This thesis portfolio includes two studies, a qualitative grounded theory of treatment adherence in people who inject drugs (PWID) and a systematic review of staff turnover in substance misuse services. The empirical paper is presented first, the findings of which led to the systematic review. The qualitative interview study arose from observations made within a clinical trial for the treatment of chronic Hepatitis C (HCV). The Chief Investigator of the ERADICATE trial team initially approached the Adult Psychological Therapies Service to investigate what seemed to be an anomaly – patient engagement with HCV treatment had far exceeded expectations. Indeed, positive treatment adherence is not common among PWID. What is more remarkable is participants continued the trial while experiencing the highly aversive side-effects of interferon, a medication known to mimic opioid withdrawal. It is important, if not crucial, to acknowledge the wider socio-cultural context in which this thesis portfolio was produced; the political landscape changed significantly over the course of writing. Divisive judgements about what characteristics make a person worthy and deserving of resources, became more dominant in public discourse and heightened the author’s awareness to these aspects in the data. PWID are among the most marginalised, and stigmatised groups in society. Several of the participants interviewed were homeless and all were at various points on a relapsing trajectory of injecting drug use. Perhaps positive treatment adherence in this population is counter-intuitive because intuition is often based on assumptions derived from implicit biases. Indeed, until 2008, Scottish policy systematically denied HCV treatment to PWID. Due to the assumption that re-infection was inevitable, treatment was seen to be wasteful. Epidemiological studies now show is that public health is significantly improved when PWID are treated, as population prevalence goes down. Completing this thesis led to an examination of fundamental assumptions, not just relating to the participants or the data, but also relating to the question of what Clinical Psychology is. What can we contribute to the science of human behaviour? How does a self-aware mind arise and become autonomous? What leads adults to mentalize and enact their intentionality through particular behaviours, like taking medication? In grappling with these questions, the reader will detect the influence of developmental theorists, Vygotsky, Erikson and Bowlby. Seminal experiments, such as Tronick’s still face (Tronick, 1989)1 and Harlow’s monkeys (Harlow and Zimmerman, 1958)2, alongside newer fields of interpersonal neurobiology and developmental trauma have supplied the soil in which to ground the data gathered in this study. From our earliest days we are designed to absorb stimuli and integrate our perception into a gestalt. When PWID are characterised as “chaotic”, there is a failure to appreciate what this may really reflect: difficulty making sense of internal experience resulting in the absence of order, coherence and meaning. Therefore, the ontological presupposition underlying both the empirical paper and systematic review, is that humans are resilient, relational beings. When the correct conditions and contingencies are in place, our innate propensity to learn and grow can manifest in positive, adaptive behaviour. Narratives are not only ways of seeing the world, but ways of constructing it; we live through and are created by the stories told by others and ourselves (Murray, 2003)3. The public narrative of scepticism that has emerged around scientific endeavour, makes it all the more incumbent upon researchers to carry out their work with personal conviction, integrity and transparency (Rea, 2017, February 22)4. This qualitative analysis was completed with a high level of scientific rigour. Indicators of quality were employed throughout, for example, particular attention was paid to preserving the colloquial expression of participants in transcription and substantiates the authentic representation of their voice. The resultant grounded theory shows that the interpersonal context is a key part of adherence behaviour among PWID. This finding precipitated another question, if good quality relationships are important for patient engagement, how do staff stay engaged in the task of providing consistent, sensitive care on a sustained basis? The current evidence base on supporting and preserving compassion did not substantiate a systematic review, however, the opposite phenomenon, people leaving their jobs has been explored. As Clinical Psychologists we are able to connect with and influence different audiences by skilfully adapting our language. In order to appeal to managers and team leaders, the most pragmatic way of framing staff disengagement, was to examine actual staff turnover as a ‘hard’, concrete outcome. The methodological quality of studies included for review was reasonable in the context of methodological limitations. Findings point to the importance of collective support, good quality relationships and job satisfaction in mitigating against turnover in substance misuse services. This thesis portfolio is a sensitive and pragmatic understanding of engagement in both PWID and staff with the respective systems within which they are embedded. The results are contextualised and oriented toward medical colleagues working in HCV treatment, service leaders and fellow applied psychologists.

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Made available in DSpace on 2014-06-11T19:24:15Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-04-07Bitstream added on 2014-06-13T20:51:48Z : No. of bitstreams: 1 gryninger_g_me_botfm.pdf: 272447 bytes, checksum: 5ed6892f68f886811597fca3fd900973 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Universidade Estadual Paulista (UNESP) / O vírus da hepatite C é uma das principais causas de doença hepática no mundo inteiro. O estudo histopatológico é de grande importância no prognóstico e indicação de tratamento. A coinfecção com o vírus da hepatite B oculta pode agravar a lesão hepática e diminuir a resposta ao tratamento. As citocinas IL-2, INF, TNF- induzem lesão hepática e fibrose. A IL-10 apresenta atividade antiinflamatória e o TGF- induz o desenvolvimento e depósito de matriz extracelular causando fibrose. Este estudo avaliou, em pacientes com HCC, a presença da hepatite B oculta, a dosagem das citocinas IL-2, INF, TNF , TGF e IL-10, correlacionando com o estágio de fibrose em pacientes tratados e não tratados com interferon, comparando também com indivíduos saudáveis. Foram estudados 55 pacientes com HCC crônica, atendidos na Faculdade de Medicina de Botucatu, excluindo-se pacientes imunossuprimidos e gestantes. O grupo controle foi constituído de 20 indivíduos doadores de sangue. O vírus da hepatite B oculto foi pesquisado por de PCR in house, segundo técnica de Kaneno, com limite de detecção menor que 100 cópias/ml. A dosagem de citocinas foi determinada por método de Elisa. A avaliação da fibrose hepática seguiu aquela proposta pela Sociedade Brasileira de Patologia. Os resultados mostraram predominância do gênero masculino, adulto jovem, 36,4% foram usuários de drogas endovenosas e 41,8% haviam sido hemotransfundidos. Nenhum paciente apresentou coinfecção pelo vírus da hepatite B oculto. Na biópsia hepática predominou fibrose leve ou ausência de fibrose (47,2%). As citocinas analisadas não discriminaram o grau de fibrose nos indivíduos com HCC crônica, mesmo quando separados em pacientes que foram submetidos ao tratamento e pacientes que não receberam o tratamento. Não houve também discriminação das citocinas... / The Hepatitis C virus is one of the major causes of hepatic diseases worldwide. Histopathological analyses play a leading role in determining disease outcome and treatment. Co-infection with occult Hepatitis B can aggravate liver injury and diminish treatment response. Cytokines such as IL-2, INF and TNF- induce liver injury and fibrosis. IL-10 has an antiinflamatory action and TGF- induces extracellular matrix development and deposition causing fibrosis. In this study, the presence of occult Hepatitis B and the expression of IL-2, INF, TNF , TGF and IL-10 were assessed in HCC patients and correlated with fibrosis stage in patients treated and non-treated with interferon, as well as healthy individuals. A total of 55 patients with chronic HCC seen at Botucatu Medical School were included. Immunosuppressed or pregnant patients were excluded. The control group consisted of 20 blood donors. The occult Hepatitis B virus was detected by in-house PCR according to the technique of Kaneno with a detection limit < 100 clones/ml. Cytokine levels were determined by the Elisa method. Hepatic fibrosis was assessed as proposed by the Brazilian Society of Pathology. The results showed a predominance of male young adults of whom 36.4% had used endovenous drugs and 41.8% had been hemotransfused. No patient showed occult Hepatitis B co-infection. Hepatic biopsy revealed that fibrosis was either absent or mild in most cases (47.2%). The cytokines under study did not correlate with fibrosis stage in individuals with chronic HCC no matter whether they had or not received treatment. In addition, no correlations with cytokine levels were observed when VHC patients were separated into groups of individuals treated and non-treated with interferon . However, cytokine expressions were significantly increased in all cases in comparison with the control group.

Orientador: Jussara Marcondes Machado / Banca: Sueli Aparecida Calvi / Banca: Maria Cassia Jacintho Mendes Correa / Resumo: O vírus da hepatite C é uma das principais causas de doença hepática no mundo inteiro. O estudo histopatológico é de grande importância no prognóstico e indicação de tratamento. A coinfecção com o vírus da hepatite B oculta pode agravar a lesão hepática e diminuir a resposta ao tratamento. As citocinas IL-2, INF, TNF- induzem lesão hepática e fibrose. A IL-10 apresenta atividade antiinflamatória e o TGF- induz o desenvolvimento e depósito de matriz extracelular causando fibrose. Este estudo avaliou, em pacientes com HCC, a presença da hepatite B oculta, a dosagem das citocinas IL-2, INF, TNF , TGF e IL-10, correlacionando com o estágio de fibrose em pacientes tratados e não tratados com interferon, comparando também com indivíduos saudáveis. Foram estudados 55 pacientes com HCC crônica, atendidos na Faculdade de Medicina de Botucatu, excluindo-se pacientes imunossuprimidos e gestantes. O grupo controle foi constituído de 20 indivíduos doadores de sangue. O vírus da hepatite B oculto foi pesquisado por de PCR in house, segundo técnica de Kaneno, com limite de detecção menor que 100 cópias/ml. A dosagem de citocinas foi determinada por método de Elisa. A avaliação da fibrose hepática seguiu aquela proposta pela Sociedade Brasileira de Patologia. Os resultados mostraram predominância do gênero masculino, adulto jovem, 36,4% foram usuários de drogas endovenosas e 41,8% haviam sido hemotransfundidos. Nenhum paciente apresentou coinfecção pelo vírus da hepatite B oculto. Na biópsia hepática predominou fibrose leve ou ausência de fibrose (47,2%). As citocinas analisadas não discriminaram o grau de fibrose nos indivíduos com HCC crônica, mesmo quando separados em pacientes que foram submetidos ao tratamento e pacientes que não receberam o tratamento. Não houve também discriminação das citocinas... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The Hepatitis C virus is one of the major causes of hepatic diseases worldwide. Histopathological analyses play a leading role in determining disease outcome and treatment. Co-infection with occult Hepatitis B can aggravate liver injury and diminish treatment response. Cytokines such as IL-2, INF and TNF- induce liver injury and fibrosis. IL-10 has an antiinflamatory action and TGF- induces extracellular matrix development and deposition causing fibrosis. In this study, the presence of occult Hepatitis B and the expression of IL-2, INF, TNF , TGF and IL-10 were assessed in HCC patients and correlated with fibrosis stage in patients treated and non-treated with interferon, as well as healthy individuals. A total of 55 patients with chronic HCC seen at Botucatu Medical School were included. Immunosuppressed or pregnant patients were excluded. The control group consisted of 20 blood donors. The occult Hepatitis B virus was detected by in-house PCR according to the technique of Kaneno with a detection limit < 100 clones/ml. Cytokine levels were determined by the Elisa method. Hepatic fibrosis was assessed as proposed by the Brazilian Society of Pathology. The results showed a predominance of male young adults of whom 36.4% had used endovenous drugs and 41.8% had been hemotransfused. No patient showed occult Hepatitis B co-infection. Hepatic biopsy revealed that fibrosis was either absent or mild in most cases (47.2%). The cytokines under study did not correlate with fibrosis stage in individuals with chronic HCC no matter whether they had or not received treatment. In addition, no correlations with cytokine levels were observed when VHC patients were separated into groups of individuals treated and non-treated with interferon . However, cytokine expressions were significantly increased in all cases in comparison with the control group. / Mestre

Orientador: Sidney José Lima Ribeiro / Co-orientador: Marli Leite de Moraes / Banca: Eduardo Maffud Cilli / Banca: Orlando Fatibello Filho / Resumo: Neste trabalho foram investigados a fibroína da seda (silk fibroin, SF) com o peptídeo antigênico da proteína NS5A-1 derivado do vírus da hepatite C (HCV) e nanopartículas de vanadato de ítrio dopadas com európio em filmes nanoestruturados. Dois foram os tópicos abordados: i) interação e organização estrutural do peptídeo com a fibroína. ii) imobilização do peptídeo, da fibroína e nanopartículas em filmes automontados (Layer-by-Layer, LbL), visando estudar a interação específica peptídeo antigênico-anticorpo e a produção de protótipos de imunossensores. As interações fibroína-peptídeo foram estudadas em solução e em filmes LbL pelas técnicas espectroscópicas de dicroísmo circular e luminescência. Os resultados indicaram que há uma mudança conformacional da fibroína em solução para a fibroína em filmes, de aleatória para folha-β, respectivamente, e que o filme de fibroína induz a estrutura secundária do peptídeo que não possui uma conformação bioativa em solução. O crescimento dos filmes LbL foi monitorado por espectroscopia UV-visível, e pôde-se observar um crescimento linear a cada deposição realizada. Além do estudo fundamental das interações a nível molecular, os sistemas foram utilizados para o desenvolvimento de protótipos de imunossensores. A interação peptídeo antigênico-anticorpo foi estudada por medidas de detecção eletroquímica, elétrica e óptica. Para a detecção eletroquímica realizou-se medidas de voltametria cíclica, indicando uma diminuição na corrente quando em presença dos anticorpos anti-HCV e testes em amostras reais soropositivas para o vírus, que indicaram uma maior densidade de elétrons nos voltamogramas referentes às amostras infectadas. A detecção elétrica foi analisada por espectroscopia de impedância elétrica, e observou-se que há um aumento no sinal da capacitância e das perdas dielétricas de acordo com o aumento da concentração... / Abstract: The present study investigated the silk fibroin (SF) with the antigenic peptide of the NS5A-1 protein of the hepatitis C virus (HCV) and nanoparticles of yttrium vanadate doped with europium immobilized on nanostructured films. Two main topics were explored: i) interaction and structural organization of the peptide with fibroin. ii) immobilization of the peptide together with fibroin and nanoparticles in LbL films (Layer- by- Layer), in order to study the specific interaction peptide antigen-antibody and production of prototype immunosensors. The fibroin-peptide interactions were studied in solution and in LbL films by spectroscopic techniques of circular dichroism and luminescence. The results indicate that there is a conformational change of fibroin in the fibroin solution in film, sheet to random coil-B, respectively, and that the fibroin film induces the secondary structure of the peptide does not possess a bioactive conformation in solution. The growth of the LbL films was monitored by UV-visible spectroscopy, and could observe a linear growth every deposit made. Besides the fundamental study of interactions at the molecular level, the systems were used for the development of prototype immunosensors. The peptide antigen-antibody interaction was studied by electrochemical, electrical and optical detection measures. For electrochemical detection, were made cyclic voltammetry measurements indicating a decrease in current when in the presence of anti-HCV antibodies, and were made tests on real samples seropositive for the virus, which indicated a higher density of electrons in voltammograms respect to infected samples. The electrical detection was analyzed by electrical impedance spectroscopy, and it was observed that there is an increase in the signal of capacitance and the dielectric losses in accordance with the increase in antibody concentration. This increase in signal is higher for films containing smaller number of bilayers and... / Mestre

Introdução: O tratamento da hepatite C crônica com intereferon dura de 48 a 72 semanas, dependendo do genótipo. Os efeitos adversos mais prevalentes são dores pelo corpo, sintomas depressivos e piora na qualidade de vida. O tratamento torna o paciente incapacitado para suas tarefas diárias e atrapalha a adesão ao tratamento. Dessa forma, faz-se necessário buscar novas alternativas para minimizar os danos tornando o tratamento menos agressivo ao paciente e diminuindo os sintomas. Objetivo: Foram testadas duas hipóteses. A primeira foi explorar se a estimulação transcraniana por corrente continua (ETCC) seria mais eficaz em pacientes tratados com interferon peguilhado (PegINF) no tratamento da hepatite C crônica do que um placebo-sham para a redução dos sintomas dolorosos avaliados por meio dos níveis de dor e do limiar de dor a pressão. A segunda foi testar se os efeitos da ETCC nos sintomas relacionados ao uso de PegINF estariam relacionados ao processo de neuroplasticidade avaliado por meio dos níveis séricos de BDNF. Métodos: Foram recrutados 28 pacientes com hepatite C crônica, destros, com idades entre 40-74 anos, com escore de dor na escala numérica acima de 4 e com e limitações funcionais para realizar atividades de rotina devido à dor. Estes pacientes foram randomizados para um dos grupos de tratamento – placebo-sham (n=14) ou ETCC ativo (n=14). O tratamento consistiu em uma sessão diária de ETCC durante cinco dias consecutivos com a estimulação de 2mA aplicada na área do córtex motor primário(M1) do lado dominante. Os instrumentos de avaliação utilizados foram questionário para avaliar nível socioeconômico e dados demográficos, Escala Analógica Visual de dor (VAS), Escala do perfil de dor crônica (B-PCP:S) e níveis séricos de BDNF. Resultados: Comparando ETCC ativo com placebo-sham, ETCC ativa apresentou escores de dor significativamente mais baixos de VAS (P<0,003). A interação entre grupo e tratamento não foi significativa (P=0,07). A ETCC ativa resultou em redução da média de dor em 56% em comparação com o placebo-sham (P<0,001). Além disso, em comparação com placebo-sham, ETCC ativa resultou em melhora significativa no limiar de dor por pressão (P = 0,007) e no B-PCP: S (P <0,001), bem como reduziu o numero de doses analgésicas (P <0,03). O grupo da ETCC ativa também teve aumento significativo do BDNF no soro a partir da linha de base que foi de 37,48% (ETCC ativo) em comparação com 1,48% (diminuição do placebo-sham), esta diferença foi significativa (P <0,01). Conclusão: Concluímos que há grande potencial de utilização dessa técnica no tratamento de pacientes com hepatite c crônica, no que diz respeito ao alívio da dor, limiar de dor e diminuição dos níveis de BDNF. / Background: The treatment of chronic hepatitis C with intereferon lasts 48-72 weeks depending on the genotype. The most prevalent adverse effects are body pain, depressive symptoms and poor quality of life. The treatment makes the patient incapacitated for their daily tasks and interfere with treatment adherence. Thus, it is necessary to seek new alternatives to minimize the damage becoming less aggressive treatment to the patient and decreasing symptoms. Objective: Two hypotheses were tested . The first was to test whether transcranial direct current stimulation ( tDCS ) would be more effective in patients treated with interferon pegylated (PegINF) in the treatment of chronic hepatitis C than placebo-sham to reduce painful symptoms assessed by levels of pain and pressure pain threshold. The second was to test whether the effect of the tDCS related to use of PegINF symptoms would be related to the neuroplasticity process evaluated by means of BDNF serum. Methods: We recruited 28 patients with chronic hepatitis C, right-handed, aged 40-74 years, with a pain score on a scale above 4 and with functional limitations to perform routine activities due to pain. These patients were randomized to one of the treatment groups - placebo-sham (n = 14) or active tDCS (n=14). The treatment consisted of a daily session of 2mA tDCS for five consecutive days, applied in the primary motor cortex (M1) of the dominant hand area. The assessment instruments were used questionnaire to assess socioeconomic and demographic data, visual analogue scale for pain (VAS), scale profile of chronic pain (B-PCP:S) and serum BDNF levels. Results: Compared active tDCS with placebo-sham, active tDCS scores showed significantly lower pain VAS (P<0.003). The interaction between group and treatment was not significant (P =0.07). The active tDCS resulted in a reduction in average pain by 56% compared with the placebo -sham (P < 0.001). Moreover, active tDCS compared with placebo-sham, active tDCS resulted in significant improvement in the pain pressure threshold (P = 0.007) and the B -PCP:S (P<0.001) and reduced the number of analgesic doses (P < 0.03). The active tDCS group also had significantly increased BDNF in serum from the baseline that was 37.48 % (active tDCS) compared to 1.48% (reduced placebo-sham), this difference was significant (P < 0.01). Conclusion: We conclude that there is great potential for using this technique in the treatment of patients with chronic hepatitis C, with regard to pain relief, pain threshold and decreased levels of BDNF.

Introdução: Pacientes com infecção crônica pelo VHC e superinfecção pelo vírus da hepatite A (VHA) ou o vírus da hepatite B (VHB), têm maior morbi-mortalidade quando comparados com pacientes que apresentam infecção aguda somente pelo VHA ou VHB. A mortalidade associada à hepatite A aguda pode estar particularmente elevada em pacientes com pré-existência de hepatite crônica causada pelo VHC. Por esta razão, a imunização ativa com vacinas contra o VHA e o VHB vem a ser obrigatória nesta população, e consequentemente esta sorologia deve ser determinada. Objetivos: O objetivo deste trabalho foi avaliar a prevalência de marcadores sorológicos da hepatite A e hepatite B em 1.000 pacientes com infecção crônica pelo VHC atendidos no Ambulatório de Hepatites da Divisão de Gastroenterologia e Hepatologia Clínica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Resultados: O anti-VHA IgG foi positivo em 923 de 1000 pacientes (92,3%). Quando estratificados por idade, o anti-VHA IgG foi encontrado em 61% dos pacientes entre 20 e 29 anos, 70% entre 30 e 39 anos, 85% entre 40 e 49 anos, 94% entre 50 e 59 anos e 99% nos pacientes com mais de 60 anos . O anti-HBc total foi positivo em 244 pacientes (24%). Estratificados por idade, em 4,3% dos pacientes entre 20 e 29 anos, 17% entre 30e 39 anos, 21% entre 40 e 49 anos, 24% entre 50 e 59 anos, e 28% dos pacientes com mais de 60 anos. Dos 244 pacientes anti-HBc IgG positivos, 0,8% são HBsAg positivo, 8,5% anti-HBc IgG isolado e 16% anti-HBs positivo. Conclusões: A prevalência de anti-VHA IgG nod nossos pacientes com hepatite C crônica foi semelhante à da população geral no município de São Paulo. No entanto, o anti-HBc totaI foi maior em nossos pacientes, quando comparada historicamente à população geral dos países ocidentais, sugerindo fatores de risco semelhantes para as hepatites B e C, o que enfatiza a importância dos programas de imunização nesta população / Background and Aims: Patients with chronic HCV and superinfection by hepatitis A virus (HAV) or hepatitis B virus (HBV) have higher morbidity and mortality when compared with those without HCV. For this reason, HAV and HBV active immunization has become mandatory in this population and hence their serological markers must be determined. The aim of this study was to evaluate the prevalence of serological markers of HAV and HBV infection in patients with chronic HCV. Methods: 1.000 chronic HCV infected patients at the University of Sao Paulo School of Medicine outpatient Liver Clinic were evaluated for the prevalence of serological markers of HAV and HBV infection. Results: Anti-HAV IgG was positive in 923 of 1000 patients (92.3%). When stratified by age, the anti-HAV IgG was found in 61% of patients between 20-29 years, 70% between 30-39 years, 85% between 40-49 years, 94% between 50-59 years, and 99% over 60 years of age. Anti-HBc IgG was positive in 244 patients (24%). Stratified by age, anti-HBc IgG was found in 4.3% of patients between 20-29 years, 17% between 30-39 years, 21% between 40 -49 years, 24% between 50-59 years, and 28% of patients over 60 years of age. Of the 244 anti-HBc IgG positive patients, 0.8% were also HBsAg positive, 8.5% were anti-HBc IgG isolated and 16% were also anti-HBs positive. Conclusions: The prevalence of anti-HAV IgG was similar to the general population in the city of São Paulo. However, anti-HBc IgG was higher in our chronic HCV patients, when compared historically to the general population of western countries, suggesting similar risk factors for HBV and HCV acquisition, so emphasizing the importance of immunization programs in this population. Keywords: Hepatitis C, Chronic; Hepatitis C; Hepacivirus, Prevalence; Hepatitis A; Hepatitis B Título: Prevalência de Marcadores Sorológicos das Hepatites A e B em Pacientes com Hepatite C Crônica atendidos no Ambulatório de Hepatites do Serviço de Gastroenterologia Clínica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - HCFMUSP Background and Aims: Patients with chronic HCV and superinfection by hepatitis A virus (HAV) or hepatitis B virus (HBV) have higher morbidity and mortality when compared with those without HCV. For this reason, HAV and HBV active immunization has become mandatory in this population and hence their serological markers must be determined. The aim of this study was to evaluate the prevalence of serological markers of HAV and HBV infection in patients with chronic HCV. Methods: 1.000 chronic HCV infected patients at the University of Sao Paulo School of Medicine outpatient Liver Clinic were evaluated for the prevalence of serological markers of HAV and HBV infection. Results: Anti-HAV IgG was positive in 923 of 1000 patients (92.3%). When stratified by age, the anti-HAV IgG was found in 61% of patients between 20-29 years, 70% between 30-39 years, 85% between 40-49 years, 94% between 50-59 years, and 99% over 60 years of age. Anti-HBc IgG was positive in 244 patients (24%). Stratified by age, anti-HBc IgG was found in 4.3% of patients between 20-29 years, 17% between 30-39 years, 21% between 40 -49 years, 24% between 50-59 years, and 28% of patients over 60 years of age. Of the 244 anti-HBc IgG positive patients, 0.8% were also HBsAg positive, 8.5% were anti-HBc IgG isolated and 16% were also anti-HBs positive. Conclusions: The prevalence of anti-HAV IgG was similar to the general population in the city of São Paulo. However, anti-HBc IgG was higher in our chronic HCV patients, when compared historically to the general population of western countries, suggesting similar risk factors for HBV and HCV acquisition, so emphasizing the importance of immunization programs in this population

Introdução: O tratamento da hepatite C crônica com intereferon dura de 48 a 72 semanas, dependendo do genótipo. Os efeitos adversos mais prevalentes são dores pelo corpo, sintomas depressivos e piora na qualidade de vida. O tratamento torna o paciente incapacitado para suas tarefas diárias e atrapalha a adesão ao tratamento. Dessa forma, faz-se necessário buscar novas alternativas para minimizar os danos tornando o tratamento menos agressivo ao paciente e diminuindo os sintomas. Objetivo: Foram testadas duas hipóteses. A primeira foi explorar se a estimulação transcraniana por corrente continua (ETCC) seria mais eficaz em pacientes tratados com interferon peguilhado (PegINF) no tratamento da hepatite C crônica do que um placebo-sham para a redução dos sintomas dolorosos avaliados por meio dos níveis de dor e do limiar de dor a pressão. A segunda foi testar se os efeitos da ETCC nos sintomas relacionados ao uso de PegINF estariam relacionados ao processo de neuroplasticidade avaliado por meio dos níveis séricos de BDNF. Métodos: Foram recrutados 28 pacientes com hepatite C crônica, destros, com idades entre 40-74 anos, com escore de dor na escala numérica acima de 4 e com e limitações funcionais para realizar atividades de rotina devido à dor. Estes pacientes foram randomizados para um dos grupos de tratamento – placebo-sham (n=14) ou ETCC ativo (n=14). O tratamento consistiu em uma sessão diária de ETCC durante cinco dias consecutivos com a estimulação de 2mA aplicada na área do córtex motor primário(M1) do lado dominante. Os instrumentos de avaliação utilizados foram questionário para avaliar nível socioeconômico e dados demográficos, Escala Analógica Visual de dor (VAS), Escala do perfil de dor crônica (B-PCP:S) e níveis séricos de BDNF. Resultados: Comparando ETCC ativo com placebo-sham, ETCC ativa apresentou escores de dor significativamente mais baixos de VAS (P<0,003). A interação entre grupo e tratamento não foi significativa (P=0,07). A ETCC ativa resultou em redução da média de dor em 56% em comparação com o placebo-sham (P<0,001). Além disso, em comparação com placebo-sham, ETCC ativa resultou em melhora significativa no limiar de dor por pressão (P = 0,007) e no B-PCP: S (P <0,001), bem como reduziu o numero de doses analgésicas (P <0,03). O grupo da ETCC ativa também teve aumento significativo do BDNF no soro a partir da linha de base que foi de 37,48% (ETCC ativo) em comparação com 1,48% (diminuição do placebo-sham), esta diferença foi significativa (P <0,01). Conclusão: Concluímos que há grande potencial de utilização dessa técnica no tratamento de pacientes com hepatite c crônica, no que diz respeito ao alívio da dor, limiar de dor e diminuição dos níveis de BDNF. / Background: The treatment of chronic hepatitis C with intereferon lasts 48-72 weeks depending on the genotype. The most prevalent adverse effects are body pain, depressive symptoms and poor quality of life. The treatment makes the patient incapacitated for their daily tasks and interfere with treatment adherence. Thus, it is necessary to seek new alternatives to minimize the damage becoming less aggressive treatment to the patient and decreasing symptoms. Objective: Two hypotheses were tested . The first was to test whether transcranial direct current stimulation ( tDCS ) would be more effective in patients treated with interferon pegylated (PegINF) in the treatment of chronic hepatitis C than placebo-sham to reduce painful symptoms assessed by levels of pain and pressure pain threshold. The second was to test whether the effect of the tDCS related to use of PegINF symptoms would be related to the neuroplasticity process evaluated by means of BDNF serum. Methods: We recruited 28 patients with chronic hepatitis C, right-handed, aged 40-74 years, with a pain score on a scale above 4 and with functional limitations to perform routine activities due to pain. These patients were randomized to one of the treatment groups - placebo-sham (n = 14) or active tDCS (n=14). The treatment consisted of a daily session of 2mA tDCS for five consecutive days, applied in the primary motor cortex (M1) of the dominant hand area. The assessment instruments were used questionnaire to assess socioeconomic and demographic data, visual analogue scale for pain (VAS), scale profile of chronic pain (B-PCP:S) and serum BDNF levels. Results: Compared active tDCS with placebo-sham, active tDCS scores showed significantly lower pain VAS (P<0.003). The interaction between group and treatment was not significant (P =0.07). The active tDCS resulted in a reduction in average pain by 56% compared with the placebo -sham (P < 0.001). Moreover, active tDCS compared with placebo-sham, active tDCS resulted in significant improvement in the pain pressure threshold (P = 0.007) and the B -PCP:S (P<0.001) and reduced the number of analgesic doses (P < 0.03). The active tDCS group also had significantly increased BDNF in serum from the baseline that was 37.48 % (active tDCS) compared to 1.48% (reduced placebo-sham), this difference was significant (P < 0.01). Conclusion: We conclude that there is great potential for using this technique in the treatment of patients with chronic hepatitis C, with regard to pain relief, pain threshold and decreased levels of BDNF.

Orientadores: Adriana Maria Alves De Tommaso, Gabriel Hessel / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-08T20:45:32Z (GMT). No. of bitstreams: 1 Rosa_MarianaNogueiradePaula_M.pdf: 1246789 bytes, checksum: 4d75875746a0c9dddc300904721c7941 (MD5) Previous issue date: 2007 / Resumo: Anualmente ocorrem, no Brasil, cerca de 130 casos novos de hepatite A por 100000 habitantes e o país é considerado área de risco para a doença. A soroprevalência vai aumentando com a idade. Estima-se que, aproximadamente, 15% da população já entrou em contato com o vírus da hepatite B e que 1% apresenta doença crônica. A resposta à vacina da hepatite A está diminuída em pacientes com doença hepática crônica descompensada e a taxa de resposta à vacinação rotineira contra o vírus B em indivíduos imunossuprimidos é menor que em indivíduos saudáveis. A hipertensão portal pode determinar esplenomegalia e levar ao hiperesplenismo com redução nos números absoluto e percentual de células T, podendo determinar, dessa forma, uma diminuição da resposta à vacinação. Este estudo tem por objetivo avaliar a resposta à vacinação contra as hepatites A e B, em pacientes com hipertensão portal secundária a hepatopatia crônica ou trombose de veia porta. Foram avaliados 36 pacientes, de 2 a IS anos, com hipertensão portal, atendidos no Ambulatório de Hepatologia Pediátrica do Hospital de Clínicas da Universidade Estadual de Campinas, no período de 1994 a 2006. As sorologias para hepatites A e B foram realizadas nos pacientes já vacinados e nos pacientes que nunca receberam as vacinas. Os pacientes não vacinados receberam as vacinas durante o período do estudo. Os pacientes com títulos negativos de anti-HBs foram submetidos a dose de reforço e a sorologia foi repetida após o reforço. Avaliações hematimétricas dos pacientes foram realizadas, juntamente com as sorologias, para avaliar as alterações decorrentes da imunossupressão secundária à doença de base e ao hiperesplenismo. Dezenove pacientes receberam a vacina contra hepatite A e todos apresentaram resposta à vacina. Todos os pacientes receberam 3 doses da vacina contra hepatite B e vinte e sete pacientes (75%) apresentavam anti-HBs positivo. Nove pacientes foram submetidos à dose de reforço e nove apresentaram anti-HBs positivo após o reforço. A análise estatística realizada, por meio do teste de Mann-Whitney, para a comparação dos pacientes anti-HBs positivo e anti-HBs negativo com relação às variáveis idade, leucócitos, linfócitos e tempo entre a vacinação e a realização da sorologia não demonstrou diferença estatisticamente significativa. Os resultados permitem concluir que: 1. a vacina contra hepatite A apresentou 100% de resposta em pacientes com hipertensão portal e 2. a vacina contra hepatite B parece conferir proteção e induzir à resposta anamnéstica nesses pacientes. / Abstract: Anually, about 130 new cases of hepatitis A per 100000 inhabitants occur in Brazil, and the country is considered a risk area for the disease. About 15% of brazilian population has been in contact with hepatitis B virus and 1% has chronic disease. Hepatitis A vaccine response is diminished in patients with decompensated chronic disease, and response to routine vaccination against VHB in imunossupressed subjects is lower than in healthy subjects. Portal hypertension lead to hypersplenysm and decrease of absolute and percentual numbers of T cells, and a lower response to vaccination could occur. The purpose of this study was to evaluate response to hepatitis A e B vaccination in patients with portal hypertension secondary to chronic liver disease or portal vein thrombosis. Thirty six patients (2 to 18 years) with portal hypertension were evaluated, assisted at Pediatric Hepatology Service of the Hospital das Clínicas da Universidade Estadual de Campinas, from 1994 to 2006. Hepatitis A and B serologies were done in all patients. Patients who weren't vaccinated received vaccines during the study period and patients with negative anti-HBs received a booster dose, and serology was repeated after booster. Hematimetric evaluation of patients was done as the same time as serologies, for evaluation of immunosupression secondary to chronic liver disease and to hypersplenism. Nineteen patients received hepatitis A vaccine and all presented positive anti-VHA. All patients received hepatitis B vaccine, and 27 patients (75%) presented positive anti-HBs. Nine patients received a booster dose, and nine presented positive anti-HBs after booster. Statistic analysis was done by Mann-Whitney test to compare positive anti-HBs group and negative anti-HBs group. Variables age, leucocytes, limphocytes and time between vaccination and serology were analyzed, and there wasn't statistically significative diference between the groups. These results demonstrate that vaccine against hepatitis A presented a 100% response in patients with portal hypertension, and vaccine against hepatitis B seems to confer protection and to induce an anamnestic response in these patients. / Mestrado / Pediatria / Mestre em Saude da Criança e do Adolescente

L’hépatite C est un problème majeur de santé publique qui touche environ 160 millions de personnes dans le monde. L’agent étiologique responsable de cette maladie, le virus de l’hépatite C (HCV), est un petit virus enveloppé dont le génome est codé par un acide ribonucléique (ARN) simple brin de polarité positive. Actuellement, il n’existe aucun vaccin contre ce pathogène et les traitements utilisés sont insatisfaisants du fait de leur spécificité d’action limitée. Ainsi, afin d’établir une thérapie antivirale efficace évitant l’apparition et la sélection de mutants de résistance aux antiviraux, l’utilisation de plusieurs agents antiviraux ciblant directement la particule virale (direct acting antiviral agents ou DAAs) en combinaison est préconisée. C’est pourquoi la découverte de nouveaux DAAs à large spectre d’action ciblant diverses étapes du cycle viral infectieux est indispensable.Au cours de ma thèse, nous avons identifié un nouvel inhibiteur de l’entrée du HCV : l’épigallocatéchine-3-gallate (EGCG). Cette molécule, extraite du thé vert, inhibe l’infection des cellules par le HCV. Plus précisément, en utilisant des particules rétrovirales pseudotypées avec les glycoprotéines d’enveloppe E1 et E2 du HCV, nous avons démontré que cette catéchine naturelle, agit à une étape très précoce de l’entrée virale, indépendamment du génotype. De même, en nous servant du virus produit en culture cellulaire, nous avons montré que cette molécule agit directement sur la particule virale. Puis, par RT-PCR quantitative (quantitative real-time polymerase chain reaction), nous avons confirmé l’inhibition de la liaison du virus à la surface cellulaire, en présence d’EGCG. Par conséquent, nos travaux suggèrent que l’EGCG interagit avec la particule virale, probablement en se liant aux glycoprotéines d’enveloppe virales, bloquant ainsi une étape initiale d’attachement entre le virus et les facteurs cellulaires présents à la surface de l’hépatocyte. Puis, en inhibant la transmission libre du virus, à l’aide, soit d’agarose, soit d’anticorps neutralisants, nous avons démontré que l’EGCG inhibe la transmission du virus de cellule à cellule. Enfin, nous avons montré que l’EGCG élimine le virus présent dans le surnageant de culture cellulaire après quatre passages successifs sur des cellules naïves.La concentration d’EGCG nécessaire pour inhiber la moitié de l’infection virale (IC50) en culture cellulaire est 11 µM. Ainsi, afin d’identifier de nouvelles molécules présentant un mode d’action similaire à celui de l’EGCG et possédant une meilleure activité antivirale, nous avons sélectionnés différentes molécules naturelles et les avons testés pour leur potentiel effet anti-HCV. C’est ainsi que le chlorure de delphinidine, une anthocyanidine, a également été identifié en tant que nouvelle molécule inhibitrice de l’entrée du HCV. De même que l’EGCG, le chlorure de delphinidine cible directement la particule virale à une étape précoce de l’entrée, indépendamment du génotype, probablement en inhibant l’attachement du virus à la surface cellulaire et sans affecter ni l’étape de réplication, ni l’étape d’assemblage/maturation. De plus, le chlorure de delphinidine présente une activité anti-HCV améliorée avec une IC50 de 3 µM.Finalement, au cours de cette thèse, nous avons identifié deux nouvelles molécules naturelles inhibant l’étape d’entrée virale du HCV. Ces molécules pourraient être utilisées comme nouveau traitement en combinaison avec d’autres DAAs et pourraient également servir d’outil afin d’étudier les mécanismes d’entrée du HCV dans l’hépatocyte. / Hepatitis C is a major global health burden with 160 million infected individuals worldwide. This long-term disease, caused by a small positive-strand ribonucleic acid (RNA) enveloped virus, namely hepatitis C virus (HCV) evolves slowly. Nowadays, no vaccine is available and current treatments are unsatisfactory due to their restricted spectrum of action. For this reason, it is suggested that the combination of several drugs will prevent viral resistance and might conduct to an efficient antiviral therapy. Thus, the discovery of new direct acting antiviral agents (DAAs), with a broad spectrum of action, targeting different steps of the virus life cycle is still needed. Here, we identified (-)-epigallocatechin-3-gallate (EGCG) as a new inhibitor of HCV entry. Epigallocatechin-3-gallate, extracted from green tea, inhibits HCV infection. More precisely, this natural catechin molecule acts at a very early step of entry regardless of the genotype as illustrated with HCV pseudoparticles expressing HCV envelope glycoproteins E1 and E2 assays and cell-cultured HCV assays. Moreover, this molecule inhibits the docking of the virus to the cell surface as showed by the quantification of bound viruses during the attachment step using quantitative real-time polymerase chain reaction. Furthermore, EGCG inhibits viral cell-to-cell transmission as demonstrated by inhibiting cell-free transmission using agarose or neutralizing antibodies assays. Finally, EGCG clears HCV from cell culture supernatants after four passages.The half maximal inhibitory concentration (IC50) of EGCG in cell culture is approximately 11 µM. In order to identify new molecules exhibiting an enhanced anti-HCV activity and displaying similarities from EGCG scaffold, a series of natural compounds were selected and were tested for their anti-HCV activities. Thus, the anthocyanidin delphinidin chloride was identified as another inhibitor of HCV entry. Like EGCG, delphinidin chloride acts directly on the virus at a very early step of entry, regardless of the genotype, probably by inhibiting the docking of the virus to the cell surface without affecting replication or viral assembly/secretion. Finally, with an IC50 of 3 µM, delphinidin chloride displays a more potent anti-HCV activity.Together, these data indicate that EGCG and delphinidin chloride are new interesting anti-HCV molecules that inhibit entry and might be used as a new treatment in combination with other DAAs. Furthermore, these two inhibitors might be novel tools to further dissect the mechanisms of HCV entry into the hepatocyte.