Ce mémoire décrit la mutation et la continuité dans les pratiques judiciaires dans l’institution de l’héritage en Chine au début du vingtième siècle. Il dépeint comment les formes (rituelle et matérielle) d'héritage chinoises ont été graduellement reconceptualisées. Les concepts de propriété individuelle occidentale influencèrent l’évolution des formes substantielles etprocédurales pendant les réformes juridiques et judiciaires. Ce travail se concentre principalement sur trois sujets: premièrement, sur les réactions locales envers l'héritage occidental présentées dans des rapports d'enquête surles pratiques civiles, deuxièmement, sur le compromis effectué par le Dali Yuan concernant les lois et les normes anciennes et nouvelles, et troisièmement sur les procédures judiciaires locales de succession concernantveuves et filles. La succession portant à la fois sur le culte des ancêtres et le patrimoine était deux aspects du même problème profondément enracinés dans les pratiques populaires et dans la loi Qing, même après la transformation de 1910 du code Qing en une version intermédiaire partiellement occidentalisée, intitulé « Code Criminel actuellement en vigueur » (xianxing xinglü現行刑律). Les réformateurs Qing qui furent pour la transplantation d’un système occidental imposèrent un cadre de droit civil au questionnaire unifié sur les «coutumes civiles» envoyé à chaque province en 1910. Ce questionnaire qui délaissait la forme rituelle de l'héritage fut révisé alors par les notables chinois et les responsables locaux. Tout au long de l'ère républicaine, les lois sur l'héritage du Code Criminel actuellement en vigueur ont continué à être appliquées. Le Dali Yuan 大理院, assumant la fonction de Cour Suprême, a établi une série d'interprétations sur l'héritage dans le cadre de ce code. Il défendait les droits des femmes en leur donnant le droit de désigner ou d'abroger un héritier institué, de gérer le patrimoine au nom de leurs jeunes enfants au décès de leurs maris, et de conférer à une fille un transfert discrétionnaire, même si cette part d’héritage était moindre que celle d'un héritier mâle. La Cour suprême a également tenu compte des principes procéduraux occidentaux. Par exemple, une plainte contre un héritier illégal venant d'une personne qui n’était pas qualifiée pour déposer au procès ne serait pas acceptée, ou une question qui n'avait pas été préalablement mentionnée ne serait pas jugée. Malgré cela, dirigé par des juristes traditionnels et modernes, le Dali Yuan a fréquemment rendu des décisions judiciaires civiles sur la base des lois Qing et a accepté de restreindre les droits des femmes favorisant les membres aînés de la famille, les fils adultes, et les parents agnats. Influencé par les juges du Dali Yuan et sous sa supervision, les tribunaux modernes et les bureaux de magistrats des comtés (plus traditionnels), c’est à dire les deux principaux types d'organismes judiciaires des provinces du Jiangsu et du Zhejiang, ont adopté des styles de jugement différents pour les affaires de succession de 1912 à 1931. Les tribunaux modernes ont suivi souvent avec beaucoup d'attention les interprétations judiciaires du Dali Yuan de manière substantielle et procédurale, tandis que les magistrats de comté ont souvent eu du mal à suivre les normes procédurales énoncées par le Yuan et inscrites dans la loi de procédure, même s’ils se référaient parfois aux décisions du Dali Yuan. [...] / This thesis discusses the mutation and continuity in judicial practices of the Chinese inheritance system in the early twentieth century. It depicts howChinese ritual and material forms of inheritance were graduallyr econceptualized, influenced by a Western individual property system from both substantial and procedural perspectives during legal and judicial reforms.It focuses mainly on three topics: local attitudes towards a Western inheritancesystem presented in survey reports of civil practices, the Dali Yuan’s compromise of new and old laws and norms, and local judicial practices ofadjudicating succession cases involving widows and daughters.Succession to the ancestral cult and the patrimony were two aspects of the same issue deeply entrenched in both people’s practices and the Qing law,even after the Qing code had been turned into a partly westernizedintermediary version called the Criminal Code Currently in Force (Xianxingxinglü 現行刑律). To transplant a Western civil justice system, in 1910 a Western civil law framework was imposed on a unified questionnaire on “civilcustoms” which the Qing reformers sent to every province. This questionnaire neglected the ritual forms of inheritance and was revised by the Chinesenotables and local officials. All along the Republican era, laws on inheritance of the Criminal Code currently in force continued to be effective. The Dali Yuan 大理院, assuming the Supreme Court function, established a set of judicial interpretations on inheritance within the framework of this code. It upheld women’s rights by endowing them with rights to designate or repeal an instituted heir, to manage the patrimony on behalf of their young children in default of their husbands, and to transfer to a daughter a share of the patrimony, even though lesser than the share of a male heir. The Supreme Court also took Western procedural principles into account: a complaint over an illegal heir from an unrelated person would not be accepted, and an issue that had not been claimed for would not be adjudicated. Even so, led by both traditional and modern jurists, the Dali Yuan frequently delivered civil regulatory judicial decisions on the grounds of Qing laws and admitted the restraint on women’s rights from senior and elder members, adult sons, and agnate kin. Influenced by judges from the Dali Yuan and under its supervision, modern courts and county magistrate offices (more traditional), that is to say, the two main types of judicial agencies in the Jiangsu and Zhejiang provinces, employed different style of adjudication when adjudicating succession cases from 1912 to 1931. Modern courts often carefully followed the Dali Yuan’s judicial interpretations substantially and procedurally, whereas, county magistrate offices often found it difficult to follow the Dali Yuan’s proceduralrules, even though they sometimes referred to the Dali Yuan’s rules. As a result, under a neutral style of adjudication in modern jurisdictions, illegal heir designation would not be rectified by court if it was not necessary; limited amounts to a daughter or her son and husband were strictly obeyed. By contrast, county jurisdictions performed an active style of adjudication: they positively corrected illegal choices and considered elements beyond the law, such as duty to support the aged and the parents’ affection. [...]

O transplante de fígado é definido como a terapêutica de escolha para as doenças hepáticas em estágio terminal. Por muitos anos, o sucesso deste procedimento foi mensurado pelas taxas de mortalidade e a freqüência de complicações nas anastomoses biliares e complicações infecciosas. No entanto, mais recentemente um novo foco de preocupação voltou-se para a avaliação da qualidade de vida no grupo de pacientes transplantados. Os benefícios do transplante hepático sobre a qualidade de vida dos pacientes é um evento já demonstrado previamente em alguns estudos que utilizaram questionários genéricos de avaliação de qualidade de vida. A qualidade de vida em saúde também pode ser acessada através de questionários específicos, como o LDQOL (Liver Disease Quality of Life). Este é um instrumento voltado especificamente para sintomas relacionados às doenças hepáticas, desenvolvido nos Estados Unidos e recentemente traduzido para o Português e adaptado culturalmente para à população brasileira. Objetivo Aplicar este novo instrumento na população de pacientes em lista de espera de transplante de fígado e naqueles submetidos a transplante, reavaliando diferentes aspectos da qualidade de vida destes pacientes e avaliando o impacto da recidiva da doença de base após o transplante hepático. Método: Foram aplicados os questionários LDQOL e SF?36 a 126 pacientes em acompanhamento ambulatorial regular no Serviço de Transplante e Cirurgia do Fígado do Hospital das Clínicas da Universidade de São Paulo, dos quais 65 eram pacientes cirróticos em lista de espera de transplante de fígado e 61 deles eram pacientes submetidos a transplante hepático há pelo menos 6 meses e no máximo há 60 meses. Também foi aplicado o questionário SF-36 a um grupo de doadores de sangue sadios, pareados por sexo e idade e que funcionou como grupo controle. As avaliações, realizadas a partir da formação destes 3 grupos, incluiram a comparação da qualidade de vida entre cirróticos e transplantados, a comparação entre indivíduos saudáveis e portadores de hepatopatia e a influência de outros aspectos como etiologia da doença hepática, escore do MELD, classificação de Child-Pugh, presença de co-morbidades, tempo decorrido do transplante e efeito da recidiva da doença hepática sobre a qualidade de vida do paciente transplantado. O método estatístico aplicado foi o teste de Mann- Whitney. Resultados: As pontuações atingidas para os pacientes em lista de transplante hepático para mensuração da qualidade de vida foram significantemente mais baixas do que aquelas atingidas pelo grupo controle. Na comparação entre cirróticos com MELD <= 15 e cirróticos com MELD > 15, tanto o SF-36 como o LDQOL mostraram pior qualidade de vida nos pacientes com MELD mais elevado. A comparação entre indivíduos antes e depois do transplante evidenciou melhor qualidade de vida no grupo de pacientes transplantados. Isto ficou evidenciado tanto pelo LDQOL como SF-36. No grupo de pacientes pré-transplante, o questionário LDQOL mostrou maior comprometimento da qualidade de vida naqueles pacientes com cirrose por VHC, quando comparado a outras etiologias, enquanto o SF-36 não teve a mesma acurácia em demonstrar esta diferença. Nos pacientes transplantados, a recidiva da hepatite C determina comprometimento da qualidade de vida, quando avaliados pelo LDQOL, mas não pelo SF-36. Conclusões: O uso de um instrumento de medida de qualidade de vida - o LDQOL - pôde demonstrar, com maior acurácia, o seu comprometimento nos pacientes cirróticos, a melhora observada nos pacientes transplantados e o impacto negativo da recidiva da hepatite C no pós-transplante. / Liver transplantation has been established as the standard treatment for patients with end stage liver disease and for many years the outcomes of its procedure has been measured as mortality rates and biliary and infectious complications. More recently a new issue has been raised and many studies have been changing the focus to analyze the health related quality of life among the population of transplanted patients. A positive effect of liver transplantation on health-related quality of life (HRQOL) has been documented in many studies using generic instruments. Health-related quality of life can also be assessed with specific instruments, as the Liver Disease Quality of Life(LDQOL), a questionnaire targeted to symptoms of hepatic disease, that has been recently translated to Portuguese and culturally adapted to Brazilian population. Our aim was to reevaluate different aspects of HRQOL before and after liver transplantation with this new instrument, and determinate the impact of liver disease recurrence after the surgical procedure. Methods: The LDQOL and SF-36 questionnaires were applied to 126 patients at the Service of Transplant and Liver Surgery of Clinical Hospital of University of São Paulo, 65 of them on the transplant waiting list and 61 of them after 6 to 60 months of liver transplantation. It was also analyzed the quality of life, by using the SF-36 questionnaire, of health blood donors, paired by sex and age, to serve as control group. Multiple comparisons were made concerning etiology of cirrhosis, co-morbidities, MELD scores, time elapsed of transplant, recurrence of liver disease after liver transplantation, using the Mann-Whitney test. Results: HRQOL scores for patients waiting for transplantation were significantly lower than those for the control group. Patients with MELD scores > 15 showed worse healthrelated quality of life than patients with MELD scores <= 15, both with SF-36 and LDQOL. When the group of transplanted patients was compared with patients before transplant, an improvement of HRQOL was found in the transplanted group with both SF-36 and LDQOL. Quality of life in pretransplant patients was found to be worse in those with cirrhosis due to hepatitis C than in those with cirrhosis due to other etiologies; the reduction in quality of life was found to be greater using LDQOL than using SF-36. Transplanted patients with recurrence of hepatitis C had worse HRQOL when measured with LDQOL, but not with SF-36. Conclusions: LDQOL, a specific instrument for measuring quality of life is more reliable than SF-36 in showing quality of life impairment. A deterioration in health-related quality of life after recurrence of hepatitis C could be observed with LDQOL.

A tolerância operacional (TO) é um estado de estabilidade funcional do órgão transplantado, após a parada de drogas imunossupressoras, por um período maior ou igual a um ano. Os microRNAs são pequenas moléculas de RNA não codificantes que regulam, negativamente, a expressão gênica de seus alvos, incluindo de moléculas relacionadas ao sistema imune, desempenhando um papel crítico na manutenção da homeostase. Nosso objetivo foi determinar se há um perfil diferencial de microRNAs na TO no transplante renal humano, indicando sua potencial participação nos mecanismos de tolerância. Analisamos o perfil sérico dos níveis de microRNAs na tolerância operacional (TO) (n= 8), comparando com rejeição crônica (RC) (n= 5), estáveis em uso de imunossupressão convencional (EST) (n= 5) e indivíduos saudáveis (SAU) (n= 5), utilizando, inicialmente, um painel de primers para 768 miRNAs, pela tecnologia TLDA (TaqMan Low Density Array). Detectamos um perfil diferencial nos níveis de microRNAs entre TO e o seu desfecho clínico oposto - RC- sugerindo que microRNAs podem integrar a rede de mecanismos envolvidos na tolerância ao transplante. Nesse perfil diferencial, alguns tiveram níveis maiores na TO: miR-885-5p (p=0,031), miR-331 (p=0,009), miR-27a (p=0,033), em comparação com RC, enquanto outros, o miR-1233-3p (p=0,029), miR-572 (p=0,028), miR-1260a (p=0.017) e o miR-638 (p=0,047) apresentaram menores níveis na TO. Na comparação de TO com o estado fisiológico (SAU), 2 dos microRNAs do perfil diferencial TO x RC apresentaram níveis diminuídos na TO: miR-27a-5p, (p=0,033) miR-1260a (p=0,017) e, para os demais, não encontramos diferenças de níveis, indicando predomínio de preservação do perfil na TO, em relação ao estado fisiológico. Por bioinformática, foram preditas vias de sinalização e observamos que os genes alvos desses microRNAs tiveram, predominantemente, relação com morte celular, integrando as vias de granzima e receptor de morte. Considerando os diversos alvos dos microRNAs do perfil diferencial e seus potenciais efeitos de favorecer vida e morte, nessas duas vias, encontramos uma razão de vida/morte de 1,95 na TO e de 0,39 na RC, indicando o maior potencial de promoção de morte na RC e, de vida, na TO, pela ação desses microRNAs. Esses dados indicam que a regulação de vias relacionadas à morte celular pode integrar os mecanismos de tolerância imunológica no transplante renal humano. Selecionamos o miR-885-5p para validar os achados, em um número maior de amostras, e confirmamos maiores níveis na TO (n=8), em relação à RC (n=12; p=0,0063) e também em relação ao SAU (n=12; p=0,0035). Considerando que CASP3 é um dos alvos do miR-885, interpretamos que a sua ação, na TO, pode promover a menor expressão de CASP3 e, consequentemente, favorecer a sobrevivência celular. Concluímos que mecanismos epigenéticos podem integrar a rede de mecanismos da tolerância ao transplante, como por meio da ação de microRNAs regulando a expressão de genes envolvidos com sobrevida/morte celular / Operational tolerance (OT) is a state of functional stability of the transplanted organ, after stopping immunosuppressive drugs for a period of at least one year. MicroRNAs are small non-coding RNA that downregulate gene expression of their targets, including genes related to the immune system, playing a critical role in keeping homeostasis. Our objective was to determine whether there is a differential profile of microRNAs in OT in human renal transplantation, indicating their potential participation in the mechanisms of tolerance. We analyzed the serum profile of microRNAs levels in operational tolerance (OT) (n = 8), compared with chronic rejection (CR) (n=5), stable subjects using conventional immunosuppression (STA) (n = 5) and healthy individuals (HI) (n = 5), initially using a panel of primers for 768 miRNAs, by TaqMan Low Density Array (TLDA) technology. We detected a differential profile in the levels of microRNAs between OT and its opposing clinical outcome - CR - suggesting that the microRNAs can integrate the network of mechanisms involved in human transplantation tolerance. Within this differential profile, some microRNAs showed higher levels in OT: miR-885-5p (p = 0.031), miR-331 (p = 0.009), miR-27a (p = 0.033) compared to CR, while others, miR-1233-3p (p = 0.029), miR-572 (p = 0.028), miR-1260a (p=0.017) and miR-638 (p = 0.047) had lower levels in OT. Comparing OT with the physiological state (HI), 2 microRNAs of the differential profile presented decreased levels in OT: miR-27a-5p, (p = 0.033) miR-1260a (p = 0.017) but no differences for the others, indicating the predominance of preservation of the profile in OT, in relation to the physiological state. Using bioinformatics, we predicted signaling pathways and we found that the target genes of these microRNAs were, predominantly, related to cell death, integrating the granzyme and death receptor pathways. Considering the various targets of the microRNAs comprised in the differential profile and their potential life-and-death effects, in these two pathways, we found a life-to-death ratio of 1.95 in OT and 0.39 in CR, indicating the greater potential to promote death in CR, and life in OT, by the action of these microRNAs. These data indicate that the regulation of pathways related to cell death may integrate the mechanisms of immune tolerance in human renal transplantation. We selected miR-885-5p to validate the findings in a larger number of subjects, and confirmed higher levels in OT (n = 8), in relation to CR (n = 12, p = 0.0063) and in relation to HI (n = 12, p = 0.0035). Considering that CASP3 is a relevant target of miR-885, we interpret that its action in OT can promote a decrease in CASP3 expression and, consequently, favor the preservation of cell survival. We conclude that epigenetic mechanisms can integrate the network of mechanisms of transplantation tolerance, such as by the action of microRNAs, regulating the expression of genes involved in cell survival and death

Regulatory T cells (Tregs), lymphocytes that suppress immunological reactions, are of great interest for our comprehension of basic immunology and as a therapeutic agent to treat immune-mediated pathologies. Understanding the physiology of these cells will help to inform clinical strategies targeting Tregs. In order to study the homing of human Tregs, we utilised genetic engineering to drive expression of fluorescent protein in human Tregs, permitting in vivo cell tracking. We optimised a protocol for lentivirus-mediated transduction of human Tregs during in vitro expansion, to generate high yields of stably-engineered cells. After infusing labelled cells into a humanised mouse model of skin allotransplantation, we detected human Tregs within a human skin graft by PCR and visualised Tregs moving in the graft, in a live mouse, by two-photon microscopy. Through reverse genetic analyses, we explored molecular mechanisms that allow Tregs to respond adaptively to environmental cues. Neuropilin-1 (NRP1), a transmembrane co-receptor, has been implicated in the function of mouse Tregs. Tregs transduced with shRNA to knock down NRP1 were severely impaired in their capacity to suppress cell proliferation in vitro and to prolong allograft survival in a humanised mouse model. qRT-PCR analysis revealed that transcription the gene encoding the anti-inflammatory cytokine IL-10, and the autophagy-associated genes BECN1, COPS4 and MAP1LC3B, was significantly diminished in NRP1-deficient Tregs. We concluded that in human Tregs, NRP1 is necessary for suppressive function, most likely via regulation of NRP1-dependent regulation of cytokine production and metabolism. Having identified a molecular target via which Treg function might be potentiated, we explored methods to target such molecules for cell therapy applications. Tregs engineered to over-express IL-10, but not NRP1, exerted significantly enhanced suppression of cell proliferation in vitro. Thus, relatively straightforward genetic engineering, compatible with generation of therapeutic cell yields, could be exploited to improve the efficacy of Treg cellular therapy.

Made available in DSpace on 2016-01-26T12:51:54Z (GMT). No. of bitstreams: 1 elisabetemelo_tese.pdf: 1119413 bytes, checksum: 4be114b65ecba8ea4e5468dff03f2f12 (MD5) Previous issue date: 2006-08-14 / Hepatopulmonary syndrome (HPS), caused by abnormal intrapulmonary vasodilatation (IPVD), when associated with severe hypoxemia has been related to increased morbid-mortality in liver transplant candidates. The progression of hypoxemia in cirrhotic patients with IPVD is not well known. The aim of this study is to determine the probability of developing hypoxemia (Pa02 <70mmHg) in IPVD patients waiting for liver transplantation over two years. Thirty-two transplant candidates with IPVD detected by contrast-enhanced echocardiography (GI) were prospectively studied and the Pa02 of then was measured at the start and at the end of 12 and 24 months. Eleven patients without IPVD were taken as control group (GII). Paired t test showed that mean Pa02 was significantly lower at 24 months compared with basal mean at GI (78,5 ± 18,9 vs 94,05 ± 14,9; p=0,001). GI patients had significantly lower mean Pa02 at 12 months (84,6 ± 14,8 vs 95,7 ± 7,3; p=0,003) and at 24 months (78,5 ± 19,0 vs 88,7 ± 7,1; p=0,036) compared with GII patients. The Kaplan-Meier estimated ratio for the appearance of hypoxemia was approximately 10% ±5% at 12 months and 28% ± 10% at 2 years. The mean variation for Pa02 in GI patients was 4,6±13,4mmHg at 12 months and 15,5±15,5mmHg at the end of two years. There was no appearance of either hypoxemia or IPVD in GII patients. The variables: age, Child-Pugh score, smoking habit, pré-transplant Pa02 and PaC02 values did not discriminated patients who presented hypoxemia during the period of two years study. In conclusion, we demonstrate prospectively the progressive course of HPS, even on it s subclinical stage; the estimated risk for the appearance of hypoxemia in patients with IPVD was at least 30% at the end of 2 years. The identification of the early appearance of hypoxemia can lead to a better understanding of the hepatopulmonary syndrome natural history and may be helpful to optimize timing and to predict the outcomes of liver transplantation. / A síndrome hepatopulmonar (SHP) é causada por dilatação anormal da vasculatura intrapulmonar (DVP) em indivíduos com doença hepática, tendo como consequência graus variados de hipoxemia arterial. A hipoxemia grave aumenta a morbimortalidade em candidatos a transplante de fígado, e sua progressão na história natural da SHP não é bem conhecida. O objetivo deste estudo é determinar a probabilidade de desenvolvimento de hipoxemia (Pa02 <70mmHg) em pacientes com DVP em lista de espera para o transplante de fígado, em um período de dois anos. Foram estudados prospectivamente 32 pacientes com DVP (GI), detectada pela ecocardiografia com contraste e a Pa02 foi medida ao início, aos 12 e aos 24 meses do estudo. Como grupo controle (GII), foram incluídos 11 pacientes sem DVP. Os testes t de Student e exato de Fisher foram usados para comparação dos resultados. A curva de Kaplan-Meier foi empregada para verificar a probabilidade de hipoxemia nos dois grupos. A média da Pa02 aos 12 e 24 meses foi significativamente menor no GI quando comparada ao GII (84,6±14,8mmHg vs 95,7±7,3mmHg; p=0,003 e 78,5±19,0mmHg vs 88,7±7,1mmHg; p=0,036, respectivamente). No GI há evidência de que a média dos valores da Pa02 aos 24 meses é menor do que a média basal (78,5±18,9 vs 94,0±14,9; p=0,001). A razão estimada para o aparecimento da hipoxemia foi aproximadamente 10%±5% aos 12 meses e 28%±10% aos 24 meses (Curva Kaplan-Meier), para o GI. A média da variação da Pa02 no GI foi de 4,6&#61617;13,4mmHg aos 12 meses e de 15,5&#61617;15,5mmHg aos 24 meses. Nenhum paciente apresentou hipoxemia nem DVP no GII durante o período de estudo. Os parâmetros: idade, Child-Pugh, tabagismo, Pa02 e PaC02 iniciais, não identificaram os indivíduos com DVP que desenvolveram hipoxemia em dois anos de observação. Conclui-se que: Demonstramos o curso progressivo da SHP, mesmo em condições subclínicas; O risco estimado para hipoxemia em portadores de DVP foi de pelo menos 30% em dois anos; A identificação precoce do aparecimento da hipoxemia pode levar a um melhor entendimento da história natural da SHP e ser útil para a otimização da indicação do transplante de fígado e obtenção de melhores resultados.

Submitted by Fabíola Silva (fabiola.silva@famerp.br) on 2017-02-14T12:02:30Z No. of bitstreams: 1 lidianemiottobarretta_dissert.pdf: 1992056 bytes, checksum: ac02b0ad50d5f0c3528b7470603f6213 (MD5) / Made available in DSpace on 2017-02-14T12:02:30Z (GMT). No. of bitstreams: 1 lidianemiottobarretta_dissert.pdf: 1992056 bytes, checksum: ac02b0ad50d5f0c3528b7470603f6213 (MD5) Previous issue date: 2014-10-31 / Introduction: Hematopoietic Stem Cell Transplantation is a long, complex, and high-cost process, which demands an appropriate hospital infrastructure and a qualified multidisciplinary team. The major cause of morbidity and mortality in transplanted patients is infection. The insertion of a semi-implantable, long-term central venous indwelling catheter poses a risk of complications, such as obstruction, fracture or breakage, migration, infection, and death. Objectives: The aims of the present study were to characterize the patients undergoing hematopoietic stem cell transplantation and to identify complications related to the central venous catheter and to describe the associated complications between the variables (sex, age, diagnosis, kind of transplantation, type of catheter, site of catheter insertion, and the length of time with the catheter. Methods: This was a retrospective, quantitative study conducted at a teaching hospital in inland of São Paulo State. Transplanted patients’ names were retrieved from the medical records and from the nursing forms. Files were reviewed retrospectively. The study involved the analysis of 188 patients’ files from 2007 to 2011. Association between variables was compared using the Chi-square test and the univariate analysis. Continuous variables were compared using Student’s t-test. Independent variables were analyzed using the Mann-Whitney test, Anova and the Kruskal-Wallis test. P = 0.05 was considered statistically significant. We used the correspondence analysis and multivariate technique to analyze the categorical variables. Results: Most patients were married man with age ranging from 40 to 60 years. They worked in general services and came from the cities of São Paulo and Mato Grosso States. They were patients from the Unified Health System (SUS) diagnosed with Hodgkin's lymphoma, multiple myeloma and non-Hodgkin lymphoma undergoing autologous transplantation. The major complications were constipation, diarrhea, urinary tract infection, respiratory infection and graft versus host disease. However, most patients survived the transplant and were discharged. The Hickman catheter was the most used catheter, with a mean length of time with the catheter of 47.6 days. The fever/bacteremia complication was more incident in young males with non-Hodgkin lymphoma and autologous transplantation, who remained with the catheter for a long period in the subclavian vein. Conclusion: Characterizing the patients’ profile, identifying the diagnosis, complications of treatment, the current situation of the post transplanted patients, provide grants to nursing professionals in search of a safer practice with actions related to prevention. Complications of catheter and its relation to age, gender, medical diagnosis, type of transplant, catheter model, mean residence time and insertion site should be analyzed considering the conditioning protocol, which directly affects the occurrence of complications and injury Related catheter. / Introdução: O transplante de células tronco hematopoéticas é um processo longo, complexo, de alto custo, que exige infraestrutura hospitalar apropriada e equipe multiprofissional qualificada. As maiores causas de morbidade e mortalidade de pacientes transplantados são as infecções. Faz parte do transplante a inserção de um cateter venoso central semi-implantável de longa permanência, com risco de complicações como obstrução, fratura ou ruptura, migração, infecção e morte. Objetivos: Caracterizar os pacientes submetidos ao transplante de células tronco hematopoéticas; identificar as intercorrências associadas ao cateter venoso central e descrever a relação de correspondência entre as complicações e as variáveis: sexo, idade, diagnóstico médico, tipo de transplante, modelo de cateter, local de inserção e tempo de permanência com o cateter. Método: Estudo retrospectivo, quantitativo, realizado em um hospital de ensino do interior do estado de São Paulo, por meio do prontuário e planilhas de enfermagem de 188 pacientes transplantados entre 2007 e 2011. Foram realizados testes estatísticos de associação (qui-quadrado), de comparação univariada, teste T, para amostras independentes, Mann-Whitney, ANOVA e Kruskal-Wallis, todos ao nível de significância 0,05 e análise de correspondência e técnica multivariada para as variáveis categóricas. Resultados: A maioria dos pacientes era do sexo masculino, idade 40 a 60 anos, casada, trabalhavam na área de serviços gerais, procedentes de cidades do estado de São Paulo e Mato Grosso, atendidos pelo SUS, com diagnóstico de linfoma de Hodgkin, mieloma múltiplo e linfoma não Hodgkin, submetidos ao transplante autólogo. As complicações foram: constipação, diarreia, infecção urinária, infecção respiratória e doença do enxerto contra o hospedeiro, entretanto, a maioria sobreviveu ao transplante e teve alta hospitalar. O Hickman foi o cateter mais utilizado, com permanência média de 47,6 dias. A complicação febre/bacteremia mais incidente em jovens, sexo masculino, com Linfoma não Hodgkin e transplante autólogo, que permaneceram com o cateter por longo período, em veia subclávia. Conclusão: Caracterizar o perfil, identificar o diagnóstico, as complicações decorrentes do tratamento, a situação atual do paciente pós transplante, oferece subsídios aos profissionais de enfermagem na busca de uma prática mais segura. As complicações do cateter e suas relações com idade, sexo, diagnóstico médico, modalidade de transplante, modelo de cateter, tempo médio de permanência e local de inserção, devem ser analisadas considerando o protocolo de condicionamento, que interfere diretamente na ocorrência e agravo das complicações relacionadas ao cateter.

Há evidências de que a ciclosporina, imunossupressor utilizado nos transplantes de células- tronco hematopoéticas, impregna nos cateteres de silicone quando os mesmos são utilizados para a sua infusão; podendo a coleta de amostras para dosagem sérica do medicamento por essa via resultar em níveis falsamente elevados. Apesar de já existirem dados comprovando a possibilidade de se coletar as amostras da via do cateter venoso central não utilizada para a infusão, há escassez de estudos e também controvérsias quanto ao melhor momento para realizar o procedimento, assim como divergências quanto ao volume de sangue ideal a ser descartado. Esse ensaio clínico controlado randomizado teve como objetivo verificar o efeito do tempo transcorrido entre a interrupção da infusão de ciclosporina e a coleta das amostras na dosagem sérica do medicamento, em relação à via utilizada para a coleta e ao volume de descarte. Os sujeitos foram aleatorizados em dois grupos. No grupo A, a coleta das amostras em acesso venoso periférico, via do cateter utilizada para a infusão da ciclosporina e via não utilizada para infusão foi realizada imediatamente após a interrupção da infusão do medicamento, sendo que na última a coleta foi realizada após descarte de 5 mL e de 10 mL de sangue. No grupo B os mesmos procedimentos foram realizados, porém cinco minutos depois da interrupção. Participaram 32 sujeitos adultos, a maioria do sexo masculino (68,75%), portadores de leucemia (59,37%), com doadores aparentados (84,37%) e histocompatibilidade total (90,62%). A coleta realizada previamente ao início da infusão da ciclosporina atestou ausência desta no sangue e impregnada nos cateteres. As demais foram realizadas nos 32 sujeitos depois de 24 horas do início da infusão; em 12 do grupo A e 16 do grupo B sete dias depois; e em nove do grupo A e 13 do B 14 dias após iniciado o uso do medicamento. O principal motivo que levou à interrupção da coleta foi a transição da ciclosporina para via oral (71,87%). Inicialmente, nas análises intra sujeitos, a diferença entre a dosagem sérica obtida na via do cateter utilizada para a infusão da ciclosporina e as outras vias foi significativa (p < 0,001), enquanto entre o acesso venoso periférico e via não utilizada para a infusão, independente do volume de descarte, não houve diferença (p > 0,05). Quando realizadas as comparações entre os grupos, não foram observadas diferenças (p > 0,05) quanto à influência do tempo transcorrido entre a interrupção da infusão e a coleta das amostras de sangue, independente da via de coleta utilizada e do volume descartado. Conclui-se que a via do cateter não utilizada para infusão da ciclosporina é segura para ser utilizada na coleta das amostras para dosagem sérica desse medicamento; e o procedimento pode ser realizado imediatamente após a interrupção da infusão, desde que empregada a técnica adequada com descarte de 5 mL de sangue. Assim evita-se que o sujeito, já fragilizado e submetido a um tratamento complexo, seja exposto a mais um procedimento doloroso e associado ao estresse que é punção venosa periférica / There is evidence that cyclosporine, an immunosuppressant used in hematopoietic stem cell transplantation, impregnate in silicone catheters when they are used for its infusion; and the sample collection for serum levels of medication through this line may result in falsely elevated levels. Although there are data demonstrating the possibility to collect samples through the line of the central venous catheter not used for the infusion, there are few studies and also controversies regarding the best time to perform the procedure, as well as disagreement about the optimal volume of blood to be discarded. This randomized controlled trial aimed to verify the effect of time elapsed between discontinuation of the infusion and serum sample collection in relation to the line used for collection and volume of discard. The subjects were randomized into two groups. In group A, samples collected from a peripheral venous access, through catheter line used for cyclosporine infusion and catheter line not used for cyclosporine infusion was performed immediately after discontinuation of the drug infusion, and the last collection was performed after discarding 5ml and 10ml of blood. In group B, the same procedures were done, but five minutes after the interruption. The participants were 32 adults, most males (68,75%), with leukemia (59,37%), with related donors (84,37%), and total histocompatibility (90,62%). The collection performed prior to the start of cyclosporine infusion attested absence of cyclosporine in blood and presence of it in catheters. The others were performed in 32 subjects after 24 hours prior the start of infusion; in 12 of group A and 16 of group B after seven days; and in 9 of group A and 13 of B fourteen days after starting the medication. The main reason that led to discontinuation of the collection was the switch of cyclosporine to oral administration (71,87%). Initially, in the intra-subject analysis, the difference between the serum levels obtained in the line used for cyclosporine infusion of and other lines was significant (p < 0,001), while there was no difference between the peripheral venous access and the line not used for infusion, independently of the volume of discard (p > 0,05). When performed comparisons between groups, no differences were observed (p > 0,05) in the influence of time elapsed between discontinuation of the infusion and collection of blood samples, regardless the line used for collection and volume of discard. It is concluded that the catheter line not used for infusion of cyclosporine seems to be safe for use in serum samples collection of this medication; and the procedure can be performed immediately after discontinuation of the infusion, since used the technique with adequate discard of 5ml of blood. This avoids that the subject, already weakened and subordinated to a complex treatment, be exposed to a painful and stressful procedure such as peripheral venipuncture

A mucosite é um efeito grave e dose-limitante do tratamento antineoplásico, cujas lesões ulceradas apresentam grande impacto na morbidade e mortalidade dos pacientes, por apresentar dor, restrição alimentar e servindo como porta de entrada para infecções originadas da mucosa bucal, com incidência variável de acordo com a doença de base, idade, condição de saúde bucal, dose e frequência da quimioterapia. A ocorrência de mucosite oral é frequente nos pacientes que receberam altas doses de quimioterapia seguidas de transplante autólogo de células tronco hematopoiéticas. O objetivo deste estudo foi analisar os fatores que influenciam o desenvolvimento da mucosite oral. Foi realizada uma análise retrospectiva em 413 prontuários de pacientes consecutivos submetidos ao transplante autólogo de células tronco hematopoiéticas e os dados coletados incluíram dados demográficos (sexo, idade, doença de base), dados do TCTH (tipo de transplante, regime de condicionamento) e incidência de mucosite oral. Os resultados deste estudo mostraram que a incidência de mucosite foi maior em pacientes do sexo masculino e nos pacientes do sexo feminino com idade média de 29 anos, nos pacientes submetidos ao regime de condicionamento BU/MEL e naqueles pacientes portadores de LMA. Os resultados deste estudo permitiram concluir que a incidência de mucosite oral na casuística analisada foi maior nos pacientes do sexo masculino; nas mulheres jovens quando analisados sexo e idade separadamente, nos pacientes portadores de LMA e naqueles submetidos ao regime de condicionamento BU/MEL / Oral mucositis remains as a serious and dose-limiting side-effect of antineoplastic treatment and ulcerated lesions lead to a great impact on morbidity and mortality of patients due to pain, food restriction and serving as a gateway to originate infections of the oral mucosa patients. The incidence of oral mucositis remains uncertain and it is variable according to the underlying disease, age, oral health condition, dose and frequency of chemotherapy. The incidence of oral mucositis is high in patients receiving high-dose chemotherapy followed by autologous transplantation of hematopoietic stem cells. The aim of this study was to analyze the factors that influence the development of oral mucositis. a retrospective analysis of 413 medical records of consecutive patients undergoing autologous hematopoietic stem cell transplantation. Data collected included demographic data was performed (sex, age, underlying disease), HSCT data (type of transplant conditioning regimen) and incidence oral mucositis. The results of this study showed that the incidence of mucositis was higher in male patients and female patients with a mean age of 29 years, in patients undergoing conditioning regimen comprises BU / MEL and in those patients with AML. The results of this study showed that the incidence of oral mucositis in the analyzed sample was higher in males; in young women when analyzed separately sex and age, in patients with AML and those submitted to the BU / MEL conditioning regimen

Bei 85 Patienten (61 % Männer, 39 % Frauen, Altersmedian: 49 Jahre) nach Leber- (38), Herz- (34) und Lungentransplantation (13) wurde die orale Besiedlung mit Candida-Spezies und deren Biotypen sowie klinische Manifestationen einer Candidiasis bestimmt. Eine orale Candidiasis wurde bei 21/85 Patienten (24,7 %) diagnostiziert (pseudomembranöse Form: 15,3 %; erythematöse Form: 9,4 %; Cheilitis angularis: 3,5 %). Bei 63/85 Patienten (74,1%) wurden Candida spp. nachgewiesen. Von allen gefundenen Candida-Isolaten war C. albicans die am häufigsten isolierte Spezies (73 %), gefolgt von C. glabrata, C. krusei und C. famata (9,5 %; 6,3 %; 3,2 %). Außerdem wurden C. lusitaniae, C. guilliermondii, C. kefyr, C. magnoliae, Pichia ohmeri und C. dubliniensis, eine Spezies, die anfänglich nur bei HIV-positiven Individuen auftrat, identifiziert. Für C. albicans konnten sieben Biotypen nachgewiesen werden. Eine Korrelation der klinischen Manifestationen der Candidiasis und der identifizierten Spezies bzw. Biotypen konnte nicht gefunden werden. Während bei Patienten ohne Antimykotikatherapie neben C. albicans (87 %) nur drei verschiedene non-albicans-Spezies (C. glabrata: 8%; C. dubliniensis: 3 % und C. famata 3 %) identifiziert wurden, konnten bei Patienten mit Antimykotikatherapie sieben verschiedene non-albicans-Spezies nachgewiesen werden. C. albicans wurde nur noch zu 50 %, andere Spezies, wie C. krusei und C. glabrata, jedoch vermehrt identifiziert (C. krusei: 17 %; C. glabrata: 13 %; C. famata, C. guilliermondii, C. kefyr, C. lusitaniae C. magnoliae: 4 %). Die vorliegende Studie weist darauf hin, dass eine Dauertherapie bzw. notwendig verbreitete prophylaktische Gabe von Antimykotika (Amphotericin B; Fluconazol/Itraconazol) das Auftreten von non-albicans-Spezies fördert. Resistenzentwicklung und das Auftreten bisher apathogener Spezies und Biotypen spielen bei Patienten nach Organtransplantation eine bedeutende Rolle. / For evaluation of Candida carriage, oral swabs were taken from the tongue of 85 patients after liver- (38), heart- (34) and lung transplantation (13) (61 % men, 39 % women, median age: 49 years). Oral candidiasis was found in 21/85 patients (24,7 %) (pseudomembranous form: 15,3 %; erythematous form: 9,4 %; angular cheilitis: 3,5 %). Candida species were cultured in 63/85 patients (74,1 %). C. albicans was the most common isolate (73 %), followed by C. glabrata, C. krusei and C. famata (9,5 %; 6,3 %; 3,2 %). Other isolated species were C. lusitaniae, C. guilliermondii, C. kefyr, C. magnoliae, Pichia ohmeri and C. dubliniensis, the latter being a species first described in oral cavities of HIV-infected individuals. According to the API 20C AUX assimilation profiles seven different phenotypes were identified. No correlation was seen between clinical features and isolated species or biotypes. In patients without antimycotic therapy four different Candida species (C. albicans: 87 %; C. glabrata: 8 %; C. dubliniensis: 3 % and C. famata: 3 %) were identified, whereas, in patients with antifungal therapy eight different Candida species (C. famata, C. guilliermondii, C. kefyr, C. lusitaniae C. magnoliae: 4 %) were isolated. In only 50 % of the latter group C. albicans was detected, while C. glabrata in 17 % and C. krusei in 13 % were identified Long-term therapy and prophylaxis with antifungal agents (amphotericin B; fluconazole/itraconazole) to suppress fungal infections in immunosuppressed patients have contributed to a significant increase in non-albicans-infections because of the high incidence of resistance of the species to these drugs. On the other hand, risk of infection caused by less virulent species is increasing.

La bronchiolite oblitérante (BO) est la principale cause de décès à long terme après transplantation pulmonaire. La BO se manifeste par une diminution des capacités respiratoires liée à l'obstruction des petites voies aériennes par un tissu inflammatoire et fibroprolifératif. Dans cette thèse nous avons étudié l'hypothèse de l'implication de la kinase nucléaire MSK1 dans la BO. Nous avons utilisé la transplantation hétérotopique de trachée comme modèle murin de BO. La pertinence du choix de ce modèle a été confirmée par l'étude de la re-vascularisation fonctionnelle de la greffe après transplantation. Dans ce modèle nous avons montré une augmentation de l'expression et de l'activité de MSK1 pendant le développement de la BO. Le traitement des souris transplantées avec des inhibiteurs pharmacologiques de MSK1 a permis d'inhiber l'inflammation et la fibroprolifération, montrant le rôle de MSK1 dans la BO. Nous avons également mis en place un essai de criblage utilisant la technologie HTRF pour rechercher de nouveaux inhibiteurs de MSK1. Les résultats décrits dans cette thèse, montrent que la kinase MSK1 est une potentielle cible thérapeutique pour combattre la BO.