Dissertations / Theses: 'Fibromes'

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MOLLARD, JOELLE. "Endometriose, fibromes et traitement substitutif de la menopause." Aix-Marseille 2, 1994. http://www.theses.fr/1994AIX20703.

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HUYS, CHRISTIAN. "Imagerie des fibromes pleuraux : a propos de 4 cas." Angers, 1994. http://www.theses.fr/1994ANGE1075.

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Nassif, Elie. "Les fibromes sous-pleuraux : revue générale à propos d'un cas." Montpellier 1, 1994. http://www.theses.fr/1994MON11171.

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LICATA, JACQUES. "Tactiques operatoires des fibromes uterins : a propos d'une serie personnelle." Aix-Marseille 2, 1990. http://www.theses.fr/1990AIX20318.

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Sabourdy, Frédérique. "Poxivirus et tumeurs : influence des facteurs de croissance viraux sur la formation des fibromes de Shope." Toulouse 3, 2004. http://www.theses.fr/2004TOU30277.

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La famille des Poxviridae compte trois virus tumorigènes. Les mécanismes empruntés par ces virus pour induire des tumeurs sont inconnus et semblent originaux. Certains poxvirus codent des homologues de l'EGF qui représentent de bons candidats pour participer à la tumorigénèse. Après une présentation générale de la biologie des Poxviridae, l'auteur s'interesse plus particulièrement au virus du fibrome de Shope (VFS), responsable de fibromes cutanés chez le lapin, dont il présente la symptomatologie et la pathogénie. Elle rappelle les caractéristiques des facteurs de croissance EGF-like cellulaires et viraux et leurs liens avec la tumorigénèse. L'auteur montre que le facteur de croissance du VFS, SFGF, active la prolifération des fibroblastes dans les tumeurs, et pourrait participer aux modifications morphologiques dont ils sont les cibles. Le facteur de croissance du virus myxomateux, MGF, ne peut le remplacer
Only three poxviruses are tumorigenic. The mechanisms they use to induce tumours remain unknown. Some of them encode EGF-like homologs, which represent good candidates for triggering tumorigenesis. The author first gives a general overview of the poxvirus biology. Then, she presents poxvirus tumorigenesis characteristics, using Shope fibroma virus (SFV) as an example. She describes cellular and viral EGF-like growth factors, showing how these peptides could be linked with tumour formation. According to her experimental results, SFV growth factor, SFGF, activates fibroblasts proliferation in fibromas, and could also be involved in their morphological abnormalities. Myxoma virus growth factor, MGF, cannot substitute for SFGF

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Payafar, Alireza. "L'évaluation par l'I. R. M. Des fibromes utérins traités par la triptolérine." Montpellier 1, 1993. http://www.theses.fr/1993MON11144.

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AVISSE, LAMARRE ANNABELLE. "Donnees cliniques actuelles sur les fibromes pleuraux : a propos de cinq observations." Amiens, 1992. http://www.theses.fr/1992AMIEM109.

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DELVINCOURT, BARTHES MONIQUE, and NICOLAS VIRNOT. "Les fibromes cardiaques : 1 cas chez un nourrisson ; revue de la litterature depuis 1971." Lille 2, 1988. http://www.theses.fr/1988LIL2M028.

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Jourdain, Olivier. "Une nouvelle méthode de traitement des fibromes : la thermothérapie interstitielle au laser Nd:Yag : étude préliminaire." Bordeaux 2, 1994. http://www.theses.fr/1994BOR23009.

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Banegas, Danielle. "Contribution à l'étude de la dégénérescence sarcomateuse des fibromes de l'utérus : à propos d'une observation." Montpellier 1, 1989. http://www.theses.fr/1989MON11215.

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LEGGHE, MANIAC HELENE. "Modalites et resultats de l'embolisation preoperatoire des fibromes naso-pharyngiens : a propos de 12 cas." Lille 2, 1994. http://www.theses.fr/1994LIL2M232.

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BEYNEL, MELINAND FABIENNE. "Tumeurs fibreuses benignes de la plevre : a propos de 2 cas de fibromes pleuraux reveles par une pathologie articulaire." Lyon 1, 1988. http://www.theses.fr/1988LYO1M442.

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Enes, Giovana da Silva Tavares 1982. "Fibrose cística = estreitando laços maternos = Cystic fibrosis : strengthening maternal ties." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308361.

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Orientador: Antonio Fernando Ribeiro
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: A Fibrose Cística é uma doença autossômica recessiva, sistêmica, hereditária, crônica e progressiva e pode levar à morte. São características da doença as secreções mucosas espessas e viscosas que obstrui os ductos das glândulas exócrinas e contribuem para o aparecimento de doença pulmonar obstrutiva crônica, insuficiência pancreática com má digestão e má absorção e conseqüente desnutrição secundária, além de níveis elevados de eletrólitos no suor. Por ser uma doença crônica, ela exige cuidados sistemáticos pela vida toda, e na maioria dos casos quem exerce a função de cuidadora é a mãe. Além de viver uma nova experiência de ser mãe, ela terá que conviver com a frustração dele ser doente.Com este estudo foi possível compreender a relação que mãe e filho doente crônico constroem desde o momento do diagnóstico e conhecimento do tratamento, permeados por sentimentos como culpa e solidão. Assim, essas mães renunciam suas próprias vidas em função do cuidado do filho. Cuidados esse compartilhado com uma equipe de saúde multiprofissional ainda deficitária. Apesar de ter sido avaliado por elas como positivo, as sugestões por melhorias também surgiram: como uma melhor articulação entre os serviços de saúde nos diversos níveis, uma maior divulgação da doença e o aumento do número de dias de atendimento. Outro aspecto importante encontrado foi sobre importância do papel do psicólogo não só na atuação com o paciente e a família durante todo o tratamento; mas também na necessidade de oferecer um espaço para que os profissionais de saúde despreparados pudessem compartilhar suas angústias e frustrações o que reflete diretamente na assistência prestada
Abstract: The Cystic Fibrosis is a disease systemic, hereditary, chronic and progressive and it can lead to the death. There are characteristic of the disease the thick and viscous mucous secretions what it obstructs the ducts of the exocrine glands and contribute to the appearance of chronic obstructive pulmonary disease, pancreatic insufficiency with bad digestion and bad absorption and consequent secondary malnutrition, besides elevated levels of electrolytes in the sweat. Because of being a chronic disease, she demands systematic cares for the life completely, and in most of the cases who plays the function of care is the mother. Besides surviving a new experience of being a mother, she will have to coexist in spite of the fact that his frustration to be doente.Com this study there were possible understood the relation what mother and chronic sick son build from the moment of the diagnosis and knowledge of the treatment, permeated by feelings as fault and solitude. So, these mothers renounce his lives themselves in function of the care of the son. Taken care this shared one with a team of still deficient multiprofessional health. In spite of having been valued by them like positive, the suggestions for improvements also appeared: like a better articulation between the health services in several levels, a bigger spread of the disease and the increase of the number of service days. Another considered important aspect was on importance of the paper of the psychologist not alone in the acting with the patient and the family during the whole treatment; but also in the necessity of offering a space so that the unprepared health professionals could share his anguishes and frustrations what thinks straightly about the given presence
Mestrado
Saude da Criança e do Adolescente
Mestre em Ciências

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Correia, Cyntia Arivabeni de Araujo. "Estudo dos genes TNF alfa, ADIPOQ e STATH entre portadores de fibrose cistica." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308583.

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Orientador: Carmen Silvia Bertuzzo
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: A Fibrose Cística (FC) possui uma grande variabilidade de expressão fenotípica, o que significa que crianças com o mesmo genótipo podem diferir quanto à sua apresentação. A proteína defeituosa formada é chamada CFTR (proteína reguladora da conductância iônica), causa transporte anormal de sódio e cloro através da membrana apical das células epiteliais das vias aéreas, pâncreas, intestino e aparelho reprodutor. Essa proteína é codificada por um único gene que recebe o mesmo nome da proteína, CFTR, e localiza-se no braço longo do cromossomo 7, região 7q3.1. Gêmeos monozigóticos apresentam maior concordância em relação à gravidade da doença pulmonar que os dizigóticos, sugerindo que a FC seja modulada por fatores genéticos secundários - genes modificadores - além do gene CFTR. A característica mais importante na FC é a sobrevida que é influenciada pela doença pulmonar. Portanto, genes que estejam envolvidos na imunidade, inflamação, reparação do epitélio e produção de muco são candidatos a genes modificadores da doença. Os objetivos foram: 1) determinar a prevalência dos polimorfismos -308G/A e -238G/A do gene TNF a entre portadores de FC e verificar existência de associação entre esses polimorfismos e a gravidade do quadro pulmonar, 2) identificar alterações de sequencia nos exons e junções exon/ intron dos genes ADIPOQ e STATH e verificar existência de associação entre possíveis variações nesses genes e a gravidade da FC. Foi realizada PCR seguida por digestão enzimática para o polimorfismo -308G/A do gene TNF a, reação em cadeia da polimerase ARMS para o polimorfismo -238G/A do gene TNF a, e para os genes ADIPOQ e STATH foi feita a triagem de mutações através de cromatografia líquida de alta resolução por desnaturação - DHPLC com posterior sequenciamento da região onde foi encontrada alteração. Foram analisados 49 pacientes com FC em seguimento no Ambulatório de Mucoviscidose do HC/UNICAMP, homozigotos para a mutação F508 ou heterozigotos compostos para mutações de classe I ou II ou homozigotos para mutações de classe II, que são alterações que não levam à formação de proteína funcional. Além disso, foram selecionados indivíduos que apresentem alteração de eletrólitos no suor. Para o polimorfismo -308G/A do gene TNFa os genótipos GG, AA e GA foram encontrados com as seguintes frequencias: 14,28, 67,35 e 18,36% respectivamente. Estes dados se opõem ao relatado na literatura. Tal diferença deve ocorrer pelas características populacionais da população brasileira. Para o polimorfismo -238G/A do gene TNFa, os genótipos GG e AG tiveram as seguintes frequencias: 79,59 e 20,41% respectivamente. O genótipo AA não foi encontrado na amostra analisada. A alta frequencia do genótipo GG comparado com o AA, concorda com a literatura. Não foi encontrada alteração na sequencia dos genes STATH e ADIPOQ. Não foi possível estabelecer uma associação entre a gravidade da FC e os genes TNFa, STATH e ADIPOQ, nas regiões analisadas.
Abstract: Cystic Fibrosis (CF) has a great variety expression, which means that the seriousness of the disease can vary a lot among people who have it. The defective protein, called CFTR (Cystic Fibrosis Transmenbrane Regulator), causes abnormal transportation of chloride and sodium through the apical membrane of the epithelial cells of the airway, liver, intestine and masculine reproductive tract. This protein is encoded by a single gene which has the same name, CFTR, and is located within the long arm of chromosome 7, region 7q3.1. CF is a disease which expressivity is much variable, with different degrees of damage and the age when the symptoms begins is also much variable, even within individuals of the same family, like twins. Because of it, it is been said that others genetic factors besides CFTR, can be modulating the clinical presentation. As the pulmonary state is the great responsible for the mortality of the disease genes that are involved in host defense, inflammation, epithelial repair, mucin production, and airway reponsiveness are of great interest. Base on this the objectives of this work were: determine the prevalence of the polymorphisms -308G/A e -238G/A from the TNF a gene and verify if there is an association between these polymorphisms pulmonary disease severity, and identify alterations on ADIPOQ and STATH genes and verify if there is an association between these polymorphisms and CF severity. PCR followed by restriction enzyme digestion was performed to detect the polymorphism -308G/A from the TNF a gene, ARMS PCR to the polymorphism -238G/A from the TNF a gene the DHPLC method associated to the sequencing to analyze ADIPOQ and STATH genes, were used. We performed analyses of 49 cystic fibrosis patients that are followed in a Cystic Fibrosis center from HC/UNICAMP, that are \F508 homozygous or compound heterozygous to mutations from class I or II, or that are homozygous to class II mutations, which are alterations that do not produce functional protein. Besides this, were selected individuals that have sweat test altered. To the polymorphism 308G/A from TNFa gene the genotypes GG, AA e AG were in the following frequencies: 14,28, 67,35 e 18,36%. This data is contradictory to the literature and may occur because of the racial admixture of the Brazilian population. To the polymorphism -238G/A from TNFa gene, the genotypes GG AG were in the following frequencies 79,59 e 20,41%. The genotype AA was not found in the analyzed group. The high frequency of the genotype GG is in agreement of the data. It was not possible to find any alteration on ADIPOQ and STATH genes. And also it was not possible to make any correlation between the severity of the CF disease and the genes TNFa, STATH and ADIPOQ between the analyzed regions.
Doutorado
Ciencias Biomedicas
Doutor em Ciências Médicas

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Mekus, Frauke. "Cystic fibrosis as a genetically complex disease Cystische Fibrose: eine genetisch komplexe Erkrankung /." [S.l.] : [s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=959242287.

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Dentini, Priscila. "Complexo Burkholderia cepacia em pacientes com fibrose cística em um Centro de Referência no Brasil = identificação, prevalência e importância clínica." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/309992.

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Orientador: José Dirceu Ribeiro
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Objetivos: Determinar a prevalência da colonização/infecção pelo Complexo Burkholderia cepacia (CBc) e os respectivos genomovares em pacientes com fibrose cística (FC) e comparar os indicadores clínicos, nutricionais, tomográficos e funcionais de gravidade da lesão pulmonar em dois grupos de pacientes: GI: pacientes colonizados/infectados pelo CBc e GII: pacientes sem colonização/infecção pelo CBc, com a finalidade de avaliar o impacto deste microrganismo na deterioração pulmonar. Métodos: Foi realizado um estudo clínico-laboratorial, prospectivo, com 222 pacientes com FC, acompanhados nos ambulatórios pediatria e adultos da UNICAMP. Os pacientes foram divididos em 2 grupos: GI (n=50) e GII (n=134). Os microrganismos foram identificados por meio de testes bioquímicos convencionais, pelo Vitek2®Compact, PCR do gene recA, e nested-PCR com primers espécie-específicos. O seqüenciamento do gene recA foi realizado para cepas com PCR inconclusivas. Os pacientes foram classificados pelo escore clínico de Schwachman e as medidas de peso/idade, estatura/idade e IMC/idade foram utilizadas para avaliar o estado nutricional. As alterações tomográficas foram classificadas pelo escore de Bhalla e a função pulmonar foi avaliada por espirometria. Os dados foram comparados entre os grupos com a finalidade de avaliar o impacto do CBc na lesão pulmonar. Resultados: A prevalência do CBc foi de 22,5% e dos genomovares: Bukholderia multivorans (30,0%), seguido de Burkholderia cepacia (24,0%), Burkholderia cenocepacia IIIA (10,0%), Burkholderia cenocepacia IIIB (2%) e Burkholderia vietnamiensis (2,0%). No grupo I, 26,0% dos pacientes estavam infectados, 18,0% apresentaram colonização transitória e 56,0% colonização intermitente pelo CBc. Não houve diferença estatística na média de pontos do escore de Schwachman (p=0,07), nem na classificação da gravidade (p=0,611), porém houve diferença nas variáveis: estado nutricional (p=0,020) e atividade geral (p=0,026). Houve diferença estatística na média de pontos do escore de Bhalla (p=0,04) e entre os parâmetros: gravidade da bronquiectasia (p=0,007), espessamento peribrônquico (p=0,013), extensão das bronquiectasias (p=0,010), generalidades da árvore bronquial (p=0,020). O teste de função pulmonar mostrou: CVF(%) (p=0,076), VEF1(%) (p=0,066), FEF25-75% no (p=0,312) e VEF1/CVF (p=0,312). Classificação dos distúrbios ventilatórios: DVO no GI=4,8% e GII=23,8%, DVR no GI e GII=9,5%, DVM no GI=19,0% e GII=1,6% e DVM com CVF reduzida no GI=47,6% e GII=30,2%. Na avaliação nutricional houve diferença significante entre as médias de peso(kg) e estatura(cm) (p=0,02). Conclusões: A prevalência do CBc em nosso centro é significativamente superior aos dados apresentados pela literatura nacional e internacional. A maior prevalência da Burkholderia multivorans difere da maioria dos estudos. Há a suspeita de que possa ter ocorrido infecção cruzada entre os pacientes ou que seja uma característica regional. Os escore de Shwachman, escore de Bhalla, espirometria e dados nutricionais mostraram que o CBc tem sério impacto na deterioração pulmonar e na piora clínica. Os métodos fenotípicos são úteis para a identificação presuntiva do CBc. O Vitek® apresentou boa acurácia na identificação do CBc, porém com alguns erros decorrentes de limitações do método/equipamento. O PCR, nested-PCR e seqüenciamento do gene recA apresentaram boa especificidade na identificação do CBc e dos genomovares, entretanto, ainda ocorrem algumas limitações, decorrentes da variedade genotípica, sendo necessária a utilização de métodos mais abrangentes, como o MSLT
Abstract: Objectives: Determine the Burkholderia cepacia complex (BCC) colonization/infection and genomovar prevalence in cystic fibrosis patients and compare the clinical, tomographic and functional severity indicators of lung injury in two groups of patients: GI - patients colonized or infected with BCC and GII - patients without BCC colonization or infection, with the aim of assessing the impact of this microorganism in pulmonary deterioration. Methods: A clinical-laboratory and prospective study was conducted with 222 CF patients seen in the CF outpatient (pediatrics and adults) in UNICAMP. Patients were divided into two groups: GI (n = 50) and GII (n = 134). Microorganisms were identified by conventional biochemical tests, Vitek2®Compact, recA-PCR and recA-nested-PCR with species-specific primers. The recA gene sequencing was performed for strains with inconclusive PCR reactions. Patients were classified by Schwachman's clinical score and measures of weight/age, height/age and BMI/age were used to assess nutritional status. The tomography changes were classified by Bhalla's score and lung function was assessed by spirometry. Data were compared between groups with the aim of assessing the CBC impact in lung injury. Results: The BCC prevalence was 22.5% and the most prevalent genomovars was: Bukholderia multivorans (30.0%), followed by Burkholderia cepacia (24.0%), Burkholderia cenocepacia IIIA (10.0%), Burkholderia cenocepacia IIIB (2%) and Burkholderia vietnamiensis (2.0%). In group I, 26.0% of patients were infected, 18.0% had transient colonization and 56.0% intermittent colonization by BCC. There was no statistical difference in the average point of Schwachman's score (p = 0.07) or in the severity classification (p = 0.611) but had differences in variables: nutritional status (p = 0.020) and general activity (p = 0.026). In the average point Bhalla's score was statistical difference (p = 0.04) and between the parameters: severity of bronchiectasis (p = 0.007), peribronchial thickening (p = 0.013), extent of bronchiectasis (p = 0.010), general the bronchial tree (p = 0.020). The pulmonary function test showed: FVC (%) (p = 0.076), FEV1 (%) (p = 0.066), FEF25-75% (p = 0.312) and FEV1/FVC (p = 0.312). Respiratory disorders classification: DVO in GI and GII = 4.8% = 23.8%, DVR in GI and GII = 9.5%, DVM in GI and GII = 19.0% = 1.6% and with DVM FVC decreased in GI and GII = 47.6% = 30.2%. Nutritional assessment was significant difference between the mean weight (kg) and height (cm) (p = 0.02.) CCoonncclluussiioonnss:: The BCC prevalence in our center is significantly higher than the dates provided by national and international literature. The increased Burkholderia multivorans prevalence differs from the most studies. It is suspected that may have been cross-infection between patients or is a regional characteristic. The Shwachman's and Bhalla score, spirometry and nutritional data showed that the BCC has serious impact on the deterioration and worsening pulmonary clinic. The phenotypic methods are useful for the presumptive BCC identification. The Vitek2®Compact showed good accuracy in BCC identification of, but with some errors due to limitations of the method/equipment. PCR, nested-PCR and recA sequencing showed good specificity in BCC genomovars identifying, however, there are still some limitations, stemming from different genotype, being necessary to use more comprehensive methods, such as the MSLT
Mestrado
Saude da Criança e do Adolescente
Mestre em Saude da Criança e do Adolescente

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Fernandes, Flávia Ferreira. "ELF (Enhanced Liver Fibrosis) como marcador não invasivo de fibrose hepáticana hepatite C crônica." Universidade do Estado do Rio de Janeiro, 2014. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=8773.

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A fibrose hepática é o aspecto mais relevante e o mais importante determinante de morbimortalidade na hepatite C crônica (HCC). Historicamente, a biópsia hepática é o método de referência para avaliação da fibrose causada pela HCC, apesar de apresentar limitações. O estudo de marcadores não invasivos, que possam obviar a necessidade da biópsia, é uma área de constante interesse na hepatologia. Idealmente, a avaliação da fibrose hepática deveria ser acurada, simples, prontamente disponível, de baixo custo e informar sobre o prognóstico da patologia. Os marcadores não invasivos mais estudados são a elastografia hepática transitória (EHT) e os laboratoriais. A EHT já foi extensamente validada na HCC e está inserida na rotina de avaliação destes pacientes. Dentre os laboratoriais, existem diversos testes em continua experimentação e, até o momento, nenhum foi integrado à prática clínica no Brasil, embora já aplicados rotineiramente em outros países. O Enhanced Liver Fibrosis (ELF), um teste que dosa no soro ácido hialurônico, pró-peptídeo amino-terminal do colágeno tipo III e inibidor tissular da metaloproteinase 1, tem se mostrado bastante eficaz na detecção de fibrose hepática significativa e de cirrose na HCC. Neste estudo o ELF teve o seu desempenho avaliado em relação a biópsia hepática e demonstrou apresentar boa acurácia na detecção tanto de fibrose significativa quanto de cirrose. Na comparação com a EHT apresentou acurácia semelhante para estes mesmos desfechos, com significância estatística. No entanto, foi observada uma superestimação da fibrose com a utilização dos pontos de corte propostos pelo fabricante. Este achado está em acordo com a literatura, onde não há consenso sobre o melhor ponto de corte a ser empregado na prática clínica. Com a ampliação da casuística foi possível propor novos pontos de corte, através da análise clássica, com a biópsia hepática como padrão ouro. O resultado obtido vai ao encontro do observado por outros autores. Em seguida, os novos pontos de corte do ELF foram reavaliados sem que a biópsia hepática fosse a referência, através da análise de classes latentes. Mais uma vez o ELF apresentou bom desempenho, inclusive com melhora de suas sensibilidade e especificidade em comparação com a análise clássica, onde a biópsia hepática é a referência. Assim sendo, é possível concluir que o ELF é um bom marcador não invasivo de fibrose hepática. No entanto, para detecção de fibrose significativa e cirrose, deve ser considerada a aplicação na prática clínica dos novos pontos de corte aqui propostos.
Liver fibrosis is the most relevant issue concerning chronic hepatitis C (CHC) and determines its prognosis. Historically, liver biopsy has been the reference method for evaluating fibrosis related to CHC, though it presents many drawbacks. There is a continuing interest in the development of non invasive markers capable of replacing liver biopsy. The ideal surrogate for fibrosis evaluation should be accurate, simple, low cost and yield prognostic information. So far, the most well known non invasive methods are transient hepatic elastography (TE) and laboratory panels. TE has already been extensively validated and is integrated in patients routine. There is plenty of laboratory panels in continuing evaluation and some are already integrated in daily practice abroad. In Brasil, until the present moment, it is not a reality. Enhanced Liver Fibrosis (ELF) panel comprises the serum concentration of hyaluronic acid, tissue inhibitor of matrix metalloproteinases-1, and aminoterminal propeptide of type III procollagen and has demonstrated good performance in detecting significant fibrosis and cirrhosis in CHC patients. In the present study ELF had its performance evaluated against liver biopsy and obtained satisfactory accuracy in detecting significant fibrosis and cirrhosis. In comparison to TE no statistically significant diference was observed, for the same endpoints mentioned before. However, the application of manufacturers cutoff points produced overestimation of fibrosis stages. These findings are in accordance with other authors results, in that there is no consensus so far on the most adequate cutoff points for main clinical end points. Enlarging the data permited calculating new cutoff points, through the classical statistical approach, using liver biopsy as the gold standard. The results once more matched those published in literature. Following this, the ELF new cutoff points were evaluated in a statistical modeling where there are no gold standards, the latent classes analysis. Besides showing a satisfactory performance, in this new approach, ELF experimented an improvement in sensitivity and specificity, if compared with the classical analisys, with liver biopsy as reference. ELF panel has a good performance as a noninvasive fibrosis marker. However, new cutoff points need to be applied to improve its performance for the discrimination of different stages of fibrosis in CHC patients.

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Ribeiro, Ana Carolina Prado 1981. "Análise das características clinicopatológicas de displasias fibrosas e fibromas ossificantes centrais envolvendo mandíbula e maxila = estudo colaborativo internacional." [s.n.], 2011. http://repositorio.unicamp.br/jspui/handle/REPOSIP/288415.

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Orientador: Pablo Agustin Vargas
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Resumo: A displasia fibrosa (DF) e o fibroma ossificante central (FOC) fazem parte de um grupo de lesões conhecido como fibro-ósseas benignas (LFOB) e afetam principalmente a maxila, a mandíbula e ossos da região craniofacial. Caracterizam-se pela substituição do tecido ósseo normal por uma matriz de tecido conjuntivo fibroso com níveis variados de material mineralizado. As DFs e os FOCs costumam apresentar características clínicas e histopatológicas similares, entretanto, possuem padrões distintos de progressão e comportamento biológico. Portanto é muito importante fazer a distinção diagnóstica entre estas lesões. Este trabalho teve como objetivos analisar e comparar as características demográficas, clínicas, imaginológicas e histopatológicas de pacientes diagnosticados com DFs e FOCs. Foi realizada uma análise retrospectiva internacional e multi-institucional que selecionou 68 casos de DF e 37 casos de FOC e permitiu o estudo de características clinicopatológicas. As DFs (n=41; 60,2%) e os FOCs (n=24; 64,9%) foram mais comuns em pacientes do gênero feminino na segunda e terceira década de vida. As DFs acometeram preferencialmente a maxila (n=38; 56%) e os FOCs a mandíbula (n=23; 62,2%). Com relação aos aspectos imaginológicos, as DFs apresentaram-se predominantemente como lesões radiopacas com limites mal definidos e os FOCs como lesões radiolúcidas bem delimitadas. Microscopicamente, foi possível evidenciar continuidade do osso lesional com a cortical óssea de revestimento nas DFs e, interessantemente, um fenômeno de separação entre as trabéculas ósseas lesionais e o estroma adjacente também foi evidente nas DFs. Nos FOCs, foi possível evidenciar a descontinuidade da lesão com a cortical óssea de revestimento externo e a presença de estruturas semelhante ao cemento. Em conclusão, o diagnóstico de DF e FOC deve ser realizado a partir da correlação das características clínicas, imaginológicas e histopatológicas. No entanto, foi possível observar algumas características peculiares em cada uma das lesões, o que poderá auxiliar o diagnóstico e consequentemente favorecer o tratamento dos pacientes acometidos por estas patologias ósseas
Abstract: Fibrous dysplasia (FD) and ossifying fibroma (OF) comprehend a group of benign fibro-osseous lesions (BFOL) which mainly affects the maxilla, mandible and craniofacial bones. They are characterized by the replacement of normal bone tissue by a matrix of fibrous connective tissue with varying degrees of mineralization. Both lesions frequently share clinical and microscopic features and the final diagnose require a combined analysis of clinical, radiologic and histological data. There might be significant cosmetic and functional impairment despite having a distinct pattern of progression and biological behavior, therefore, it is important to distinguish them from each other at the final diagnose. This research focused on the study and comparison of the demographic, clinical, imaging and microscopic aspects of patients with FD and OF, at the moment of the diagnostics. A retrospective multiinstitucional research was conducted in which there were 68 FD cases and 37 of OF. Characteristics such as gender, age and anatomic site of the tumor samples were obtained from the medical records. FDs (n=41; 60,2%) and OFs (n=24; 64,9%) were more frequently detected in female patients who were at the second or third decade of life. The maxilla was more prominently affected among the FD cases (n=38; 56%) contrasting to the prevalence of the mandible in the OF cases (n=23 62.2%). According to the radiographic aspects, FDs frequently presented as radiopaque lesions, with ill-defined limits, and OFs had well defined margins and were radiolucid. Microscopically, a continuity of the lesion with the bone cortical was evident in the FDs, as well as a separation phenomenon between the bone trabeculae and the surrounding connective tissue of the adjacent stroma. In OFs, the discontinuity of the lesion with the bone cortical was noticed, so were the presence of cement-like structures. In conclusion, the diagnose of FD and OF must be done based on the sum of the clinical, radiographic and microscopic features, although it was possible to observe a few peculiar characteristics in each one of them, which might serve as a diagnostic tool and therefore improve the treatment of the patients
Doutorado
Patologia
Doutor em Estomatopatologia

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Pasinetti, Nadia. "Wound healing signals mediated by Rho/ROCK activation in response to radiotherapy and consequences fot treatmeny of late damage within normal tissues." Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-00714360.

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Radiotherapy is the second most important treatment modality after surgery in the treatment of cancer. Recent technical advancements, such as intensity-modulated radiation therapy (IMRT) or image-guided radiation therapy (IGRT), combined with new targeted drugs have significant promise for therapeutic outcome. However radiation treatment could result in disabling normal tissue injury and in the development of progressive fibrosis in a subset of sensitive patients and in long-term cancer survivors. The main feature of tissue fibrosis is excessive accumulation of abnormal and cross-linked collagen mainly composed of fibrillar and immature extracellular matrix (ECM) components.The organs that can be affected by this phenomenon are liver, skin, intestine, kidneys and lungs. From a clinical point of view, fibrosis can be seen as an irreversible condition, without solution. We and others recently showed that beside the activation of the canonical TGF-β/Smad pathway, other intracellular signaling cascades including the Rho/ROCK pathway are switched on in fibrotic tissues. Interestingly, the Rho/ROCK pathway seems differentially activated in radiation-induced intestinal fibrosis, thereby providing a rationale for a specific, targeted anti-fibrotic strategy. Pharmacological inhibition of Rho using statins indeed prevent and even reverse intestinal radiation fibrosis.In our studies, we showed the role of Statin (Pravastatin e Simvastatin) and a specific inhibitor ROCK inhibitors (Y-27632) in a mice model of pulmonary induced-fibrosis obtained by a pharmacological approach (Bleomycin - BLM). Indeed, we developed a model of lung fibrosis by complete irradiation of chest and tested Pravastatin action. Confirmation of the involvement of Rho/ROCK/CTGF pathway in lung fibrosis are shown by immunohistochemistry: Pravastatin-treament normalized the expression of three markers: RhoB, TGF-RII and CTGF.Then, in models of radiation induced gut and lung fibrosis, we analysed, from a immunohistological point of view, the underlying mechanisms of the antifibrotic action of Pravastatin via MMP2-TIMP2 axis. Interestingly we found a different impact on fibrolysis when Pravastatin was administered preventively or curatively.Finally, in vitro, we investigate by zymography the expression of Gelatinases (MMP2 and MMP9) in primary lung fibroblasts cultures exposure at the different radiation and Pravastatin doses. Metalloproteases would appear to be in turn involved in pro-fibrolytic mechanisms induced by statin.The multiplicity of actors involved in the pathogenesis of fibrotic lesions explains why the definition of an effective therapeutic strategy is so complex.Researches in mechanistic processes of normal tissue damage paved the way for new therapeutic approaches. These new targets include reduction of vascular activation, inflammation and thrombosis and new molecular targets definition. Effective strategies are multiple on preclinical models, but numerous efforts have to be made to achieve the complicated goal of protection of normal tissues from the side effects of radiation therapy.

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Titinchi, Fadi. "Ossifying fibroma : a clinical and radiological study at the University of the Western Cape Oral Health Centre." Thesis, University of the Western Cape, 2016. http://hdl.handle.net/11394/5258.

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Magister Scientiae Dentium - MSc(Dent)
Ossifying fibroma (OF) is the most frequent of the three fibro-osseous lesions of the jaws. It occurs mostly in patients between the age of 20 and 40 years. Females are more commonly affected than males. Clinically, OF usually presents as a painless expansive intra-bony mass. Swelling and pain may be present in some cases while some lesions are discovered incidentally. Radiographically, OF is usually well-defined and unilocular or multilocular. Early lesions present as well-defined radiolucency that are small in size. Over time, the lesions tend to enlarge in size and become mixed radiolucent-radiopaque and finally become completely radiopaque. The aim of this study was to determine the clinical and radiological features of ossifying fibroma presenting at the Departments of Maxillo-Facial and Oral Surgery and Diagnostics and Radiology, University of the Western Cape Oral Health Centre as well as to assess its management and recurrence patterns. A retrospective case series analysis was performed of all histopathologically diagnosed ossifying fibroma cases available at the Departments of Maxillo-Facial and Oral Surgery and Diagnostics and Radiology at the Faculty of Dentistry, University of the Western Cape from 1976-2014. Patient's age, gender and ethnicity were recorded. The clinical presentation of the lesion as well as the history was analyzed. Radiographic features including density, size, shape, location, locularity and its effect on adjacent structures was noted. Management of each case and follow-up was also documented. A total 61 cases were included in the study. The majority of patients were females (63.9%) and below 40 years of age (73.9%). Few cases were symptomatic (29.5%) with an average period 22 months from first symptoms to presentation. The mandibular posterior region was most affected (55.5%) while larger lesions occurred more frequently in younger patients. Majority of lesions were radiopaque (49.2%) and had well-defined margins (93.6%). Most cases were managed by surgical curettage (68.2%). Following an average follow-up period of 20 months only one case recurred (recurrence rate =6.7%). In conclusion, the majority of the clinical and radiographic findings of ossifying fibroma were similar in South African patients as those of other populations. Differences include that the lesions in this population were more radio-opaque and larger in size than in the reported literature. Surgical curettage is an acceptable management protocol with low rate of recurrence.

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Aguiar, Kátia Cristina Alberto 1979. "Convivendo com a fibrose cística = visão dos adolescentes atendidos em um centro de referência = Living with cystic fibrosis: vision of adolescents attended in a reference center." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/309985.

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Orientador: José Dirceu Ribeiro
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Introdução: As características emocionais da Fibrose Cistica na adolescência, na visão pessoal de quem a vivencia é um tema pouco referenciado na literatura científica. A adolescência é um período por si próprio, carregado de possibilidades de conflitos emocionais. A associação com uma doença crônica e seu manejo, nesta etapa da vida pode maximizar estes conflitos. Objetivo: O presente estudo teve como objetivo compreender como é para o adolescente vivenciar a fibrose cística (FC), doença que necessita tratamento diário por toda vida e participação ativa do próprio paciente. A pesquisa estudou como os adolescentes convivem com a doença, quais suas necessidades e como eles percebem o futuro. Método: Utilizou-se o método clinico qualitativo, empregando-se a técnica de entrevista semi estruturada de questões abertas. Quarenta e dois pacientes aceitaram participar do estudo. Suas falas foram divididas em oito categorias e dez subcategorias que descrevem suas respostas em relação á vivência com a FC. Resultados: Os resultados evidenciam que os adolescentes apresentam sentimentos de medo da morte, vergonha, raiva, perda da liberdade, da escola, dos amigos e da confiança em si mesmo, necessidade de ajustamento ás rotinas diferenciadas, necessidade de igualdade e aceitação, perspectiva negativa e positiva em relação ao futuro e expectativas em relação ao futuro com FC. Conclusões: Os sentimentos relatados são influenciados pela doença e dificultam a maneira como eles lidam com ela. Espera-se que a compreensão dessas vivências possa estimular estudos longitudinais nos centros que atendem pacientes com FC
Abstract: Introduction: The emotional characteristics of a chronic disease in adolescence, in a personal vision of those who experience it, is a topic not much referenced in the scientific literature. Adolescence by itself is a life period full of emotional conflict possibilities. The association with a chronic disease and how to cope with it at this specific stage of life can increase these conflicts. Objective: The present research goal is to understand how adolescents deal with cystic fibrosis (CF), an illness which needs a diary treatment for a lifetime and active patient participation. It highlighted how adolescents live with the disease, what are their needs and what they expect from the future. Method: A clinical qualitative method was used employing a semi structured interview technique of open questions. A total of forty two patients accept to be involved in the study. Their speeches were divided into eight categories that describe the patient's answers according to how adolescents cope with CF. Results: Results highlighted that adolescents show feelings like fear of death, shame, rage, lost of freedom, school year, friend and self-confidence, needs of adjustment to differentiated routines, needs of equality and acceptance, negative perspective for the future, positive perspective for the future and expectations about the future with CF. Conclusions: Such feelings are influenced by the disease and input barriers on how adolescents cope with it. The comprehension of how to deal with a chronic disease should stimulate longitudinal studies at all centers that assist CF patients
Mestrado
Saude da Criança e do Adolescente
Mestra em Ciências

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Meziani, Lydia. "Study of Interaction Between the Inflammatory Response and Radiation-Induced Fibrosis." Thesis, Paris 11, 2015. http://www.theses.fr/2015PA11T041.

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La fibrose radio-induite (FRI) est une complication tardive de la radiothérapie souvent associée à une réponse inflammatoire chronique et à un infiltrat de macrophages. Aujourd’hui, les macrophages sont pressentis comme des médiateurs cellulaires important dans le processus de fibrose mais leur rôle n’a jamais été étudié dans le contexte de la FRI. Dans une précédente étude nous avions montré que l’irradiation (IR) induit une polarisation M1 des macrophages cardiaques après irradiation de souris ApoE-/- et est associée un score de fibrose élevé, ce qui suggérait que la polarisation des macrophages pourrait contribuer à la fibrogénèse radio-induite. Afin de valider cette hypothèse, nous avons cherché à caractériser le rôle des macrophages dans la FRI en utilisant un modèle classique de fibrose pulmonaire chez la souris C57Bl/6 induit après IR thoracique à 16Gy. Nous avons caractérisé les phénotypes et la fonction des macrophages alvéolaires (MA) et interstitiels (MI). Durant la phase précoce, les résultats montrent une déplétion des MA accompagnée de la sécrétion de CXCL1, MCP-1 et de MCSF. Cette déplétion est suivie d’une repopulation suite au recrutement et à la prolifération des monocytes/macrophages d’origine médullaire. La nouvelle population de MA présente une polarisation hybride accompagnée d’une augmentation simultanée de la sécrétion de cytokines Th1 et Th2. Durant la phase tardive les MI présentent une polarisation de type M2 accompagnée d’une diminution des cytokines Th1 et d’une augmentation de cytokines Th2 dans le lysat tissulaire. Nous avons ensuite cherché à caractériser la contribution des MA hybrides vs MI M2 dans le processus de fibrose. Nous avons montré que contrairement au MA hybrides, les MI M2 étaient capables d’induire l’activation des fibroblastes in vitro et l’expression de TGF-β1. De plus, la déplétion des MA hybrides avec une administration intranasale de clodronate exacerbe la FRI et induit l’augmentation de l’infiltrat de MI M2. Ensuite, nous nous somme interrogés à la contribution du processus de fibrose dans la polarisation des macrophages. Après 24h de coculture entre fibroblastes irradiés et macrophages pulmonaires non irradiés, une sécrétion de cytokines telles que M-CSF et TIMP-1 qui pourraient stimuler l’activation des fibroblastes est observée. De plus, l’inhibition de la FRI avec de la pravastatine montre que l’inhibition de la fibrose est accompagnée d’une augmentation des MI M1 et d’une diminution des MI M2 dans le poumon. En résumé, nos résultats montrent une contribution opposée des Macrophages Alvéolaires et des Macrophages Interstitiels dans le processus de fibrose radio-induite ainsi qu’une contribution du processus de fibrose dans le type d’activation des Macrophages interstitiels formant ainsi une boucle d’activation fibrogénique chronique
Radiation-induced fibrosis (RIF) is a delayed complication of radiotherapy often associated with chronic inflammatory process and macrophage infiltration. Nowadays, macrophages are suggested to be important cellular contributors to fibrogenic process, but their implication in the context of RIF has never been investigated. In a previous study we have shown that irradiation (IR) induced the polarization of cardiac macrophages into M1 in ApoE-/- mice and was associated with a high fibrosis score in ApoE-/- mice, suggesting that macrophage polarization could drive tissue sensitivity to ionizing radiation. This observation prompted us to investigate the role of macrophages in RIF using a classical experimental model of lung fibrosis developed in C57Bl/6 mice after 16Gy thorax-IR. We profiled both alveolar macrophages (AM) and interstitial macrophages (IM). During the acute phase we found AM depletion associated with CXCL1, MCP-1 and M-CSF secretion, followed by a repopulation phase mediated by recruitment and proliferation of monocytes/macrophages from the bone marrow. Interestingly, the newly recruited AM exhibited a yet never described hybrid polarization (M1/M2), associated with the up-regulation of both Th1 and Th2 cytokines. At delayed times points, IM were M2-polarized and associated with downregulation of Th1 cytokines and upregulation of Th2 cytokines in tissue lysates. These results suggest a differential contribution of hybrid AM vs M2 IM to fibrogenesis. Interestingly, in contrast to activated hybrid AM, activated M2 IM were able to induce fibroblast activation in vitro mediated by an enhanced TGF-β1 expression. Therefore, specific depletion of hybrid AM using intranasal administration of clodrosome increased RIF score and enhanced M2 IM infiltration. We next evaluated if the fibrogenic process can in turn affect macrophage polarization. Interestingly, after coculture of irradiated fibroblast with non-irradiated pulmonary macrophages, secretion of cytokines such as M-CSF and TIMP-1, which can stimulate macrophage activation, was observed. Furthermore, RIF inhibition using pravastatin treatment showed that fibrosis inhibition was associated with a decrease in M2 IM accompanied by an increase in M1 IM, but had no effect on polarization of AM. These present study shows a dual and opposite contribution of alevolar versus intertitial macrophages in RIF and the contribution of the fibrogenic process to IM polarization, resulting thereby in a chronical fibrogenic loop

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Buonafine, Mathieu. "Rôle de la Neutrophil Gelatinase-Associated Lipocalin dans les effets cardiovasculaires et rénaux de l'activation du récepteur minéralocorticoïde. Spécificité et mécanismes d’action." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066216/document.

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L’activation du récepteur minéralocorticoïde par l’aldostérone joue un rôle majeur dans le remodelage cardiovasculaire en participant à l’hypertension, à la fibrose et à l’inflammation. Notre laboratoire a récemment mis en évidence le rôle critique de la Neutrophil Gelatinase-Associated Lipocalin (NGAL), une nouvelle cible du MR, dans les effets délétères de son activation. Afin de mieux comprendre le rôle de NGAL dans ces effets, nous avons réalisé différents modèles profibrotiques chez des souris présentant une invalidation génique totale de NGAL ou une déplétion de NGAL dans leurs cellules immunitaires spécifiquement. Nos résultats démontrent un rôle primordial de la NGAL produite par les cellules immunitaires dans les lésions cardio-rénales induite par l’activation du MR. De plus, nos données suggèrent que le contexte inflammatoire pourrait être un élément déterminant de l’implication physiopathologique de NGAL
Mineralocorticoid receptor (MR) activation by aldosterone plays a major role in cardiovascular remodeling by participating in hypertension, fibrosis and inflammation. Our group has recently evidenced a critical implication of the Neutrophil Gelatinase-Associated Lipocalin (NGAL), a new target of the MR, in the deleterious effects of its activation. In order to better understand the role of NGAL in these effects, we carried out several models of fibrosis in mice presenting a genetic invalidation for NGAL or in mice lacking NGAL in their immune cells specifically. Our results demonstrate that NGAL produced by immune cells plays a pivotal role in MR mediated cardiac and renal damage. Furthermore, our data suggest that inflammatory context could represent a key factor in the pathophysiological implications of NGAL

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Bantsimba-Malanda, Claudie. "Cellules dendritiques et fibrose pulmonaire : étude sur un modèle animal de fibrose induite par la bléomycine chez la souris." Thesis, Paris Est, 2009. http://www.theses.fr/2009PEST0059.

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Les cellules dendritiques, puissantes cellules présentatrices d'antigène, jouent un rôle-clé dans l'initiation et la régulation des réponses immunitaires et inflammatoires (Lipscomb et al., 2002). Elles sont présentes à l'état de cellules immatures dans la plupart des muqueuses, disséminées dans le tissu interstitiel et les épithéliums. Elles sont chargées de capter les antigènes exogènes, de les apprêter et de migrer vers les organes lymphoïdes pour les présenter aux lymphocytes T spécifiques. Au cours de cette migration, elles acquièrent les caractéristiques des cellules dendritiques matures présentes dans les organes lymphoïdes (expression forte des molécules HLA de classe II et des molécules de costimulation CD40, CD80, CD83, CD86). Les cellules dendritiques sont présentes dans le poumon normal (Vermaelen et al., 2005). Elles sont impliquées dans la physiopathologie de différentes maladies pulmonaires et jouent un rôle pathogénique essentiel dans certaines d'entre elles comme l'histiocytose langerhansienne ou l'asthme (Tazi et al ., 2000; Lambrecht et Hammad, 2003). Leur rôle au cours des processus fibrosants n'a cependant jamais été évalué. En effet, contrairement à d'autres cellules présentatrices d'antigènes que sont les macrophages, dont le rôle dans la réaction fibrosante est clairement établi (Agostini et al ., 1997), le rôle des cellules dendritiques au cours des processus de réparation alvéolaire n'a pas été étudié. Notre travail visait à étudier in vivo le rôle des cellules dendritiques au cours de la fibrose pulmonaire sur un modèle animal par induction d’une fibrose à la bléomycine chez la souris. Les premières étapes du projet ont consisté à caratériser par cytométrie en flux la présence de cellules dendritiques dans le poumon des animaux 3, 7 et 14 jours après instillation intratrachéale de bléomycine. L'étude s'est poursuivie par une caractérisation du phénotype de surface des cellules dendritiques en cherchant à préciser leur état d’activation et de maturation. L'étape suivante a consisté à rechercher par RT-QPCR les principales chimiokines responsables du recrutement des cellules dendritiques. Les résultats montrent une augmentation du nombre des cellules dendritiques CD11c+ / CMH II+ infiltrant le poumon dès J7, avec une sous-population de cellules activées exprimant fortement les molécules CMH II. Ces résultats sont corroborés par une augmentation de la population cellulaire totale du broyat de poumon dès J3, ainsi que par une augmentation de la cellularité totale et du nombre de cellules inflammatoires dans les lavages bronchoalvéolaires (LBA) à J7 et J14. L'étude a été complétée par une caractérisation plus approfondie du phénotype de surface des cellules dendritiques en cherchant à préciser leur état d’activation/maturation. [...]
Dendritic cells (DCs), potent antigen-presenting cells, play a key role in the initiation and regulation of immune and inflammatory responses (Lipscomb et al., 2002). Immature DCs are present in the most of mucous membranes, disseminated in the interstitial tissue and the epithelia. They are able to deal with exogenous antigens, to process them and to migrate to lymphoid organs and to present them to T lymphocytes. During their migration, they have the characteristics of mature DCs in lymphoid organs (higher expression of MHC class-II molecules and costimulation-molecules (CD40, CD80, CD83, CD86). Dendritic cells are present in the normal lung (Vermarlen et al., 2005). They are implicated in the pathophysiology of different pulmonary diseases and play a crucial pathogenic role in some of them like Langerhan’s cell Histiocytosis or asthma (Tazi et al., 2000; Lambrecht et Hammad, 2003). However, their role in the fibrosing process has never been studied. In fact, the role of macrophages (other antigen presenting cells (APCs)) in fibrosing reaction has been clearly established (Agostini et al., 1997), but DCs function during the alveolar healing process has not been studied. The purpose of this thesis is to study the in vivo role of DCs in bleomycin-induced pulmonary fibrosis in mice. The first step of this project is to demonstrate by flow cytometry the presence of DCs in the lung of these animals 3, 7 and 14 days after intratracheal bleomycin instillation. We continued our research with the surface phenotypic characterization of DCs identifying their activation state and maturation. The next step consists to search the main chemokines which are responsive for dendritic cells recruitment by RT-qPCR. Our results show an increase of CD11c+ / MHC class II+ DCs number infiltrating the lung after D7, with an activated cell subpopulation which strongly express MHC class II molecules. The results are corroborated by an increase of the total cell population in the lung homogenate after D3 and by an increase of the total cellularity and inflammatory cells number in broncho-alveolar lavages (BAL) at D7 and at D14. This study was completed by the surface phenotypic characterization of DCs identifying their activation state and maturation. [...]

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Machado, Luciana Araújo Lima. "Jovens de Fibra: a Visão sobre o Tratamento de Fisioterapia." Instituto Fernandes Figueira, 2012. https://www.arca.fiocruz.br/handle/icict/4098.

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Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Departamento de Ensino. Programa de Pós-Graduação em Saúde da Criança e da Mulher. Rio de Janeiro, RJ, Brasil
A adequação das necessidades dos jovens que sofrem com adoecimento crônico às demandas do tratamento prolongado foi sempre um desafio para a equipe de saúde, o paciente e sua família. Nesse cenário, a fisioterapia compõe a complexa rede de cuidados na rotina dos adolescentes com Fibrose Cística (FC). O objetivo desse estudo consistiu na análise da vivência do adoecimento crônico dos adolescentes com Fibrose Cística, em relação ao tratamento de fisioterapia. Para tanto, a metodologia utilizada foi baseada na análise temática obtida por meio de entrevistas semiestruturadas com os adolescentes de FC. Os sujeitos tinham entre 10 a 18 anos e eram acompanhados pelo setor de Pneumologia do Instituto Fernandes Figueira. Os resultados apontaram, a partir dos relatos, que a fisioterapia limita a realização de outras atividades de interesse dos jovens, em virtude da disciplina e regularidade do tratamento. A realização dos exercícios era geralmente desagradável e foi identificada como um momento de enfrentamento da doença. Muitos sujeitos desconheciam a função das técnicas aplicadas durante o atendimento fisioterapêutico e, por vezes, não viam sentido no que foi proposto. Na ótica dos adolescentes entrevistados, a fisioterapia apareceu como uma intervenção pontual no cotidiano e não relacionavam seus benefícios à qualidade de vida. A conduta restrita à técnica e, em muitos casos, a promoção da participação passiva do jovem, dificultavam sua aproximação com o tratamento fisioterapêutico. Discussão: Os diferentes aspectos presentes na vida dos adolescentes com FC influenciam não só o adoecimento crônico, mas também seu tratamento. Considerando a interação entre profissional de saúde - paciente, o fisioterapeuta deve estar atento para o seu papel no processo de tratamento destes sujeitos. Sua atuação deve transcender às questões da doença, priorizando também o bem estar e a vida social dos adolescentes com FC. Sendo assim, o olhar ampliado do fisioterapeuta e a humanização no cuidado com esse público são tão fundamentais quanto a técnica escolhida, consistindo, muitas vezes, em um valioso auxílio para o enfrentamento da doença.
The adequacy of young people needs that suffers with chronic illness to the demands of prolonged treatment has always been a challenge for the health care team, patients and their family. In this context, physiotherapy forms the complex network of health care in the routine of adolescents with Cystic Fibrosis (CF). The aim of this study was the analysis about living with chronic illness through the perspectives of adolescents with Cystic Fibrosis, in relation to physiotherapy treatment. Hence, the methodology applied was based on the thematic analysis obtained through semi-structured interviews with adolescents with CF. Subjects were between 10 and 18 years old and were undergoing treatment at Pulmonology clinic in the Instituto Fernandes Figueira. The results from data collected signify that physiotherapy limits young people to enroll in others activities of their interest, on account of discipline and regularity of the treatment. The exercises regime was normally unpleasant and was shown as a moment of facing their disease. Many subjects did not know about the function of techniques that were applied during physiotherapy assistance, and sometimes, could not make any sense of what was proposed. In the interviewed adolescent’s opinion, physiotherapy was revealed as a punctual intervention in their daily life and its benefits were not related to quality of life. A narrow view of care, and in many cases, an incentive for the young to participate in a submission way, hindered their approach to physiotherapy. Discussion: The different aspects present in the lives of adolescents with CF not only influence chronic illness, but also its treatment. Considering the interaction between health care professional and patient, the physiotherapist must be aware of their role in the organizational of work of these subjects. The actions of this professional should go beyond the issues of disease, also prioritizing the well-being and social life of adolescents with CF. Thus, the physiotherapist’s broader view and humanization care of young people with CF is as important as the chosen technique, consisting often in a valuable aid for facing the disease.
The adequacy of young people needs that suffers with chronic illness to the demands of prolonged treatment has always been a challenge for the health care team, patients and their family. In this context, physiotherapy forms the complex network of health care in the routine of adolescents with Cystic Fibrosis (CF). The aim of this study was the analysis about living with chronic illness through the perspectives of adolescents with Cystic Fibrosis, in relation to physiotherapy treatment. Hence, the methodology applied was based on the thematic analysis obtained through semi-structured interviews with adolescents with CF. Subjects were between 10 and 18 years old and were undergoing treatment at Pulmonology clinic in the Instituto Fernandes Figueira. The results from data collected signify that physiotherapy limits young people to enroll in others activities of their interest, on account of discipline and regularity of the treatment. The exercises regime was normally unpleasant and was shown as a moment of facing their disease. Many subjects did not know about the function of techniques that were applied during physiotherapy assistance, and sometimes, could not make any sense of what was proposed. In the interviewed adolescent’s opinion, physiotherapy was revealed as a punctual intervention in their daily life and its benefits were not related to quality of life. A narrow view of care, and in many cases, an incentive for the young to participate in a submission way, hindered their approach to physiotherapy. Discussion: The different aspects present in the lives of adolescents with CF not only influence chronic illness, but also its treatment. Considering the interaction between health care professional and patient, the physiotherapist must be aware of their role in the organizational of work of these subjects. The actions of this professional should go beyond the issues of disease, also prioritizing the well-being and social life of adolescents with CF. Thus, the physiotherapist’s broader view and humanization care of young people with CF is as important as the chosen technique, consisting often in a valuable aid for facing the disease.

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Felix, Renato Gonçalves [UNESP]. "Contribuição da terapia celular com células tronco em fibrose em ratos." Universidade Estadual Paulista (UNESP), 2013. http://hdl.handle.net/11449/88090.

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A FPI é definida como um tipo de doença intersticial fibrosante crônica, de etiologia desconhecida, limitada aos pulmões e que apresenta padrão histológico de pneumonia intersticial usual. A prevalência da FPI é estimada em aproximadamente 20/100000 nos homens e 13/100000 nas mulheres, sendo que a média da idade quando do diagnóstico é de 67 anos e a sobrevida média é de 2 a 5 anos. Estima‐se cerca de 5 milhões de pessoas afetadas em todo o mundo. O tratamento clínico atual está associado à melhora parcial e transitória com resultados duvidosos ou insatisfatórios. A abordagem cirúrgica da FPI compreende o transplante de pulmão e é raro em decorrência da escassez de doadores e pela limitação de equipes capacitadas para realizar os procedimentos. A terapia celular apresenta‐se como uma alternativa terapêutica com grande potencial de aplicabilidade em fibrose pulmonar. Este estudo tem como objetivo a validação do modelo de fibrose pulmonar induzido pela instilação de bleomicina e a análise da contribuição da terapia celular utilizando a injeção de células‐tronco mesenquimais, alogênicas, obtidas de tecido adiposo para o tratamento de fibrose pulmonar. Foram utilizados 60 ratos machos, albinos, da raça Wistar, com peso médio de 250g com idade de 8 semanas. Foram constituídos 4 grupos experimentais compostos por 15 animais sendo monitorados: peso e o índice de saturação em 3 momentos: D0, D14 e D28. Em D0 foi realizada a instilação da bleomicina na dose de 1,5U/Kg. Em D14 a infusão das células tronco mesenquimais quantificadas e fenotipadas por citometria de fluxo. Em D28 foi realizado o sacrifício dos animais para análise macro e microscópica. A média de tecido adiposo retirado foi de 3,35g sendo que após a dissociação com o uso de colagenase tipo I a contagem celular foi de 5,3 x 104 células...
The IPF is defined as a type of chronic fibrosing interstitial lung disease of unknown etiology, limited to the lungs and that presents histological pattern of usual interstitial pneumonia. The prevalence of IPF is estimated at approximately 20/100000 in men and 13/100000 in women, and the mean age at diagnosis is 67 years and the median survival is 2 to 5 years. It is estimated about 5 million affected people worldwide. The current clinical treatment is associated with transient and partial improvement with equivocal or unsatisfactory. The surgical approach consists of IPF and lung transplantation is rare due to the scarcity of donors and by limiting teams trained to perform the procedures. Cell therapy is presented as an alternative therapy with a potential application in pulmonary fibrosis. This study aims to validate the model of pulmonary fibrosis induced by bleomycin instillation and analysis of the contribution of cell therapy using injection of mesenchymal stem cells, allogeneic, obtained from adipose tissue for the treatment of pulmonary fibrosis. A total of 60 male rats, albino Wistar rats, weighing 250g aged 8 weeks. 4 experimental groups were formed consisting of 15 animals being monitored: weight and saturation index in 3 stages: D0, D14 and D28. In D0 was performed instillation of bleomycin at a dose of 1.5 U / Kg. In D14 infusion of mesenchymal stem cells quantified and phenotyped by flow cytometry. In D28 was the sacrifice of animals for macro and microscopic analyzes. The mean adipose tissue removed was 3.35 g and that after dissociation using collagenase type I cell count was 5.3 x 104 lymphomononuclear cells/g of adipose tissue. These cells were expanded in culture for 21 days Knockout DMEM‐F12 medium added with 10% fetal bovine serum. Three criteria were considered proof of MSC: adhesion to plastic... (Complete abstract click electronic access below)

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Felix, Renato Gonçalves. "Contribuição da terapia celular com células tronco em fibrose em ratos /." Botucatu, 2013. http://hdl.handle.net/11449/88090.

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Orientador: Elenice Deffune
Banca: Lisete Ribeiro Teixeira
Banca: Hugo Hyung Bok Yoo
Resumo: A FPI é definida como um tipo de doença intersticial fibrosante crônica, de etiologia desconhecida, limitada aos pulmões e que apresenta padrão histológico de pneumonia intersticial usual. A prevalência da FPI é estimada em aproximadamente 20/100000 nos homens e 13/100000 nas mulheres, sendo que a média da idade quando do diagnóstico é de 67 anos e a sobrevida média é de 2 a 5 anos. Estima‐se cerca de 5 milhões de pessoas afetadas em todo o mundo. O tratamento clínico atual está associado à melhora parcial e transitória com resultados duvidosos ou insatisfatórios. A abordagem cirúrgica da FPI compreende o transplante de pulmão e é raro em decorrência da escassez de doadores e pela limitação de equipes capacitadas para realizar os procedimentos. A terapia celular apresenta‐se como uma alternativa terapêutica com grande potencial de aplicabilidade em fibrose pulmonar. Este estudo tem como objetivo a validação do modelo de fibrose pulmonar induzido pela instilação de bleomicina e a análise da contribuição da terapia celular utilizando a injeção de células‐tronco mesenquimais, alogênicas, obtidas de tecido adiposo para o tratamento de fibrose pulmonar. Foram utilizados 60 ratos machos, albinos, da raça Wistar, com peso médio de 250g com idade de 8 semanas. Foram constituídos 4 grupos experimentais compostos por 15 animais sendo monitorados: peso e o índice de saturação em 3 momentos: D0, D14 e D28. Em D0 foi realizada a instilação da bleomicina na dose de 1,5U/Kg. Em D14 a infusão das células tronco mesenquimais quantificadas e fenotipadas por citometria de fluxo. Em D28 foi realizado o sacrifício dos animais para análise macro e microscópica. A média de tecido adiposo retirado foi de 3,35g sendo que após a dissociação com o uso de colagenase tipo I a contagem celular foi de 5,3 x 104 células... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The IPF is defined as a type of chronic fibrosing interstitial lung disease of unknown etiology, limited to the lungs and that presents histological pattern of usual interstitial pneumonia. The prevalence of IPF is estimated at approximately 20/100000 in men and 13/100000 in women, and the mean age at diagnosis is 67 years and the median survival is 2 to 5 years. It is estimated about 5 million affected people worldwide. The current clinical treatment is associated with transient and partial improvement with equivocal or unsatisfactory. The surgical approach consists of IPF and lung transplantation is rare due to the scarcity of donors and by limiting teams trained to perform the procedures. Cell therapy is presented as an alternative therapy with a potential application in pulmonary fibrosis. This study aims to validate the model of pulmonary fibrosis induced by bleomycin instillation and analysis of the contribution of cell therapy using injection of mesenchymal stem cells, allogeneic, obtained from adipose tissue for the treatment of pulmonary fibrosis. A total of 60 male rats, albino Wistar rats, weighing 250g aged 8 weeks. 4 experimental groups were formed consisting of 15 animals being monitored: weight and saturation index in 3 stages: D0, D14 and D28. In D0 was performed instillation of bleomycin at a dose of 1.5 U / Kg. In D14 infusion of mesenchymal stem cells quantified and phenotyped by flow cytometry. In D28 was the sacrifice of animals for macro and microscopic analyzes. The mean adipose tissue removed was 3.35 g and that after dissociation using collagenase type I cell count was 5.3 x 104 lymphomononuclear cells/g of adipose tissue. These cells were expanded in culture for 21 days Knockout DMEM‐F12 medium added with 10% fetal bovine serum. Three criteria were considered proof of MSC: adhesion to plastic... (Complete abstract click electronic access below)
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Almeida, Débora de Fátima. "Fibrose pulmonar na paracoccidioidomicose influência do fungo e do hospedeiro na fibrogênese /." Botucatu, 2017. http://hdl.handle.net/11449/151552.

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Orientador: James Venturini
Resumo: Paracoccidioidomicose (PCM) é uma micose sistêmica causada por fungos do gênero Paracoccidioides; suas principais formas clínicas são aguda/subaguda e crônica (FC). Restrita à América Latina, a PCM apresenta alta incidência no Brasil, Colômbia e Venezuela, especialmente entre os trabalhadores rurais. A maioria dos pacientes com a forma crônica da doença, mesmo após tratamento eficaz, apresentam sequelas, incluindo fibrose pulmonar (FP). Os problemas sociais, econômicos e psicológicos desencadeados pela FP são subestimados. Apesar da fibrogênese na PCM ser reconhecida como um processo precoce, seus mecanismos não estão totalmente conhecidos. Assim, o presente estudo tem por objetivo avaliar a influência de componentes dos isolados fúngicos e do hospedeiro sobre fibroblastos pulmonares. Foram utilizados fibroblastos pulmonares humanos da linhagem MRC-5 e fibroblastos pulmonares murinos, isolados de camundongos BALB/c. Fibroblastos foram cultivados in vitro com exoantígenos de isolados das espécies P. brasiliensis (Pb18 e Pb326) e P. lutzii (Pb01, Pb8334 e Pb66); gp43 purificada, e soros de pacientes com FC em diferentes momentos do tratamento (antes do tratamento, cura clínica, cura sorológica e cura aparente). Após 24 horas de cultivo, foram avaliadas a proliferação celular e produção de citocinas e fatores de crescimento por fibroblastos murinos e humanos. Nossos resultados demonstraram que componentes do fungo interferem em fibroblastos pulmonares, pela indução da proliferaç... (Resumo completo, clicar acesso eletrônico abaixo)
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Geyer, Lúcia Bencke. "Limiares auditivos em altas frequências e emissões otoacústicas em pacientes com fibrose cística." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2014. http://hdl.handle.net/10183/98476.

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Introdução: O tratamento dos pacientes com fibrose cística envolve o uso de medicamentos ototóxicos, sendo que os mais frequentemente utilizados são os antibióticos aminoglicosídeos. Devido ao uso frequente deste tipo de medicamento, os pacientes com fibrose cística apresentam risco de desenvolver perda auditiva. Objetivo: o objetivo deste estudo foi avaliar a audição dos pacientes com fibrose cística pela audiometria de altas frequências (AAF) e emissões otoacústicas por produto de distorção (EOAPD). Pacientes e métodos: estudo transversal retrospectivo e prospectivo, incluindo 75 indivíduos, sendo 39 do grupo de estudo e 36 do grupo controle. Foram realizados os exames de AAF (de 250 a 16.000 Hz) e EOAPD. Resultados: o grupo de estudo apresentou limiares na AAF significativamente mais elevados em 250, 1.000, 8.000, 9.000, 10.000, 12.500 e 16.000 Hz. (p=0,004) e maior prevalência de alterações nas EOAPD em 1.000 e 6.000 Hz (p=0,001), com amplitudes significativamente mais baixas em 1.000, 1.400 e 6.000 Hz. Houve associação significativa entre as alterações dos limiares auditivos na AAF com o número de cursos de aminoglicosídeos realizados (p=0,005). Oitenta e três por cento dos pacientes que realizaram mais de 10 cursos de aminoglicosídeos apresentaram perda auditiva na AAF. Conclusão: Um número expressivo de pacientes com fibrose cística que receberam repetidos cursos de aminoglicosídeos apresentou alterações na AAF e EOAPD. realização de 10 ou mais cursos de aminoglicosídeos esteve associada às alterações na AAF.
Introduction: the treatment of patients with cystic fibrosis involves the use of ototoxic drugs, and the most frequently used are the aminoglycoside antibiotics. Due to the frequent use of this drug, cystic fibrosis patients are at risk to develop hearing loss. Objective: the aim of this study was to evaluate the hearing of patients with cystic fibrosis by high frequency audiometry (HFA) and distortion product otoacoustic emissions (DPOAE). Patients and methods: retrospective and prospective crosssectional study including 75 individuals, 39 of the study group and 36 in the control group. HFA (250 – 16,000 Hz) and DPOAE tests were conducted. Results: the study group had thresholds significantly higher in the HFA in 250, 1,000, 8,000, 9,000, 10,000, 12,500 and 16,000 Hz (p=0.004) and higher prevalence of abnormal DPOAE at 1,000 and 6,000 Hz (p=0.001), with significantly lower amplitudes of 1,000, 1,400 and 6,000 Hz. There was a significant association between changes in hearing thresholds in HFA with the number of courses of aminoglycosides performed (p=0.005). Eighty-three percent of patients who completed more than 10 courses of aminoglycosides had hearing loss in HFA. Conclusion: a significant number of patients with cystic fibrosis who received repeated courses of aminoglycosides showed alterations in HFA and DPOAE.

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Henaoui, Imène-Sarah. "MiR-199a-5p, un " fibromiR " amplificateur de la voie du TGF-beta dans la fibrose pulmonaire idiopathique." Phd thesis, Université Nice Sophia Antipolis, 2013. http://tel.archives-ouvertes.fr/tel-00931984.

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La Fibrose Pulmonaire idiopathique (FPI) est une maladie fibroproliférative pour laquelle il n'existe aucun traitement efficace. Les mécanismes à l'origine de cette pathologie sont méconnus et impliquent plusieurs types cellulaires et facteurs de croissance, comme le TGF-β responsable de la différenciation de fibroblastes en myofibroblastes. Pour mieux comprendre ces mécanismes physiopathologiques, nous nous sommes intéressés à l'implication des miARN dans ce processus. Une analyse par puces à ADN de l'ensemble des miARN modulés dans des échantillons pulmonaires de souris, résistantes ou sensibles à la fibrose pulmonaire induite par la bléomycine, nous a permis d'identifier miR-199a-5p comme le meilleur candidat associé à la fibrose pulmonaire mais aussi fibrose rénale et hépatique. J'ai ensuite démontré que l'expression de miR-199a-5p était induite par le TGF-β in vitro, et que sa surexpression ectopique induisait la différenciation des fibroblastes. Une combinaison d'approche in silico et expérimentale, m'a permis d'identifier la Cavéoline-1 (CAV-1) comme cible de ce miARN. La CAV-1 est impliquée dans la dégradation du récepteur TGF-β. Ainsi, l'inhibition de CAV-1 par miR-199a-5p constitue une boucle de rétrocontrôle positif exacerbant la voie TGF-β. De manière intéressante, l'inhibition de miR-199a-5p in vitro régule la différenciation, la prolifération et la migration des fibroblastes pulmonaires par le TGF-β. Par ailleurs, nos résultats précliniques indiquent que l'inhibition de ce miARN diminue les marqueurs de fibrose, permettant d'envisager le développement de nouvelles approches thérapeutiques dans le traitement de la FPI et d'autres maladies fibroprolifératives.

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Henaoui, Imène Sarah. "MiR-199a-5p, un « fibromiR » amplificateur de la voie du TGF-beta dans la fibrose pulmonaire idiopathique." Electronic Thesis or Diss., Nice, 2013. http://www.theses.fr/2013NICE4136.

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La Fibrose Pulmonaire idiopathique (FPI) est une maladie fibroproliférative pour laquelle il n’existe aucun traitement efficace. Les mécanismes à l’origine de cette pathologie sont méconnus et impliquent plusieurs types cellulaires et facteurs de croissance, comme le TGF-β responsable de la différenciation de fibroblastes en myofibroblastes. Pour mieux comprendre ces mécanismes physiopathologiques, nous nous sommes intéressés à l’implication des miARN dans ce processus. Une analyse par puces à ADN de l’ensemble des miARN modulés dans des échantillons pulmonaires de souris, résistantes ou sensibles à la fibrose pulmonaire induite par la bléomycine, nous a permis d’identifier miR-199a-5p comme le meilleur candidat associé à la fibrose pulmonaire mais aussi fibrose rénale et hépatique. J’ai ensuite démontré que l’expression de miR-199a-5p était induite par le TGF-β in vitro, et que sa surexpression ectopique induisait la différenciation des fibroblastes. Une combinaison d’approche in silico et expérimentale, m’a permis d’identifier la Cavéoline-1 (CAV-1) comme cible de ce miARN. La CAV-1 est impliquée dans la dégradation du récepteur TGF-β. Ainsi, l’inhibition de CAV-1 par miR-199a-5p constitue une boucle de rétrocontrôle positif exacerbant la voie TGF-β. De manière intéressante, l’inhibition de miR-199a-5p in vitro régule la différenciation, la prolifération et la migration des fibroblastes pulmonaires par le TGF-β. Par ailleurs, nos résultats précliniques indiquent que l’inhibition de ce miARN diminue les marqueurs de fibrose, permettant d’envisager le développement de nouvelles approches thérapeutiques dans le traitement de la FPI et d’autres maladies fibroprolifératives
Idiopathic Pulmonary Fibrosis (IPF) is a fibroproliferative disease with poor prognosis and for which no effective treatment exists. The mechanisms of this disease remain poorly understood and involve numerous cell types and growth factors such as TGF-β, which leads to the activation of lung fibroblasts into myofibroblasts; the key cell type driving the fibrogenic process. In this context, we focused the involvement of miRNAs in fibrosis process. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to lung fibrosis after bleomycin exposure. We identified miR- 199a-5p as the best candidate associated with lung fibrosis but also kidney and liver fibrosis. I observed that miR-199a-5p expression was induced upon TGF-β exposure, and that its ectopic expression was sufficient to promote the pathogenic activation of pulmonary fibroblasts. Using combination of targets miRNA prediction tools and a transcriptomic approach we identified the Caveolin-1 (CAV-1), a critical mediator of pulmonary fibrosis, as a specific target of miR-199a-5p. Thus, we shown that miR-199a-5p is a key effector of TGF-β signaling in lung fibroblasts by regulating CAV1. Interestingly, inhibition of miR-199a-5p in vitro prevents the differentiation, proliferation and migration of fibroblasts after TGF-β stimulation. Finally, our preclinical results indicate that inhibition of this miRNA decreases fibrosis markers. Thus, miR-199a-5p behaves as a major regulator of tissue fibrosis with therapeutic potency for the treatment of IPF and fibroproliferative diseases

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Dal'Maso, Vinícius Buaes. "Contribuição da análise molecular do gene CFTR na investigação diagnóstica de pacientes com suspeita de fibrose cística leve ou doença atípica." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2012. http://hdl.handle.net/10183/79587.

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A fibrose cística (FC) é diagnosticada na presença de achados fenotípicos, história familiar ou triagem neonatal positiva acompanhada de evidência laboratorial de disfunção da CFTR, seja pelo teste do suor, diferença de potencial nasal ou pela identificação de duas mutações conhecidas como causa de FC nos genes da CFTR. Objetivos: Avaliar a contribuição da análise molecular do gene CFTR na investigação diagnóstica da fibrose cística em pacientes com suspeita de FC leve ou doença atípica. Secundariamente, comparar as características dos pacientes em 3 grupos: grupo com identificação de duas mutações conhecidas como causadoras da FC, grupo com identificação de apenas uma mutação e grupo sem mutação identificada. Métodos: Estudo transversal em adolescentes e adultos (≥14 anos). Os pacientes foram submetidos à avaliação clínica, laboratorial e radiológica; espirometria, microbiologia do escarro, ecografia hepática, teste do suor e análise molecular do gene CFTR. Resultados: Foram avaliados 37 pacientes com achados fenotípicos de FC, com ou sem confirmação pelo teste do suor. Houve predomínio do sexo feminino (75,7%) com média de idade de 32,5 ± 13,6 anos. A análise molecular contribuiu para o diagnóstico definitivo de FC em 3 casos (8,1%) dentre 37 pacientes em avaliação. Em 7 pacientes (18,9%) foram identificadas apenas uma mutação causadora de FC e em 26 pacientes (70,3%) não foram identificadas mutações. Nenhuma característica clínica estudada se associou com o diagnóstico genético. A mutação p.F508del foi a mais comum, encontrada em 5 pacientes. A associação de p.V232D e p.F508del foi encontrada em 2 pacientes. Outras mutações encontradas foram: p.A559T, p.D1152H, p.T1057A, p.I148T, p.V754M, p.P1290P e p.R1066H e p.T351S. Conclusão: A análise molecular da região codificante do gene CFTR apresentou contribuição limitada para investigação diagnóstica de pacientes com suspeita de fibrose cística leve ou doença atípica. Além disso, não houve associação entre as características clínicas e o diagnóstico genético.
Cystic fibrosis (CF) is diagnosed in the presence of phenotypic findings, family history or positive neonatal screening accompanied by laboratory evidence of CFTR dysfunction, either by sweat test, nasal potential difference or the identification of two mutations known to cause CF in the CFTR gene. Objectives: To evaluate the contribution of molecular analysis of CFTR gene in cystic fibrosis diagnostic investigation in patients with suspected mild FC or atypical disease. Secondarily, to compare the characteristics of patients into 3 groups: group with identification of two mutations known to cause CF, group with identification of just one mutation and group without mutations. Methods: Cross-sectional study in adolescent and adult (≥ 14 years). The patient underwent clinical, laboratory and radiological spirometry, sputum microbiology, liver ultrasound, sweat test and molecular analysis of the CFTR gene. Results: We evaluated 37 patients with phenotypic findings of FC, with or without confirmation by the sweat test. There was a predominance of females (75.7%) with a mean age of 32.5 ± 13.6 years. Molecular analysis contributed to the definitive diagnosis of CF in 3 cases (8.1%) among 37 patients under evaluation. In 7 patients (18.9%) were identified only one mutation that causes CF and in 26 patients (70.3%) were not identified mutations. No clinical feature studied was associated with genetic diagnosis. The P.F508del mutation was the most common, found in 5 patients. The association p.V232D and p.F508del was found in 2 patients. Other mutations found were: p.A559T, p.D1152H, p.T1057A, p.I148T, p.V754M, and p.P1290P p.R1066H and p.T351S. Conclusion: Molecular analysis of the CFTR gene coding region showed limited contribution to the diagnostic investigation of patients with suspected cystic fibrosis mild or atypical disease. Moreover, there was no association between clinical features and genetic diagnosis.

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Marchal, Pierre-Olivier. "Rôle de NOV/CCN3 dans différents modèles in vivo de néphropathies et pathologies cardiovasculaires." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066321.

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La maladie rénale chronique (MRC) est un véritable problème de santé publique. Bien qu'elle puisse avoir plusieurs origines, celle-ci est caractérisée par le développement d'une inflammation chronique ainsi qu'une fibrose conduisant à une diminution progressive de la fonction rénale. Il est nécessaire de trouver de nouvelles cibles thérapeutiques pour arrêter la progression de cette pathologie. La protéine NOV/CCN3 a été identifiée comme étant une cible potentiellement intéressante. Dans cette étude, nous avons montré que dans un modèle in vivo de néphropathie obstructive, NOV avait un rôle proinflammatoire et profibrotique. Dans un autre modèle in vivo de néphropathie hypertensive, nous avons montré que NOV était régulée par l'Angiotensine II (AngII) et pouvait inhiber l'expression du récepteur AT1R de l'AngII et ainsi limiter les effets délétères de cette hormone. Bien que contradictoires, ces résultats montrent un rôle important de NOV au cours du développement des néphropathies indiquant que cette protéine peut avoir des effets opposés en fonction du contexte pathologique. Enfin, du fait de l'étroite relation entre NOV et l'AngII, nous avons montré que NOV était aussi régulée par cette hormone au niveau aortique et avait un effet proinflammatoire au niveau vasculaire dans des conditions d'hypertension. L'ensemble de nos résultats montrent un rôle important de NOV dans ces différents types de pathologies et que cette protéine pourrait être une cible intéressante pour traiter les néphropathies ou encore les pathologies cardiovasculaires
Chronic kidney disease (CKD) is a major public health problem. Regardless of the primary cause, CKD is characterized by the development of chronic inflammation and fibrosis leading to progressive decline of renal function and eventually end-stage renal disease (ESRD). Actually, regular hemodialysis and renal transplantation are the only available therapies for ESRD patients. Therefore, there is an urgent need for new therapeutically targets against this incurable disease. Recently, the NOV/CNN3 protein was shown to be an interesting candidate. In this study we have shown that, in obstructive nephropathy in mice, NOV has profinflammatory and profibrotic effects. In addition, we have shown in a mouse model of hypertensive nephropathy, that NOV was regulated by Angiotensin II (AngII) and could inhibit AT1R receptor expression to limit the deleterious effects of this hormone. These results show an important role of NOV during the development of two different types of nephropathies and may indicate that this protein can have model specific effects. Finally, we have shown that NOV itself was also regulated by AngII in the aorta and has proinflammatory effects in hypertensive conditions. Taken together our results show an important role of NOV in these different types of pathologies and that this protein could be a key player in the development of CKD as well as vascular diseases. Nevertheless, further investigations are still required to better characterize the precise role of NOV in these pathological contexts

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Parazzi, Paloma Lopes Francisco 1982. "Alterações ventilatórias em pacientes com fibrose cística submetidos a teste submáximo de seis minutos." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/309995.

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Orientadores: José Dirceu Ribeiro, Camila Isabel Santos Schivinski
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Introdução: Na fibrose cística (FC) os testes que avaliam a aptidão física tem sido estudado como marcador de prognóstico ou como ferramenta de avaliação da condição cardiorrespiratória. Objetivo: avaliar e comparar variáveis da ventilação pulmonar utilizando a capnografia volumétrica (capV): VE, VCO2, VE/VCO2, VD/VT, PetCO2; variáveis de espirometria: VEF1%, CVF% e VEF1/CVF; e parâmetros cardiorrespiratórios: FCar, FR, SpO2 no repouso e durante teste de esforço em crianças, adolescentes e adultos jovens entre 6 a 25 anos de idade, com (GFC) e sem fibrose cística (GC). Método: estudo clínico, prospectivo, controlado, com 128 indivíduos, 64 com FC, de ambos os gêneros, de Hospital Universitário. Todos realizaram exercício em esteira e os exames propostos após aprovação do Comitê de Ética da Instituição e assinatura do termo de Consentimento Livre e Esclarecido. Resultados: os pacientes com FC apresentaram valores estatisticamente diferentes para as variáveis de CapV e espirometria ao longo do teste de exercício. Antes do exercício as variáveis também foram diferentes, porém com significância estatística para: espirometria, SpO2, FR, VCO2, VE/VCO2, PetCO2 e escala de Borg. A comparação entre os grupos de pacientes com FC e GC foi realizada pelos testes Kruskal-Wallis e Mann-Whitney. Conclusão: a CapV é um instrumento que pode ser utilizado para análise de parâmetros ventilatórios durante o exercício físico. Todas as variáveis cardiorrespiratórias, da espirometria e da capnografia foram diferentes nos pacientes com FC quando comparados aos indivíduos saudáveis antes, durante e após exercício físico
Abstract: Introduction: In cystic fibrosis (CF) tests that assess physical fitness has been studied as a prognostic marker or as a tool for assessing the cardiorespiratory fitness Objective: To evaluate and compare variables of pulmonary ventilation using volumetric capnography (CAPV): VE, VCO2, VE/VCO2, VD/VT, PetCO2; spirometric variables: % FEV1 , FVC and FEV1/FVC % ; and cardiorespiratory parameters: FCar , RR, SpO2 at rest and during exercise testing in children, adolescents and young adults aged 6-25 years of age with (GFC) and without cystic fibrosis (GC). Method: Clinical, prospective, controlled study with 128 subjects, 64 with CF, of both genders, of University Hospital. All patients underwent treadmill exercise tests and proposed after approval by the Institutional Review Board and signing the consent form. Results: CF patients had statistically different values for the variables CAPV and spirometry throughout the exercise test. Before exercise variables were also different, but with statistical significance for spirometry, SpO2, RR, VCO2, VE/VCO2, PetCO2 Borg scale. The comparison between groups of patients with CF and control groups was performed by Kruskal - Wallis and Mann - Whitney tests. Conclusion: CAPV is a tool that can be used for analysis of ventilatory parameters during exercise. All cardiorespiratory variables, spirometry and capnography were different in CF patients compared to healthy subjects before and after exercise
Mestrado
Saude da Criança e do Adolescente
Mestra em Ciências

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Santos, Pedro Paulo de Andrade. "Express?o imuno-histoqu?mica da triptase em mast?citos nos fibromas de c?lulas gigantes e hiperplasias fibrosas de mucosa oral." Universidade Federal do Rio Grande do Norte, 2008. http://repositorio.ufrn.br:8080/jspui/handle/123456789/17103.

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Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico
The giant cell fibroma is a benign neoplasm characterized by the presence of mono, bi or multinucleate cells, which can have a connection to the presence of mast cells. This research aims to analyze, descriptively and comparatively, the immunohystochemistry expression of the tryptase in mast cells of the giant cell f ibroma, f ibrous hyperplasia and samples of the normal oral mucosa. Thirty cases of giant cell fibroma, ten cases of fibrous hyperplasia and ten cases of normal oral mucosa were selected for the analysis of the immunohistochemistry expression, determination of the number of present mast cells, as well as their location and shape. It could be stated that there was a statistically signif icant difference (p<0,001) in relation to the quantity of mast cells among other samples analyzed where the giant cell f ibroma presented lesser quantity of mast cell and the hyperplasia showed higher concentration of this cellular type. Although the oral mucosa has presented a higher quantity of mast cells when compared to the giant cells fibroma, these were found in usual locations in the connective tissue in normal tissues. There could be noticed a statistically significant difference in relation to the number of non-granulated mast cells (p<0,001). On the areas of fibrosis, we could observe a statistically signif icant difference (p<0,006) among the samples. In relation to the present mast cells in perivascular location, no statistically signif icant difference was found. On the morphological analysis there was a predominance of oval mast cells. It was concluded that despite of the fact there was a lesser quantity of mast cells present in cases of giant cell f ibroma, they appeared to have a stronger relation to the present giant fibroblasts in this lesions, around 59,62%, being also evidenced a strong relation between these cells and the fibrosis areas in both cases of giant cell f ibroma and f ibrous hyperplasias and samples of normal oral mucosa, used as control group in our study, confirming, this way, the role of the mast cells as fibrinogenous inductor
O fibroma de c?lulas gigantes constitui-se de uma neoplasia benigna, caracterizada pela presen?a de c?lulas gigantes, mono, bi ou multinucleadas, c?lulas estas que podem guardar rela??o com a presen?a de mast?citos. O prop?sito desta pesquisa consistiu em analisar descritiva e comparativamente a express?o imuno-histoqu?mica da triptase em mast?citos de fibroma de c?lulas gigantes, hiperplasia fibrosa e esp?cimes de mucosa oral normal. Foram selecionados 30 casos de fibroma de c?lulas gigantes, 10 casos de hiperplasia fibrosa e 10 casos de mucosa oral normal, para a an?lise da express?o imuno-histoqu?mica, determina??o do n?mero de mast?citos presentes, bem como a sua forma e localiza??o. Constatou-se diferen?a estatisticamente significativa (p<0,001) em rela??o a quantidade de mast?citos entre os esp?cimes analisados, onde o fibroma de c?lulas gigantes apresentou a menor quantidade de mast?citos e a hiperplasia exibiu a maior concentra??o deste tipo celular. Embora a mucosa oral tenha apresentado uma maior quantidade de mast?citos quando comparado com os casos de f ibroma de c?lulas gigantes, estes se encontravam em localiza??es usuais no tecido conjuntivo em tecidos normais. Verif icou-se, diferen?a estatisticamente significativa, no que diz respeito ao n?mero de mast?citos n?o degranulados (p<0,001). Nas ?reas de fibrose, observamos diferen?a estatisticamente signif icativa (p<0,006) entre os esp?cimes. Com rela??o aos mast?citos presentes em localiza??o perivascular n?o se observou diferen?a estatisticamente significativa. Na an?lise morfol?gica verif icou-se uma predomin?ncia de mast?citos ovais. Concluiu-se que embora uma menor quantidade de mast?citos estivesse presente nos casos de fibroma de c?lulas gigantes, estes exibiam maior rela??o com os fibroblastos gigantes presentes nestas les?es em torno de 59,62%, sendo evidenciada tamb?m uma forte rela??o entre estas c?lulas e ?reas de fibrose tanto nos casos de fibroma de c?lulas gigantes como de hiperplasias fibrosas e esp?cimes de mucosa oral normal, utilizados como controle em nosso estudo, confirmando desta forma, o papel dos mast?citos como indutor fibrinog?nico

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Chokr, Dina. "Monoacylglycerol Lipase, a new anti-inflammatory and anti-fibrogenic target in the liver." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC283.

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L'inflammation soutenue médiée par les macrophages est une force motrice de la progression et la résolution de la fibrose. La monoacylglycérol lipase (MAGL) est l'enzyme qui ralentit la dégradation des monoacylglycérols. C‟est une enzyme proinflammatoire qui métabolise le 2-arachidonoylglycérol, un ligand des récepteurs endocannabinoïdes, en acide arachidonique. Ici, nous avons étudié l'impact de la MAGL sur l'inflammation et la fibrose au cours des lésions hépatiques chroniques. Les souris présentant une invalidation globale ou myéloïde (Mye-/-) du gène codant pour la MAGL et exposées de manière chronique au tétrachlorure de carbone (CCl4) étaient plus résistantes à l'inflammation et à la fibrose que les souris sauvages (WT). De même, l‟inhibition pharmacologique de la MAGL avec le MJN110 réduit l'expression des gènes pro-inflammatoires et ralenti la progression de la fibrose chez les souris ayant subi à une ligature de la voie biliaire principale. De plus, MJN110, un inhibiteur de la MAGL, a accéléré la régression de la fibrose après l'arrêt de l'administration de CCl4. Les expériences in vitro ont montré que les macrophages exposés à MJN110 ou isolés de souris MAGL Mye-/- présentent une sécrétion réduite des cytokines et des chimiokines après stimulation par le LPS. Ces effets étaient indépendants du récepteur des cannabinoïdes CB2 puisqu‟ils sont conservés chez des souris déficientes pour ce récepteur. Ils sont dépendants de l'autophagie dans les macrophages car ils ne sont plus observés dans des macrophages isolés de souris présentant une délétion du gène codant pour ATG5 dans la lignée myéloïde. Inversement, une augmentation du flux autophagique est observée après invalidation génétique ou inhibition pharmacologique de la MAGL. Ces données suggèrent que la MAGL pourrait être une nouvelle cible immuno-métabolique dans le foie, et démontrent que les inhibiteurs de la MAGL pourraient être intéressants pour la prise en charge de la fibrose associée aux maladies chroniques du foie
Sustained inflammation originating from macrophages is a driving force of fibrosis progression and fibrosis resolution. Monoacylglycerol lipase (MAGL) is the rate limiting enzyme in the degradation of monoacylglycerols, and is a proinflammatory enzyme that metabolizes 2-arachidonoylglycerol, an endocannabinoid receptor ligand, into arachidonic acid. Here, we investigated the impact of MAGL on inflammation and fibrosis during chronic liver injury. Mice with either global or myeloid-specific (Mye-/-)invalidation of MAGL chronically exposed to carbon tetrachloride (CCl4) were more resistant to inflammation and fibrosis than wild type counterparts. Therapeutic intervention with MJN110 also reduced inflammatory gene expression and slowed down fibrosis progression in bile duct-ligated mice. Moreover, the MAGL inhibitor MJN110 accelerated fibrosis regression following discontinuation of CCl4 administration. In vitro, macrophages exposed to MJN110 or isolated from MAGL Mye-/- mice displayed reduced LPS-stimulated secretion of cytokines and chemokines. These effects were independent of the cannabinoid receptor CB2, as they were preserved in mice with myeloid specific deletion of CB2. They relied on macrophage autophagy, as they were lost in mice with myeloid-specific deletion of the autophagic gene ATG5, and associated with increased autophagic flux when MAGL was genetically or pharmacologically inhibited. These data unravel MAGL as a novel immunometabolic target in the liver, and demonstrate that MAGL inhibitors may show promising anti-fibrogenic effects during chronic liver injury

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Reungoat, Emma. "Altérations du microenvironnement hépatocytaire suite à l'infection par le virus de l'hépatite C : implication dans la fibrogenèse hépatique précoce." Thesis, Lyon, 2018. http://www.theses.fr/2018LYSE1222/document.

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L’hépatite C est une maladie due à l’infection par le virus de l’hépatite C (VHC), qui se transmet par le sang. On considère que ce virus infecte 3 à 4 millions de personnes chaque année, sa prévalence pouvant aller jusqu’à 22% de la population. Ces dernières années, le développement de thérapies antivirales spécifiques du virus à agents antiviraux directs (AAD) a permis de faire fortement régresser l’infection dans les pays développés. Cependant, les traitements sont encore extrêmement couteux, et les mécanismes de l’infection sont toujours mal compris. En effet, le virus de l’hépatite C appartient au groupe des virus oncogènes, au même titre que celui de l’hépatite B ou le papillomavirus. Il n’a cependant jamais été démontré que le VHC induit des perturbations au niveau génétique des cellules infectées, et les processus viraux qui mènent à la transformation cellulaire sont inconnus. Le VHC est un virus qui infecte les hépatocytes, les cellules épithéliales du foie. Il a précédemment été montré que l’infection induit de fortes perturbations métaboliques dans ces cellules qui participent à la pathogenèse virale. Par ailleurs, l’infection induit également une accumulation anormale de tissu cicatriciel dans le foie (fibrose) pouvant sur le long terme conduire à des dérèglements fonctionnels et architecturaux de l’organe (cirrhose) qui deviennent irréversibles. L’ultime étape dans la progression de l’hépatite C est le carcinome hépatocellulaire (CHC) dans 1 à 5% des cas, et une large partie de ces patients meurent dans l’année suivant le diagnostic. Nous nous sommes particulièrement intéressés aux étapes précoces de la pathogenèse virale, en particulier l’établissement de la fibrose hépatique. Celle-ci résulte de l’accumulation de composés de la matrice extracellulaire (MEC) dans l’espace intercellulaire du foie, alimentée d’une part par la surproduction de ces composés, et d’autre part par la diminution de leur dégradation par leurs enzymes spécifiques. La MEC est un espace complexe qui contrôle la signalisation entre les cellules. Ceci dépend en grande partie de l’espace situé immédiatement au-dessus de la membrane plasmique, appelé manteau cellulaire ou glycocalyx. Cet espace est majoritairement composé de protéoglycanes comportant un corps protéique sur lequel sont ancrées de nombreuses chaînes de sucres sulfatés capables ou non de fixer les facteurs de signalisation présents dans la MEC pour les rapprocher ou non de leurs récepteurs. Après avoir démontré dans une première étude que l’infection par le VHC induisait une diminution de l’expression d’un composant majeur du glycocalyx dans les cellules infectées, nous nous sommes intéressés plus globalement à l’évolution de cet espace suite à l’infection. Nos travaux reposent sur des approches pluridisciplinaires regroupant biologie moléculaire, biochimie, et biologie cellulaire. Nous avons pu étudier en détail les composés du glycocalyx présents à la surface des cellules infectées ou non par le VHC, ainsi que les facteurs d’une des voies de leur biosynthèse. Ces études ont été réalisées dans un premier temps en modèle d’infection in vitro, mais également sur échantillons biologiques de patients. Nous avons observé un remaniement important des composés du glycocalyx à la surface des cellules infectées, quantitatif et qualitatif, corrélé à des altérations majeures dans la voie de biosynthèse de composants de cet espace. Nous avons constaté que la profondeur de ces altérations descendait à l’échelle du simple sucre (xylose) dont la concentration varie entre les conditions contrôle et infectée. Cette variation de quantité de xylose dans les cellules infectées semble être reflétée dans l’altération d’une importante voie de signalisation contrôlant la destinée cellulaire. Ce travail de thèse permet donc d’éclairer une partie de la pathogenèse virale du VHC encore jamais explorée, soulignant des problèmes majeurs de communication cellulaire dans les organes infectés
Hepatitis C is a chronic liver disease due to the infection by the hepatitis C virus (HCV), through exposure to contaminated blood. An estimated 3 to 4 million people are infected every year, with a viral prevalence rising up to 22% in the general population in Egypt. Over the past years, directacting antivirals (DAA) have emerged on the market, allowing a strong regression of the infection in developed countries. However these treatments are very expensive, and the underlying mechanisms of HCV infection remain ill-defined. HCV is an oncovirus, as are among others, the hepatitis B virus, human papilloma viruses, and herpes viruses. Contrary to those viruses, HCV does not seem to alter the genetic background of infected cells. Therefore, infectious mechanisms leading to cellular transformation are still unknown. HCV infects the epithelial cells of the liver, the hepatocytes. Infection leads to strong disruptions of glucide and lipid metabolism in these cells, contributing to HCV pathogenesis. Moreover HCV infection induces the accumulation of scarring tissue in the intercellular space of the liver, called fibrosis, which can evolve into cirrhosis with irreversible architectural and functional disorders. The ultimate step in hepatitis C progression is the development of an hepatocellular carcinoma (HCC) in 1-5% of cases, and many of these patients die the year following cancer diagnosis. We aimed at studying the early steps of viral pathogenesis, especially the establishment of liver fibrosis. This is the consequence of extracellular matrix (ECM) deposition in the intercellular space of the liver, fueled by both an oversecretion of ECM components and a lack of ECM degradation by specialized enzymes. The ECM is a complex compartment of the liver which controls molecular cellto- cell signaling. This greatly depends on what happens in the area situated right above the plasma membrane, called the cell coat or glycocalyx. This area mainly consists of proteoglycans, composed of a core protein on which long chains of sulfated sugars are anchored. These sugar chains are able to recognize and capture a myriad of signaling molecules in the ECM, in order to bring them closer to their receptors. Our first study demonstrated that one major proteoglycan was downregulated following HCV infection (Grigorov et al, 2017). We then decided to study on a more global scale how the glycocalyx evolved following this infection. Our work here is based on a multi-disciplinary approach combining molecular biology, biochemistry and cellular biology. We studied in details the glycocalyx components present at the surface of cells infected or not, as well as the expression of factors involved in their biosynthesis. This was first done in in vitro cellular models of infection, and extended where possible to biological samples from patients at various stages of chronic hepatitis. We observed a strong quantitative and qualitative reshuffling of the glycocalyx at the surface of infected cells, which correlated with major alterations in the biosynthesis of some proteoglycans. These abnormalities seemed to originate from the amount of a simple sugar, xylose, the main component of the biosynthesis of some proteoglycans. Indeed, intracellular concentrations of xylose were decreased in infected cells. This might bear a link to the observed alterations of a major signaling pathway controlling cell fate, which is partly regulated by xylose. This study sheds light on a previously unexplored aspect of HCV pathogenesis. Our results could contribute to explain the complications linked to this infection, since they underline major cellto- cell communication issues. Since most of the DAA-based therapies work badly once liver cirrhosis has settled, it could be interesting to combine antiviral treatments with anti-fibrotic agents in patients suffering from advanced hepatitis C

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Bigé, Naïke. "Rôle de la Thrombospondine-1 et du récepteur CD47 dans le développement de la fibrose rénale." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066705/document.

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La Thrombospondine-1 (TSP-1) représente l'un des principaux activateurs endogènes du TGF-?1 et possède des propriétés anti-angiogéniques et immunomodulatrices. L'un de ses récepteurs, le CD47, joue un rôle critique dans son effet anti-angiogénique et module l'inflammation. Après obstruction urétérale unilatérale (UUO), l'expression de la TSP-1 augmente, est corrélée à celle du TGF-?1 et du collagène III et décroît avec la réparation tissulaire qui accompagne la désobstruction urétérale. L'utilisation de souris knock-out pour la TSP-1 a permis de montrer qu'elle participe au développement des lésions tubulaires rénales en favorisant les altérations vasculaires et le recrutement des cellules inflammatoires. Cet effet pro-inflammatoire dépend, au moins en partie, du facteur chimiotactique MCP-1, de l'augmentation du rolling leucocytaire et de l'activation de la voie Th17. Les souris knock-out pour CD47 bénéficient également d'une protection tubulaire et vasculaire. Cependant, elles présentent une fibrose interstitielle accrue associée à une augmentation de l'expression de la TSP-1 et du TGF-?1 qui pourrait compromettre une éventuelle récupération rénale. L'étude préliminaire de modèles de néphroangiosclérose chez le rat et la souris révèle que la TSP-1 est surexprimée dans le parenchyme rénal au cours de l'hypertension artérielle. L'intensité de son expression est corrélée à la sévérité des lésions histologiques, suggérant son rôle physiopathologique. Ces résultats montrent que la TSP-1 et le récepteur CD47 participent au développement de la fibrose rénale et représentent donc des cibles thérapeutiques potentielles au cours des maladies rénales chroniques
Thrombospondin-1 (TSP-1) is a major endogenous activator of TGF-β1 and has anti-angiogenic and immunomodulatory properties. One of its partners, receptor CD47, plays a critical role in its anti-angiogenic activity and also regulates inflammation. After unilateral ureteral obstruction (UUO), TSP-1 expression increases, correlates to TGF-β1 and collagen III expression and decreases with renal repair after desobstruction. Use of TSP-1 knock-out mice allowed us to demonstrate that TSP-1 favours renal injury by increasing vascular lesions and inflammatory cells recruitment. This pro-inflammatory effect depends, at least in part, on chemotactic factor MCP-1, increasing in leukocyte rolling and engagement of T cells in Th17 pathway. CD47 knock-out mice also benefit from tubular and vascular protection after UUO. However, they exhibit increased interstitial fibrosis associated with higher expression of TSP-1 and TGF-β1, which could compromise renal repair. Preliminary study of nephroangiosclerosis models in rats and mice revealed that TSP-1 expression is induced in renal tissue by arterial hypertension and is correlated to the severity of histological lesions, suggesting its physiopathological role. These results show that TSP-1 and CD47 are involved in renal fibrosis and that they represent potential therapeutic target in the management of chronic kidney disease

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Mintet, Elodie. "Implication de la transition endothélium-mésenchyme dans le développement des complications digestives des radiothérapies." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066551/document.

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La fibrose digestive est une complication secondaire tardive de la radiothérapie dans 5 à 10% des patients traités pour des tumeurs de la sphère abdomino-pelvienne. Elle est caractérisée par une accumulation de matrice extracellulaire synthétisée par les cellules mésenchymateuses. La transition endothélium-mésenchyme (EndoMT), est un processus au cours duquel les cellules endothéliales expriment des marqueurs mésenchymateux en réponse au stress. L'EndoMT a été identifiée comme une source de cellules mésenchymateuses participant à la fibrose chez des patients atteints de maladie inflammatoire chronique de l'intestin. Cette étude s'est donc concentrée sur le rôle de l'EndoMT dans le développement de la fibrose intestinale radio-induite et d'identifier des cibles thérapeutiques potentielles.Nos résultats ont révélé pour la première fois l'existence de l'EndoMT au niveau de la paroi rectale chez l'homme après radiothérapie. L'utilisation de souris exprimant la GFP sous le contrôle du promoteur endothélial Tie2, nous a permis de localiser les cellules mésenchymateuses possédant une origine endothéliale, confirmant l'existence de l'EndoMT radio-induite dans notre modèle préclinique de rectite radique. In vitro, nous avons confirmé le changement phénotypique des cellules endothéliales irradiées.Ce projet s'est ensuite concentré sur un acteur potentiel de l'EndoMT radio-induite, Hey2. La génération d'un modèle murin déficient pour Hey2 dans l'endothélium a révélé une diminution des dommages muqueux et de la fréquence l'EndoMT après irradiation. L'inhibition de Hey2 représente une nouvelle approche thérapeutique attrayante dans la réduction de la fibrose digestive radio-induite
Fibrosis is identified as a chronic side effect occurring after radiotherapy for pelvic tumors in 5 to 10 % of patients. This pathological healing process is characterized by an accumulation of extracellular matrix synthesized by mesenchymal cells. Endothelial to mesenchymal transition (EndoMT), is a processes during which endothelial cells express mesenchymal markers in response to stress. EndoMT is identified as a source of mesenchymal cells taking part to fibrosis development in patients suffering from inflammatory bowel diseases. Then, this study focused on the potential participation of EndoMT in radiation-induced intestinal fibrosis and tried to identify new therapeutics targets. Interestingly, our results showed for the first time EndoMT in rectal tissues from patients who developed radiation proctitis following radiotherapy. We used an in vivo approach to follow the mesenchymal cells having an endothelial origin in a mouse model expressing the GFP under the control of an endothelial promoter, Tie2 (Tie2-GFP). Thereby, our results confirmed the existence of radiation-induced EndoMT in our preclinical model of radiation proctitis. In vitro characterization showed that irradiation induced a modulation of the endothelial phenotype through a mesenchymal profile, a hallmark of EndoMT. This project also focused on a potential molecular actor, Hey2. In this context, we generated a transgenic mouse model in which Hey2 gene expression is repressed specifically in the endothelial compartment and observed a decrease in radiation-induced mucosal damages and EndoMT frequency. Consequently, inhibiting Hey2 expression could represent a new interesting therapeutic strategy

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Blirando, Karl. "Rôle des mastocytes dans le développement de la rectite radique in vivo et la réponse endothéliale à l’irradiation in vitro." Thesis, Paris Est, 2011. http://www.theses.fr/2011PEST0080.

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La radiothérapie est utilisée seule ou en association avec la chimiothérapie dans le traitement de plus de 50% des cancers. En dépit des progrès techniques dans la balistique, l'irradiation des tissus sains entourant la tumeur et les effets secondaires qui lui sont associés sont une limite à la dose d'irradiation utilisée. Ces effets secondaires, lorsqu'ils concernent le tube digestif, ont un retentissement important sur la qualité de vie des patients et peuvent même engager leur pronostic vital. La compréhension des mécanismes impliqués dans le développement de ces lésions est donc un enjeu majeur dans l'identification de cibles thérapeutiques permettant leur prévention et leur traitement. Durant ma thèse nous avons étudié le rôle des mastocytes dans le développement de la rectite radique in vivo et dans la réponse endothéliale à l'irradiation in vitro. Nos résultats suggèrent un rôle délétère des mastocytes dans le développement de la rectite radique humaine et murine, notamment par l'influence de certains de leurs médiateurs tels que l'histamine et les protéases sur le phénotype des cellules musculaires lisses de la muscularis propria. Le ciblage de certains médiateurs mastocytaires pourrait représenter une nouvelle stratégie thérapeutique pour prévenir et/ou limiter les atteintes radiques digestives. D'autre part, nos travaux montrent que des médiateurs mastocytaires comme l'histamine peuvent exacerber la réponse inflammatoire de l'endothélium à l'irradiation par des mécanismes de signalisation impliquant l'activation de la voie p38 MAPKinase et du facteur de transcription NF-B. L'étude approfondie des voies de signalisation activées lors du développement des lésions radiques pourrait offrir de nouvelles possibilités thérapeutiques dans la gestion des dommages radiques aux tissus sains
Radiation therapy is used alone or in combination with chemotherapy in more than 50% of cancer treatments. Despite recent advances in treatment delivery such as dose-sculpting techniques, irradiation of healthy tissues surrounding the tumor and the associated side effects limit the radiation amount used. Those side effects when concerning the gastrointestinal tract, have profound repercussions on patient's quality of life and may even engage their vital prognosis. The comprehension of the mechanisms implicated in the development of these lesions is thus a major stake in the identification of therapeutic targets allowing their prevention and treatment. During my PhD, we studied the role of mast cells in the development of radiation proctitis in vivo and in the endothelial response to irradiation in vitro. Our results suggest that mast cells have a deleterious role in the development of human and murine radiation proctitis, in particular by the influence of some of its mediators such as histamine and proteases on the phenotype of the smooth muscle cells of the muscularis propria. Targeting mast cells'mediators may represent new therapeutic tools to prevent and/or limit digestive radiation damage. Other shares our work shows that mast cells mediators such as histamine can exacerbate the endothelial inflammatory response to irradiation by mechanisms involving the activation of the p38MAPKinase pathway and the transcription factor NF-B. The study of intracellular signaling pathways activated during radiation damage development may offer new therapeutic possibilities in the management of healthy tissues radiation damage

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Arruda, Leonardo Vicentini. "Incidenicia da fibrose cistica calculada atraves de portadores do alelo ?F508 no Nordeste e Sudeste do Brasil." [s.n.], 2006. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308589.

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Orientador: Carmen Silvia Bertuzzo
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: A incidência da fibrose cística no Brasil é significativamente variável, com diferenças de até 20 vezes de acordo com o grupo étnico e região geográfica estudada. A população brasileira é composta da mistura de muitos grupos étnicos. Os portugueses começaram a colonização no século XVI. Os holandeses invadiram o nordeste em 1630. Os africanos foram trazidos ao Brasil, numa contínua migração forçada, que perdurou do século XVI ao século XIX. No final do século XIX, tiveram início novos movimentos migratórios, principalmente da Alemanha, Itália, Arábia e Espanha. Durante as três primeiras décadas do século XX, nova corrente migratória ocorreu, principalmente da Itália, Espanha e Portugal Após a segunda guerra mundial, o Brasil recebeu novos imigrantes (japoneses, judeus) compondo esta população. Este estudo gerou os primeiros dados sobre a incidência da FC no nordeste e também foram obtidos novos dados para a região sudeste. Na época do estudo, na cidade de Campinas estão sob atendimento no ambulatório 70 pacientes não aparentados com dois testes de suor alterados. Nestes pacientes, foram triadas as seguintes mutações. ?F508 (50%), G542X (4,29%), R1162X (2,14%), N1303K (1,43%) e R553X (0,71%). A mutação G551D não foi encontrada. A mutação ?F508 também foi analisada em 1.138 mulheres saudáveis, sendo 694 da cidade de Campinas - SP e 444 de João Pessoa ¿ PB com idade média de 26,3 anos (15-39, ±6,8), que participaram voluntariamente de projeto de pesquisa anterior. Nas amostras coletadas em Campinas n=694 não foi encontrado nenhum alelo mutante 0/1.388, o que nos impediu de calcular a incidência nesta cidade através deste método. Dos 888 alelos analisados de João Pessoa, foram encontrados quatro alelos mutantes (p=0,0045). Sabendo que a mutação ?F508 corresponde a aproximadamente 50% dos alelos de indivíduos com FC no Brasil, a freqüência dos alelos causadores da FC foi estimada utilizando a proporção: (0,0045/0,5)=0,0090. Com isso, para a cidade de João Pessoa a incidência estimada desta doença autossômica recessiva é de 1:12.321 indivíduos. Esta incidência é similar à encontrada por afro-brasileiros, entretanto difere por exemplo, da encontrada na população do RS. Quando utilizamos o método de cruzamento de dados étnicos das duas regiões estudadas com dados literários da doença nos diferentes grupos étnicos, na cidade de Campinas a incidência da FC ficaria em 1/4.434 e na cidade de João Pessoa ficaria 1/6.087
Abstract: The incidence of the Cystic Fibrosis (CF) is significantly variable in Brazil, with differences larger than 20 fold, according with the ethnic group and geographic studied region. Brazilian population is composed by ethnic admixture. Portuguese started colonization in the 16th century. The Netherlander invaded the northeast in 1630. The Africans were brought to Brazil, in a continuous forced migration, which lasted from 16th to 19th centuries. In the 19th century, new migratory movements have begun from Germany, Italy, Arab and Spain. In the first three decades of the 20th century, started a new migratory flow, mainly from Italy, Spain and Portugal. After the World War II, Brazil received additional immigrants (Japanese, Jewish) compounding its population. These studies generated the first data about the CF incidence on the Brazilian northeast and also were obtained new data about the southeast region. At the time of this study, 70 non related patients were attended at the local CF center in Campinas, with two positive sweat tests in the city of Campinas-SP. On theses patients were screened the following mutations: ?F508 (50%), G542X (4.29%), R1162X (2.14%), N1303K (1.43%) and R553X (0.71%). The mutation G551D wasn¿t found. The ?F508 mutation was also analyzed in 1,138 healthy voluntary women, 694 from Campinas ¿ SP and 444 from João Pessoa ¿ PB, with average age of 26.3 years (15-39, ±6.8), who previously participated from another research. In the samples collected in Campinas ¿ SP n=694 wasn¿t found any mutated allele 0/1,388 and so, we wasn¿t able to make any incidence calculation through this method. In the 888 alleles from João Pessoa, four carry the ?F508 mutation (p=0.0045). Knowing that this mutation accounts for approximately 50% of the FC patients alleles in Brazil, the incidence of the CF in this region was estimated using the proportion: (0.0045/0.5)=0.009. Thus, the estimated incidence of this recessive disease in João Pessoa was 1:12,321. This incidence is similar to the found in African-Brazilians, although differs for example, to the found on the RS population. When we use the method of crossing ethnic data of both studied regions with literary data of the disease in the different ethnic groups, in the city of Campinas, the incidence of the CF would be in 1/4,434 and in the city of João Pessoa would be 1/6,087
Mestrado
Mestre em Farmacologia

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Aquino, Evanirso da Silva. "Avaliação dos nebulizadores utilizados na fibrose cística : protocolo e padronização de um método alternativo - um estudo de equivalência." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/99/99131/tde-13022019-094320/.

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INTRODUÇÃO: O tratamento da fibrose cística (FC) envolve o uso de medicamentos fornecidos através de nebulizadores e seu funcionamento adequado é essencial. OBJETIVOS: Avaliar o desempenho de nebulizadores a jato utilizados por pacientes com FC e comparar dois manômetros para avaliação dos compressores. MÉTODOS: Estudo descritivo, transversal, de avaliação dos nebulizadores usados pelos pacientes com FC da Associação Mineira de Assistência a Mucoviscidose. Os pacientes trouxeram compressores (Proneb Ultra®) e nebulizadores (Pari LC plus®) para avaliação. O desempenho do compressor foi avaliado por medidas de pressão operacional através dos manômetros PARI PG101® (PARI GmbH, Starnberg, Alemanha) e FSA analógico (Famabras, Itaquaquecetuba, Brasil).As variáveis de eficiência do nebulizador foram: O débito de volume nebulizado (DVN), taxa de oferta da medicação (TOR) e volume residual (VR) foram calculados por diferenças de peso de cada nebulizador após 10 minutos de nebulização de solução salina (2,5ml). O diâmetro médio de massa da partícula (DMM) foi calculado através da equação proposta por Standaert et al. A análise estatística incluiu o pacote R (v.2.15) e MINITAB, com alfa=0,05. O coeficiente Kappa foi calculado para avaliar concordância de valores entre os equipamentos, e curva ROC construída para calcular o valor aferido no manômetro FSA com melhor sensibilidade/especificidade, utilizando o manômetro PARI PG101® como referência. A associação entre valores de pressão, DVN, TOR e VR foi calculada pela correlação de Spearman. RESULTADOS: Avaliados 146 sistemas com tempo mediano de uso de 32(12-60) meses±36 meses. Cinquenta e sete (39%) não funcionaram adequadamente, com valores pressóricos inferiores à metade da referência. Os sistemas com funcionamento inadequado comprometeram as variáveis de eficiência dos nebulizadores A concordância entre os diferentes métodos de avaliação de acordo com a classificação; com funcionamento adequado e inadequado através do coeficiente Kappa foi 0,81(IC95%- 0,65-0,97), p<0,001. Na avaliação da sensibilidade e especificidade foi observado o ponto de corte de 23,5 PSI no manômetro FSA mostrou sensibilidade=99% e especificidade=79% (p<0,001). Houve associação significativa entre DVN, VR e pressões aferidas. CONCLUSÕES: Uma proporção significativa dos sistemas de nebulização não funcionou adequadamente. As variáveis de eficiência da nebulização estavam comprometidas indicando que a pressão gerada no compressor é um aspecto crítico na eficiência do tratamento. O método alternativo da avaliação dos compressores se apresentou adequado para ser utilizado nos compressores utilizados no tratamento da FC.
INTRODUCTION: Cystic fibrosis (CF) treatment of involves the use of medications supplied through nebulizers and their proper functioning is essential. OBJECTIVES: To evaluate the performance of jet nebulizers used by CF patients and to compare two pressure gauges Compressors evaluation. METHODS: This was a descriptive, cross - sectional study of the nebulizers used by patients with CF of the Mucoviscidosis Care Association of Minas Gerais. The patients brought compressors (Proneb Ultra®) and nebulizers (Pari LC plus®) for evaluation. The performance of the compressor was evaluated by operating pressure measurements using PARI PG101® manometers (PARI GmbH, Starnberg, Germany) and analog FSA (Famabras, Itaquaquecetuba, Brazil). The variables of efficiency of nebulization under study were: nebulizer delivery volume (NDV), drug output rate (DOR), and residual volume (RV), which were calculated by weighing each nebulizer before nebulization and 10 minutes after nebulization using a saline solution (2.5 mL). The mass median diameter (MMD) was calculated using the equation proposed by Standaert et al. Statistical analysis included the package R (v.2.15) and MINITAB, with alpha = 0.05. The Kappa coefficient was calculated to evaluate agreement of values between the equipment\'s, and ROC curve constructed to calculate the value measured in the FSA manometer with better sensitivity / specificity, using the PARI PG101® manometer as reference. The association between pressure values, NDV, DOR and RV was calculated by the Spearman correlation. RESULTS: We evaluated 146 systems with a median time of use of 32 (12-60) months ± 36 months. Fifty-seven (39%) did not function properly, with pressure values lower than half the reference. The systems with inadequate functioning compromised the efficiency variables of the nebulizers. The agreement between the different evaluation methods according to the classification; with adequate and inadequate functioning through the Kappa coefficient was 0.81 (95% CI -0.65-0.97), p <0.001. In the evaluation of sensitivity and specificity, the cut-off point of 23.5 PSI on the FSA manometer showed sensitivity = 99% and specificity = 79% (p <0.001). There was a significant association between NDV, DOR, RV and measured pressures. CONCLUSIONS: A significant number of the nebulizer systems were ineffective. The variables of nebulization efficiency were compromised, which indicated that the pressure generated by the compressor was a critical aspect for treatment efficiency. The alternative method of compressors evaluation was suitable for use in CF treatment routine.

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Fabro, Alexandre Todorovic. "Remodelamento parenquimatoso pulmonar em dois modelos experimentais de fibrose /." Botucatu, 2012. http://hdl.handle.net/11449/104550.

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Orientador: Vera Luiza Capelozzi
Coorientador: Claudia Aparecida Rainho
Banca: João Lauro Viana de Camargo
Banca: Thais Helena A. Thomaz Queluz
Banca: Alexandra Muxfeldt Ab'Saber
Banca: Rimarcs Gomes Ferreira
Resumo: A fibrose pulmonar é a base patológica de uma variedade de doenças crônicas incuráveis. A IL-17A, uma glicoproteína secretada de células Th17, é uma citocina pró-fibrótica relacionada recentemente à síntese de colágeno V e fibrose pulmonar. O remodelamento parenquimatoso pulmonar da matriz extracelular pelo colágeno I e V, apoptose e resposta Th17 foi estudado em camundongos Balb/c, C57/B6J selvagens e com knockout para o receptor A da IL-17; para determinar as vias fisiopatológicas que prolongam a fase tardia do processo fibrótico induzido por bleomicina e paraquat. Microscopia eletrônica, imunofluorescência, imunohistoquímica, detecção in situ da apoptose, morfometria, reconstrução tridimensional e reação em cadeia da polimerase em tempo real foram usados para avaliar a quantidade, estrutura e cadeias moleculares dos tipos de colágenos, apoptose e células imunes. Verificamos um aumento da síntese e secreção do colágeno V que promove a perpetuação da fibrose pulmonar de maneira IL-17A dependente. Além disso, observou-se que marcadores críticos da resposta Th17 como IL17, STAT3, TGF-β, IL-6, IL- 21, IL-23 e células T CD4+ foram significantemente aumentados em cepas susceptíveis a fibrose pulmonar e intensificadas na ausência do receptor A da IL-17. O aumento de marcadores Th17 resulta em um aumento de células T CD4+ através de uma resposta imune que efetivamente bloqueia a degradação do colágeno V, o qual contribui para o bloqueio da apoptose. Nosso estudo indica que o colágeno V participa da perpetuação da fibrose pulmonar por mecanismos IL-17 dependente e independentes, indicando o potencial alvo terapêutico do colágeno V e das vias de sinalização da resposta IL-17 no tratamento das doenças fibroproliferativas pulmonares
Abstract: Pulmonary fibrosis is the pathologic basis for a variety of incurable human chronic lung diseases. IL-17A, a glycoprotein secreted from IL-17- producing cells, has recently been shown to be a profibrotic cytokine involved in type V collagen synthesis and pulmonary fibrosis. Remodeling of the extracellular matrix by collagen I and V, cell death and Th-17 immune response were evaluated in Balb/c, wild and IL-17 receptor A knockout C57/B6J mice, to determine the pathways that prolong the late phase of the fibrotic process induced by bleomycin and paraquat. Electron microscopy, immunofluorescence, immunohistochemistry, in situ detection of apoptosis, morphometry, tridimensional reconstruction and a real-time PCR were used to evaluate the amount, structure and molecular chains of collagen types, apoptosis and immune cells. We verified increased synthesis and secretion of type V collagen that promoted the maintenance of pulmonary fibrosis in a IL-17A dependent manner. However, we observed that the critical Th17 markers, IL-17, STAT3, TGF-β, IL-6, IL-21, IL-23 and CD4+ T cells, were significantly increased in the fibrosis-susceptible strain and intensified in the absence of IL-17 receptor A. Increased Th17 markers resulted in an increase in CD4+ T cells in fibrotic lung tissue toward an immune response that effectively blocked degradation of collagen V, which contributes to block apoptosis. Our studies indicate that collagen V participates in the maintenance of pulmonary fibrosis in both Th-17 - dependent and -independent manners and that collagen V and the components of the Th-17 signaling pathway are potential therapeutic targets for the treatment of fibroproliferative lung diseases
Doutor

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Mazali, Fernanda Cristina 1978. "Nefropatia crônica por ciclosporina : papel do ácido úrico e do sistema renina angiotensina aldosterona como mediadores de disfunção endotelial, inflamação e vasculopatia." [s.n.], 2011. http://repositorio.unicamp.br/jspui/handle/REPOSIP/309125.

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Orientadores: Marilda Mazzali, José Butori Lopes de Faria
Tese ( doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: A nefrotoxicidade por ciclosporina caracteriza-se, do ponto de vista histológico, por fibrose intersticial em faixa, atrofia tubular e hialinose de arteríolas aferentes glomerulares, ou seja, um quadro compatível com doença renal isquêmica. Esta isquemia provocada pela ciclosporina leva a redução da taxa de filtração glomerular, com consequente elevação dos níveis séricos de ácido úrico. Além disto, a ciclosporina altera o transporte tubular de urato, favorecendo o desenvolvimento de hiperuricemia. No modelo experimental de nefropatia pela ciclosporina, a elevação dos níveis de ácido úrico apresenta associação com lesão túbulo intersticial mais severa, além de maior frequência de hialinose de arteríola aferente. Em estudos anteriores demonstramos que a hiperuricemia agrava a nefrotoxicidade pela ciclosporina e também que, a administração concomitante de agentes hipouricemiantes previne a lesão renal pela CsA. Assim, consideramos a hipótese de que, em um modelo experimental de nefropatia crônica pela ciclosporina, instalada, a normalização dos níveis de ácido úrico com alopurinol ou benzbromarona poderia reverter a lesão renal estabelecida. Nefropatia pela ciclosporina foi induzida em ratos Sprague Dawley com injeções subcutâneas diárias de ciclosporina, em associação com dieta hipossódica, por 5 semanas. Ao final deste período, grupos experimentais foram divididos com interrupção da ciclosporina, tratamento com CsA isolada ou em associação com alopurinol ou benzbromarona por um período adicional de 4 semanas. Ao final de 9 semanas de estudo, foram realizadas avaliações funcionais e histológicas. Neste modelo, a co-administração de alopurinol ou benzbromarona cursou com redução dos níveis de ácido úrico e minimizou o quadro de nefrotoxicidade estabelecida por ciclosporina, através da redução de hialinose arteriolar, glomeruloesclerose e fibrose intersticial, além da melhora da função renal, do estresse oxidativo e da apoptose, porém sem efeito anti inflamatório, avaliado pelo infiltrado de macrófagos e pela expressão de osteopontina. Os resultados mais significativos no grupo tratado com alopurinol sugerem que, além do efeito hipouricemiante, o alopurinol pode também apresentar um mecanismo antioxidante, conforme demonstrado pela redução da peroxidação lipídica e da geração de radicais livres, resultando em menor intensidade de apoptose de células tubulares renais. Assim, a redução dos níveis de ácido úrico neste modelo atuou como protetor na progressão da lesão de microvasculatura e na redução da área de fibrose intersticial, mas não da lesão inflamatória. No modelo de nefropatia pela ciclosporina, assim como no de hiperuricemia, ocorre elevação da atividade de renina, sugerindo a participação do sistema renina angiotensina aldosterona na fibrose renal. Para determinar este efeito, um segundo estudo utilizou a associação de um inibidor de enzima conversora da angiotensina (enalapril), um bloqueador de receptor AT1 de angiotensina (losartan) ou um inibidor competitivo da aldosterona (espironolactona) ao tratamento com ciclosporina, após a instalação da lesão. Os animais experimentais receberam ciclosporina por 5 semanas, e após a instalação da nefropatia, foram divididos em um dos grupos experimentais e acompanhados por um período adicional de 4 semanas. A utilização de moduladores do SRAA também cursou com melhora funcional e histológica da nefropatia pela ciclosporina, sem alteração dos marcadores de inflamação intersticial. A melhora da vasculopatia pode ser atribuída à redução do remodelamento vascular com estas drogas, porém com efeito limitado sobre a geração de radicais livres de oxigênio e apoptose de células tubulares. Em resumo, os resultados do presente estudo indicam que em modelo experimental de nefrotoxicidade por CsA, o uso de hipouricemiantes ou de modeladores do sistema-renina-angiotensina-aldosterona apresentaram um importante efeito renoprotetor, comparável, do ponto de vista funcional, à interrupção do tratamento com ciclosporina. As duas abordagens terapêuticas foram eficientes na limitação da progressão da nefropatia, com reversão parcial da fibrose intersticial, provavelmente mediada por melhora de oxigenação tecidual secundária à redução da vasculopatia e do remodelamento vascular. A manutenção do estímulo tóxico da ciclosporina, com manutenção da inflamação, da geração de radicais livres de O2 e da apoptose de células tubulares, entretanto, não foi completamente neutralizado pela intervenção farmacológica
Abstract: Chronic allograft nephropathy is characterized by stripped tubular atrophy and interstitial fibrosis, in presence of arteriolar hyalinosis, resembling an ischemic pattern of chronic kidney disease. Chronic ischemia is associated with reduced glomerular filtration rate, and increase in serum uric acid levels. Cyclosporine per se also has a direct effect on tubular urate handling that facilitates the development of hyperuricemia. Hyperuricemia exacerbates chronic cyclosporine nephropathy, with a more severe tubulointerstitial fibrosis and atrophy, as well as worsening of arteriolar hyalinosis. In a previous study we have shown that concomitant treatment with uric acid lowering agents limits the development of experimental CsA nephropathy. The hypothesis of the present study was that treatment with uric acid lowering agents, after the development of CsA nephropathy could reverse or reduce the severity of tubulointerstitial disease. Male Sprague Dawley rats received daily SC injections of cyclosporine in presence of low salt diet, during 5 weeks. At the end of this period, experimental groups were assigned for CsA withdrawal, maintenance of daily CsA alone or associated with allopurinol or benzbromarone in drinking water for an additional period of 4 weeks. At the end of 9 weeks of study, rats were sacrificed for functional and morphological analysis of kidneys. In this model, concomitant treatment with allopurinol or benzbromaroes was associated with reduction of serum uric acid levels, improvement in renal function and renal disease, characterized by lower arteriolar hyalinosis index, less glomerulosclerosis and significant reduction in interstitial fibrosis area. Other findings included reduction in oxidative stress markers and apoptotic cells, despite of maintenance of inflammatory status, quantified by macrophage infiltration and osteopontin expression. Allopurinol treatment was associated with more significant changes, with reduction of free radical generation, and lower grade of apoptotic cells in renal cortex, suggesting a participation of antioxidant effects in association with uric acid reduction. Taken together, these datsa suggests that reduction of serum uric acid in the stablished model of CsA nephropathy has a protective effect in microvascular lesions and progression of interstitial disease, despite the maintenance of interstitial inflammation. In cyclosporine nephropathy, as well as in the experimental hyperuricemia model, renal disease is associated with increased renin activity, suggesting the participation of renin angiotensin aldosterone system (RAS) in the mechanism of disease. In order to analyze the effect of RAS in CsA nephropathy model, a second study tested the treatment with angiotensin converting enzyme inhibitor (enalapril), a angiotensin II AT1 receptor blocker (losartan) or an aldosterone inhibitor (espironolactone) in association with cyclosporine after the development of chronic nephropathy. Experimental animals were treated with cyclosporine and low salt diet for 5 weeks, and then assigned for one treatment group, including cyclosporine withdrawal, cyclosporine alone, CsA and enalapril, CsA and losartan or CsA and espironolactone for an additional period of 4 weeks. RAS blockade in the established model of CsA nephropathy was associated with improvement in renal function and interstitial fibrosis, despite the maintenance of interstitial inflammation. The most striking finding was the improvement of arteriolar hyalinosis and glomerulosclerosis, suggesting that the most important effect was protecting against vascular remodeling. The improvement in vasculopathy was associated with reduction in tissue hypoxia, with a partial reduction in oxidative stress and tubular cell apoptosis. Both therapeutic interventions proved to be efficient in limiting progression of renal disease, with a partial reversion of interstitial fibrosis. The main mechanism is associated with improvement in renal tissue O2 delivery, as a consequence of recovery of arteriolar hyalinosis and control of vascular remodeling. However, maintenance of CsA therapy was associated with a persistent toxic effect, with maintained interstitial inflammation, free radical generation and tubular cell apoptosis that was not neutralized by intervention
Doutorado
Ciencias Basicas
Doutor em Clínica Médica

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Marcelino, Aline Roberta Bariani 1985. "Polimorfismos -765G>C e 8473T>C no gene COX2 e 57460C>T no gene IFRD1 como modificadores da gravidade da fibrose cística." [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308605.

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Orientador: Carmen Sílvia Bertuzzo
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: A Fibrose Cística (FC) é uma doença autossômica recessiva causada por mutações no gene CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) que acarretam em defeito ou na ausência da proteína por ele sintetizada. A CFTR, produto deste gene é uma proteína canal, localizada na membrana apical das células, responsável pela condução de íons cloreto. As mutações levam à ausência da proteína CFTR ou a alteração qualitativa/quantitativa da proteína, que acarreta no desequilíbrio osmótico entre os meios intra e extracelular. Como consequência há a ocorrência de muco viscoso e de difícil excreção nos pulmões e obstrução dos ductos pancreáticos, afetando desta forma o sistema respiratório e digestório. São conhecidas mais de 1.900 mutações no gene CFTR, sendo que mesmo em pacientes com mutações iguais como a F508del - com alta prevalência na população brasileira - há divergência entre os fenótipos observados. Dessa forma, o genótipo CFTR parece não ser determinante na modulação da gravidade clínica, uma vez que, indivíduos com mesmo genótipo CFTR apresentam manifestações clínicas diferentes. Outros genes, diferentes do CFTR foram associados à gravidade clínica dos pacientes, revelando que os produtos por eles expressos exercem algum tipo de ação modificadora do fenótipo da FC. Tais genes foram denominados modificadores e atuam em fatores secundários relacionados à evolução do quadro clínico, como a articulação do sistema imune. Os genes COX2 e IFRD1, com ação importante no sistema imune e no recrutamento de células de defesa foram identificados como modificadores da FC em estudos prévios realizados em uma população diferente da brasileira. No presente estudo, os polimorfismos -765G>C e 8473T>C no gene COX2 e 57460C>T no gene IFRD1, candidatos a modificadores, foram identificados nos pacientes e um estudo de associação genótipo-fenótipo foi conduzido a fim de verificar a ação moduladora de tais polimorfismos nos pacientes estudados. Nenhuma associação foi encontrada, exceto para o íleo meconial (p=0,028 - em pacientes com duas mutações identificadas no gene CFTR pertencentes à classe I, II e III) e para a polipose nasal (p=0,022 - em pacientes sem considerar o genótipo CFTR) para o polimorfismo 8473T>C no gene COX2
Abstract: Cystic fibrosis (CF) is an autosomal recessive disease caused by CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene mutations that lead to defective polypeptide or lack of the protein CFTR. The CFTR is a channel protein located in the apical cells membrane, responsible for chloride ions conductance. The mutations lead to an osmotic disequilibrium between intra and extracellular mediums, which causes viscous mucus production that is hard to be eliminated from lungs and pancreatic ducts, affecting, this way, respiratory and digestive systems. More than 1,900 CFTR different mutations are known, and even patients that carries identical mutations as F508del - the most common one in Brazilian population - shows a great discrepancy between the phenotypes that are observed. Thus, CFTR genotype seems not to be crucial in disease clinical course modulation, once different subjects carrying the same CFTR mutations reveal distinctive clinical manifestations. Genes besides CFTR were associated to CF patients clinical manifestation, revealing that the molecules they express have some kind of modifier activity in CF phenotype. Such genes were labeled as modifier genes and they act in secondary factors related to clinical course evolution as immune system response. The genes COX2 and IFRD1 have an important role in immune system and defense cell recruitment and they were identified as CF modifiers in previous studies that analyzed different population from the Brazilian one. In this current study, the polymorphisms -765G>C, 8473T>C and 57460C>T located in these genes were identified in our patients and association genotype-phenotype were carried out in order to verify the modulator activity of such variants in the studied casuistic. There was not found association, except for meconium ileus (p=0,028 - in patients with two CFTR mutations from class I, II and III) and for nasal polyposis (p=0,022 - in patients whose CFTR genotype was not considered) to 8473T>C polymorphism in COX2 gene
Mestrado
Ciencias Biomedicas
Mestre em Ciências Médicas

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46

Mauch, Renan Marrichi 1988. "Sorologia anti-IgG para detecção da infecção pulmonar por Pseudomonas aeruginosa em pacientes com fibrose cística atendidos no Hospital de Clínicas da Universidade Estadual de Campinas." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308550.

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Orientador: Carlos Emilio Levy
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: A Fibrose Cística (FC) é uma doença genética decorrente da disfunção da proteína reguladora da condutância transmembrana (CFTR), essencial para o transporte de íons e água pela membrana celular, sendo a doença pulmonar a mais preponderante das manifestações, havendo colonização bacteriana seguida de infecções, principalmente por Pseudomonas aeruginosa, bactéria de maior relevância para pacientes com FC. Neste estudo, buscamos padronizar e avaliar o valor diagnóstico e prognóstico de um teste de ELISA (Enzyme-linked immunosorbent assay) para pesquisa de anticorpos séricos IgG anti-P. aeruginosa, comparando os resultados com a cultura microbiológica de material respiratório (padrão-ouro atual). Os níveis de anticorpos foram avaliados primeiramente em um estudo transversal, com 117 pacientes com FC atentidos no HC-Unicamp, buscando determinar a acurácia do teste, e paralelamente em um estudo longitudinal, com 78 pacientes inicialmente sem infecção crônica por P. aeruginosa, buscando monitorar a variação dos níveis de anticorpos em diferentes períodos de coleta de amostras. Observamos que a taxa de soropositividade e a mediana dos níveis de IgG anti-Pseudomonas foram significativamente maiores em pacientes cronicamente infectados pela bactéria, tendo o teste sensibilidade de 96,8%, especificidade de 98,1%, valor preditivo positivo de 96,8% e valor preditivo negativo de 98,1% para a detecção da infecção crônica. Houve aumento progressivo dos níveis de anticorpos dos pacientes ao longo do tempo, com maior significância em dois períodos de coleta, entre pacientes que apresentaram evolução no perfil de colonização/infecção por P. aeruginosa. Foi possível, pela pesquisa de anticorpos, a detecção da bactéria até 15 meses antes do primeiro isolamento positivo em cultura e pacientes com níveis de anticorpos elevados no início do estudo apresentaram maior risco de posterior evolução no perfil de colonização/infecção por P. aeruginosa. Concluímos que a sorologia pode ser um recurso diagnóstico de grande utilidade para a detecção precoce da infecção pulmonar P. aeruginosa em pacientes com FC, complementando resultados da cultura microbiológica. Introduzindo-a na rotina de acompanhamento dos pacientes, será possível a terapia antimicrobiana precoce, o que poderá ajudar a melhorar a função pulmonar dos pacientes e sua qualidade de vida
Abstract: Cystic Fibrosis (CF) is a genetic disease, resulting from disfunction of the CFTR protein, which is essential for the transportation of ions and water across the cell membrane, being the pulmonary disease the most prominent manifestation, where there is bacterial colonization followed by infections, mainly caused by Pseudomonas aeruginosa, the most relevant bacterium for CF patients. The aim of this study was to standardize and to evaluate the diagnostic and prognostic values of an ELISA (Enzyme-linked immunosorbent assay) test for detection of serum anti-P. aeruginosa IgG antibodies, comparing the results with the microbiological respiratory culture (current gold standard). The antibody levels were first evaluated in a cross sectional study, with 117 CF patients attended at the HC-Unicamp, seeking to evaluate the accuracy of the test, and in a parallel longitudinal study, with 78 patients initially without P. aeruginosa chronic infection, seeking to monitor the variation in the antibody levels in different periods of sample collection. We observed that the seropositivity rate and the median of the anti-Pseudomonas IgG antibody levels were significantly higher in chronically infected patients, with the serological test presenting a sensitivity of 96.8%, specificity of 98.1%, positive predictive value of 96.8% and negative predictive value of 98.1% for detection of chronic infection. There was a progressive increase of the antibody levels in the patients over time, with greater significance, in two collection periods, among patients who presented evolution in the P. aeruginosa colonization/infection status. Through antibody measurement, we could detect the bacterium until 15 months before the first positive isolation in microbiological culture and the patients with elevated antibody levels in the baseline showed higher risk for later evolution in the P. aeruginosa colonization/infection status. We conclude that serology can be a very useful diagnostic resource for early detection of P. aeruginosa pulmonary infection, complementing microbiological results. By introducing it on the follow-up routine, the early antimicrobial therapy will be possible, which will help to improve the patients¿ lung function and quality of life
Mestrado
Saude da Criança e do Adolescente
Mestre em Ciências

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Capizzani, Carolina Paulino da Costa. "Epidemiologia das infecções bacterianas em pacientes com fibrose cística envolvendo Achromobacter e bactérias do complexo Burkholderia cepacia." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/60/60135/tde-23112017-100715/.

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Achromobacter sp. e Burkholderia sp. são considerados patógenos problemáticos em pacientes com fibrose cística (FC), principalmente por apresentarem linhagens que podem ser transmissíveis e multidroga resistentes. Este trabalho teve como objetivo analisar isolados de Achromobacter e do complexo Burkholderia cepacia (CBc) de pacientes com FC atendidos no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto (HCFMRP-USP) e no Hospital das Clínicas da Faculdade de Ciências Médicas de Campinas (HCFCM-UNICAMP): identificar gênero/espécies; avaliar a sensibilidade a antimicrobianos; investigar relações genéticas entre os isolados por Pulsed-field Gel Electrophoresis (PFGE); elucidar a taxonomia e epidemiologia molecular dos isolados por Multilocus Sequence Typing (MLST) e correlacionar os resultados com dados clínicos. Entre julho/2011 a setembro/2014, nos dois hospitais, as espécies mais prevalentes de Achromobacter e CBc foram A. xylosoxidans e B. vietnamiensis, respectivamente. Os antibióticos mais efetivos contra isolados de Achromobacter sp. de pacientes do HCFMRP-USP foram imipenem e meropenem e do HCFCM-UNICAMP foram meropenem e ceftazidima. Os antibióticos mais efetivos contra CBc de pacientes do HCFMRP-USP foram sulfametoxazol-trimetoprim e meropenem e do HCFCM-UNICAMP foram ceftazidima e meropenem. Houve suspeita de contaminação cruzada entre alguns pacientes que apresentaram isolados com o mesmo perfil de PFGE. No HCFMRP-USP, isolados de B. vietnamiensis de pacientes diferentes tiveram o mesmo perfil de PFGE e apenas 2 pacientes tinham infecção crônica. No HCFCM-UNICAMP, isolados de B. cenocepacia IIIB de 4 pacientes apresentaram o mesmo pulsotipo, porém nenhum dos pacientes tinha infecção crônica. Isolados de B. vietnamiensis e B. multivorans de pacientes diferentes no HCFCM-UNICAMP também apresentaram o mesmo pulsotipo, e apenas um paciente colonizado por B. multivorans tinha infecção crônica. No HCFCM-UNICAMP, isolados de Achromobacter apresentaram perfis únicos de PFGE, enquanto que no HCFMRP-USP houve suspeita de contaminação cruzada somente entre pacientes colonizados por A. xylosoxidans, sendo que 3 destes pacientes estavam com infecção crônica. Nos dois hospitais, 17 STs foram identificados em isolados do CBc, 14 deles pela primeira vez e 3 STs (ST17, ST369 e ST911) apresentaram distribuição intercontinental. Em isolados de pacientes dos dois hospitais foram identificados alguns STs em comum (STs 1056, 1057, 369 e 911), o que pode sugerir ancestral comum. No total, 6 STs diferentes foram identificados em isolados de A. xylosoxidans de pacientes do HCFMRP-USP, dos quais 3 STs apareceram pela primeira vez e os outros 3 STs apresentaram distribuição intercontinental. Nenhuma das espécies apresentou linhagens epidêmicas descritas. Os pacientes colonizados cronicamente por A. xylosoxidans apresentaram valores de escore de Shwachman, índice de massa corporal (IMC) e função pulmonar menos preservados e exacerbações ligeiramente mais frequentes do que pacientes colonizados por bactérias do CBc. Este estudo possibilitou a correta identificação dos patógenos proporcionando a adoção de medidas de controle mais efetivas e tratamentos mais adequados, além de atualização do banco de dados epidemiológicos, o que facilita a análise colaborativa multicêntrica e auxilia no controle de infecção global destes patógenos.
Achromobacter sp. and Burkholderia sp. are troublesome pathogens in cystic fibrosis (CF) patients, mainly because they may have transmissible and multidrug resistant strains. The aim of this study was to analyze the Achromobacter and Burkholderia cepacia complex (Bcc) isolates from CF patients treated at the Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto (HCFMRP-USP) and Hospital das Clínicas da Faculdade de Ciências Médicas de Campinas (HCFCM-UNICAMP); to identify genus/species; to evaluate antimicrobial susceptibility; to investigate clonal relatedness among isolates by Pulsed-field Gel Electrophoresis (PFGE); to elucidate taxonomy and molecular epidemiology of the isolates by Multilocus Sequence Typing (MLST), and to relate the results to clinical data. Between July/2011 and September/2014, in both hospitals, the most prevalent species of Achromobacter and Bcc were A. xylosoxidans and B. vietnamiensis, respectively. The most effective antibiotics against Achromobacter sp. isolates of patients from HCFMRP-USP were imipenem and meropenem, and from HCFCM-UNICAMP were meropenem and ceftazidime. The most effective antibiotics against Bcc isolates of patients from HCFMRP-USP were sulfamethoxazole-trimethoprim and meropenem, and from HCFCM-UNICAMP were ceftazidime and meropenem. Cross-contamination was suspected among some patients who presented isolates with the same PFGE profile. In HCFMRP-USP, isolates of B. vietnamiensis from different patients showed the same PFGE profile, and only 2 patients had chronic infection. In HCFCM-UNICAMP, isolates of B. cenocepacia IIIB of 4 patients showed the same pulsetype, but none of the patients had chronic infection. Isolates of B. vietnamiensis and B. multivorans from different patients from HCFCM-UNICAMP also showed the same pulsetype, and only one patient colonized by B. multivorans had chronic infection. In HCFCM-UNICAMP, Achromobacter isolates showed unique profiles of PFGE, whereas in HCFMRP-USP cross-contamination was only suspected among patients colonized by A. xylosoxidans, and 3 of these patients had chronic infection. In both hospitals, 17 STs were identified in Bcc isolates, 14 of them for the first time and 3 STs (ST17, ST369 and ST911) presented intercontinental distribution. In both hospitals, some common STs (STs 1056, 1057, 369 and 911) were identified, which may suggest a common ancestor. In total, 6 different STs were identified in A. xylosoxidans isolates of patients from HCFMRP-USP, of which 3 STs were identified for the first time, and the other 3 STs presented intercontinental distribution. None of the species presented described epidemic strains. Patients chronically colonized by A. xylosoxidans showed less preserved Shwachman score, body mass index (BMI) and lung function, and slightly more frequent exacerbations than patients colonized by Bcc bacteria. This study provided the correct identification of the pathogens, allowing the adoption of more effective control measures and adequate treatments, besides updating the epidemiological database, which facilitates the multicentric collaborative analysis and assists in the control of global infection of these pathogens

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Rodrigues, Alexandro dos Santos. "Expressão e distribuição da conexina 32 em fígados com fibrose experimentalmente induzida." Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/10/10132/tde-12042007-182154/.

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A conexina 32 (Cx32) é uma estrutura protéica que constitui os canais que promovem as comunicações intercelulares via junções comunicantes (GJIC), permitindo difusão de pequenas moléculas citoplasmáticas de uma célula à outra. Este trabalho objetivou os estudos destas estruturas devido a sua importância em processos hepáticos, mais especificamente, a fibrose hepática. O presente estudo foi realizado através da administração oral da droga hepatotoxica dimetilnitrosamina (DMN) em ratas Wistar duas vezes por semana em dias consecutivos no prazo de cinco semanas. A necropsia destes animais foi realizada após cinco semanas da última administração da droga e revelou um quadro de fibrose hepática, em contra partida aos resultados obtidos em um grupo controle com a mesma quantidade de animais. O material fibrótico foi submetido à análise imunohistoquímica que revelou uma presença preferencial de Cx32 dispersa no citoplasma, o que pode levar à hipótese de problemas no mecanismo de transporte citoplasmático destas estruturas, em contrapartida ao material pertencente ao grupo controle que evidenciou a presença das Cx32 na membrana plasmática formando placas juncionais. Quando submetido à análises moleculares o fígado fibrótico revelou uma diminuição da expressão gênica embora o produto protéico deste material quando comparado ao grupo controle não tenha se mostrado diminuído.
The connexin 32 (Cx32) is a proteic structure that constitute the channels that promote the cell communication by means of the gap junction (GJIC), allowing the diffusion of short cytoplasmic molecules from a cell to another. This work aimed to study these structures due to their importance in the hepatic metabolic processes. The hepatic fibrosis was triggered by the oral administration of dimethylnitrosamine (DMN) in the female rat Wistars twice a week in consecutive days during five weeks. The necropsy of these animals was carried out after the last drug administration. They presented a hepatic fibrosis state. The fibrotic material was submitted to the imunohistochemical analysis, which showed a preferencial presence of Cx32 in the cytoplasm, whereas in the control group the Cx32 was located at the membranes, in the junctional plaques. The molecular analysis showed a decrease of the genic expresson of the fibrotic material, however the proteic product wasn? t reduced in comparison with the control group as it was shown by western blot. We concluded that the fibrotic state introduced a disturbance in the intracellular distribution and genic expression of the connexin 32.

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Capizzani, Carolina Paulino da Costa. "Epidemiologia das infecções bacterianas em pacientes com fibroses cística envolvendo bactérias gram-negativas não fermentadoras emergentes." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/60/60135/tde-21062013-152337/.

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A infecção crônica do trato respiratório é responsável pela grande morbidade e mortalidade em pacientes com fibrose cística (FC). P. aeruginosa, S. aureus e bactérias do complexo Burkholderia cepacia (CBc) estão entre os patógenos mais encontrados em pulmões de pacientes com FC, mas também são encontradas outros bacilos gram-negativos não fermentadores (BGN-NF) emergentes como Achromobacter sp., Stenotrophomonas maltophilia, Ralstonia sp., Pandoraea sp., entre outros. A correta caracterização desses patógenos impacta na sobrevida e qualidade de vida desses pacientes, e é um dos grandes desafios para laboratórios de microbiologia clínica devido à similaridade fenotípica entre eles. Este estudo tem como objetivo avaliar e propor estratégias e esquema de identificação acessível à maioria dos laboratórios para a identificação de BGN-NF emergentes e listar bactérias isoladas de pacientes com FC atendidos no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP (HCFMRP-USP), com ênfase nos BGN-NF emergentes. Foram utilizados meios de cultura seletivos, reação em cadeia da polimerase (PCR), análise de polimorfirmos (RFLP). Foram coletadas 264 amostras clínicas de 107 pacientes com FC no HCFMRP-USP entre julho/2011 a setembro/2012. Inicialmente, para selecionar os BGNNF dos pacientes com FC, deve ser realizada triagem fenotípica (coloração de Gram, teste da oxidação/fermentação de glicose e produção de oxidase). Devido à dificuldade de identificação dos BGN-NF emergentes por provas bioquímicas, deve ser realizada PCR com DNA destes microrganismos para identificação de gênero e/ou espécie, utilizando os primers específicos, nas condições estabelecidas pela padronização, a qual foi realizada para aumentar a especificidade de alguns primers que apresentaram amplificação de produtos inespecíficos. Provas bioquímicas convencionais devem ser realizadas para confirmar gêneros e identificar algumas espécies não detectadas por PCR, e para resultados fenotípicos diferente da PCR deve ser realizado API® - NE. Para identificação das bactérias do CBc, deve ser realizado análise de polimorfismo, o qual se mostrou mais efetivo do que PCR para identificação de espécies e genomovares. Dos 107 pacientes, 17 estavam colonizados por bactérias do CBc, 13 colonizados por Achromobacter sp., 10 colonizados por S. maltophilia, 2 colonizados por Ralstonia sp. e um paciente colonizado por Cupriavidus sp. e Pandoraea sp., com um isolamento de cada gênero. Os genomovares mais prevalentes foram B. cenocepacia IIIB, seguido de B. vietnamiensis, B. pyrrocinia, B. cepacia e B. multivorans. A maioria dos BGNNF esteve presente em crianças com idade até 17 anos. Os meios de cultura seletivos foram extremamente necessários por permitir o isolamento de vários BGN-NF, não isolados em outros meios de cultura utilizados. A metodologia de identificação empregada foi capaz de identificar todos BNG-NF isolados e pode ser muito útil e acessível à maioria dos laboratórios clínicos.
Chronic infection of the respiratory tract accounts for the high rate of morbidity and mortality of patients suffering from cystic fibrosis (CF). P. aeruginosa, S. aureus and bacteria of the Burkholderia cepacia (BCc) complex are among the pathogens most commonly found in the lungs of CF patients, but other emergent non-fermenting gram-negative bacilli (NFGNB), such as Achromobacter sp., Stenotrophomonas maltophilia, Ralstonia sp., Pandoraea sp., among others, are found as well. The correct identification of these pathogens affects the survival rate of patients and, due to their phenotypic similarity, presents itself as one of the great challenges that clinical microbiology laboratories face. The purpose of this study is to evaluate and propose strategies and methods that are accessible to the majority of laboratories for identifying emergent NFGNBs and listing isolated bacteria (with a focus on emergent NFGNB) in CF patients receiving routine care at the Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo - USP (HCFMRPUSP). The study employed selective culture media, polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). From July 2011 to September 2012, 264 clinical samples were gathered from 107 CF patients at the HCFMRP-USP. A phenotypic screening (Gram staining, oxidase production and oxidation/fermentation of glucose) should be conducted as the first step to select the NFGNBs of CF patients. Due to the difficulty in identifying emergent NFGNBs via biochemical tests, a PCR using the DNA of these microorganisms should be carried out to identify their genus and/or species. The PCR should utilize the specific primers, at conditions established by this study, which was performed to increase the specificity of some primers that showed nonspecific amplification products. Conventional biochemical tests should be conducted to confirm genera and identify some species that the PCR failed to detect, and, in the case of phenotypic results that differ from those of the PCR, an API bacterial identification test should be conducted. RFLP analysis proven more effective than PCR in identifying species and genomovars, should be conducted to identify BCc bacteria. Of the 107 patients, 17 had positive cultures for BCc, 13 for Achromobacter sp., 10 for S. maltophilia, two for Ralstonia sp. and one patient had positive culture for Cupriavidus sp. and Pandoraea sp., with the genera isolated from each other. The most prevalent genomovar was the B. cenocepacia IIIB, followed by B. vietnamiensis, B. pyrrocinia, B. cepacia and B. multivorans. The majority of the NFGNBs were present in children up to age 17. Selective culture media were extremely necessary to allow the isolation of various NFGNBs that could not be isolated via alternative culture media. The identification methodology employed enabled the identification of all isolated NFGNBs and can be very useful and accessible to the majority of clinical laboratories.

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SOUZA, Mariane de Amarante. "DIABETES MELLITUS ESTÁ ASSOCIADO À DOENÇA HEPÁTICA MAIS AVANÇADA EM PORTADORES DA INFECÇÃO CRÔNICA PELO VÍRUS DA HEPATITE C." Universidade Federal do Maranhão, 2017. http://tedebc.ufma.br:8080/jspui/handle/tede/1765.

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Introduction: Hepatitis C virus (HCV) is an RNA virus with six different genotypes (1 to 6). This virus is mainly transmitted through parenteral route. An estimated 170 million individuals are HCV carriers worldwide. HCV infection is considered as the main cause of liver cirrhosis in the West. The natural history of HCV is related to viral and host factors. Among the latter, type 2 diabetes mellitus (T2DM) has been related with more rapid progression of liver fibrosis. Aim: To evaluate HCV carriers and identify factors associated with more advanced degrees of liver fibrosis. Methods: A cross-sectional study with chronic HCV carriers. The study was performed at the Center for Liver Study Outpatient Clinic of the Presidente Dutra University Hospital, Federal University of Maranhão, São Luís, Maranhão, northeast Brazil. The patients had their medical records analysed. The subjects with the following features were not enrolled for this study: incomplete data, HIV or HBV coinfection, end-stage chronic renal disease on dialysis and individuals who underwent kidney or liver transplantation. Demographic data (sex and age), alcohol intake (yes or no), T2DM (presence or absence), HCV genotype and degrees of liver fibrosis were retrieved from the patients’ medical records. The patients were classified as less or more advanced fibrosis. Both groups were compared to demographic variables, viral genotypes, T2DM presence and alcohol intake. We used the chi-square test and student’s t-test for nominal and numerical variables respectively. Multivariate logistic regression analysis was performed to identify factors independently associated with more advanced degrees of liver fibrosis. We used the SPSS version 23.0 for statistical analyses. Results: A total of 235 patients participated of this study. These patients had complete data on their medical records and met all the inclusion and exclusion criteria. Most of them were male (138/235; 59%) ranging from 18 to 78 years of age (53 ± 10). They were associated with more advanced degrees of fibrosis: Age (OR=1.061, 95% CI: 1.025- 1.098, p<0.001), presence of T2DM (OR 2.227, 95%CI: 1.059-4.142, p = 0.035) and alcohol intake (OR 1.921, 95%CI: 1.129-3.269, p=0.036). Conclusion: T2DM was associated with more advanced degrees of liver fibrosis among the HCV carriers. Thus, diagnosis and treatment of HCV carriers with diabetes are of great importance for interrupting the progression of liver cirrhosis.
Introdução: O vírus da Hepatite C (HCV) é um RNA vírus, que apresenta seis genótipos diferentes (1 a 6) e é transmitido por via predominantemente parenteral. Existem cerca de 170 milhões de indivíduos portadores do HCV em todo o mundo. É a principal causa de cirrose hepática no mundo ocidental. A história natural da infecção pelo HCV é modulada pela interação de fatores virais e do hospedeiro. Entre os fatores associados ao hospedeiro, Diabetes mellitus tipo 2 (T2DM) tem sido associada a maior progressão da doença hepática. Objetivo: avaliar portadores do HCV e identificar fatores associados a graus mais avançados de fibrose hepática. Metodologia: Estudo transversal com portadores da infecção crônica pelo HCV. Foram analisados dados dos prontuários de pacientes atendidos no ambulatório do Núcleo de Estudo do Fígado do Hospital Universitário da Universidade Federal do Maranhão, excluídos portadores de co-infecção com vírus da imunodeficiência humana (HIV) ou vírus da hepatite B (HBV), portadores de doença renal crônica terminal em diálise e transplantados de fígado ou rim. Resgatados dados demográficos (idade e gênero), graus de fibrose hepática, genótipo viral, história de ingestão alcoólica e diagnóstico de T2DM. Os portadores foram categorizados em graus mais e menos avançados de fibrose e comparados quanto aos dados demográficos (idade e sexo), genótipo viral, presença ou não de T2DM e ingestão alcoólica. Diferenças entre variáveis numéricas foram calculadas pelo teste t de Student e entre nominais pelo Quiquadrado. Foi realizada regressão logística multivariada para identificar fatores independentemente associados com graus mais avançados de fibrose. O programa SPSS versão 23.0 foi utilizado. Resultados: Incluídos 225 pacientes, a maioria do sexo masculino (138/235, 59%), com média de idade 53 ± 10 anos. Foram associados a graus mais avançados de fibrose: idade (OR=1,061 (IC 95% 1.025-1,098) P<0.001), presença de T2DM (OR 2,227 (IC 95% 1,059-4,142) P= 0,035) e ingestão alcoólica (OR 1,921(IC 95% 1,129-3,269) P=0,036). Conclusão: Entre portadores crônicos do HCV no Maranhão, a presença de T2DM esteve associada a graus mais avançados de fibrose hepática, sugerindo que é importante o diagnóstico da infecção crônica pelo HCV entre diabéticos, para que o tratamento da infecção seja feito, prevenindo progressão para cirrose hepática.

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Dissertations / Theses on the topic 'Fibromes'

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