This thesis investigated how virologic and serologic kinetics of the hepatitis B virus (HBV) could influence the natural history and treatment of chronic hepatitis B (CHB). Virologic kinetics were described in the first five studies, with serologic kinetics being described in the next five. The first study delineated the HBV DNA profiles of 1,400 treatment-naive Asian CHB patients. Increasing viremia was noted with increasing age, highlighting the large therapeutic demand in Asian patients with hepatitis B e antigen (HBeAg)-negative CHB. The second study analyzed the association between viral load and liver histology in 319 patients, showing HBV DNA levels to have strong association with HBeAg-negative disease severity. The next three studies investigated the efficacy of baseline and on-treatment HBV DNA levels in predicting clinical outcomes in 117, 165 and 222 patients on telbivudine, lamivudine plus adefovir and entecavir respectively. Absolute on-treatment HBV DNA levels at week 12 or 24 predicted favorable outcome with telbivudine and lamivudine / adefovir therapy, while excellent viremic suppression with very low rate of resistance development was shown in the entecavir study. The following three studies examined the role of serum HBsAg measurements in different disease phases of CHB. First, histology specimens of 140 HBeAg-positive patients were analyzed together with HBsAg levels. High HBsAg titers (>25,000 IU/mL) were found to be predictive of insignificant fibrosis. In the next study involving 300 treatment-naive HBeAg-negative patients stratified by their viral loads, combination of low HBsAg and HBV DNA levels predicted significant HBsAg decline. This is followed by a study comparing HBsAg levels of 203 CHB patients achieving HBsAg seroclearance with 203 age- and sex-matched controls over a 3-year period. Serum HBsAg <200 IU/mL and a significant annual HBsAg reduction were found to be predictive of HBsAg seroclearance. The penultimate study investigated the usage of two novel HBV serologic markers, linearized HBsAg and hepatitis B core-related antigen, in 329 CHB patients achieving HBsAg seroclearance with a conventional HBsAg assay. More than 40% of patients had seropositivity to one or both serologic tests. Finally, the last study of this thesis investigated and compared the changes in serum HBsAg, intrahepatic HBV DNA and covalently closed circular DNA (cccDNA) after 1 year of nucleoside analogue therapy. Minimal changes in both serum HBsAg and intrahepatic cccDNA were noted after 1 year of therapy, but in patients with a significant decline in serum HBsAg levels, there was a corresponding significant reduction in cccDNA. This series of studies illustrated how the monitoring of serum HBV DNA and HBsAg levels could assist in optimizing management strategies for CHB. / published_or_final_version / Medicine / Master / Doctor of Medicine

Thesis (M. Med. Sc.)--University of Hong Kong, 2010. / Includes bibliographical references (p. 51-58).

Thesis (M.Res.(Med.))--University of Hong Kong, 2003. / Includes bibliographical references (leaves 68-77) Also available in print.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Blimp-1 (B lymphocyte induced maturation protein-1) kontrolliert die Regulation der terminalen B-Zelldifferenzierung. So ist die ektopische Expression von Blimp-1 ausreichend, damit naive B-Zellen zu antikörpersezernierenden Zellen differenzieren können. Dabei wirkt Blimp-1 als transkriptioneller Repressor, der zusammen mit Kofaktoren die Chromatinstruktur in der Promotorregion der Zielgene modifiziert und so deren Expression steuert. Neben der ursprünglich beschriebnen Blimp-1 mRNA existiert eine weitere mRNA, welcher das Exon 7 fehlt (Blimp-1?exon7). In diesem Exon sind die ersten zwei von insgesamt fünf Zinkfingern kodiert, welche nachweislich essentiell für die sequenzspezifische DNA-Interaktion von Blimp-1 sind. In dieser Arbeit konnte gezeigt werden, dass die Blimp-1?exon7 Deletionsmutante vorwiegend in ruhenden CD19+ B-Zellen der Maus und in unstimulierten humanen B-Zellen exprimiert wird. Obwohl die Blimp-1 sequenzspezifische DNA-Bindung des Proteins (Blimp-1?Ex7) nicht mehr gegeben ist, lokalisiert es teilweise in den Kern, interagiert ebenfalls mit Korepressoren wie Histondeacetylase-2, und assoziiert mit heterochromatischen Bereichen der DNA. Die ektopische Expression von Blimp-1?Ex7 in einer murinen B-Zell-Lymphomlinie, führt zu Zellzyklusarrest und Apoptose, ohne jedoch die Differenzierung zur Plasmazelle zu ermöglichen. Darüber hinaus ist in Gegenwart von Blimp-1?Ex7 die LPS-induzierte B-Zelldifferenzierung blockiert. Die Unterdrückung der Differenzierung korreliert mit einer verminderten Blimp-1 Expression. Zusammenfassend legen die Ergebnisse den Schluss nahe, dass Blimp-1?Ex7 in naiven B-Zellen exprimiert wird und eine vorzeitige Differenzierung verhindert, indem es autoregulativ die Promotoraktivität herabsetzt und damit Blimp-1 kontrolliert. / Blimp-1 (B lymphocyte induced maturation protein-1) is the key regulator of terminal B cell differentiation. Ectopic expression of Blimp-1 is sufficient to drive naive B cells to differentiate into antibody-secreting cells. In this context, Blimp-1 acts as a transcriptional repressor that modifies, together with cofactors, the chromatin structure in the promoter region of its target genes and thereby controls their expression. In addition to Blimp-1 mRNA there is another mRNA existing lacking exon 7 (Blimp-1?exon7). This exon codifies two of the five zinc fingers that are absolutely essential for sequence-specific DNA interaction of Blimp-1. The Blimp-1?exon7 deletion mutant is predominantly expressed in resting or unstimulated CD19+ B cells of mice or humans, respectively. Although the protein (Blimp-1?Ex7) cannot bind to the Blimp-1-specific DNA sequences, it partially localizes to the nucleus where it interacts with corepressors like histone deacetylase-2 and is associated with heterochromatic DNA. Ectopic expression of Blimp-1?Ex7 in a murine B cell lymphoma line leads to cell cycle arrest and apoptosis without prior induction of plasma cell differentiation. Furthermore, in the presence of Blimp-1?Ex7, LPS induced B cell differentiation is blocked. This block of differentiation correlates with a reduction in endogenous Blimp-1 expression. Taken together, the data imply that Blimp-1?Ex7 is expressed in naïve B cells to block premature differentiation by regulating the promoter activity in an auto-regulatory manner and is thereby controlling Blimp-1.

Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 157-186). Also available in print.

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Medicina, 2010. / Submitted by Larissa Ferreira dos Angelos (ferreirangelos@gmail.com) on 2011-05-10T19:33:03Z No. of bitstreams: 1 2010_MarceloAbrahãoCosta.pdf: 4749695 bytes, checksum: 1b035f8db97056a2edd6efb3c2d337c1 (MD5) / Approved for entry into archive by Raquel Viana(tempestade_b@hotmail.com) on 2011-05-10T20:03:58Z (GMT) No. of bitstreams: 1 2010_MarceloAbrahãoCosta.pdf: 4749695 bytes, checksum: 1b035f8db97056a2edd6efb3c2d337c1 (MD5) / Made available in DSpace on 2011-05-10T20:03:58Z (GMT). No. of bitstreams: 1 2010_MarceloAbrahãoCosta.pdf: 4749695 bytes, checksum: 1b035f8db97056a2edd6efb3c2d337c1 (MD5) / INTRODUÇÃO: Para a infecção crônica pelo vírus da hepatite B (HBV) HBeAg negativo, a aplicabilidade clinica da quantificação do HBVDNA (carga viral) ficou mais clara nos últimos cinco anos, principalmente quanto ao diagnostico, a evolução e ao tratamento da infecção, influenciando, sobremaneira, a decisão de tratar. OBJETIVOS: Analisar a concordância dos títulos de carga viral quantificados por dois métodos distintos de biologia molecular e estimar as associações existentes entre carga viral e achados histológicos, ajustando por variáveis clinicas e laboratoriais selecionadas. MÉTODOS: Portadores de hepatite B crônica HBeAg negativo foram estudados quanto as suas características clinicas, laboratoriais, ecográficas e histológicas. Analises de correlação entre essas variáveis e as cargas virais – quantificadas com Amplicor (AMPL) e Taqman (TQM) foram realizadas. As concordâncias brutas e ajustadas por chance (índice Kappa) entre cargas virais obtidas pelas técnicas baseadas na reação de cadeia de polimerize (PCR) foram analisadas. RESULTADOS: Avaliados 54 pacientes (homens=33, 61,1%), a media de idade foi de 41,22 anos. Consumo de etanol era nulo em 66,7% (36/54). TGO estava aumentada em 48% (26/54) dos pacientes, com media de 30,83 ui/ml. TGP apresentava-se aumentada em aproximadamente 60% (32/54) dos pacientes estudados, com valor médio de 39,17 ui/mL. Quando os dois testes foram simultâneos em amostras pareadas, a media das cargas virais aferidas pelo TQM foi superior a media daquelas aferidas pelo AMPL (p<0,0001). AMPL detectou cargas virais < 2.000ui/ml em 74% dos pacientes (37/50). Para esse grupo, TQM detectou cargas virais ≥2.000ui/ml em 46% (17/37) dos pacientes. As variáveis independentes associadas a fibrose foram: idade, plaquetas, bilirrubina total e carga viral TQM. CONCLUSÃO: A concordância Kappa=0,31 entre os dois testes quantitativos de carga viral foi considerável (p<0,0001). Sem os resultados do teste TQM, mais da metade (54,8%) dos pacientes que tivessem sua avaliação limitada ao teste AMPL nao seriam considerados candidatos a tratamento. _______________________________________________________________________________________ ABSTRACT / INTRODUCTION: In chronic hepatitis B virus (HBV) infected patients with hepatitis B e antigen (HBeAg) negative strand, the clinical relevance of serum HBV DNA measurement became clearer in the past five years regarding diagnosis, evolution and treatment. Starting therapy is directly influenced by quantitative evaluation of HBV viral load among other relevant variables. AIM: evaluate HBVDNA quantification concordance using two distinct PCR assays, Amplicor (AMPL) and Taqman (TQM), and estimate associations between viral load and biopsy findings, adjusting for clinical and laboratory variables. METHODS: 54 patients with HBeAg-negative chronic HBV infection were studied. Correlations between demographic, clinical, laboratory and HBVDNA variables were estimated. Serum HBV DNA quantification was obtained using two distinct assays. The concordance between these tests was estimated by Kappa index. RESULTS: Mean age was 41,9years, male patients predominant (61,1%). Ethanol use was absent in 36 individuals (66,7%), and less than 40g/day for all subjects enrolled. AST activity and ALT activity were abnormal at baseline in 48% (26/54) and in 60% (32/54), with mean values of 30,83 iu/ml and 39,17 iu/ml, respectively. For simultaneous quantification of HBVDNA, the mean viral load obtained with TQM assay was greater compared to AMPL assay (p<0,0001). Viral load obtained with AMPL was less than 2,000 iu/ml in 74% of patients (37/50). The TQM assay was able to detect HBVDNA levels greater than 2,000 iu/ml in 46% (17/37) of patients in this group. Independent variables associated with fibrosis were: age, platelets, total bilirubin and TQM viral load. CONCLUSION: The concordance of 0.31 between TQM and AMPL quantitative tests estimated by Kappa was considered considerable (p<0,0001). However, without simultaneous testing using TQM assay approximately half of patients with their evaluation limited to AMPL testing would not be adequately considered candidates for therapy.

published_or_final_version / Medicine / Master / Master of Medical Sciences

Objetivo : Determinar los factores de riesgo asociados a la transmisión del virus de la Hepatitis B (VHB) en el Centro Médico Naval durante el período de estudio. Material y métodos : Estudio de casos y controles. Se evaluaron los pacientes hospitalizados en la Sala de Enfermedades Transmisibles con el diagnóstico de Síndrome ictérico mas hipertransaminasemia ( TGO y/o TGP > 500 u/l ). Los factores de riesgo reportados entre los sujetos infectados con el VHB (B+); fueron comparados con los sujetos no infectados (B-), mediante el análisis bivariado y multivariado. Resultados : Un total de 74 sujetos fueron evaluados serológicamente para VHB, de los cuales 37 fueron positivos ( 35 infección aguda y 2 infección no aguda ). Los sujetos B+ fueron en su mayoría de sexo masculino y tuvieron como factor de riesgo mas significativo una hospitalización previa ( OR:13.33 ). Además se describen los cuadros clínicos y exámenes de laboratorio encontrados en ambos grupos. Conclusión : La fuerte asociación encontrada entre hepatitis B y hospitalización previa, sugiere que la transmisión horizontal nosocomial tiene un rol protagónico en la transmisión del VHB en el Centro Médico Naval.

The essence of the paper is the characteristic of Bed & Breakfast (B&B) in Kenting, analyzing the pioneer¡¦s story and its successful condition thoroughly. To start an enterprise is a process to revise the interaction between individual and the environment. The pioneers are not satisfied with the mode of life, so they expect to pursue the ideal life by starting an enterprise. Economy used to be one of the major reason but not anymore. Therefore, starting an enterprise is the way to pursue the dreamland. Everyone has his dream, and it will affect the operation of the B&B. The commercial operation, the emotional operation, or humanities concern etc, all create an unique life style and operation. Not only the poineer¡¦s life has being changed, but the new features of Kenting was formed because of the blossom on the B&B. In order to combine the industry with the local environment and features, B&B becomes an extended knowledge of local. In recent years, the Internet was limitless, people can use the Blog and guestbook to update the information about the hostel anytime, share their traveling experience, and set up a platform for communication. Its high instantaneity and geniality promote the marketing efficiency. Analyzing the characteristic of B&B in Kenting, we will detect the enterprise filled with the essence of creating survival esthetics. Facing the dilemma of the previous environment, the pioneer creates the ideal life style with the positive attitude, finding the way to solve the difficulty actively. Whether the personal thought, life style, or the adaption to the environment, were all showing their originality and enthusiasm and conduct ¡§strategic creation¡¨. Foucault¡¦s survival esthetics explains the spirit of the pioneer and the change B&B brings about, the mode of the enterprise also shows the poineer¡¦s unique life style.