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Epidemiologia molecular e características genéticas de adaptação de Pseudomonas aeruginosa causando infecção crônica em pacientes com Fibrose Cística e sua correlação com dados clínicos / Molecular epidemiology and adaptive genetic characteristics of Pseudomonas aeruginosa related to chronic infection in patients with Cystic Fibrosis and their correlation with clinical dataNatália Candido Caçador 29 August 2016 (has links)
A infecção crônica das vias aéreas por Pseudomonas aeruginosa (PA) é a principal causa de morbidade e mortalidade em pacientes com fibrose cística (FC), devido à contínua degradação do tecido pulmonar, que leva ao declínio da função pulmonar, gerada pela infecção e pelo processo inflamatório. O objetivo do presente estudo foi analisar características genéticas de PA que levam à sua adaptação às vias aéreas destes pacientes com infecção pulmonar crônica, atendidos no Centro de Referência em FC do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP e relacionar com resultados de tipagem molecular, resistência a antibióticos, cronicidade e dados clínicos dos pacientes em acompanhamento clínico no período de julho/2011 a abril/2014. As características genéticas dos isolados investigados englobam pesquisa de 18 genes de virulência e genes do sistema quorum sensing (genes lasR e rhlR), associação entre mutações e conversão para fenótipo mucoide (operon algTmucABD) e caracterização de linhagens hipermutantes (genes mutS e mutL). A identificação de P. aeruginosa foi realizada por PCR e MALDI-TOF, que mostraram alta concordância. Foram considerados os dados clínicos dos pacientes: índice de massa corpórea, escore de Shwachman, medidas de capacidade vital forçada e volume expiratório forçado no primeiro segundo. A porcentagem de pacientes com infecção pulmonar crônica por PA observada foi similar aos dados disponíveis na literatura, entretanto, a alta incidência em pacientes jovens foi preocupante. O perfil de macrorrestrição do DNA genômico por PFGE se mostrou útil para definição de colonização crônica/intermitente em associação com critérios clínicos e, juntamente com a detecção de mutações nos genes mucA e mucD confirmaram transmissão interpacientes. Foi observada alta ocorrência dos genes de fatores de virulência pesquisados para grande maioria dos isolados de pacientes crônicos. A resistência aos antibióticos pesquisados dos isolados de P. aeruginosa foi baixa e está de acordo com a literatura nacional e internacional e com a antibioticoterapia adotada no hospital. Não foi observada resistência aos carbapenêmicos e às fluoroquinolonas devido à presença de genes de resistência plasmideais. As mutações no gene mucA foram o principal mecanismo de conversão para o fenótipo mucoide e o fenótipo revertente não-mucoide ocorreu principalmente por mutações no gene algT. Foram detectadas novas mutações nos genes mutS e mutL que também suportam a ideia que hipermutação em PA está associada com mutações do sistema mismatch de reparo do DNA. O sistema quorum sensing dos isolados estudados está parcialmente prejudicado devido às várias mutações no gene lasR, mas todos conservam o gene rhlR intacto, que sustenta alguma atividade quorum sensing envolvida na produção de fatores de virulência importantes. Pacientes com infecção pulmonar crônica por PA com isolamento de outros bacilos gram-negativos não-fermentadores apresentaram maior alteração da função pulmonar quando comparados com pacientes com infecção pulmonar crônica por PA com ou sem isolamento de Staphylococcus aureus. As alterações presentes no operon algTmucABD, quorum sensing e hipermutabilidade contribuem para a cronicidade dos pacientes com FC em relação à infecção por P. aeruginosa. / The chronic airway infection by P. aeruginosa (PA) is the leading cause of morbidity and mortality in cystic fibrosis (CF) patients, due to continuous degradation of the pulmonary tissue. This leads to decline in lung function, which is generated by the related infection and inflammation. The aim of this study was to analyze genetic characteristics associated with the adaptation of PA to the airways of patients with chronic pulmonary infection attended at the CF Reference Center from the Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP; and to correlate these findings with the results of molecular typing, antibiotic resistance, chronicity and clinical data of patients in clinical follow-up from July/2011 to April/2014. The genetic characteristics of isolates investigated includes the research of 18 virulence genes and the quorum sensing system genes (lasR and rhlR genes), association between mutations and conversion to the mucoid phenotype (algTmucABD operon), and characterization of hypermutable strains (mutS and mutL genes). Identification of PA was performed by PCR and MALDI-TOF, which showed a high correlation. The patients\' clinical data considered were: body mass index, Shwachman score, forced vital capacity measures and forced expiratory volume in one second. The percentage of patients with chronic PA infection observed was similar to the data available in the literature; however, a worrying high incidence in young patients was noticed. The macrorestriction profile of genomic DNA by PFGE proved to be useful to define chronic/intermittent colonization in association with clinical criteria and it confirmed interpatient transmission, in combination with the detection of mutations in the mucA and mucD genes. High occurrence of virulence genes was detected for the vast majority of isolates from chronic CF patients. Antibiotic resistance for PA isolates was low and is in accordance with national and international literature and antibiotic therapy adopted in the hospital. There was no resistance to carbapenems and fluoroquinolones by the presence of plasmid mediated resistance genes. Mutations in the mucA gene were the main mechanism to conversion to mucoidy, and the non-mucoid revertants occurred mainly by mutations in the algT gene. New mutations in mutS and mutL genes were detected, which support the idea that hypermutation in PA is associated with mutations in the DNA mismatch repair system. The quorum sensing system of the isolates is partially damaged due to several mutations in the lasR gene, but all isolates maintain an intact rhlR gene, which holds some quorum sensing activity with production of important virulence factors. Patients with chronic PA infection with isolation of other non-fermenting gram-negative rods had greater change in lung function compared with patients with chronic PA infection with or without isolation of Staphylococcus aureus. The changes presented in the algTmucABD operon, quorum sensing and hypermutability contribute to the chronicity of CF patients in relation to infection by P. aeruginosa.
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Role of A20 in Interferon-α-Mediated Functional Restoration of Myeloid Dendritic Cells in Patients With Chronic Hepatitis CMa, Li, Zhou, Yun, Zhang, Ying, Li, Yuan, Guo, Yonghong, He, Yu, Wang, Jiuping, Lian, Jianqi, Hao, Chunqiu, Moorman, Jonathan P., Yao, Zhi Q., Zhou, Yongxing, Jia, Zhansheng 01 January 2014 (has links)
Hepatitis C virus (HCV) infection is a global health problem characterized by a high rate of chronic infection, which may in part be due to a defect in myeloid dendritic cells (mDCs). This defect appears to be remedied by treatment with interferon-α (IFN-α) -based antiviral therapies; however, the molecular mechanisms underlying mDC dysfunction in HCV infection and restoration by IFN-α treatment are unclear. The ubiquitin-editing protein A20 plays a crucial role in controlling the maturation, cytokine production and immunostimulatory function of mDCs. We propose that the expression of A20 correlates with the function of mDCs during HCV infection and IFN-α therapy. In this study, we observed that A20 expression in mDCs isolated from chronically HCV-infected subjects was significantly higher than healthy subjects or subjects achieving sustained virological responses (SVR) following antiviral treatment. Notably, A20 expression in mDCs from HCV patients during IFN-α treatment was significantly lower than for untreated patients, SVR patients, or healthy subjects. Besides, A20 expression in mDCs stimulated by polyI:C differed between HCV patients and healthy subjects, and this difference could be abrogated by the treatment with IFN-α in vitro. Additionally, A20 expression by polyI:C-activated mDCs, with or without IFN-α treatment, negatively correlated with the expression of HLA-DR, CD86 and CCR7, and the secretion of interleukin-12 (IL-12), but positively associated with the production of IL-10. Importantly, silencing A20 expression using small interfering RNAs increased the production of IL-12 in mDCs of chronically HCV-infected individuals. These findings suggest that A20 plays a crucial role in negative regulation of innate immune responses during chronic viral infection.
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Natural killer cells dictate outcomes of infection by orchestrating innate and adaptive immunity.Ali, Ayad 05 October 2021 (has links)
No description available.
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Basic research for the development of hepatitis C vaccine / C型肝炎ワクチン開発に向けた基盤研究Suzuki, Saori 23 March 2016 (has links)
Contents of the present thesis were published in the following articles. 1. Suzuki S, Mori K, Higashino A, Iwasaki Y, Yasutomi Y, Maki N, Akari H. 2016. Persistent replication of a hepatitis C virus genotype 1b-based chimeric clone carrying E1, E2 and p6 regions from GB virus B in a New World monkey. Microbiol Immunol 60:26-34. Copyright © 1999-2016 John Wiley & Sons, Inc.2. Yoshida T, Suzuki S, Iwasaki Y, Kaneko A, Saito A, Enomoto Y, Higashino A, Watanabe A, Suzuki J, Inoue K, Kuroda T, Takada M, Ito R, Ito M, Akari H. 2013. Efficient in vivo depletion of CD8+ T lymphocytes in common marmosets by novel CD8 monoclonal antibody administration. Immunol Lett 154:12-17.Copyright © 2013 Elsevier B. V. / 京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第19546号 / 理博第4206号 / 新制||理||1604(附属図書館) / 32582 / 京都大学大学院理学研究科生物科学専攻 / (主査)教授 明里 宏文, 教授 岡本 宗裕, 教授 中村 克樹 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DFAM
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Salmonella Biofilm Extracellular Polymeric Substances: Visualization and Role in Innate ImmunityHahn, Mark M. January 2021 (has links)
No description available.
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Avaliação do potencial terapêutico e perfil imunológico de triterpenos ácidos na fase crônica da infecção experimental por Trypanosoma cruzi / Evaluation of therapeutic and immunological potential of acid triterpenes in the chronic phase of experimental infection by Trypanosoma cruziSilva, Mariana Rosa da 23 August 2013 (has links)
A doença de Chagas é um problema de saúde pública, com dados preocupantes referentes ao número de pessoas contaminadas e daquelas que ainda permanecem expostas ao risco de infecção. A dificuldade do combate a Trypanosoma cruzi, agente etiológico da doença, está intimamente relacionada às interações existentes entre o parasito e o hospedeiro, sendo que até o momento, nenhum medicamento ou substância tem demonstrado real eficácia ao combate ao parasito. Em estudos recentes realizados por nosso grupo de pesquisa, os ácidos ursólico e oleanólico demonstraram um bom potencial tripanocida, além de um efeito imunomodulatório, promovendo a inibição da produção de IFN-? quando de suas utilizações por via intraperitoneal em elevadas concentrações. Considerando essas evidências encontradas em relação a essas substâncias e os efeitos promovidos no processo de avaliação biológica, propusemos como objetivo avaliar o potencial terapêutico dos triterpenos ácido ursólico e ácido oleanólico na fase crônica da infecção chagásica e suas associações ao benzonidazol, fármaco referência indicado ao tratamento da parasitose, verificando a possibilidade de geração de benefícios sobre a patogênese da infecção crônica experimental. A quantificação de linfócitos T CD4+ e T CD8+, e das citocinas IL-2, IL-10, IL-12, IFN-? e TNF-??pela técnica de citometria de fluxo, utilizando o kit BD Cytometric Bead Array®, indicaram que essas substâncias não apresentam efeitos imunomodulatórios significativos sobre a resposta Th1 e Th2 nessa fase da doença, na comparação entre grupos infectados e tratados e aquele que recebeu apenas solvente. O parasitismo tecidual determinado por Real Time PCR e as observações realizadas em cortes histológicos, mostraram, respectivamente, baixo número de cópias de DNA de T. cruzi, e ausência de ninhos amastigotas, porém, com marcante presença de infiltrado inflamatório em todos os grupos. Assim, os dados obtidos levam à conclusão de que apesar da atividade apresentada pelos triterpenos ácidos em estudo na fase aguda da doença de Chagas, o mesmo não ocorre na fase crônica, como seria desejável para favorecer uma melhora do quadro patológico, mesmo não havendo a cura da doença, considerando as conseqüências da infecção de longo prazo. / Chagas disease is a public health problem, with disturbing data about the number of infected people and those who remain at risk of infection. The difficulty of eliminating Trypanosoma cruzi, etiologic agent of the disease is closely related to the interactions between the parasite and the host, and until now, no medicine or substance has demonstrated real effectiveness against the parasite. In recent studies by our research group, the ursolic and oleanolic acids revealed considerable trypanocidal activity, and an immunomodulatory effect, promoting the inhibition of IFN-? with intraperitoneal administration in high concentrations. Considering these evidences and the effects observed during the biological evaluation, our objective was to evaluate the biological potential of the triterpenoids ursolic acid and oleanolic acid in the chronic phase of chagasic infection and their associations to benznidazole, the reference drug indicated for the treatment of this disease, verifying the possibility of benefits on the pathogenesis of experimental chronic infection. Quantification of T CD4+ and T CD8+ cells and of the cytokines IL-2, IL-10, IL-12, IFN-? and TNF-? by flow cytometry using the kit BD cytometric Bead Array®, indicated that these substances do not exhibit significant immunomodulatory effects on Th1 and Th2 responses in this stage of the disease, comparing infected and treated groups and that who received only solvent. The tissue parasitism determined by Real Time PCR and in histological observations showed, respectively, low copy number of T. cruzi DNA, and absence of amastigote nests, however, with marked inflammatory infiltration in all groups. Thus, our data lead to the conclusion that despite the activity presented by the triterpene acids studied in the acute phase of Chagas disease, the same does not occur in the chronic phase, as would be desirable to the reduction of the pathological conditions, even if there is no cure of the disease, considering the consequences of long term infection.
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Analise do tratamento das hepatites virais B e C nos usuários atendidos pelo Sistema Único de Saúde no estado do Amapá / Analysis of treatment to the viral hepatitis B and C for users attended by the Unified Health System (SUS) in the state of Amapa.Kubota, Kaori 22 December 2010 (has links)
As hepatites são as causas mais comuns de cirrose hepática e carcinoma hepatocelular (HCC) no mundo, sendo as infecções por Vírus da Hepatite B (HBV) e Vírus da Hepatite C (HCV) consideradas aquelas de maior importância como problemas de saúde pública, devido ao grande número de indivíduos atingidos (cerca de 350 milhões com hepatite B crônica e 170 milhões com HCV). No Brasil, avaliações realizadas nas últimas décadas sugerem que a endemicidade da hepatite B na região amazônica não tem decaído, com o agravante da precariedade do acesso aos cuidados de saúde nessa região. Assim, este estudo tem por objetivo avaliar o tratamento dispensado aos pacientes com hepatites virais B e C no Amapá, que faz parte da Amazônia Legal, para que seja possível conhecer a situação da saúde publica dessa localidade. A coleta de dados foi realizada em um centro de referência que centraliza o atendimento aos pacientes portadores de hepatite B e C, por meio de instrumento de coleta de dados previamente validado e aprovado pelo Comitê de Ética em Pesquisa da Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo (CEPFCFRP/USP), entre 1º de julho de 2007 e 30 de junho de 2009, e o programa estatístico EPI INFO, versão 3.5.1, foi utilizado para o lançamento e análise dos dados coletados. Foram incluídos 123 pacientes suspeitos ou portadores de hepatites virais B e/ou C, com idade média de 48,3 anos e 85,4% dos indivíduos entre 30 e 69 anos de idade, sendo 55,3% do sexo masculino, 61,0% casados, 82,1% residentes em Macapá, e 39,0% encaminhados por detecção de suspeita através de exames de rotina/pré-operatório ou pelo HEMOAP. Somando-se monoinfecções e coinfecções, 66,4% e 33,6% eram de pacientes infectados por HCV e HBV, respectivamente, sendo que os crônicos eram 61,0%. O acompanhamento clínico/ambulatorial desses pacientes foi inferior a 6 meses em 52% dos casos, e 40,0% apresentavam algum grau de severidade da doença, mas em 28,6% e 65,1% desses pacientes houve ausência de exames de ultrassonografia abdominal e determinação de níveis de aminotransferases, respectivamente. O genótipo para HCV só foi determinado em 30,6% dos casos de HCV e houve falha de notificação no SINAN em 25,2% dos pacientes do estudo. Três (7,0%) portadores de HBV e 16 (18,8%) de HCV receberam tratamento farmacológico específico, entretanto, outros seis pacientes com HBV e 19 com HCV apresentavam um critério de inclusão no tratamento, mas não foram tratados por ausência de exames de monitoramento. Na avaliação dos protocolos clínicos brasileiros para tratamento de HBV e HCV em relação aos internacionais, os primeiros se mostraram adequados e atualizados, entretanto, as falhas em seu seguimento pelas unidades de saúde que integram a rede assistencial para pacientes com HBV e HCV resultaram em deficiências nos serviços oferecidos, possivelmente decorrentes de treinamentos e capacitações insuficientes, ausência serviços de maior complexidade, e também devido isolamento natural da região. Diante dessas evidências, verifica-se a necessidade de ações governamentais no combate às hepatites virais mais abrangentes e que alcancem essa região. / Hepatitis are the most common cause for cirrhosis and hepatocelullar carcinoma (HCC) in the worldwide, and infections by the Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) are considered the most importance as public health problems, due to the large number of affected individuals (about 350 millions with chronic hepatitis B and 170 millions with HCV). In Brazil, evaluations made in the last decades suggest that the endemicity in Amazon area has not decreased, with the worsen situation of uncertain access to the health care in this location. Therefore, this research has the purpose to evaluate the treatment delivered to the patients infected by hepatitis virus B and C in Amapa, which belongs to the Legal Amazon, due to become possible to know the public health situation in this location. The data collection was placed in a reference center which concentrates the attendance to the hepatitis B and C carriers, using a data collection instrument previously validated and approved by the Ethics Committee in Research of the College of Pharmaceuticals Sciences of Ribeirão Preto, University of São Paulo (CEP-FCFRP/USP), between July 1st 2007 and June 30th 2009, in addition, the statistical software EPI INFO, version 3.5.1, was used to register and analyze the collected data. The 123 included individuals were suspected to have the infection or hepatitis B and/or C carriers, mean age of 48.3 years and 85.4% of these individuals were aged between 30 and 69 years old, 55.3% were men, 61.0% of them were married, 82.1% were resident in Macapa, and 39.0% of them were forwarded to the reference center due to detection of the infection by the routine exams / before surgery or by the HEMOAP, the blood bank. By the total of monoinfections and coinfections, 66.4% and 33.6% were patients infected by HCV and HBV, respectively, and the chronic patients were 61.0%. The clinical/ambulatorial follow-up of these patients were less than 6 months in 52.0% from the total, and 40.0% showed some severity grade due to the disease, however, 28.6% and 65.1 of these patients were lack of abdominal ultrasonography and aminotransferases determination exams, respectively. The genotype for HCV were determinate only in 30.6% of HCV infections and there were in SINAN notification failure in 25.2% of patients of study. Three (7.0%) HBV carriers and 16 (18.8%) HCV carriers receipt specific pharmacological treatment, nevertheless, others six HBV patients and 19 HCV patients had at least one criteria of inclusion in the treatment, but they were not treated because of monitoring exams absence. In the evaluation of Brazilian clinical protocol to HBV and HCV in regard to the international ones, those ones showed to be appropriates and updated, however, the failures in their following by the health units that integrate the assistance network to the HBV and HCV infected patients had outcomes in lack of offered services, probably due to insufficient training and qualification of the professionals, lack of more complex services, and also due to natural isolation of this area. Because of these evidences, it verifies the need of more including and reaching government actions to fight the viral hepatitis in this location.
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Avaliação do potencial terapêutico e perfil imunológico de triterpenos ácidos na fase crônica da infecção experimental por Trypanosoma cruzi / Evaluation of therapeutic and immunological potential of acid triterpenes in the chronic phase of experimental infection by Trypanosoma cruziMariana Rosa da Silva 23 August 2013 (has links)
A doença de Chagas é um problema de saúde pública, com dados preocupantes referentes ao número de pessoas contaminadas e daquelas que ainda permanecem expostas ao risco de infecção. A dificuldade do combate a Trypanosoma cruzi, agente etiológico da doença, está intimamente relacionada às interações existentes entre o parasito e o hospedeiro, sendo que até o momento, nenhum medicamento ou substância tem demonstrado real eficácia ao combate ao parasito. Em estudos recentes realizados por nosso grupo de pesquisa, os ácidos ursólico e oleanólico demonstraram um bom potencial tripanocida, além de um efeito imunomodulatório, promovendo a inibição da produção de IFN-? quando de suas utilizações por via intraperitoneal em elevadas concentrações. Considerando essas evidências encontradas em relação a essas substâncias e os efeitos promovidos no processo de avaliação biológica, propusemos como objetivo avaliar o potencial terapêutico dos triterpenos ácido ursólico e ácido oleanólico na fase crônica da infecção chagásica e suas associações ao benzonidazol, fármaco referência indicado ao tratamento da parasitose, verificando a possibilidade de geração de benefícios sobre a patogênese da infecção crônica experimental. A quantificação de linfócitos T CD4+ e T CD8+, e das citocinas IL-2, IL-10, IL-12, IFN-? e TNF-??pela técnica de citometria de fluxo, utilizando o kit BD Cytometric Bead Array®, indicaram que essas substâncias não apresentam efeitos imunomodulatórios significativos sobre a resposta Th1 e Th2 nessa fase da doença, na comparação entre grupos infectados e tratados e aquele que recebeu apenas solvente. O parasitismo tecidual determinado por Real Time PCR e as observações realizadas em cortes histológicos, mostraram, respectivamente, baixo número de cópias de DNA de T. cruzi, e ausência de ninhos amastigotas, porém, com marcante presença de infiltrado inflamatório em todos os grupos. Assim, os dados obtidos levam à conclusão de que apesar da atividade apresentada pelos triterpenos ácidos em estudo na fase aguda da doença de Chagas, o mesmo não ocorre na fase crônica, como seria desejável para favorecer uma melhora do quadro patológico, mesmo não havendo a cura da doença, considerando as conseqüências da infecção de longo prazo. / Chagas disease is a public health problem, with disturbing data about the number of infected people and those who remain at risk of infection. The difficulty of eliminating Trypanosoma cruzi, etiologic agent of the disease is closely related to the interactions between the parasite and the host, and until now, no medicine or substance has demonstrated real effectiveness against the parasite. In recent studies by our research group, the ursolic and oleanolic acids revealed considerable trypanocidal activity, and an immunomodulatory effect, promoting the inhibition of IFN-? with intraperitoneal administration in high concentrations. Considering these evidences and the effects observed during the biological evaluation, our objective was to evaluate the biological potential of the triterpenoids ursolic acid and oleanolic acid in the chronic phase of chagasic infection and their associations to benznidazole, the reference drug indicated for the treatment of this disease, verifying the possibility of benefits on the pathogenesis of experimental chronic infection. Quantification of T CD4+ and T CD8+ cells and of the cytokines IL-2, IL-10, IL-12, IFN-? and TNF-? by flow cytometry using the kit BD cytometric Bead Array®, indicated that these substances do not exhibit significant immunomodulatory effects on Th1 and Th2 responses in this stage of the disease, comparing infected and treated groups and that who received only solvent. The tissue parasitism determined by Real Time PCR and in histological observations showed, respectively, low copy number of T. cruzi DNA, and absence of amastigote nests, however, with marked inflammatory infiltration in all groups. Thus, our data lead to the conclusion that despite the activity presented by the triterpene acids studied in the acute phase of Chagas disease, the same does not occur in the chronic phase, as would be desirable to the reduction of the pathological conditions, even if there is no cure of the disease, considering the consequences of long term infection.
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Analise do tratamento das hepatites virais B e C nos usuários atendidos pelo Sistema Único de Saúde no estado do Amapá / Analysis of treatment to the viral hepatitis B and C for users attended by the Unified Health System (SUS) in the state of Amapa.Kaori Kubota 22 December 2010 (has links)
As hepatites são as causas mais comuns de cirrose hepática e carcinoma hepatocelular (HCC) no mundo, sendo as infecções por Vírus da Hepatite B (HBV) e Vírus da Hepatite C (HCV) consideradas aquelas de maior importância como problemas de saúde pública, devido ao grande número de indivíduos atingidos (cerca de 350 milhões com hepatite B crônica e 170 milhões com HCV). No Brasil, avaliações realizadas nas últimas décadas sugerem que a endemicidade da hepatite B na região amazônica não tem decaído, com o agravante da precariedade do acesso aos cuidados de saúde nessa região. Assim, este estudo tem por objetivo avaliar o tratamento dispensado aos pacientes com hepatites virais B e C no Amapá, que faz parte da Amazônia Legal, para que seja possível conhecer a situação da saúde publica dessa localidade. A coleta de dados foi realizada em um centro de referência que centraliza o atendimento aos pacientes portadores de hepatite B e C, por meio de instrumento de coleta de dados previamente validado e aprovado pelo Comitê de Ética em Pesquisa da Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo (CEPFCFRP/USP), entre 1º de julho de 2007 e 30 de junho de 2009, e o programa estatístico EPI INFO, versão 3.5.1, foi utilizado para o lançamento e análise dos dados coletados. Foram incluídos 123 pacientes suspeitos ou portadores de hepatites virais B e/ou C, com idade média de 48,3 anos e 85,4% dos indivíduos entre 30 e 69 anos de idade, sendo 55,3% do sexo masculino, 61,0% casados, 82,1% residentes em Macapá, e 39,0% encaminhados por detecção de suspeita através de exames de rotina/pré-operatório ou pelo HEMOAP. Somando-se monoinfecções e coinfecções, 66,4% e 33,6% eram de pacientes infectados por HCV e HBV, respectivamente, sendo que os crônicos eram 61,0%. O acompanhamento clínico/ambulatorial desses pacientes foi inferior a 6 meses em 52% dos casos, e 40,0% apresentavam algum grau de severidade da doença, mas em 28,6% e 65,1% desses pacientes houve ausência de exames de ultrassonografia abdominal e determinação de níveis de aminotransferases, respectivamente. O genótipo para HCV só foi determinado em 30,6% dos casos de HCV e houve falha de notificação no SINAN em 25,2% dos pacientes do estudo. Três (7,0%) portadores de HBV e 16 (18,8%) de HCV receberam tratamento farmacológico específico, entretanto, outros seis pacientes com HBV e 19 com HCV apresentavam um critério de inclusão no tratamento, mas não foram tratados por ausência de exames de monitoramento. Na avaliação dos protocolos clínicos brasileiros para tratamento de HBV e HCV em relação aos internacionais, os primeiros se mostraram adequados e atualizados, entretanto, as falhas em seu seguimento pelas unidades de saúde que integram a rede assistencial para pacientes com HBV e HCV resultaram em deficiências nos serviços oferecidos, possivelmente decorrentes de treinamentos e capacitações insuficientes, ausência serviços de maior complexidade, e também devido isolamento natural da região. Diante dessas evidências, verifica-se a necessidade de ações governamentais no combate às hepatites virais mais abrangentes e que alcancem essa região. / Hepatitis are the most common cause for cirrhosis and hepatocelullar carcinoma (HCC) in the worldwide, and infections by the Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) are considered the most importance as public health problems, due to the large number of affected individuals (about 350 millions with chronic hepatitis B and 170 millions with HCV). In Brazil, evaluations made in the last decades suggest that the endemicity in Amazon area has not decreased, with the worsen situation of uncertain access to the health care in this location. Therefore, this research has the purpose to evaluate the treatment delivered to the patients infected by hepatitis virus B and C in Amapa, which belongs to the Legal Amazon, due to become possible to know the public health situation in this location. The data collection was placed in a reference center which concentrates the attendance to the hepatitis B and C carriers, using a data collection instrument previously validated and approved by the Ethics Committee in Research of the College of Pharmaceuticals Sciences of Ribeirão Preto, University of São Paulo (CEP-FCFRP/USP), between July 1st 2007 and June 30th 2009, in addition, the statistical software EPI INFO, version 3.5.1, was used to register and analyze the collected data. The 123 included individuals were suspected to have the infection or hepatitis B and/or C carriers, mean age of 48.3 years and 85.4% of these individuals were aged between 30 and 69 years old, 55.3% were men, 61.0% of them were married, 82.1% were resident in Macapa, and 39.0% of them were forwarded to the reference center due to detection of the infection by the routine exams / before surgery or by the HEMOAP, the blood bank. By the total of monoinfections and coinfections, 66.4% and 33.6% were patients infected by HCV and HBV, respectively, and the chronic patients were 61.0%. The clinical/ambulatorial follow-up of these patients were less than 6 months in 52.0% from the total, and 40.0% showed some severity grade due to the disease, however, 28.6% and 65.1 of these patients were lack of abdominal ultrasonography and aminotransferases determination exams, respectively. The genotype for HCV were determinate only in 30.6% of HCV infections and there were in SINAN notification failure in 25.2% of patients of study. Three (7.0%) HBV carriers and 16 (18.8%) HCV carriers receipt specific pharmacological treatment, nevertheless, others six HBV patients and 19 HCV patients had at least one criteria of inclusion in the treatment, but they were not treated because of monitoring exams absence. In the evaluation of Brazilian clinical protocol to HBV and HCV in regard to the international ones, those ones showed to be appropriates and updated, however, the failures in their following by the health units that integrate the assistance network to the HBV and HCV infected patients had outcomes in lack of offered services, probably due to insufficient training and qualification of the professionals, lack of more complex services, and also due to natural isolation of this area. Because of these evidences, it verifies the need of more including and reaching government actions to fight the viral hepatitis in this location.
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Control of chronic Epstein-Barr virus infection : consequences of altered B lymphocyte activation / Conséquences de l'altération de l'activation des lymphocytes B sur le contrôle de l'infection chronique par EBVSanosyan, Armen 15 December 2016 (has links)
Le virus d'Epstein-Barr (EBV), est un gamma herpes virus exclusivement humain qui infecte près de 95% de la population adulte. EBV établit un cycle de latence dans les cellules B mémoires et les cellules épithéliales. EBV entre périodiquement dans une réplication lytique avec sécrétion des virions dans la salive. L’infection EBV est associée à l’apparition de lymphomes, de cancers et de maladies auto-immunes. Les conditions favorisant le développement de ces pathologies restent mal connues mais l’immunodépression et potentiellement l’activation des lymphocytes B nécessaire à la réplication d’EBV jouent un rôle clé.Nous avons examiné l’association entre activation des cellules B dans le compartiment systémique et le contrôle sur le réservoir de l’EBV. Deux situations cliniques d’activation chronique des cellules B ont été explorées ; le syndrome de Gougerot-Sjögren et la mastite subclinique dans le contexte de l’infection par le VIH.Dans ce travail de thèse, nous avons tout d’abord développé une PCR en temps réel pour la quantification de l'ADN de EBV ciblant la région répétée BamHI-W du génome. Le travail de validation de la technique a permis d’évaluer précisément le gain de sensibilité comparativement à une qPCR LMP2 (cible unique). L’impact des variations de répétition de la séquence BamHI-W suivant les souches et isolats EBV a également été analyse.Dans un deuxième travail, nous avons montré que, la mastite subclinique était fréquente au cours de l’allaitement et qu’elle était un facteur indépendant associé à une augmentation de l'excrétion EBV par le lait maternel. Cette sécrétion est associée localement à l’inflammation et à l’excrétion du VIH ce qui témoigne de phénomène de synergie entre les deux virus. Nous avons également démontré que l'ADN EBV dans le lait maternel peut être résistant à la DNase et que le virus était est probablement encapsidé dans le lait, donc potentiellement infectieux.Enfin, bénéficiant d’un accès aux prélèvements de la cohorte ASSESS nous avons recherché de possible anomalie du contrôle de l’infection EBV dans le compartiment sanguin au cours du syndrome de Gougerot-Sjögren primaire dans lequel les lésions glandulaires salivaires et lacrymales sont associées à la présence d’EBV. Nous avons démontré que le réservoir EBV et la réplication EBV dans le compartiment systémique sont bien contrôlées au cours du syndrome de Gougerot-Sjögren primaire. La réponse anticorps contre l’antigène précoce d’EBV (EA) n'était pas associée à une augmentation de l'ADN de EBV.Ce travail de thèse, souligne le lien entre l'activation des lymphocytes B, l'inflammation chronique et le contrôle sur le réservoir d’EBV. Dans la glande mammaire le contrôle de l’infection EBV est perturbé en cas de mastite subclinique. Au contraire dans le syndrome de Gougerot-Sjögren l’infection reste bien contrôlée dans le compartiment sanguin malgré l’activation des lymphocytes B et la présence renforcée du virus dans les lésions glandulaires. / TEpstein-Barr virus (EBV), an ubiquitous human gammaherpesvirus affects 95% of adult human population and establishes a lifelong latency in memory B cells periodically entering into lytic replication with further propagation in oropharyngeal epithelia and shedding through saliva. Latent EBV infection is associated with lymphomas, carcinomas and autoimmune diseases. Although the conditions favoring the development of these pathologies are not completely understood, the immunosuppression and B cell activations play an important role in EBV-associated diseases.We examined the control over the EBV reservoir in a diseases associated with B cell activation. Two clinical situations associated with altered B cell activation were explored: primary Sjogren’s syndrome and subclinical mastitis in HIV-infected mothers.Primarily, we developed an in-house real-time PCR for EBV DNA quantification targeting the repetitive BamHI-W region of EBV DNA. The validation analyses enabled to evaluate the gain in sensitivity of the BamHI-W test relative to single repeat LMP2 qPCR. The impact of the variations in BamHI-W reiteration on EBV DNA quantification was further assessed on different EBV strains and clinical samples.In a second study, we showed that subclinical mastitis was common during breastfeeding, and it was an independent factor associated with increased EBV breast milk shedding. This secretion was associated with local inflammation and HIV shedding, reflecting synergy between the two viruses. We have also demonstrated that breast milk EBV DNA may be resistant to DNase, and the virus was probably encapsidated in the breast milk and thus potentially infectious.Finally, with an access to ASSESS cohort we looked for possible abnormal control over EBV infection in the blood compartment in primary Sjögren's syndrome, where salivary and lacrimal gland lesions were shown to be associated with the local activation of EBV. We have demonstrated that in primary Sjogren's syndrome EBV reservoir and replication in the systemic compartment are well controlled. The antibody response against EBV early antigen (EA) was not associated with increased DNA EBV.This thesis points out the link between the activation of B cells, chronic inflammation and control over the reservoir of EBV. In the mammary gland disturbed control of EBV infection is linked with subclinical mastitis. In contrast, in primary Sjogren’s syndrome EBV infection remains well controlled in the blood compartment despite the activation of B cells and the increased presence of the virus in glandular lesions.
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