtenga una nube de puntos de la úlcera cutánea. 3/ Detecta el contorno de la úlcera de forma asistida basándose en su respuesta espectral. 4/ Clasifica las zonas de la úlcera cutánea según su tipo de tejido utilizando un árbol de decisión. 5/ Mide las siguientes variables morfométricas de la úlcera cutánea: coeficiente de circularidad, coeficiente de lisura, longitud máxima, perímetro, profundidad máxima, área proyectada, área de la superficie excavada, área de la superficie de referencia y volumen. 6/ Presenta los resultados con un informe HTML que facilita la interpretación por personal sanitario. / [CA] La Fotogrametria és una ciència i tecnologia que té utilitat mèdica creixent. Una aplicació mèdica destacable de la Fotogrametria és el mesurament de les úlceres de la pell. Les úlceres de la pell constitueixen un problema mèdic i social important: pel seu elevat cost econòmic, afectació de la salut i qualitat de vida, freqüent cronicitat i complicacions. El mesurament de l'úlcera és necessària i útil per al seguiment clínic. La disminució de variables de mida de l'úlcera indica la seva progressió cap a la cicatrització. Els procediments tradicionals de mesurament unidimensional i bidimensional, com el regle graduat i la planimetria amb acetat, es continuen utilitzant per la seva senzillesa i comoditat d'ús. No obstant això, són invasius i tenen inconvenients tècnics, com inexactitud i imprecisió. Altres procediments de mesurament tridimensional (3D), com la injecció de líquid i els motles de pasta, poden tenir, a més, efectes adversos, com dolor, irritació o reaccions al·lèrgiques. Alguns procediments sense contacte que utilitzen tècniques d'escaneig amb llum estructurada o làser: 1 / necessiten dispositius d'escaneig específics; 2 / no s'ha demostrat la seva utilitat en la pràctica clínica; 3 / tenen un cost elevat. D'altra banda, no hi ha un procediment de referència (patró or) per al mesurament del volum de les úlceres cutànies. Una optimització de les tècniques utilitzades per a la valoració objectiva de l'evolució de les úlceres de la pell ajudaria a comparar l'eficàcia dels diferents tractaments i seleccionar els més adequats, així com predir el temps de curació. Per tot l'anterior, es justifica el desenvolupament d'un procediment de mesurament de úlceres basat en una tècnica fotogramètrica sense contacte, com la estereofotogrametría. L'objectiu general d'aquesta tesi és desenvolupar un procediment fotogramètric per a l'escaneig, mesurament, classificació tissular i seguiment clínic d'úlceres cutànies; i validar aquest procediment en un estudi clínic amb pacients, avaluant la seva fiabilitat i exactitud. El procediment SFM-3DULC està basat en les tècniques estereofotogramétricas SFM (Structure from Motion) i MVS (Multi View Stereo) i utilitza com a programari d'escaneig Agisoft PhotoScan i com a programari de mesurament de el model 3D el programa 3DULC, creat pels autors. Aquest procediment escaneja i reconstrueix un model digital 3D de l'úlcera utilitzant una càmera digital, amb la qual s'adquireixen una sèrie de fotografies des de diverses localitzacions i orientacions. Per a la validació de l'procediment SFM-3DULC, es va realitzar un estudi pilot en el qual es va avaluar la seva fiabilitat i exactitud. També es va proposar una nova variant del procediment ImageJ, en què s'utilitza una ortofotografia (Ortho-ImageJ), per mesurar l'àrea projectada. Finalment, es van comparar les mesures realitzades per un grup de dermatòlegs i un altre grup de no experts. Totes les variables mesures per dermatòlegs usant SFM-3DULC van mostrar excel·lents puntuacions de fiabilitat intra-avaluador (ICC> 0.99) i inter-avaluador (ICC> 0.98). En conclusió, el programari 3DULC desenvolupat, en la seva versió 1.0: 1 / Intervé en la fase de mesurament de l'úlcera cutània, després de la seva exploració. 2 / És autònom respecte a l'procediment d'escaneig, i podria utilitzar-costat de qualsevol altra tècnica que obtingui un núvol de punts de l'úlcera cutània. 3 / Detecta el contorn de l'úlcera de forma assistida basant-se en la seva resposta espectral. 4 / Classifica les zones de l'úlcera cutània segons el seu tipus de teixit utilitzant un arbre de decisió. 5 / Mesura les variables morfomètriques de l'úlcera cutània: coeficient de circularitat, coeficient de llisor, longitud màxima, perímetre, profunditat màxima, àrea projectada, àrea de la superfície excavada, àrea de la superfície de referència i volum. 6 / Presenta els resultats amb un informe HTML que facilita la interpretació per personal sanitari. / [EN] Photogrammetry is a science and technology of increasing medical utility. A notable medical application of photogrammetry is the measurement of skin ulcers. Skin ulcers are a major medical and social problem: due to their high economic cost, impact on health and quality of life, frequent chronicity and complications. Ulcer measurement is necessary and useful for the clinical follow-up. Decreasing ulcer size variables indicate progression towards healing. Traditional one- and two-dimensional measurement procedures, such as the graduated ruler and acetate planimetry, are still used because of their simplicity and ease of use. However, they are invasive and have technical drawbacks, such as inaccuracy and imprecision. Other three-dimensional (3D) measurement procedures, such as liquid injection and paste moulds, may also have adverse effects, such as pain, irritation or allergic reaction. Some non-contact procedures that use structured light or laser scanning techniques: 1/ require specific scanning devices; 2/ have not been demonstrated to be useful in clinical practice; 3/ are expensive. Moreover, there is no reference procedure (gold standard) for the measurement of skin ulcer volume. Optimisation of the techniques used for the objective assessment of the evolution of skin ulcers would help to compare the efficacy of different treatments and to select the most appropriate ones, as well as to predict healing time. Therefore, the development of an ulcer measurement procedure based on a non-contact photogrammetric technique, such as stereophotogrammetry, is justified. The main objective of this thesis is to develop a photogrammetric procedure for the scanning, measurement, tissue classification and clinical follow-up of skin ulcers; and to validate this procedure in a clinical study with patients, evaluating its reliability and accuracy. The SfM-3DULC procedure is based on the stereophotogrammetric techniques SfM (Structure from Motion) and MVS (Multi View Stereo) and uses Agisoft PhotoScan as scanning software and 3DULC as 3D model measurement software. This procedure scans and reconstructs a 3D digital model of the ulcer using a digital camera, which acquires photographs from various locations and orientations. In order to validate the SfM-3DULC procedure, a pilot study was conducted to assess its reliability and accuracy. A new variant of the ImageJ procedure was also proposed, in which an orthophotography (Ortho-ImageJ) is used to measure the projected area. Finally, measurements made by a group of dermatologists and a group of non-experts were compared. All the variables measured by dermatologists using SfM-3DULC showed excellent scores of intra-rater reliability (ICC > 0.99) and inter-rater reliability (ICC > 0.98). In conclusion, the 3DULC software developed, in its version 1.0: 1/ Is used to measure the skin ulcer, after its scan. 2/ Is autonomous with respect to the scanning procedure, and could be used with any other technique that obtains a point cloud of the skin ulcer. 3/ Outlines the edge of the ulcer semi-automatically, based on its spectral response. 4/ Classifies skin ulcer areas according to their tissue type, using a decision tree. 5/ Measures the following morphometric variables of the skin ulcer: circularity coefficient, evenness coefficient, maximum length, perimeter, maximum depth, projected area, surface area, reference surface area and volume. 6/ Presents the results with an HTML report that facilitates its interpretation by healthcare personnel. / Esta tesis doctoral fue financiada con una beca predoctoral de la Generalitat Valenciana – Consellería de Educación, Investigación, Cultura y Deporte, y el Fondo Social Europeo (ACIF/2018/160). / Sánchez Jiménez, D. (2022). SfM-3DULC: Desarrollo y validación de un procedimiento fotogramétrico para el escaneo, medición, clasificación tisular y seguimiento clínico de úlceras cutáneas [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/181691 / TESIS

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