京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19226号 / 医博第4025号 / 新制||医||1011(附属図書館) / 32225 / 京都大学大学院医学研究科医学専攻 / (主査)教授 福田 和彦, 教授 木村 剛, 教授 三嶋 理晃 / 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19556号 / 医博第4063号 / 新制||医||1012(附属図書館) / 32592 / 京都大学大学院医学研究科医学専攻 / (主査)教授 小池 薫, 教授 福田 和彦, 教授 三嶋 理晃 / 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19923号 / 医博第4143号 / 新制||医||1017(附属図書館) / 33009 / 京都大学大学院医学研究科医学専攻 / (主査)教授 木村 剛, 教授 福田 和彦, 教授 羽賀 博典 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24501号 / 医博第4943号 / 新制||医||1064(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 永井 洋士, 教授 大鶴 繁, 教授 江木 盛時 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23782号 / 医博第4828号 / 新制||医||1057(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 羽賀 博典, 教授 波多野 悦朗, 教授 溝脇 尚志 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25189号 / 医博第5075号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 平井 豊博, 教授 江木 盛時, 教授 後藤 慎平 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Despite decades of changes in allocation policies for lung transplantation, the field is plagued by outdated and ethically problematic processes that impact candidate selection. Transplant centers screen potential organ recipients with a psychosocial evaluation in an attempt to identify potential barriers to post transplant success. Professional guidelines note the problematic nature of basing transplant candidacy on social factors. The prohibitive nature of the process in conjunction with the coercive pressures of impending demise forces individuals and their social support systems to make concessions that directly impact their individual dignities. Precluding eligible candidates based upon nonadherence does not improve clinical outcomes and thus does not benefit the net population. Psychosocial evaluation needs to be reimagined. The current practice, as it stands, fails to meet national ethical standards, but with its diverse widespread utilization, the psychosocial evaluation can become a tool to identify potential gaps and empower transplant teams to support individuals in addressing perceived deficiencies. / Urban Bioethics

As infecções são a causa mais freqüente de morbidade e mortalidade observadas tanto aguda como tardiamente nos pacientes receptores de transplante pulmonar, o que pode estar diretamente relacionado a uma deficiência no transporte mucociliar do sistema respiratório. Nosso objetivo foi avaliar a influência de dois fatores envolvidos com o transplante pulmonar sobre o transporte mucociliar de ratos: a secção e anastomose brônquica e a imunossupressão pela ciclosporina A. Setenta e dois ratos foram distribuídos aleatoriamente em cinco grupos de acordo com: i) procedimento operatório e ii) terapia a que seriam submetidos. Os resultados mostram que houve uma diminuição significativa da Freqüência de Batimento Ciliar in situ, da Transportabilidade do Muco in vitro e da Velocidade de Transporte Mucociliar in situ medidos a partir do brônquio principal esquerdo dos ratos tratados com ciclosporina A (p<0,001). A Freqüência de Batimento Ciliar in situ dos brônquios operados mostrou-se diminuída também no grupo tratado com solução salina e sacrificado no 30º dia após a operação (p=0,001). Já a Velocidade de Transporte Mucociliar in situ mostrou uma diminuição significativa em todos os grupos submetidos à secção brônquica (p<0,001). Houve um efeito sinérgico entre a terapia com ciclosporina A e a secção brônquica, causando um prejuízo ao transporte mucociliar ainda maior do que quando analisados isoladamente. Concluímos que a Velocidade de Transporte Mucociliar in situ foi agudamente prejudicada após a secção brônquica e terapia imunossupressora pela ciclosporina A, havendo diminuição da freqüência de batimento dos cílios e alteração das propriedades viscoelásticas do muco respiratório. / Infections are the most common cause of early and late morbidity and mortality in lung transplant recipient, and can be directly related to impaired mucociliary transport. Our aim was to assess the influence of bronchial section and imunossupression on mucociliary transport in rats. Seventy two rats were randomly distributed in five groups according to i) surgical procedure and ii) drug therapy. There was a significant impairment on Ciliary Beating Frequency in situ, Mucus Transportability Rate in vitro and Mucociliary Transport Speed in situ from operated bronchus of cyclosporine A-treated rats (p<0.001). Ciliary Beating Frequency from operated bronchus was also impaired in saline-treated rats that were killed on 30th postoperative day (p=0.001). Mucociliary Transport Speed was impaired in all bronchi underwent to section (p<0.001). We conclude that bronchial section and cyclosporine therapy impaired all factors analyzed. Also there was a synergic effect between cyclosporine therapy and bronchial section on ciliary beating frequency.

Background: In times of limited organs for transplantation, anti-HBc positive organs can be accepted for lung transplantation to increase the number of donors. Transplant recipients should be vaccinated against hepatitis B to prevent HBV infection. However, response after HBV vaccination has only been poorly evaluated in patients with end-stage pulmonary disease. Material/Methods: Anti-HBs titers of 40 anti-HBc negative patients with end-stage pulmonary disease evaluated for lung transplantation were analyzed with the Architect® system (Abbott, Germany). Responders, partial responders, or non-responders after HBV vaccination were defined by anti-HBs titers >100 IU/L, 10–100 IU/L, and <10 IU/L, respectively. Results: There were 34/40 individuals (85%) vaccinated against hepatitis B, and 6 were not vaccinated. Response, partial response, and non-response after vaccination were observed in 10/34 (29.4%), 11/34 (32.4%), and 13/34 (38.2%) of patients, respectively. Response to vaccination did not correlate with sex, pulmonary disease, comorbidities, immunosuppressive therapy, or smoking status. Conclusions: Although 85% of patients evaluated for lung transplantation were vaccinated against hepatitis B, 38.2% did not show an anti-HBs titer >10 IU/L. Thus, anti-HBs titers should be regularly monitored. Nonresponders should be considered for booster vaccinations, alternative vaccination schedules, or prophylactic treatment with a nucleos(t)ide analogue in case of transplantation of an anti-HBc–positive organ.

Introdução: O transplante de pulmão é uma opção terapêutica bem estabelecida para o tratamento de pneumopatias em estágio final. Uma complicação frequente relacionada aos transplantes é a lesão de isquemia e reperfusão (IR), estando o estresse oxidativo envolvido no processo. O azul de metileno (AM) é um inibidor da produção de espécies reativas de oxigênio, atuando como receptor alternativo de elétrons da xantina oxidase. Objetivo: Avaliar a eficácia do AM como inibidor da lesão de IR em transplante pulmonar de ratos. Métodos: Quarenta ratos fêmea Sprague Dawley (300g - 350g) foram divididas em quatro grupos de dez animais. Os animais foram submetidos a transplante pulmonar unilateral esquerdo. Os enxertos foram expostos a 3 ou 6 horas de isquemia fria seguido de 2 horas de reperfusão. Nos animais do grupo controle, 2 mL de solução salina foram injetados na cavidade peritoneal e, nos animais do grupo experimento, 2 mL de AM a 1% foram injetados da mesma forma. Resultados: A dosagem da PaO2 foi significativamente superior no grupo AM entre os animais submetidos a isquemia de 3 horas (AM = 150,2 ± 50,1 vs Salina = 102,6 ± 40,4 mmHg; p = 0,028), assim como a dosagem do óxido nítrico exalado foi significativamente inferior no mesmo grupo (AM = 3,2 ± 2,0 vs Salina = 5,2 ± 2,3 ppb; p = 0,05). O infiltrado neutrofílico foi menor nos animais do grupo AM submetidos a 6 horas de isquemia no lavado broncoalveolar (LBA); (AM = 11,8 ± 7,4 vs Salina = 30 ± 19,2 X 104/mL; p = 0,023). A análise histopatológica mostrou menor formação de edema perivascular no grupo AM submetido a 6 horas de isquemia (AM = 35,2 ± 7,65 vs Salina = 44,8 ± 6,39%; p = 0,001) e perialveolar no grupo AM submetido a 3 horas de isquemia (AM = 18,4 ± 14,2 vs Salina = 28,1 ± 18,2%; p = 0,041) e menor infiltrado neutrofílico perialveolar na comparação entre os grupos submetidos a 6 horas de isquemia (AM = 2,8 ± 2,2 vs Salina = 5,1 ± 3,1%; p = 0,046). Os níveis de IL-6 no LBA foram inferiores no grupo AM em ambos os tempos de isquemia (3 h - AM = 122,4 ± 24,9 vs Salina = 175.6 ± 50.3 pg/mL; p = 0.008; 6 h - AM = 142 ± 38,7 vs Salina = 351,3 ± 80,7 pg/mL; p = 0,002); Os níveis de TNF-? foram menores no grupo AM submetido a 6 horas de isquemia (AM = 189,5 ± 93,3 vs Salina = 342,9 ± 130,4 pg/mL, p = 0.007). A dosagem do ácido úrico foi significativamente maior no grupo AM em ambos os tempos de isquemia (3 h - AM = 4,7 ± 0,9 vs Salina = 2,7 ± 0,7 mg/dL; p = 0,003; 6 h - AM = 5,3 ± 2,4 vs Salina = 2,3 ± 0,9 mg/dL; p < 0,001). Não houve diferença entre os grupos em relação a apoptose. Conclusão: O AM demonstrou ser uma droga eficaz na prevenção da lesão de isquemia e reperfusão no transplante pulmonar de ratos / Introduction: Lung transplantation (LTx) has become an established therapeutic option for end-stage pulmonary disease. Ischemia reperfusion injury (IR) is a major cause of organ dysfunction after LTx and oxidative stress is involved in this process. Methylene blue (MB) is an inhibitor of reactive oxygen species production. Objective:To investigate the effects of MB on the IR in a rodent model of LTx. Methods: Forty female Sprague Dawley rats (300g - 350g) were divided into four groups (n = 10) according to treatment (saline solution or MB) and graft cold ischemic time (3 or 6 hours). Animals underwent a left-sided unilateral lung transplantation. Recipients received 2mL of intraperitoneal saline or MB 1%. After 2 hours of reperfusion, animals were killed and blood gas, exhaled nitric oxide, cell count and cytokines leves in bronchoalveolar lavage (BAL) as well as histopathology, serum uric acid and apoptosis were evaluated. Results: PaO2 was significantly higher in MB group undergoing 3 hour ischemic time (MB =150.2 ± 50.1 vs Saline = 102.6 ± 40.4 mmHg; p = 0.028). Exhaled nitric oxide values showed differences only between groups with 3 hour of ischemia (MB = 3.2 ± 2.0 vs Saline = 5.2 ± 2.3 ppb; p = 0.05). Neutrophils in BAL were different between groups subjected to 6 hours of ischemia (MB = 11.8 ± 7.4 vs Saline = 30.0 ± 19.2 x 104/mL; p = 0.023). IL-6 levels in BAL were lower in MB group in both ischemic time (3 h - MB = 122.4 ± 24.9 vs Saline = 175.6 ± 50.3 pg/mL; p = 0.008; 6 h - MB = 142 ± 38.7 vs Saline = 351.3 ± 80.7 pg/mL; p = 0.002); TNF-? levels were also lower in MB group undergoing 6 hour of ischemia (MB = 189.5 ± 93.3 vs Saline = 342.9 ± 130.4 pg/mL; p = 0.007). The number of neutrophils in lung parenchyma were reduced in MB group (6 h - MB = 2.8 ± 2.2 vs Saline = 5.1 ± 3.1%; p = 0.046) and also decreased edema in perivascular (6 h - MB = 35.2 ± 7.65 vs Saline = 44.8 ± 6.39%, p = 0.001) and perialveolar tissues (3 h - MB = 18.4 ± 14.2 vs Saline = 28.1 ± 18.2% p = 0,041) were observed. Uric acid levels were higher in MB group in both ischemic time (3 h - MB = 4.7 ± 0.9 vs Saline = 2.7 ± 0.7 mg/dL; p = 0.003; 6 h - MB = 5.3 ± 2.4 vs Saline = 2.3 ± 0.9 mg/dL; p < 0.001).There were no difference in the expression of apoptosis. Conclusion: MB was able to prevent ischemia-reperfusion injury in this lung transplantation model and represent a new option for further studies