Submitted by Isaac Francisco de Souza Dias (isaac.souzadias@ufpe.br) on 2016-05-24T16:51:31Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) DISSERTAÇÃO DE GLAUBER MELO.pdf: 1677140 bytes, checksum: 5c6c9d88c26ddb2f5f21225f906bd986 (MD5) / Made available in DSpace on 2016-05-24T16:51:31Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) DISSERTAÇÃO DE GLAUBER MELO.pdf: 1677140 bytes, checksum: 5c6c9d88c26ddb2f5f21225f906bd986 (MD5) Previous issue date: 2015-09-01 / A Esquistossomose Mansônica permanece sendo um grave problema de saúde pública e ainda pertence à lista de doenças negligenciadas no Brasil com um impacto sócio-econômico significativo. Estima-se que 207 milhões de pessoas estejam infectadas, 500 mil morrem a cada ano e 120 milhões sejam assintomáticos. O processo patológico característico é a presença do granuloma hepático caracterizado como reação de defesa do organismo para isolamento do ovo e proteção contra a liberação de seus antígenos. O objetivo do estudo foi avaliar a influência da dieta hiperlipídica no tecido hepático em um modelo experimental de esquistossomose mansônica utilizando 35 camundongos fêmeas separados em 4 grupos: Dieta Hiperlipidica e Infectado - H+I (n=9), Infectados – I (n=7), Dieta Hiperlipídica – H (n=9) e Controle – C (n=10). Fragmentos hepáticos foram fixados e realizados estudos histológicos e morfométricos como números, volumes e evoluções do granulomas, além da quantificação da densidade de colágenos. Foi evidenciada a caracterização prevalente da fase granulomatosa no grupo I do que o H+I, além de uma melhor formação de colágenos no grupo H+I em relação aos restantes dos grupos. No decorrer do estudo observou-se a ausência de esteatose no grupo H+I. O estudo demonstrou que a presença de dieta hiperlipídica altera alguns rearranjos na formação granulomatosa que levou à necessidade de observações mais intensas a cerca da temática. / Schistosomiasis remains a serious public health issue and still belongs to the list of neglected diseases in Brazil with a significant socio-economic impact. It is estimated that 207 million people are infected, 500 thousand die annually and 120 million are asymptomatic. The characteristic pathological process is the presence of hepatic granuloma characterized as the body's defense reaction to egg insulation and protection against the release of their antigens. The aim of the study was to evaluate the influence of high fat diet on liver tissue in an experimental model of schistosomiasis mansoni using 35 female mice divided into 4 groups: fat diet and Infected - H + I (n = 9), Infected - I ( n = 7), high fat diet - H (n = 9) and control - C (n = 10). Tissue specimens were fixed and made histological and morphometric studies as numbers, volumes and granulomas developments, as well as quantification of collagen density. The prevailing characterization of granulomatous phase (FG) was observed in group I than H + I, along with a better collagen formation in the H + I group compared to the other groups. During the study we observed the absence of steatosis in H + I group. The study showed that the presence of fat diet alters some rearrangements in granulomatous formation, leading to the need for more intense observations about the theme.

Sarcoidosis is a multisystem, inflammatory granulomatous disease that rarely involves breast tissue. The pathophysiology of this chronic granulomatous condition is not well understood but is thought to be multifactorial, involving environmental influences causing an amplified immune response. A key histomorphology feature in sarcoidosis is the presence of non-necrotizing granulomas. In this case, we report a 41-year-old African-American man with a known history of sarcoidosis of the lung who presented with gynecomastia and bilateral breast tenderness with palpable nodules. Subsequent biopsy and microscopic examination of the breast nodules revealed diffuse involvement with non-necrotizing granulomas in both breasts. A final diagnosis of extensive sarcoidosis involving breast tissue was rendered after excluding other causes of non-necrotizing granulomas. The patient underwent a bilateral mastectomy to remove the breast nodules. This case discusses sarcoidosis involving an unusual site.

Este estudo avaliou pacientes portadores de cromoblastomicose, sendo feita uma categorização clínica em dois grupos, de acordo com a forma clínica da lesão dermatológica: o primeiro composto por indivíduos com lesões elevadas e o segundo formado por casos com lesões planas, com biópsias realizadas antes e depois dos tratamentos. Através de critérios semiquantitativos, os elementos anatomopatológicos foram analisados, constatando-se a presença do padrão granulomatoso chamado granuloma micótico misto organizado, com baixa intensidade em lesões planas e alta em elevadas. Evidenciou-se que pacientes com lesões planas evoluíram bem clinicamente, com exames micológicos negativos e sem recidivas (bons respondedores), porém aqueles com lesões elevadas apresentaram evolução clínica desfavorável, com exames micológicos positivos e doença recidivante ou recalcitrante, apesar dos tratamentos recebidos (maus respondedores). E, entre os componentes histopatológicos reacionais à invasão fúngica, verificou-se associação significativa para fibrose, podendo levar a um pior prognóstico. Estes achados clínicos e histopatológicos conferem a esta patologia uma idéia de polaridade, à guisa dos fenômenos das formas polares da hanseníase, da fagocitose, e dos agentes de baixa virulência. Os autores propõem uma classificação morfológica dos granulomas da CBM em dois tipos polares: granuloma micótico misto organizado (GMMO) polar com alta intensidade dos elementos celulares (que corresponderia ao polar não tuberculóide) e GMMO polar com baixa intensidade (que corresponderia ao polar tuberculóide). / Patients with chromoblastomycosis were studied and dichotomized into two groups according to the clinical lesions: flat and elevated ones which were biopsied before and after treatments. Histopathological structures underwent through semiquantitatively analisys evidencing the mixed organized mycotic granuloma with low intensity of histopathological elements in flat lesions and high in elevated ones. Flat lesions have improved clinically with negative micological studies (good responders) while elevated lesions’ patients did not (bad responders). It was found significant association between evidence of fungus and fibrosis with a poor prognosis. Clinical and histopathological findings suggest a polarity concept to this disease based on the fenomenal polar forms of hanseniasis, fagocitosis and the low virulence agents. The authors proposed a morphological classification of the chromoblastomycosis’ granulomas into two polar types: polar mixed organized mycotic granuloma (MOMG) with high intensity of the cellular elements (like the polar non tuberculoid type) and the polar MOMG with low intensity (like the polar tuberculoid type).

Tuberculosis, caused by Mycobacterium tuberculosis infection, results in the development of granulomas in affected tissues. These structures are formed by a myeloid cell core including multinucleated giant cells and surrounded by T lymphocytes. We studied mechanisms of survival, formation and functions of giant cells in Mycobacterium granulomas. Previously, our group showed that the cytokine IL-17A induces the fusion of dendritic cells (DC). Here, we identified molecules induced by the IL-17A genetic program in myeloid cells: BFL1 regulated DC survival, while the chemokines CCL2 and CCL20 directed clustering required for DC fusion. In situ, in human TB granulomas, we found that IL-17A was expressed by T lymphocytes while BFL1, CCL2 and CCL20 were expressed by the mono- and multi-nucleated myeloid cells. Then we characterized phenotype, immune functions and microbicidal activity of IL-17A-treated DC and their derived giant cells. They expressed a mixed DC-macrophage phenotype, retained classical DC functions, synthesized several destructive enzymes and had increased and differential microbicidal activities against Mycobacterium species. We named GMIC (giant myeloid inflammatory cells) these IL-17A-dependent giant cells, and propose that they constitute a new inflammatory myeloid effector with potent microbicidal activities. Altogether, our results show that IL-17A may participate in the maintenance of the myeloid core of human tuberculosis granuloma by promoting the formation of GMIC with potent destructive and microbicidal functions. The molecular mechanisms we have documented should help the development of new tuberculosis therapeutic and vaccination strategies.

Este estudo avaliou pacientes portadores de cromoblastomicose, sendo feita uma categorização clínica em dois grupos, de acordo com a forma clínica da lesão dermatológica: o primeiro composto por indivíduos com lesões elevadas e o segundo formado por casos com lesões planas, com biópsias realizadas antes e depois dos tratamentos. Através de critérios semiquantitativos, os elementos anatomopatológicos foram analisados, constatando-se a presença do padrão granulomatoso chamado granuloma micótico misto organizado, com baixa intensidade em lesões planas e alta em elevadas. Evidenciou-se que pacientes com lesões planas evoluíram bem clinicamente, com exames micológicos negativos e sem recidivas (bons respondedores), porém aqueles com lesões elevadas apresentaram evolução clínica desfavorável, com exames micológicos positivos e doença recidivante ou recalcitrante, apesar dos tratamentos recebidos (maus respondedores). E, entre os componentes histopatológicos reacionais à invasão fúngica, verificou-se associação significativa para fibrose, podendo levar a um pior prognóstico. Estes achados clínicos e histopatológicos conferem a esta patologia uma idéia de polaridade, à guisa dos fenômenos das formas polares da hanseníase, da fagocitose, e dos agentes de baixa virulência. Os autores propõem uma classificação morfológica dos granulomas da CBM em dois tipos polares: granuloma micótico misto organizado (GMMO) polar com alta intensidade dos elementos celulares (que corresponderia ao polar não tuberculóide) e GMMO polar com baixa intensidade (que corresponderia ao polar tuberculóide). / Patients with chromoblastomycosis were studied and dichotomized into two groups according to the clinical lesions: flat and elevated ones which were biopsied before and after treatments. Histopathological structures underwent through semiquantitatively analisys evidencing the mixed organized mycotic granuloma with low intensity of histopathological elements in flat lesions and high in elevated ones. Flat lesions have improved clinically with negative micological studies (good responders) while elevated lesions’ patients did not (bad responders). It was found significant association between evidence of fungus and fibrosis with a poor prognosis. Clinical and histopathological findings suggest a polarity concept to this disease based on the fenomenal polar forms of hanseniasis, fagocitosis and the low virulence agents. The authors proposed a morphological classification of the chromoblastomycosis’ granulomas into two polar types: polar mixed organized mycotic granuloma (MOMG) with high intensity of the cellular elements (like the polar non tuberculoid type) and the polar MOMG with low intensity (like the polar tuberculoid type).

Este estudo avaliou pacientes portadores de cromoblastomicose, sendo feita uma categorização clínica em dois grupos, de acordo com a forma clínica da lesão dermatológica: o primeiro composto por indivíduos com lesões elevadas e o segundo formado por casos com lesões planas, com biópsias realizadas antes e depois dos tratamentos. Através de critérios semiquantitativos, os elementos anatomopatológicos foram analisados, constatando-se a presença do padrão granulomatoso chamado granuloma micótico misto organizado, com baixa intensidade em lesões planas e alta em elevadas. Evidenciou-se que pacientes com lesões planas evoluíram bem clinicamente, com exames micológicos negativos e sem recidivas (bons respondedores), porém aqueles com lesões elevadas apresentaram evolução clínica desfavorável, com exames micológicos positivos e doença recidivante ou recalcitrante, apesar dos tratamentos recebidos (maus respondedores). E, entre os componentes histopatológicos reacionais à invasão fúngica, verificou-se associação significativa para fibrose, podendo levar a um pior prognóstico. Estes achados clínicos e histopatológicos conferem a esta patologia uma idéia de polaridade, à guisa dos fenômenos das formas polares da hanseníase, da fagocitose, e dos agentes de baixa virulência. Os autores propõem uma classificação morfológica dos granulomas da CBM em dois tipos polares: granuloma micótico misto organizado (GMMO) polar com alta intensidade dos elementos celulares (que corresponderia ao polar não tuberculóide) e GMMO polar com baixa intensidade (que corresponderia ao polar tuberculóide). / Patients with chromoblastomycosis were studied and dichotomized into two groups according to the clinical lesions: flat and elevated ones which were biopsied before and after treatments. Histopathological structures underwent through semiquantitatively analisys evidencing the mixed organized mycotic granuloma with low intensity of histopathological elements in flat lesions and high in elevated ones. Flat lesions have improved clinically with negative micological studies (good responders) while elevated lesions’ patients did not (bad responders). It was found significant association between evidence of fungus and fibrosis with a poor prognosis. Clinical and histopathological findings suggest a polarity concept to this disease based on the fenomenal polar forms of hanseniasis, fagocitosis and the low virulence agents. The authors proposed a morphological classification of the chromoblastomycosis’ granulomas into two polar types: polar mixed organized mycotic granuloma (MOMG) with high intensity of the cellular elements (like the polar non tuberculoid type) and the polar MOMG with low intensity (like the polar tuberculoid type).

Submitted by CAROLINE FERNANDES RIMOLI null (carol@rimoli.med.br) on 2017-01-11T20:16:02Z No. of bitstreams: 1 Caroline Fernandes Rimoli_Dissertacao_Mestrado_FMB_UNESP_versao final após defesa frente e verso.pdf: 1745845 bytes, checksum: d465e22347663cedd8ff9ad19e5b940b (MD5) / Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-01-12T18:06:07Z (GMT) No. of bitstreams: 1 rimoli_cf_me_bot.pdf: 1745845 bytes, checksum: d465e22347663cedd8ff9ad19e5b940b (MD5) / Made available in DSpace on 2017-01-12T18:06:07Z (GMT). No. of bitstreams: 1 rimoli_cf_me_bot.pdf: 1745845 bytes, checksum: d465e22347663cedd8ff9ad19e5b940b (MD5) Previous issue date: 2016-11-17 / Introdução: os granulomas laríngeos são lesões benignas, não neoplásicas, uni ou bilaterais, de etiologia variável, que ocorrem no terço posterior das pregas vocais ou na região aritenoídea. Os sintomas são diversos, sendo o mais comum a rouquidão. Os granulomas decorrentes de intubação são altamente recidivantes e não existe consenso quanto ao melhor tratamento. Objetivo: comparar a efetividade dos tratamentos dos granulomas laríngeos decorrentes de intubação endotraqueal. Métodos: foram realizadas revisão sistemática e metanálise proporcional de estudos sobre o tratamento de granulomas laríngeos decorrentes de intubação endotraqueal, seja ele primário ou recidivante. Os critérios de elegibilidade foram: ensaios clínicos randomizados e estudos prospectivos controlados, e na ausência destes, aceitos também estudos retrospectivos e prospectivos não controlados com no mínimo cinco participantes. Os desfechos estudados foram resolução, recidiva e tempo para resolução do granuloma. Os estudos foram identificados na base de dados Pubmed, Embase, Lilacs e Cochrane. Para a análise dos dados e metanálise, utilizou-se o programa StatsDirect 3.0.121. Resultados: dentre os 578 artigos encontrados, 61 foram lidos na íntegra e seis selecionados para a revisão, totalizando 85 pacientes, com idade variando de 21 a 86 anos. Os tratamentos encontrados foram: antirrefluxo, fonoterapia, anti-inflamatórios, corticoterapia, antibioticoterapia, sulfato de zinco e cirurgia. Para o tratamento primário, foram estudados 85 pacientes, de seis estudos, divididos em dois grupos: cirúrgico ± associações (41 pacientes), com chance de resolução de 75% (IC 95%: 0,3% a 100%, I2= 90%), e risco absoluto de recidiva de 25% (IC 95%: 0,2% a 71%), e clínico (44 pacientes), com chance de resolução de 86% (IC 95%: 67% a 97%), e risco absoluto de recidiva de 14% (IC 95%: 3% a 33%). Na interpretação da metanálise, não houve diferença estatisticamente significativa entre os grupos, já que houve sobreposição dos intervalos de confiança. Três estudos, englobando 19 pacientes, estudaram o tratamento secundário (quando houve insucesso ou recidiva após o tratamento primário), sendo que três indivíduos apresentaram nova recidiva. O tempo de tratamento necessário para a resolução das lesões variou muito, desde imediato, como após as cirurgias, como até 23 meses, no caso do corticosteroide inalatório (budesonida). O sulfato de zinco levou um tempo de quatro a 12 semanas. O tratamento antirrefluxo não teve um tempo bem especificado em todos os estudos. Conclusão: não identificamos diferença estatisticamente significativa entre as modalidades de tratamento para os granulomas de intubação. Certamente, esse resultado foi influenciado pela falta de estudos mais abrangentes e criteriosos, principalmente ensaios clínicos, e também pelo número reduzido de pacientes em cada estudo. O tratamento que apresentou menor tempo médio para resolução do granuloma foi o cirúrgico, e o maior, corticosteroide (budesonida) inalatório. / Introduction: laryngeal granulomas are benign, non-neoplastic lesions that can occur unilaterally or bilaterally for various causes. They are usually located in the posterior third of the vocal folds or in the arytenoid region. Patients may present a number of symptoms, the main one being hoarseness. Post-intubation granulomas are highly recurrent and there is no consensus on the best treatment. Objective: to compare the effectiveness of treatments of laryngeal granulomas secondary to endotracheal intubation. Methods: systematic review and proportion meta-analysis of studies that address the treatment of laryngeal granulomas caused by endotracheal intubation. The eligibility criteria were: randomized controlled trials and controlled prospective studies, and in the absence of these, retrospective and prospective uncontrolled studies were also accepted, with at least five participants. The outcomes that were measured were resolution, recurrence and time to resolve the granuloma. Databases searched were Pubmed, Embase, Lilacs and Cochrane. Statistical analysis was performed with the StatsDirect version 3.0.121 software. Results: among the 578 articles found, 61 were eligible for full reading and 11 articles were included, involving 85 patients, with ages varying from 21 to 86 years). The treatments were: anti-reflux, speech therapy, anti-inflammatory drugs, corticosteroids, antibiotics, zinc sulfate and surgery. For the primary treatment, 85 patients were investigated in six studies, divided into two groups: surgical ± associations (41 patients), with chance of resolution of 75% (95% CI: 0,3% to 100%, I2= 90%), and absolute risk of recurrence of 25% (95% CI: 0,2% to 71%) and clinical (44 patients), with chance of resolution of 86% (95% CI: 67% to 97%), and absolute risk of recurrence of 14% (95% CI: 3 to 33%). In the interpretation of the meta-analysis, there was no statistical significance between the groups, since there was an overlap of confidence intervals. Three studies involving 19 patients analyzed secondary treatment (when there was failure or recidive after primary treatment). Three patients had a new recurrence. The treatment time required for the resolution of the lesions varied greatly, from immediate, as after surgery, as up to 23 months, in the case of inhaled corticosteroid (budesonide). The zinc sulfate took a time of four to 12 weeks. The antireflux treatment did not have a well-specified time in all studies. Conclusion: we have not identified a statistical significance between the treatment modalities for intubation granulomas. Certainly, this result was influenced by the lack of more comprehensive and solid studies, particularly clinical trials, and also by the small number of patients in each study. The treatment that had the lowest mean time to resolve the granuloma was surgery, and the highest was inhaled corticosteroid (budesonide).

Sarcoidosis is a disease characterized as noncaseation granulomas. Granulomas are clusters of cells that form a discrete nodule. This research was important because Black American women develop saroidosis at a higher rate than any other race. The purpose of this phenomenological qualitative study was to examine the impact of sarcoidosis in the lives of Black American women diagnosed with the disease and to consider how occupational experiences may have contributed to participants' development of sarcoidosis. Research states that domestic work such as cleaning, when performed on a daily basis or as an occupation, can contribute to adverse health effects. The framework of this study utilized the transtheoretical model of behavior change while the overall research questions centered on the effects of sarcoidosis on the quality of life of Black American women. This qualitative research included interviews with thirteen Black American women diagnosed and living with sarcoidosis at various stages. Data were collected using the software tool HyperRESEARCH. Both purposive sampling and snowball sampling technique was used for this research. Data were gathered using a general profile of the lived experiences of women with sarcoidosis. The findings revealed that the common lived experience that has potentially put Black American women at risk for developing sarcoidosis is bleach. My recommendations for further research would be to expand the locations of participants to across the United States. The implications for positive social change may result from broader knowledge of the disease through education, even for those who are not at risk for developing it. Chronic sarcoidosis can be fatal if untreated.

According to the Centers for Disease Control and Prevention (CDC), 8 million people each year are infected with Mycobacterium tuberculosis (Mtb) leading to 1.5 million deaths annually. This staggering number calls for advancements in understanding this bacterium so progress can be made in treating and preventing the disease. It is particularly important to understand mechanisms by which TB survives inside hostile host immune cells known as macrophages and within hypoxic granuloma lesions of the lung. Preliminary microarray data has shown that a TB gene known as Rv2633c is induced upon macrophage invasion. Bioinformatic analysis of Rv2633c coding sequence shows the product of Rv2633c has homology with hemerythrin-like proteins. Hemerythrins are a class of proteins commonly used to bind oxygen and sense nitric oxide and iron, leading us to hypothesize a role for Rv2633c in surviving hypoxic or nitrosative stress encountered within macrophages and granulomas. My first aim will be to generate a reporter strain of Mycobacterium smegmatis (Msm) expressing the mCherry fluorescent protein driven by the Rv2633c promoter. This tool will allow us to determine the stress conditions (i.e. hypoxia, nitric oxide treatment, acid pH) that activate expression of this gene by measuring the change in fluorescence. Linking the regulation of Rv2633c to specific environmental cues relevant to infections in vivo will provide insight into the role of this unique protein. Secondly, a knockout mutant of Rv2633c in the attenuated M. bovis BCG will be constructed and characterized to determine the importance and function of this protein during TB infections.

Dans la tuberculose, Mycobacterium tuberculosis forme des granulomes dans les poumons avec, au centre, des cellules myéloïdes mono et multi-nucléées et autour, des lymphocytes. Nous avons étudié la biologie des cellules géantes dans ces granulomes tuberculeux : formation, mécanismes de survie et fonctions. Notre groupe a publié que l’IL-17A déclenche la fusion des cellules dendritiques (DC). Notre travail démontre que cette cytokine induit BCL2A1/BFL1, qui régule la survie des DC et les chémokines CCL2 et CCL20 qui dirigent le regroupement nécessaire à leur fusion. In situ, l'IL-17A est exprimée par les lymphocytes T de la couronne du granulome tuberculeux. BCL2A1, CCL2 et CCL20 sont exprimés par les cellules myéloïdes mono-et multi-nucléées. Ensuite, nous avons caractérisé le phénotype, les fonctions immunitaires et l'activité microbicide des DC traitées par l'IL-17A. Nous avons trouvé qu’elles co-expriment des marqueurs de DC et de macrophages, conservent les fonctions classiques des DC, synthétisent un profil spécifique d’enzymes destructrices et exercent une microbicidie variable suivant les souches de Mycobactéries. Nous avons nommé GMIC (Giant Myeloid Inflammatory Cell), ces cellules géantes induites par l'IL-17A. Nous proposons qu'elles constituent un nouvel effecteur myéloïde qui contrôle les mycobactéries. Ainsi, l'IL-17A participerait au maintien du cœur myéloïde du granulome tuberculeux en favorisant la formation des cellules géantes possédant des fonctions destructrices et microbicides. Les mécanismes moléculaires que nous avons documentés devraient permettre le développement de nouvelles stratégies thérapeutiques et vaccinales contre la tuberculose. / Tuberculosis, caused by Mycobacterium tuberculosis infection, results in the development of granulomas in affected tissues. These structures are formed by a myeloid cell core including multinucleated giant cells and surrounded by T lymphocytes. We studied mechanisms of survival, formation and functions of giant cells in Mycobacterium granulomas. Previously, our group showed that the cytokine IL-17A induces the fusion of dendritic cells (DC). Here, we identified molecules induced by the IL-17A genetic program in myeloid cells: BFL1 regulated DC survival, while the chemokines CCL2 and CCL20 directed clustering required for DC fusion. In situ, in human TB granulomas, we found that IL-17A was expressed by T lymphocytes while BFL1, CCL2 and CCL20 were expressed by the mono- and multi-nucleated myeloid cells. Then we characterized phenotype, immune functions and microbicidal activity of IL-17A-treated DC and their derived giant cells. They expressed a mixed DC-macrophage phenotype, retained classical DC functions, synthesized several destructive enzymes and had increased and differential microbicidal activities against Mycobacterium species. We named GMIC (giant myeloid inflammatory cells) these IL-17A-dependent giant cells, and propose that they constitute a new inflammatory myeloid effector with potent microbicidal activities. Altogether, our results show that IL-17A may participate in the maintenance of the myeloid core of human tuberculosis granuloma by promoting the formation of GMIC with potent destructive and microbicidal functions. The molecular mechanisms we have documented should help the development of new tuberculosis therapeutic and vaccination strategies.