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published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Microbiology / Doctoral / Doctor of Philosophy

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Determina la relación entre el nivel de conocimiento y la actitud hacia la Hepatitis B que presentan los estudiantes de pre grado de la Facultad de Odontología de la Universidad Nacional Mayor de San Marcos, en el año 2015. La hipótesis planteaba una relación directa entre el nivel de conocimiento y la actitud. El tipo de estudio es descriptivo transversal. La muestra está constituida por 135 estudiantes. Aplica una encuesta tipo cuestionario con 15 preguntas de alternativas múltiple para la variable conocimiento y un cuestionario tipo Lickert con 18 items para la variable actitud. Determina que el nivel de conocimiento es mayoritariamente regular (93.3%), los items relacionados a conocimientos sobre medidas preventivas para evitar una infección con Hepatitis B son los que menos respuestas correctas tuvieron (38,1%). La pregunta con menos respuestas correctas se refiere al esquema de vacunación contra la Hepatitis B (14 alumnos), el origen viral del Hepatitis B es el ítem que obtuvo mayor número de respuestas correctas (133 alumnos). La mayoría muestra un nivel de actitud indiferente hacia la Hepatitis B (93.3%). El 25% de los alumnos piensa que no deberían atender pacientes con Hepatitis B, un 66% de los alumnos piensan que a pesar de tomar todas las medidas de bioseguridad sienten temor de atender pacientes con Hepatitis B. Según los datos obtenidos se concluye que no existe relación entre el nivel de conocimiento y la actitud hacia la Hepatitis B en los estudiantes de la Facultad de Odontología de la Universidad Nacional Mayor de San Marcos.

ABSTRACT Infection with the hepatitis B virus (HBV) is still a major global health problem with an estimated 6% of the world’s population chronically infected with the virus. Chronic infection with HBV subgenotype A1, which is hyperendemic to southern Africa, is associated with a particularly high incidence of liver cancer and cirrhosis. Understanding HBV replication and developing effective HBV treatment to prevent liver cancer remain important medical priorities. Although there is a preventative vaccine for HBV, efficacy of currently available treatment of established infection is limited. Exploiting the RNA interference (RNAi) pathway through the use of small interfering (siRNA) and short hairpin RNA (shRNA) is an attractive new approach for the development gene therapies against HBV infection. Our laboratory has designed and demonstrated the efficacy both in vitro and in vivo of several shRNAs designed to target the X open reading frame (ORF) of HBV. Thus, the objective of this study was to construct a replication competent plasmid vector of the A1 subgenotype, a reporter plasmid vector of HBV and to assess the efficacy of RNAi effecters against these vectors both in vitro and in vivo. The first HBV replication competent vector, pCR-HBVA1 1.3x, containing the sequence of an HBV subgenotype A1 isolate, was successfully constructed by generating a greater than genome length sequence of HBV, that starts just upstream of endogenous HBV basic core promoter (BCP) and ends just downstream of the unique HBV polyadenylation (pA) site. Human hepatoma (Huh7) cells transfected with this plasmid secreted HBV surface antigen (HBsAg) into Abstract viii culture supernatants. In the murine hydrodynamic injection model of HBV replication, serum HBsAg, hepatitis B e antigen (HBeAg) and viral particle levels as well as relative surface and core mRNA levels were shown to be significantly elevated as compared to mock-injected mice. The second HBV vector, pCH-FLuc, was successfully generated by replacing the surface ORF with the sequence encoding Firefly Luciferase. The ability of pCH-FLuc to express Firefly Luciferase was demonstrated in a liver cell line (Huh7 cells). Co-transfection of the reporter plasmid, pCH-FLuc, with shRNAs targeted to HBV caused a significant reduction in Luciferase expression. Co-transfection/injection of the pCR-HBVa1 1.3x with shRNAs caused significant inhibition in the level of viral antigens (HBsAg, HBeAg and hepatitis B core antigen (HBcAg) as well as relative surface and core mRNA levels. This was observed both in vitro and in vivo. Our results demonstrate the potential this model allows for the study of HBV replication as well as the assessment of potential therapeutic strategies in a regionally significant subgenotype of HBV.

Hepatitis B virus (HBV) is hyperendemic to southern Africa and parts of Asia where it is a major cause of serious liver disease. Licensed antivirals for chronically infected individuals are only partially effective and approximately one million deaths occur annually as a result ofpersistent infection with the virus. Although RNA interference (RNAi) based gene silencingof HBV has been successfully demonstrated, difficulties with delivery of anti-HBV RNAieffectors remains an obstacle to their clinical use. Recombinant adenoviruses (Ads), amongst the most efficient hepatotropic gene vectors following systemic administration, have been successfully used to deliver expressed anti-HBV RNAi sequences. However, a drawback of Ad vectors is diminished efficacy and toxicity that results from stimulation of innate andadaptive immunity.To attenuate these effects we used polyethylene glycol (PEG) to modify first generation recombinant Ad (FG Ad) vectors that express an anti-HBV short hairpin (shRNA) sequence. Efficient hepatocyte transduction occurred and expressed shRNAs were processed to generate intended HBV-targeting guides. Inhibition of HBV replication was achieved after intravenous administration of PEGylated or native recombinant first generation Ads (FG Ads) to HBV transgenic mice. Circulating HBV viral particle equivalents (VPEs) remained low for 3 weeks and began to increase after 5 weeks. A second dose of PEGylated anti-HBV Ad caused a less sustained decrease in circulating VPEs, but no silencing after a second dose was observed in animals treated with unmodified vector. Release of inflammatory cytokines was elevated in animals receiving unmodified vectors and only a modest increase in monocyte chemotactic protein-1 (MCP-1) was observed in mice that received a second dose of PEG Abstract Ads. Also, polymer-conjugated vectors induced a weaker adaptive immune response and were less hepatotoxic than their unmodified counterparts. To address concerns about the transient nature of transgene expression by FG Ads resulting from immunostimulation, third generation helper-dependent (HD Ad) were utilised to delivered anti-HBV RNAi effectors. Seven days after intravenous administration of infectious HD Ads to HBV transgenic mice, 80-90% of hepatocytes were transduced and markers of HBV replication were decreased by approximately 95% which was sustained for 8 weeks. HD Ad-induced release of proinflammatory cytokines was minimal in preparations that were enriched with infectious particles. PEGylated HD Ad vectors caused similar anti- HBV effects and may be useful to evade interaction with vector-sequestrating receptors and further attenuate immunostimulation. Collectively these observations indicate that PEG modification of Ads and the use of HD Ads may have utility for delivery of therapeutic HBVsilencing sequences. Future work will focus on improving strategies to avoid immune detection and utilisation of HD Ad vectors for other HBV targeting sequences.

Thesis (Ph.D.)--University of the Witwatersrand, Faculty of Health Sciences, 2013.

Law Man Yee. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 123-132). / Abstracts in English and Chinese; appendix in Chinese. / Precis --- p.vi / 摘要 --- p.viii / Captions for Tables --- p.x / Caption for Figure --- p.xii / Abbreviations --- p.xiii / Chapter Part 1 --- Literature Review --- p.0 / Chapter Chapter 1 --- Aims and Hypothesis --- p.1 / Chapter 1.1 --- Aims --- p.3 / Chapter 1.2 --- Hypothesis --- p.4 / Chapter Chapter 2 --- Epidemiology of HBV Infection --- p.5 / Chapter 2.1 --- Global and Local Epidemiology --- p.6 / Chapter 2.2 --- Modes of Transmission --- p.8 / Chapter 2.2.1 --- Perinatal Tansmission --- p.8 / Chapter 2.2.2 --- Percutaneous Transmission --- p.8 / Chapter 2.2.3 --- Sexual Transmission --- p.8 / Chapter 2.2.4 --- Healthcare Setting and Transplantation --- p.8 / Chapter 2.2.5 --- Transfusion --- p.9 / Chapter 2.2.6 --- Other --- p.9 / Chapter Chapter 3 --- Popularity of TCM --- p.10 / Chapter 3.1 --- Traditional Chinese Medicine Use --- p.11 / Chapter 2.2 --- Regulation on TCM Practice --- p.12 / Chapter Chapter 4 --- Philosophy of TCM on HBV Infection --- p.13 / Chapter 4.1 --- Basic Principles --- p.14 / Chapter 4.1.1 --- Yin-Yang Theory --- p.14 / Chapter 4.1.2 --- Five Elements Theory --- p.14 / Chapter 4.1.3 --- Zang Fu Theory --- p.14 / Chapter 4.2 --- Pathogenesis --- p.16 / Chapter 4.3 --- Diagnosis --- p.17 / Chapter 4.4 --- Treatment --- p.20 / Chapter Chapter 5 --- Western Medicine --- p.23 / Chapter 5.1 --- Natural History of HBV Infection --- p.24 / Chapter 5.1.1 --- Replicative Phase: Immune Tolerance --- p.24 / Chapter 5.1.2 --- Replicative Phase: Immune Clearance --- p.24 / Chapter 5.1.3 --- Noreplicating (Low-Replication) Phase --- p.25 / Chapter 5.2 --- Diagnostic Tests for HBV Infection --- p.26 / Chapter 5.2.1 --- Serologic Assays --- p.26 / Chapter 5.2.2 --- Serum Enzymes --- p.26 / Chapter 5.2.3 --- HBV DNA Assays --- p.27 / Chapter Chapter 6 --- Health-related Quality of Life --- p.29 / Chapter 6.1 --- Principle and Definition --- p.30 / Chapter 6.2 --- Assessment --- p.31 / Chapter 6.2.1 --- Generic Instrument --- p.31 / Chapter 6.2.2 --- Disease-Specific Instrument --- p.32 / Chapter Part 2 --- Studies & Results --- p.33 / Chapter Chapter 7 --- Research Methodology --- p.34 / Chapter 7.1 --- Study 1: Hospital-Based Surveys on Chronic Hepatitis B Patients: TCM Use --- p.35 / Chapter 7.1.1 --- Patients --- p.35 / Chapter 7.1.2 --- Survey Instrument & Logistic --- p.35 / Chapter 7.1.4 --- Statistical Analysis --- p.36 / Chapter 7.1.4 --- Sample Size Justification --- p.36 / Chapter 7.2 --- Study 2: Hospital-Based Survey on Chronic Hepatitis B Patients: HRQoL & Psychiatric Involvement --- p.38 / Chapter 7.2.1 --- Patients --- p.38 / Chapter 7.2.2 --- Survey Instrument and Logistic --- p.38 / Chapter 7.2.3 --- Statistical Analysis --- p.39 / Chapter 7.3 --- Study 3: Population-Based Survey on Chinese Medicine Practitioners (CMPs): Practice Behavior & Knowledge Assessment --- p.41 / Chapter 7.3.1 --- Study Population --- p.41 / Chapter 7.3.2 --- Survey Instrument --- p.41 / Chapter 7.3.3 --- Statistical Analysis & Knowledge Assessment --- p.42 / Chapter 7.4 --- Study 4: TCM Consultation Agreement --- p.44 / Chapter 7.4.1 --- Patients --- p.44 / Chapter 7.4.2 --- Chinese Medicine Practitioners --- p.44 / Chapter 7.4.3 --- Questionnaire --- p.44 / Chapter 7.4.4 --- Study Design --- p.45 / Chapter 7.4.5 --- Sample Size Estimation --- p.45 / Chapter 7.4.6 --- Data Analysis --- p.45 / Chapter 7.5 --- "Study 5: TCM Interpretation of Laboratory, Imaging & HRQoL Assessment" --- p.47 / Chapter 7.5.1 --- Patients --- p.47 / Chapter 7.5.2 --- HRQoL Assessment --- p.47 / Chapter 7.5.3 --- Statistical Analysis --- p.47 / Chapter Chapter 8 --- TCM Use on Chronic Hepatitis B Patients --- p.48 / Chapter 8.1 --- Patient Characteristics --- p.49 / Chapter 8.2 --- Health-Seeking Behavior of TCM Users --- p.51 / Chapter 8.3 --- Determinants of TCM Use --- p.53 / Chapter 8.4 --- Common Herbal Ingredients Used --- p.56 / Chapter Chapter 9 --- Impacts of HBV Infection on Patients --- p.58 / Chapter 9.1 --- Patient Socio-Demographic and Clinical Characteristics --- p.59 / Chapter 9.2 --- Patient Symptoms and Anxiety /Depression --- p.61 / Chapter 9.3 --- HRQoL & its Determinants --- p.63 / Chapter 9.3.1 --- Physical Aspect of HRQoL --- p.63 / Chapter 9.3.2 --- Mental Aspect of HRQoL --- p.67 / Chapter Chapter 10 --- Chinese Medicine Practitioners' (CMP) Practice --- p.71 / Chapter 10.1 --- CMPs Demographics and Training --- p.72 / Chapter 10.2 --- Practice Behavior --- p.75 / Chapter 10.3 --- Diagnostic and Therapeutic Approach --- p.76 / Chapter 10.4 --- Professional Knowledge Assessment --- p.79 / Chapter 10.5 --- Determinants of Diagnostic Approach --- p.82 / Chapter Chapter 11 --- Agreement of TCM Diagnosis among Different CMPs --- p.85 / Chapter 11.1 --- Patients Characteristics & Disease Severity --- p.86 / Chapter 11.2 --- Agreement of TCM Diagnosis & Treatment --- p.88 / Chapter Chapter 12 --- Interpretation of TCM diagnosis --- p.93 / Chapter 12.1 --- Patients --- p.94 / Chapter 12.2 --- Clinical Characteristics --- p.96 / Chapter 12.3 --- HRQoL Assessment --- p.98 / Chapter Part 3 --- Discussion & Conclusions --- p.100 / Chapter Chapter 13 --- Discussion --- p.101 / Chapter 13.1 --- TCM Popularity and its Practice --- p.102 / Chapter 13.2 --- Impact of TCM Symptomatology & Anxiety /Depression on HRQoL --- p.107 / Chapter 13.3 --- TCM Diagnosis Consistency --- p.111 / Chapter 13.4 --- Association of TCM Diagnosis with Western Medicine --- p.114 / Chapter 13.5 --- Limitations of the Study --- p.117 / Chapter Chapter 14 --- Conclusions --- p.120 / Reference --- p.122 / List of Publications of My Work Used in This Thesis --- p.133 / Acknowledgement --- p.136 / Appendix --- p.138

OBJETIVO: Evaluar el conocimiento del impacto en la morbilidad y mortalidad de la hepatitis B, enfermedad por Haemophilus influenzae tipo b, parotiditis y rubéola y sus respectivas vacunas en una población de médicos de la región Chavín. DISEÑO: Estudio Observacional Descriptivo MATERIAL Y METODO: Se aplicó un cuestionario-encuesta transversal en los meses de mayo y junio del 2,003. Se incluyeron a 125 médicos generales de la región Chavín, los cuales fueron distribuidos en tres grupos de acuerdo a la antigüedad de egreso de la universidad RESULTADOS: Un 30.0% respondieron correctamente con respecto a la enfermedad por el virus de la hepatitis B (13.8% correspondió a los médicos egresados desde hace menos de un año, p = 0.008) y un 32.4% con respecto a su vacuna (la mayoría correspondió a médicos egresados desde hace menos de un año, p < 0.001). Un 57.6% respondieron correctamente con respecto a la enfermedad por el Haemophilus influenzae tipo B (21.6% correspondió a los médicos egresados desde hace menos de un año, p = 0.03) y un 15.8% con respecto a su vacuna (6.6% correspondió a médicos egresados desde hace menos de un año, p = 0.094). Un 39.6% respondieron correctamente con respecto a la enfermedad paperas-rubéola-sarampión (18.6% correspondió a los médicos egresados desde hace menos de un año, p < 0.001)) y un 40.4% con respecto a su vacuna (17.8% correspondió a médicos egresados desde hace menos de un año, p = 0.004). Un 87.2% refirió a la inaccesibilidad económica como principal obstáculo para indicar estas vacunas, un 72% no informan a los padres, los que si lo hacen sólo emplean entre 1 a 5 minutos de la consulta médica, 67.2% responden conocer alguna asociación vacunal y 60% se colocaron alguna dosis. CONCLUSIONES: Existe un bajo índice de conocimientos con respecto a las enfermedades en estudio, aunque significativamente mayor en relación a sus vacunas, siendo mejor en el grupo de médicos egresados desde hace menos de un año de la universidad. No se conocen bien las indicaciones, contraindicaciones, cadena de frío e impacto de sus respectivas vacunas en la población infantil. El costo es una de las principales barreras encontradas y no se brinda información a los padres sobre estas vacunas. PALABRAS CLAVE: inmunizaciones, conocimientos, médicos, prácticas / Tesis de segunda especialidad