Thesis equivalent (M.P.H.)--University of Michigan, 1947.

Thesis equivalent (M.P.H.)--University of Michigan, 1947.

Thesis (M.P.H.)--University of Michigan, 1947.

Thesis (M.P.H.)--University of Michigan, 1947.

Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 4 uppsatser. I publ. felaktig serietitel: Umeå University medical dissertation.

Thesis (DR. P.H.)--University of Michigan.

Thesis (DR. P.H.)--University of Michigan.

Adenoviruses are common pathogens all over the world. The majority of the population has at some point been infected with an adenovirus. Although severe disease can occur in otherwise healthy individuals an adenovirus infection is most commonly self limited in these cases. For immunocompromised individuals however, adenoviruses can be life-threatening pathogens capable of causing disseminated disease and multiple organ failure. Still there is no approved drug specific for treatment of adenovirus infections. We have addressed this using a unique whole cell viral replication reporter gene assay to screen small organic molecules for anti-adenoviral effect. This RCAd11pGFP-vector based assay allowed screening without any preconceived idea of the mechanism for adenovirus inhibition. As a result of the screening campaign 2-[[2-(benzoylamino)benzoyl]amino]-benzoic acid turned out to be a potent inhibitor of adenoviral replication. To establish a structure-activity relationship a number of analogs were synthesized and evaluated for their anti-adenoviral effect. The carboxylic acid moiety of the molecule was important for efficient inhibition of adenovirus replication. There are 54 adenovirus types characterized today and these are divided into seven species, A-G. The receptors used by species B and other adenoviruses are not fully characterized. CD46 is a complement regulatory molecule suggested to be used by all species B types and some species D types but this is not established. We have designed a new bioassay for assessment of the interaction between adenoviruses and CD46 and investigated the CD46-binding capacity of adenovirus types indicated to interact with CD46. We concluded that Ad11p, Ad34, Ad35, and Ad50 clearly bind CD46 specifically, whereas Ad3p, Ad7p, Ad14, and Ad37 do not. CD46 is expressed on all human nucleated cells and serves as a receptor for a number of different bacteria and viruses. Downregulation of CD46 on the cell surface occurs upon binding by some of these pathogens. We show that early in infection Ad11p virions downregulate CD46 upon binding to a much higher extent than the complement regulatory molecules CD55 and CD59. These findings may lead to a better understanding of the pathogenesis of adenoviruses in general and species B adenoviruses in particular and hopefully we have discovered a molecule that can be the basis for development of new anti-adenoviral drugs.

Os vírus da Influenza Equina (EIV) (H3N8 e H7N7) pertencem à família Orthomyxoviridae, gênero Influenza A. Apesar de existirem poucos relatos de infecção humana pelo EIV, é conhecido o risco zoonótico e infecção interespécies. Serviços de vigilância epidemiológica da OIE e WHO informam que o subtipo H3N8 é isolado de surtos que ocorrem mundialmente, enquanto o subtipo H7N7, menos patogênico, não é isolado desde 1980, sendo então considerado um vírus extinto. Embora o EIV seja endêmico em nosso meio, há poucos trabalhos nacionais que tenham versado sobre a avaliação atual de anticorpos (Ac) anti-EIV presentes nos equídeos do Estado de São Paulo, o que motivou a realização do presente estudo. Os objetivos do presente trabalho foram: 1) avaliar a ação de diferentes tratamentos de soro descritos pela OIE e WHO para a remoção de inibidores inespecíficos da hemaglutinação em soros de 10 equinos vacinados (H3N8 A/Equi/Kentucky/1/1997), sendo eles: a) TPH: tripsina, metaperiodato de potássio seguido de adsorção de hemácias; b) KH: kaolin 20% seguido de adsorção de hemácias; e c) RDEH: RDE seguido de adsorção de hemácias; 2) avaliar a presença de Ac contra os vírus H3N8 e H7N7, em 84 equídeos não vacinados do Estado de São Paulo; 3) comparar a frequência de Ac contra H3N8 entre equídeos amostrados do estado de SP e de um painel de soros de equídeos do município de Mossoró - RN, região onde não há estudos sobre a circulação do EIV. Constatou-se que não houve diferença estatística entre os tratamentos de soro para a remoção de inibidores inespecíficos da hemaglutinação (p>0,05; confiança de 95%), todavia o tratamento RDEH apresentou resultados mais consistentes, corroborando a recomendação da OIE e da WHO de utilizar preferencialmente este tratamento. O perfil sorológico dos animais amostrados de SP sugere que circule o subtipo H3N8 e que o subtipo H7N7 circule de forma subclínica nos equídeos, o que é sustentado por outros trabalhos realizados no Brasil. Há evidências no Brasil sobre a detecção de anticorpos em equinos contra o subtipo H7N7, mesmo não havendo o isolamento deste no mundo desde 1980. No painel de soros do RN, onde a espécie Equus asinus era maioria, verificou-se a igualdade estatística entre as frequências de Equus caballus e Equus asinus positivos no teste de HI para o subtipo H3N8 (p>0,05; confiança de 95%), dado inédito em nosso meio. A frequência dos equídeos positivos no teste de HI para o subtipo H3N8 foi estatisticamente maior (p<0,05; confiança de 95%) em SP do que em RN. / The Equine influenza Virus (EIV) (H3N8 and H7N7) belong to Orthomyxoviridae family and Influenza A genus. Although there are few reports of human infection with EIV zoonotic and interspecies infection risk is known. OIE and WHO services on epidemiological surveillance report that H3N8 subtypes are isolated and characterized from worldwide outbreaks while H7N7 subtype less pathogenic has not being isolated since 1980 considered an extinct virus. Although the EIV is endemic in our country there are few national studies that had versed on the current evaluation of horses antibodies (Ab) from São Paulo State which motivated the present study. The study objectives were: 1) to evaluate the effects of different serum treatments described by OIE and WHO for the removal of nonspecific inhibitors of hemagglutination in 10 vaccinated (H3N8 - A/Equi/Kentucky/1/1997) horses sera being: a) TPH: trypsin, potassium metaperiodate followed by adsorption of erythrocytes b) KH: kaolin 20% followed by adsorption of erythrocytes and c) RDEH: RDE followed by adsorption of erythrocytes; 2) investigate the presence of antibodies against H3N8 and H7N7 viruses in 84 unvaccinated equines in São Paulo State; 3) compare the frequency of antibodies against H3N8 sampled between São Paulo State and a panel of equines sera from Mossoró - RN where there are no studies on EIV circulation. There was no statistical difference between the treatments for serum nonspecific inhibitors of hemagglutination removal (p>0.05; 95% confidence) however RDEH treatment showed results more consistent confirming OIE and WHO recommendation to use this treatment with priority. The serological profile of SP samples suggests H3N8 subtype circulates in those animals and H7N7 subtype might circulate in a subclinical form in equines, which is supported by other studies conducted in Brazil. There is evidence of antibodies detection against equine H7N7 subtype in Brazil, even without since 1980 isolation in the world. In animals from RN State which had Equus asinus representing a major fraction there was statistical equal frequencies of Equus caballus and Equus asinus positivity in HI test against H3N8 subtype (p>0.05; 95% of confidence), as unprecedented in the world. The frequency of positive equine against H3N8 subtype on HI test in SP was statistically higher (p<0.05; 95% of confidence) than in RN.

Os vírus da Influenza Equina (EIV) (H3N8 e H7N7) pertencem à família Orthomyxoviridae, gênero Influenza A. Apesar de existirem poucos relatos de infecção humana pelo EIV, é conhecido o risco zoonótico e infecção interespécies. Serviços de vigilância epidemiológica da OIE e WHO informam que o subtipo H3N8 é isolado de surtos que ocorrem mundialmente, enquanto o subtipo H7N7, menos patogênico, não é isolado desde 1980, sendo então considerado um vírus extinto. Embora o EIV seja endêmico em nosso meio, há poucos trabalhos nacionais que tenham versado sobre a avaliação atual de anticorpos (Ac) anti-EIV presentes nos equídeos do Estado de São Paulo, o que motivou a realização do presente estudo. Os objetivos do presente trabalho foram: 1) avaliar a ação de diferentes tratamentos de soro descritos pela OIE e WHO para a remoção de inibidores inespecíficos da hemaglutinação em soros de 10 equinos vacinados (H3N8 A/Equi/Kentucky/1/1997), sendo eles: a) TPH: tripsina, metaperiodato de potássio seguido de adsorção de hemácias; b) KH: kaolin 20% seguido de adsorção de hemácias; e c) RDEH: RDE seguido de adsorção de hemácias; 2) avaliar a presença de Ac contra os vírus H3N8 e H7N7, em 84 equídeos não vacinados do Estado de São Paulo; 3) comparar a frequência de Ac contra H3N8 entre equídeos amostrados do estado de SP e de um painel de soros de equídeos do município de Mossoró - RN, região onde não há estudos sobre a circulação do EIV. Constatou-se que não houve diferença estatística entre os tratamentos de soro para a remoção de inibidores inespecíficos da hemaglutinação (p>0,05; confiança de 95%), todavia o tratamento RDEH apresentou resultados mais consistentes, corroborando a recomendação da OIE e da WHO de utilizar preferencialmente este tratamento. O perfil sorológico dos animais amostrados de SP sugere que circule o subtipo H3N8 e que o subtipo H7N7 circule de forma subclínica nos equídeos, o que é sustentado por outros trabalhos realizados no Brasil. Há evidências no Brasil sobre a detecção de anticorpos em equinos contra o subtipo H7N7, mesmo não havendo o isolamento deste no mundo desde 1980. No painel de soros do RN, onde a espécie Equus asinus era maioria, verificou-se a igualdade estatística entre as frequências de Equus caballus e Equus asinus positivos no teste de HI para o subtipo H3N8 (p>0,05; confiança de 95%), dado inédito em nosso meio. A frequência dos equídeos positivos no teste de HI para o subtipo H3N8 foi estatisticamente maior (p<0,05; confiança de 95%) em SP do que em RN. / The Equine influenza Virus (EIV) (H3N8 and H7N7) belong to Orthomyxoviridae family and Influenza A genus. Although there are few reports of human infection with EIV zoonotic and interspecies infection risk is known. OIE and WHO services on epidemiological surveillance report that H3N8 subtypes are isolated and characterized from worldwide outbreaks while H7N7 subtype less pathogenic has not being isolated since 1980 considered an extinct virus. Although the EIV is endemic in our country there are few national studies that had versed on the current evaluation of horses antibodies (Ab) from São Paulo State which motivated the present study. The study objectives were: 1) to evaluate the effects of different serum treatments described by OIE and WHO for the removal of nonspecific inhibitors of hemagglutination in 10 vaccinated (H3N8 - A/Equi/Kentucky/1/1997) horses sera being: a) TPH: trypsin, potassium metaperiodate followed by adsorption of erythrocytes b) KH: kaolin 20% followed by adsorption of erythrocytes and c) RDEH: RDE followed by adsorption of erythrocytes; 2) investigate the presence of antibodies against H3N8 and H7N7 viruses in 84 unvaccinated equines in São Paulo State; 3) compare the frequency of antibodies against H3N8 sampled between São Paulo State and a panel of equines sera from Mossoró - RN where there are no studies on EIV circulation. There was no statistical difference between the treatments for serum nonspecific inhibitors of hemagglutination removal (p>0.05; 95% confidence) however RDEH treatment showed results more consistent confirming OIE and WHO recommendation to use this treatment with priority. The serological profile of SP samples suggests H3N8 subtype circulates in those animals and H7N7 subtype might circulate in a subclinical form in equines, which is supported by other studies conducted in Brazil. There is evidence of antibodies detection against equine H7N7 subtype in Brazil, even without since 1980 isolation in the world. In animals from RN State which had Equus asinus representing a major fraction there was statistical equal frequencies of Equus caballus and Equus asinus positivity in HI test against H3N8 subtype (p>0.05; 95% of confidence), as unprecedented in the world. The frequency of positive equine against H3N8 subtype on HI test in SP was statistically higher (p<0.05; 95% of confidence) than in RN.