Orientador: Maria Filomena Ceolim / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Enfermagem / Made available in DSpace on 2018-08-23T23:37:16Z (GMT). No. of bitstreams: 1 FurlaniCotrim_Renata_D.pdf: 1606137 bytes, checksum: c07e87834fa65c007065f0a1f8e21512 (MD5) Previous issue date: 2013 / Resumo: Os distúrbios de sono estão presentes nos seguimentos de transplante de células-tronco hematopoiéticas (TCTH) e fazem parte de um conjunto de sintomas que vêm associados ao decréscimo da qualidade de vida. Permanecer em um ambiente hospitalar pode precipitar o surgimento destes distúrbios. Este estudo destinou-se à avaliação da qualidade de sono de pacientes com câncer hematológico submetidos ao TCTH, no intuito de identificar fatores preditivos de qualidade de sono antes da realização do transplante (primeira etapa), durante a hospitalização (segunda etapa) e após a alta hospitalar (terceira etapa). O estudo foi realizado em um hospital público do interior do estado de São Paulo. Participaram 47 portadores de câncer hematológico que atenderam aos critérios do estudo. Os dados foram coletados por meio dos seguintes instrumentos: Questionário de Caracterização - Aspectos Sócio-Econômicos, Demográficos e Clínicos; Índice de Qualidade de Sono de Pittsburgh (PSQI-BR); instrumento de qualidade de vida Short Form-12 (SF-12), Diário de Sono (DS) e escala de fadiga. Dosagens de interleucina-6 e proteína-C reativa foram obtidas durante a hospitalização. Os dados foram submetidos a testes estatísticos não-paramétricos e a análises de regressão logística e linear. O sono de má qualidade predominou nas três etapas do estudo atingindo pior pontuação durante a hospitalização. Verificou-se associação do sono de má qualidade à presença de fadiga na primeira e na segunda etapa do estudo e melhor avaliação do componente físico (PCS) do SF-12 em sujeitos com sono de boa qualidade nas três etapas do estudo. Na primeira etapa, o sono de má qualidade foi predominante em indivíduos do sexo feminino e, na terceira etapa, observou-se uma tendência à associação do sono de má qualidade à idade igual ou superior a 40 anos. Nestas duas etapas, o sono de má qualidade associou-se, ainda, ao diagnóstico de mieloma e ao TCTH autólogo, achado contrário ao verificado em outros estudos. Na hospitalização, a prestação de assistência pela equipe de saúde e a necessidade de usar o banheiro foram as principais causas de interrupção do sono noturno. Verificou-se melhor padrão de sono depois da enxertia de neutrófilos em relação ao período anterior à enxertia, no qual as dosagens de PCR e do número de sinais e sintomas foram mais elevados. Não foi verificada variação significativa na dosagem de interleucina-6. Em T5, momento anterior à enxertia, o número de sinais e sintomas explicou 28% da variação da qualidade de sono. viii Os sujeitos com maior número de cochilos demonstraram maior necessidade de sono noturno e pior avaliação da qualidade de sono durante à hospitalização. Pertencer ao sexo feminino aumentou em quase 20% a chance de sono de má qualidade na primeira etapa do estudo e, na terceira etapa, a cada um ponto (1,0) de aumento no componente físico (PCS) e mental (MCS) de qualidade de vida, a chance de má qualidade de sono diminuiu, respectivamente, em 15% e 18%. Este estudo destaca a importância de adotar medidas que garantam um sono de boa qualidade na fase aguda do transplante, sobretudo durante a hospitalização, no intuito de minimizar o impacto provocado pelo TCTH na vida dos sujeitos. / Abstract: Sleep disturbances are present in hematopoietic stem cell transplantation (HSCT) and are part of a set of symptoms have been associated with decreased quality of life. Staying in a hospital setting may precipitate the onset of these disorders. This study aims to evaluate the quality of sleep in patients with hematological cancer undergoing HSCT, in order to identify predictors of sleep quality prior to transplantation (first stage), during hospitalization (second stage) and after discharge (third stage). The study was conducted in a public hospital in the state of Sao Paulo. Participants 47 patients with hematological cancer who met the study criteria. Data were collected using: Characterization Questionnaire - Socio-Economic, Demographic and Clinical; Index Pittsburgh Sleep Quality (PSQI-BR); quality of life Short Form-12 (SF-12), Sleep Diary (SD) and fatigue scale. Interleukin-6 and C-reactive protein doses were obtained during hospitalization. The data were subjected to non-parametric statistical tests and logistic and linear regression analyzes. The poor sleep predominated in the three stages of the study reaching worst score during hospitalization. An association of poor sleep and presence of fatigue was verified in the first and second stage of the study, and evaluation of the best physical component (PCS) of the SF-12 between subjects with good sleep quality in the three stages of the study. In the first stage, the poor quality of sleep was predominant in females and, in the third stage, there was a tendency for the association of poor sleep and age (greater than 40 years). In these two steps, the poor sleep was associated also to the diagnosis of myeloma and autologous HSCT, a opposed finding to that observed in other studies. During hospitalization, the care provision and the need to use bathroom were the main causes of nocturnal sleep disruption. Better sleeping pattern was verified after engraftment. Before engraftment, CRP dosages and the signs and symptoms number were higher. Variation in the interleukin-6 dose was not significant. At T5, prior to engraftment, the number of signs and symptoms explained 28% of the variation in quality of sleep. The subjects with the highest number of naps showed greater need for nocturnal sleep and worse sleep quality assessment during hospitalization. Being female increased by almost 20% chance of poor sleep in the first stage of the study and, in the third step, each point (1.0) increase in physical component (PCS) and mental (MCS) of quality of life, the chance of poor sleep quality decreased, respectively, 15% and 18%. This study highlights the importance of adopting measures that guarantee a good quality sleep in the acute phase of transplantation, particularly during hospitalization, in order to minimize the impact caused by HSCT in subjects' lives. / Doutorado / Enfermagem e Trabalho / Doutora em Enfermagem

Orientador: Sandra Cecilia Botelho Costa / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-07T11:25:10Z (GMT). No. of bitstreams: 1 Tavares_CarlaAparecida_M.pdf: 2590689 bytes, checksum: f1ca87aa51c2db9aa3fe97a2330a029c (MD5) Previous issue date: 2006 / Resumo: A reativação da infecção pelo Citomegalovírus humano (HCMV) e pelo Poliomavírus (BKV) no uroendotélio, vem sendo relacionada a complicações como a Cistite Hemorrágica (CH) em receptores de transplante de células progenitoras hematopoéticas (TCPH), o que representa um fator de risco para estes pacientes. Este estudo prospectivo de 41 receptores de TCPH teve como objetivos, detectar a infecção ativa pelo HCMV no sangue e pelo BKV em amostras de sangue e urina após TCPH, usando as técnicas de antigenemia (AGM), citologia urinária e Reação em Cadeia da Polimerase tipo Nested (¿Nested-PCR") para se verificar a participação do HCMV e BKV como possíveis fatores de risco para CH e o impacto clínico destas viroses nestes pacientes. O monitoramento dos receptores de TCPH foi baseado em coletas de sangue para realização de AGM e "Nested-PCR" para detecção do HCMV e Citologia urinária para verificar células Decoy como um marcador de replicação viral, e também "Nested-PCR" de urina e sangue para diagnóstico de replicação do poliomavírus de todos os receptores (independente de Citologia urinária positiva ou negativa). Nos receptores estudados, a freqüência de AGM positiva para HCMV foi de 63,4%, com "Nested-PCR" positivo de 78%. A doença pelo HCMV ocorreu em 8/41 (21,1%) dos receptores, dos quais 1/8 (12,5%) veio a óbito. Dos 41 receptores 14 (34,1 %), tiveram BKV detectado na urina e 13 (31,7%) no sangue, todos os receptores que apresentaram infecção ativa pelo BKV tiveram também pelo HCMV, sendo que 16 (39%) evoluíram com CH. Estes resultados sugerem que o BKV juntamente com o HCMV em receptores de TCPH pode estar envolvidos na patogênese da CH, sendo assim, medidas preventivas baseadas na inibição da replicação viral de ambos os vírus poderão minimizar o impacto clínico da cistite hemorrágica nesse grupo de transplantados / Abstract: The reactivation of inrection by Human Cytomegalovirus (HCMV) and by Polyomavirus (BKV) in the uroendothelium, has been related with haemorrhagic cystitis (HC) in haematopoietic stem cell transplantation (HSCT) receptors, which represents a factor of risk for those patients. This prospective study of 41 HSCT receptors has the purpose of detect the active HCMV infection in the blood and BKV in blood and urine samples after HSCT, using antigenemia assay (AGM), urine cytology and Nested polymerase chain reaction ("Nested-PCR"), to verify the chance of participation of HCMV and BKV as factor of risk for HC and the clinic impact of these virus on those patients. The HSCT receptor' s monitoring was based in blood collection for AGM and "Nested-PCR" to detect HCMV and urine cytology to verify decoy celIs as a marker of BK virus replication, and "Nested-PCR" on urine and blood in alI receptors (independently of positive or negative cytology) as welL In the HSCT receptors, the frequency of positive AGM for HCMV was 63,4%, with a positive "Nested-PCR" of 78%. The HCMV disease occurred in 8/41 (21,1%) of the receptors, and 1/8 (12,5%), dead. Among the 41 receptors, 14 (34,1%) had BKV detected in the urine and 13 (31,7%) in the blood. All the receptors that showed active infection by BKV, had active infection by HCMV, as well, and 16 (39%) developed HC. These results suggest that BKV and HCMV, together, in HSCT receptors might be involved in HC pathogenesis. Being thus , prevents measurements based on viral replication inhibition for both vírus could minimize the clinic impact of hemorrhagic cystitis on those transplanted grou / Mestrado / Mestre em Farmacologia

Orientador: Sandra Cecilia Botelho Costa / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-14T10:34:08Z (GMT). No. of bitstreams: 1 Costa_ClaudiaRaquelCantarelli.pdf: 4518268 bytes, checksum: fb54bd9384d947b72d5d29ed906ae70f (MD5) Previous issue date: 2009 / Resumo: O cytomegalovirus humano (HCMV) e o herpesvirus humano 6 (HHV-6) são ß-herpesvirus com homologia superior a 67% e alta soroprevalência na população adulta. A infecção primaria por estes herpesvirus ocorre comumente na infância e é normalmente subclinica, ou pode causar mononucleose (HCMV) ou exantema súbito (HHV-6) sendo resolvidos na maioria dos casos sem complicações. Após a infecção primária os vírus permanecem no hospedeiro por toda vida podendo ser reativado de seu estado de latência em indivíduos adultos imunocomprometidos como os receptores de células tronco hematopoiéticas (TCTH). A reativação ou reinfecção por estes vírus causam serias complicações em pacientes submetidos ao transplante de células tronco hematopoiéticas como pneumonia intersticial, febre, gastroenterite, mielossupressão, encefalite e doença do enxerto contra o hospedeiro (GVHD). A reativação do HHV-6 após o transplante é associada com o desenvolvimento de infecções oportunistas, doença causada pelo citomegalovírus humano e possíveis episódios de rejeição aguda. Com efetivos tratamentos antivirais disponíveis, um monitoramento adequado destes vírus distinguindo entre latência e reativação é critico para estes pacientes. Monitoramos 30 pacientes submetidos à TCTH quanto a infecção ativa por HCMV e HHV-6 pelas técnicas de nested-PCR em soro e células, PCR- em tempo real em soro e células e transcrição reversa acoplada a nestedPCR (RT-nPCR). 29 pacientes (96,66%) apresentaram infecção ativa por HCMV sendo 21 pacientes (70%) pela nested-PCR em células, 17 pacientes(56,66%) pela neste-PCR em soro ,23 pacientes(76,67%) pela PCR em tempo real em células,19 pacientes (63,33%) pela PCR em tempo real em soro e 15 pacientes (53,3%) pela RT-nPCR. 25pacientes (83,33%) apresentaram infecção ativa por HHV-6, sendo 14 pacientes (46,7%) pela nested-PCR em células, 2 pacientes(6,6%) pela PCR em tempo real em células,23 pacientes (76,67%) %) pela PCR em tempo real em soro e 9 pacientes (30%) pela RT-nPCR. Todos os pacientes que apresentaram infecção ativa por HCMV apresentaram também presença do HHV-6, e 25 pacientes (83,33%) apresentaram co-infecção HCMV/HHV-6, sendo a infecção por HHV-6 precoce em relação ao HCMV. O presente estudo encontrou também associação entre infecção ativa por HCMV e doença do enxerto contra o hospedeiro. / Abstract: Human cytomegalovirus (HCMV) and human herpesvirus type 6 (HHV-6) are ß-herpesvirinae extremely closely related with a homology > 67% with a high seroprevalence in the adult population. Primary infection commonly appears in early childhood and is usually subclinical, or may cause mononucleosis (HCMV) or febrile illness, including exanthema subitum (HHV-6), solving, in the majority of cases, without complications. After primary infection, the viruses persist in the infected individual through life and can be reactivated from their state of latency in immunocompromised hosts. Reactivation or reinfection causes severe clinical diseases in patients who underwent hematopoietic stem cell transplantation, like interstitial pneumonia, fever, gastroenteritis, myelossupression, encephalitis and graft-versus-host-disease (GVHD). A potential increase in virulence of HHV-6 in the course of a simultaneous CMV reactivation, leading to a great risk of CMV-associated disease. In this present study, 30 patients who received HSCT were monitoring for active HCMV and HHV-6 infection by Nested PCR in serum and peripheral blood leukocytes (PBL) samples, real time PCR in serum and PBL and RT-nPCR. In 29 patients (96,66%) active HCMV infection was detected: 21 patients (70%) by PBL nested-PCR, 17 patients (56,66%) by serum neste-PCR, 23 patients(76,67%) by PBL real-time-PCR,19 patients (63,33%) by serum real-time-PCR and 15 patients (53,3%) by RT-nPCR. In 25 patients (83,33%) active HHV-6 infection was detected : 14 patients (46,7%) by PBL nested-PCR, 2 patients(6,6%) by PBL real time -PCR,23 patients (76,67%) by serum real time-PCR and 9 patients (30%) by RT-nPCR. In all patients who had active HCMV infection, HHV-6 DNA was detected. 25 patients (83,33) had HCMV/HHV-6 co-infection, and the active HHV-6 infection was detected earlier in the majority of the cases. Our results showed a correlation between GVHD and active HCMV infection and detection of active HCMV infection by serum nested-PCR and PBL and serum real time-PCR. / Universidade Estadual de Campi / Ciencias Basicas / Doutor em Clínica Médica

Orientador: Maria Elvira Pizzigatti Corrêa / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-27T08:02:08Z (GMT). No. of bitstreams: 1 Torregrossa_ViniciusRabelo_M.pdf: 2074120 bytes, checksum: 7ac320774930da79cb9aea0a6c37ec73 (MD5) Previous issue date: 2015 / Resumo: INTRODUÇÃO: Alterações salivares quantitativas e qualitativas são complicações comuns ao Transplante de Células-Tronco Hematopoiéticas alogênico (TCTHa). Essas alterações salivares são frequentemente relacionas à fase tardia do TCTHa, principalmente na presença da Doença do Enxerto-Contra-Hospedeiro crônica (DECHc). Poucos estudos abordaram a influência da toxicidade aguda dos regimes de condicionamento sobre as alterações precoces do fluxo salivar. O objetivo deste trabalho foi avaliar a influência do TCTHa nas alterações precoces do fluxo salivar e validar critérios clínicos utilizados para o diagnóstico de hipossalivação nesta população de pacientes. MÉTODOS: O estudo prospectivo das alterações quantitativas da saliva envolveu 69 pacientes adultos submetidos ao primeiro TCTHa. A saliva não estimulada foi coletada e os pacientes foram submetidos à avaliação da saúde oral, do grau de mucosite oral, e de critérios clínicos de hipossalivação previamente ao início do regime de condicionamento, e entre os dias D+8-10 pós-TCTH. A avaliação da condição de saúde oral incluiu a obtenção do índice de Dentes Cariados, Perdidos e Obturados (CPOD), Índice Gengival (IG), e do Índice de Placa (IP). Para a avaliação da hipossalivação foram utilizados quatro critérios clínicos objetivos e quatro critérios subjetivos, considerando-se hipossalivação quando o Fluxo Salivar Não Estimulado (FSNE) ?0,2 mL/min. A avaliação da mucosite oral foi realizada entre os dias D+8-10 pós-TCTH, conforme os critérios da OMS. O estudo de validação dos critérios de hipossalivação envolveu 120 pacientes não consecutivos submetidos ao primeiro TCTH alogênico. As avaliações orais e as coletas de saliva foram realizadas simultaneamente e em diferentes períodos pós-TCTH. Para o estudo das alterações precoces do fluxo salivar, as variáveis categóricas foram analisadas pelo teste de associação Qui-quadrado, ou pelos testes de Fisher ou de Mann-Whitney. O teste t pareado foi utilizado na comparação das variáveis contínuas nos diferentes períodos. No estudo de validação dos critérios de hipossalivação, o teste alfa de Cronbach foi aplicado para medir a consistência interna e confiabilidade dos critérios clínicos utilizados. Foram então selecionados 5/8 critérios clínicos de hipossalivação, e um Sistema de Pontuação para Boca Seca (SPBS) foi elaborado. O teste de Mann-Whitney e a correlação de Pearson foram utilizados na análise da distribuição do FSNE em relação às pontuações obtidas, a partir dos critérios clínicos de hipossalivação selecionados. RESULTADOS: Foi observado um aumento do fluxo salivar (p=0.03) e do grau de inflamação gengival (p=0.03) entre os dias D+8-10 pós-TCTH. O aumento do fluxo salivar neste período foi correlacionado à gravidade da mucosite oral (p=0.02), à presença de vômito (p=0.03), ou ao uso de nutrição parenteral total (p=0.03) nos dias das coletas de saliva. Apesar da hipossalivação não ter sido um achado frequente no período estudado, mulheres e pacientes com doenças de alto risco apresentaram um menor fluxo salivar (p=0.01 e p=0.03, respectivamente). O SPBS incluiu quatro critérios clínicos validados e uma questão subjetiva de hipossalivação: 1.Alta aderência da espátula de madeira na mucosa jugal; 2.Ausência de lago sublingual; 3.Saliva espessa e viscosa; 4.Ausência de secreção salivar após ordenha do ducto parotídeo; 5. Você sente sua boca seca?. O SPBS foi dicotomizado entre as pontuações 0-1 e 2-5, de acordo com os valores obtidos do FSNE. Após a dicotomização, 66 (55%) pacientes apresentaram pontuações de 0-1, com uma média do FSNE de 0.65 mL/min (0.1-9.0 mL/min), e 54 (45%) pacientes apresentaram pontuações de 2-5 com uma média do FSNE de 0.34 mL/min (0.01-6.7 mL/min). Maiores pontuações obtidas no SPBS foram correlacionadas a um FSNE reduzido (p=0.006, r=-25%), confirmado pelo teste de Mann-Whitney (p<0.0001). CONCLUSÕES: O aumento do fluxo salivar nos dias D+8-10 pós-TCTH pode estar relacionado à intensa reação inflamatória e dano tecidual e induzidos pela toxicidade dos regimes de condicionamento, que se traduz pela gravidade da mucosite oral observada clinicamente. O SPBS provou ser uma ferramenta confiável para o diagnóstico de hipossalivação em pacientes submetidos ao TCTH alogênico / Abstract: INTRODUCTION: Qualitative and quantitative salivary changes are common complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). These salivary changes are related to late effects of HSCT, mostly in the presence of chronic graft-versus-host disease (cGVHD). Little is known about the influence of the conditioning regimens-related toxicity on the very early salivary flow changes. Thus, the aim of the present study was to understand the influence of allo-HSCT on the very early salivary flow changes. A secondary aim was to validate clinical criteria for the diagnosis of hyposalivation in allo-HSCT patients. METHODS: The prospective study of quantitative salivary changes enrolled 69 adult patients undergoing their first allo-HSCT. The unstimulated whole saliva was collected and patients were assessed for their oral health status, the degree of oral mucositis (OM), and for clinical criteria used for the diagnosis of hyposalivation before the start of the pretransplant conditioning regimens and between the days D+8-10 posttransplantation. The oral health exam included the evaluation of Decayed-Missing-Filled teeth (DMFT) index, Gingival Index (GI), and Plaque Index (PI). The clinical assessment of hyposalivation was composed by four objective clinical criteria and by four subjective questions. Hyposalivation was considered when the unstimulated whole saliva flow rate (UWSFR) was ? 0.2 mL/min. OM severity was evaluated at days D+8-10 according to the World Health Organization (WHO) criteria. The validation study of the clinical criteria for the diagnosis of hyposalivation enrolled 120 non-consecutive patients undergoing their first allo-HSCT. The oral health exams and saliva collection were taken simultaneously and in different periods of HSCT. For the study of very early salivary flow changes, chi-square or Fischer¿s test, besides of the Mann-Whitney U Test were applied according to the variable type. Pared T-test was used to compare continuous variables in different periods. For the validation study of the clinical criteria for the diagnosis of hyposalivation, a Cronbach¿s alpha test was applied in order to measure the internal consistency and satisfactory reliability of all criteria used. Five of eight clinical criteria of hyposalivation were selected, and a scoring system called Oral Dryness Score (ODS) was developed. Mann-Whitney U test was applied to analyze the UWSFR distribution among the dichotomized ODS scores, in addition to the Pearson¿s correlation coefficient. RESULTS: An increase of the UWSFR (p=0.03) and the worsening of the gingival index (p=0.03) were observed at days D+8-10 posttransplantation. A positive correlation was found between an increase of the UWSFR and a greater severity of OM (p=0.02), the use of total parenteral nutrition (TPN) (p=0.03), and with vomiting episodes (p=0.03). Although hyposalivation was not a frequent finding among the studied population, a reduced UWSFR was observed in women (p=0.01), and in the group of patients with a high risk underlying disease (p=0.03). The ODS included four validated objective clinical criteria and a subjective question of hyposalivation: 1.Higher adherence of the wood spatula to the jugal mucosa; 2.No saliva pooling in the anterior floor of mouth; 3.Increased viscosity and thickness of saliva; 4.Absence of salivary secretion of the parotid duct under manual pressure; 5.Does your mouth feels dry?. The ODI was dichotomized between 0-1 scores and 2-5 scores, respecting its behavior according to the UWSFR. After dichotomization, 66 (55%) patients presented 0¿1 scores, with a UWSFR median of 0.65 mL/min (0.1¿9.0 mL/min), and 54 (45%) patients presented 2¿5 scores with a UWSFR median of 0.34 mL/min (0.01¿6.7 mL/min). A higher ODS was correlated with a decreased UWSFR (p=0.006, r=-25%), confirmed by a Mann-Whitney U test (p<0.0001). CONCLUSIONS: The clinical impact of the conditioning regimens toxicity showed through the OM severity seemed to have influenced the very early salivary flow changes. If the influence of HSCT on the very early salivary changes could be better characterized, as well as its correlation with short and long-term oral outcomes of HSCT patients, the proper clinical management could be improved. The ODS was correlated with a decreased UWSFR, proving to be a reliable tool for the diagnosis of hyposalivation in this population / Mestrado / Estomatologia / Mestre em Estomatopatologia

Orientador: Maria Elvira Pizzigatti Corrêa / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-28T03:50:50Z (GMT). No. of bitstreams: 1 Vieira_RaizaMeira_M.pdf: 2654950 bytes, checksum: 493dac1ecf0ca2acb92f0ff8829107aa (MD5) Previous issue date: 2015 / Resumo: Complicações orais estão presentes em cerca de 80% dos pacientes durante o Transplante de Células Tronco Hematopoéticas (TCTH), sendo a mucosite oral (MO) e as alterações salivares umas da que possuem maior impacto para a qualidade de vida do paciente. A utilização do perfil proteico salivar (PPS) na abordagem diagnóstica em diversas doenças tem sido frequente. A identificação de um PPS que auxilie o entendimento das manifestações agudas orais do TCTH poderia sobremaneira, influenciar nas decisões terapêuticas visando melhora no manejo do paciente. O objetivo deste trabalho foi identificar alterações do PPS do início do regime do condicionamento pré TCTH até a recuperação medula e correlacioná- las com dados clínicos orais. Para tanto, foi utilizado o banco de dados de proteomica salivar do grupo de Odontologia do Hemocentro, encontrada por Feio et AL (2013). Nesta avaliação foram incluídos 16 pacientes submetidos ao primeiro TCTH alogênico na Unidade de Transplante de Medula Óssea do Hospital de Clínicas da UNICAMP. As amostras de saliva total não estimulada (STNE) foram coletadas em dois momentos: previamente ao condicionamento (coleta A) e a segunda (coleta B), entre os dias D+8 e D+10 pós-TCTH. Dados sobre saúde oral, grau de MO foram coletados, além da avaliação de hiposalivação. O estudo do PPS foi realizado por espectometria de massas no LNBio. Os PPS das duas coletas, A e B foram tabelados no programa Excel® 2007 (Microsoft, WA, EUA), juntamente com os dados clínicos. O teste T pareado foi utilizado para a comparação entre os PPSs com os tempos das coletas. Os critérios clínicos de hiposalivação foram comparados com as divergências proteicas durante as duas coletas por ANOVA. A comparação entre os dados clínicos de cada coleta e seu respectivo PPS, foi feito pelo teste T pareado, sendo considerado significativo p<0,005. Sete proteínas apresentaram intensidades divergentes entre as coletas A e B: Prolactin-inducible protein, Alpha-Amylase 1, Cystatin-SN, Submaxillary gland androgen-regulated protein 3B, Sthaterin, cDNA FLJ60163, highly similar to Carbonic anhydrase 6 apresentaram-se em decréscimo na coleta B comparada a coleta A e a vitamin D-binding protein isoform 1 precursor se apresentou aumentada na coleta B quando comparada a coleta A. A mucosite oral foi correlacionada com as proteinas, Immunoglobulin J chain, Pulative uncharacterized protein DKFZp686N02209 que se demonstraram com intensidade diminuída naqueles pacientes que apresentaram graus III e IV em comparação àqueles com grau 0¿II de MO; a proteína Statherin esteve presente em maior intensidade naqueles pacientes que apresentaram MO com grau III e IV. Esses resultados podem estar relacionados principalmente à toxicidade do regime de condicionamento mieloablativo nas glândulas salivares e sugerem que as proteinas Statherin, Immunoglobulin J chain e Pulative uncharacterized protein DKFZp686N02209 podem ser candidatas a um painel de PPS para a MO no TCTH / Abstract: Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for various hematological diseases. Oral Complications are present in about 80% of patients who undergo to HSCT. Oral mucositis (OM), oral infections and salivary changes, among others are the most common oral clinical founds in the acute phase of the HSCT. The use of salivary profile as a tool for diagnosis and management of treatment responses has been shown a promising future in different clinical settings. Thus the discovery of a salivary protein profile (SPP) of patients submitted to the allogeneic HSCT during the acute phase of the transplantation may be helpful on the management of the oral effects of the HSCT. The aim of this research was to identify the SPP changes during the acute phase of allogeneic HSCT and correlate them with the oral clinical manifestation of the acute phase of HSCT. This study enrrolled 16 patients with hematological diseases who, underwent to their first allogenic HSCT at the Bone Marrow Transplantation Unit ¿ UNICAMP. Unstimulated salivary samples were collected in two periods: first (collection A), it was performed prior the initiation of the conditioning regimen for the HSCT and collection B; performed between day D+8-10 days after HSCT. Oral health indices were obtained in both moments of the saliva collection. The severity of oral mucositis was collected on the collection B. The PPS analysis was performed by mass spectrometry on a previous study performed by Feio et al (2013). Student T test paired was used in order to between the 39 identified proteins equally between the collections A and B. Clinical correlations were also compared to the different PPS using one-way ANOVA analysis. For both comparisons, considered significant p < 0.05. Among the collections A and B, 7 proteins were presented with differing intensities: Prolactin-inducible protein, Alpha-Amylase 1, Cystatin SN, Submaxillary gland androgen-regulated protein 3B, Sthaterin, cDNA FLJ60163 Similar to highly Carbonic anhydrase 6 showed a decrease intensity in the collection B and the vitamin D-binding protein isoform 1 precursor quantity showed a increased in the collection B. Three proteins were shown altered intensity when correlated with the severity of OM: Immunoglobulin J chain, Pulative uncharacterized protein DKFZp686N02209v. These proteins showed a decreased of intensity in those patients grade III-IV OM when compared to patients with grade 0-II OM. The protein Statherin showed in increased intensity in patients with OM grade III-IV. These results indicate the influence of the toxicity of the conditioning regimens on the salivary protein profiles in the acute phase of the HSCT. The proteins: Immunoglobulin J chain, Pulative uncharacterized protein DKFZp686N02209v and Statherin might be a potential candidates for a panel of salivary biomarkers for OM / Mestrado / Estomatologia / Mestra em Estomatopatologia

Les infections fongiques sont une complication fréquente des patients d’hématologie et en particulier des patients ayant reçu un greffe de cellules souches hématopoïétiques (CSH). L’objectif de ce travail était d’identifier les facteurs de risque d’infections fongiques intrinsèques et la transmission.Nous avons d’abord étudié l’aspergillose invasive (AI) qui est l’infection fongique la plus fréquente chez les greffés de CSH en croisant les données du registre européen des greffés ProMise et la base de données de l’étude prospective SAIF. Nous avons mené une étude cas-témoins nichée dans une cohorte de 185 cas et 651 témoins appariés. Les facteurs associés à la survenue d’une aspergillose étaient l’irradiation corporelle totale, une GvH aiguë de grade ≥2 et la rechute de l’hémopathie. Trente-cinq cas étaient précoces (<J40), 33 tardifs (entre J40 et J100) et 117 très tardifs (>J100). Le facteur associé à la survenue d’une AI précoce était l’absence de prise de greffe. Le facteur associé à la survenue d’une AI tardive était la GvH aiguë de grade 3-4. Les facteurs associés à la survenue d’une AI très tardive étaient la GvH aiguë de grade ≥2, la rechute et la neutropénie secondaire. Tous les facteurs pré-greffe étaient effacés par les facteurs post-greffe.Puis nous avons étudié la transmission d’infection fongique par l’étude d’une épidémie de pneumocystose survenue dans le service. Douze cas de pneumocystose sont survenus en 7 mois dans le service soir beaucoup plus qu’au cours des années précédentes. L’analyse moléculaire a permis de montrer que 4 cas appartenaient au même génotype, qui est un génotype rare jamais décrit dans une série de plus de 300 génotypes en Europe. La carte de transmission a permis de constater que ces 4 patients se sont rencontrés uniquement en hôpital de jour. Cette étude est la première démonstration moléculaire d’une épidémie de pneumocystose dans un service d’hématologie. / Fungal infections are a common complication of hematology patients and especially in hematopoietic stem cell transplantation (HSCT) recipients. The objective of this work was to identify intrinsic risk factors for fungal infections and transmission.We first studied invasive aspergillosis (IA), which is the most common fungal infection after HSCT by crossing data from the European HSCT registry ProMise and the prospective study database SAIF. We conducted a nested case-control study in a cohort of 185 cases and 651 matched controls. Factors associated with onset of aspergillosis were total body irradiation, acute GVHD grade ≥2, and relapse of the underlying disease. Thirty-five IA were early (<D40), 33 late (between D40 and D100) and 117 very late (> D100). The factor associated with the occurrence of an early IA was the absence of engraftment. The factor associated with the occurrence of late IA was acute grade 3-4 GvH. Factors associated with the occurrence of very late IA were acute GVHD grade ≥2, relapse, and secondary neutropenia. All pre-transplant factors were supplanted by post-transplant factors.Then we studied the transmission of fungal infection by studying a pneumocystosis outbreak occurring in the hematology department. Twelve cases occurred within 7 months. Molecular analysis showed that 4 of them belonged to the same genotype, which is a rare genotype never described in a series of more than 300 genotypes in Europe. The transmission map permitted to identify that these 4 patients met only in the daycare center. This study is the first molecular demonstration of a pneumocystis outbreak in a hematology ward.

Le foie a des capacités de régénérations importantes qui lui permettent de reconstituer progressivement sa masse cellulaire suite à une agression. L’induction d’une régénération hépatique est une approche qui a été utilisée dans de nombreux modèles animaux afin de favoriser la prise de greffe hépatocytaire pour le traitement des maladies métaboliques héréditaires hépatiques (MMHH). Par ailleurs, les capacités de régénération du foie sont utilisées en pratique clinique courante dans le cadre de la chirurgie hépatique afin de préparer le foie à une hépatectomie majeure. Les principaux objectifs de ce travail ont été d’étudier des moyens peu invasifs pour induire une importante régénération hépatique dans deux buts précis : i) favoriser la transplantation d’hépatocytes thérapeutiques pour le traitement des MMHH ; ii) élargir les possibilités de prise en charge des patients nécessitant une hépatectomie.Dans un premier temps, nous avons évalué l’effet d’une embolisation portale partielle (EPP) au cours de la transplantation d’hépatocytes dans un des modèles animaux de l’hypercholestérolémie familiale de type IIA, le lapin Watanabe. Dans un deuxième temps, nous avons mis au point chez le rat, une technique d’EPP résorbable répétée visant à entrainer un stimulus répété de régénération hépatocytaire afin d’envisager par la suite l’utilisation de cette technique avant transplantation d’hépatocytes. En parallèle de ces travaux fondamentaux, nous avons évalué en approche clinique l’intérêt de l’EPP résorbable avant hépatectomie majeure. Nos travaux dans le modèle du lapin Watanabe ont montré la faisabilité du protocole, une correction phénotypique in vitro, une amélioration de la prise de greffe hépatocytaire et une expression prolongée du transgène. Notre équipe a développé chez le rat un stimulus additionnel de prolifération hépatocytaire qui permet une augmentation du poids et du volume du foie non embolisé en comparaison à une seule EPP résorbable. Enfin, dans une série rétrospective préliminaire, la technique d’EPP résorbable a été utilisée avant hépatectomie majeure. L’approche a été bien tolérée chez tous les patients et a permis de systématiquement envisager la chirurgie.L’EPP résorbable est une technique peu invasive capable d’induire une régénérative hépatique efficace. Cette approche pourrait permettre notamment d’augmenter les capacités de proliférations hépatiques par la répétition du stimulus d’embolisation. A terme, l’EPP résorbable répétée pourrait permettre de modeler à la demande l’organisation du volume hépatique favorisant ainsi l’hypertrophie de tel ou tel secteur en fonction des besoins. / The liver has an important regenerative capacity allowing progressive reconstitution of the hepatic volume after an aggression. The induction of liver regeneration was used in different animal models in order to increase engraftment during hepatocyte transplantation for the treatment of inherited metabolic liver diseases (IMLD). Furthermore, liver regenerative capacities are used in routine clinical practice before liver surgery in order to prepare the liver for major hepatectomy.The main objective of this doctoral thesis was to evaluate minimally invasive approaches inducing substantial liver regeneration, focusing in two specific aims: i) increasing the engraftment of therapeutic cells for the treatment of IMLD; ii) expanding the therapeutic options for patients requiring an hepatectomy In a first study, we evaluated the impact of a partial portal vein embolization (PVE) during hepatocyte transplantation in the animal model of familial hypercholesterolemia type IIA, the Watanabe rabbit. In a second investigation, we developed an approach of repeated reversible PVE in a rat model to further boost liver hypertrophy, planning to apply this approach in hepatocyte transplantation. In parallel, we evaluated the clinical interest of reversible PVE before major hepatectomy.Our results of PVE during hepatocyte transplantation in the Watanabe rabbit model demonstrated the feasibility of the procedure, in vivo phenotypic correction, increase of liver cell engraftment and stable transgene expression. Our team developed in the rat an additional stimulus of hepatocyte proliferation allowing increase of non-embolized liver lobe weight and volume in comparison to a single reversible PVE. Finally, the reversible PVE approach was evaluated before major hepatectomy in a preliminary retrospective series of 20 patients. The procedure was well tolerated and allowed to plan surgery in all patients.Reversible PVE is a minimally invasive technique allowing to successfully induce liver regeneration. This approach could increase hepatocyte proliferation capacity by using an additional stimulus of repeated embolization. In the future, reversible PVE may allow on demand modeling of liver volumes organization by supporting the hypertrophy of a specific liver lobe when required.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22359号 / 医博第4600号 / 新制||医||1042(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 長尾 美紀, 教授 滝田 順子, 教授 河本 宏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22886号 / 医博第4680号 / 新制||医||1048(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙橋 良輔, 教授 井上 治久, 教授 伊佐 正 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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