RESUMEN
BACKGROUND: Ischemic injury during the agonal period of donation after circulatory death donors remains a significant barrier to increasing abdominal transplants. A major obstacle has been the inability to improve visceral perfusion, while at the same time respecting the ethics of the organ donor. A retrievable dual-chamber stentgraft could potentially isolate the organ perfusion from systemic hypotension and hypoxia, without increasing cardiac work or committing the donor. METHODS: Retrievable dumbbell-shaped stents were laser welded from nitinol wire and covered with polytetrafluoroethylene. Yorkshire pigs were assigned to either agonal control or dumbbell-shaped dual-chamber stentgraft. A central lumen maintained aortic flow, while an outer visceral chamber was perfused with oxygenated blood. A 1-hour agonal phase of hypoxia and hypotension was simulated. Stents were removed by simple sheath advancement. Cardiac monitoring, labs, and visceral flow were recorded followed by recovery of the animal to a goal of 48 hours. RESULTS: Cardiac stress did not increase during stent deployment. Visceral pO2 and flow were dramatically improved in stented animal relative to control animals. Five of 7 control animals were killed after renal failure complications, whereas all stent animals survived. Histology confirmed increased ischemic changes among control kidneys compared to stented animals. CONCLUSION: A dual-chamber stent improved outcomes after a simulated agonal phase. The stent did not increase cardiac work, thus respecting a key ethical consideration. The ability of a dual-chamber stent to prevent ischemia during organ recovery may become a powerful tool to address the critical donor organ shortage.
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Hipotensión , Isquemia Tibia , Animales , Muerte , Humanos , Hipotensión/complicaciones , Hipoxia/complicaciones , Isquemia , Preservación de Órganos , Perfusión , Stents , Porcinos , Donantes de TejidosRESUMEN
Traditional histopathological allograft biopsy evaluation provides, within hours, diagnoses, prognostic information, and mechanistic insights into disease processes. However, proponents of an array of alternative monitoring platforms, broadly classified as "invasive" or "noninvasive" depending on whether allograft tissue is needed, question the value proposition of tissue histopathology. The authors explore the pros and cons of current analytical methods relative to the value of traditional and illustrate advancements of next-generation histopathological evaluation of tissue biopsies. We describe the continuing value of traditional histopathological tissue assessment and "next-generation pathology (NGP)," broadly defined as staining/labeling techniques coupled with digital imaging and automated image analysis. Noninvasive imaging and fluid (blood and urine) analyses promote low-risk, global organ assessment, and "molecular" data output, respectively; invasive alternatives promote objective, "mechanistic" insights by creating gene lists with variably increased/decreased expression compared with steady state/baseline. Proponents of alternative approaches contrast their preferred methods with traditional histopathology and: (1) fail to cite the main value of traditional and NGP-retention of spatial and inferred temporal context available for innumerable objective analyses and (2) belie an unfamiliarity with the impact of advances in imaging and software-guided analytics on emerging histopathology practices. Illustrative NGP examples demonstrate the value of multidimensional data that preserve tissue-based spatial and temporal contexts. We outline a path forward for clinical NGP implementation where "software-assisted sign-out" will enable pathologists to conduct objective analyses that can be incorporated into their final reports and improve patient care.
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Diagnóstico por Computador , Interpretación de Imagen Asistida por Computador , Microscopía , Trasplante de Órganos/efectos adversos , Complicaciones Posoperatorias/patología , Aloinjertos , Biopsia , Supervivencia de Injerto , Humanos , Valor Predictivo de las Pruebas , Factores de Tiempo , Resultado del Tratamiento , Flujo de TrabajoAsunto(s)
Aloinjertos/patología , Enfermedad Hepática en Estado Terminal/cirugía , Rechazo de Injerto/patología , Trasplante de Hígado/efectos adversos , Hígado/patología , Aloinjertos/inmunología , Biomarcadores/sangre , Biopsia , Enfermedad Hepática en Estado Terminal/mortalidad , Enfermedad Hepática en Estado Terminal/patología , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/inmunología , Humanos , Terapia de Inmunosupresión/métodos , Hígado/inmunología , Recurrencia , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: A proposed chronic antibody-mediated rejection (AMR) score has recently predicted 50%10-year death-censored allograft loss in patients with donor-specific alloantibodies (DSA) mean florescence intensity (MFI) greater than 10 000 and requires confirmation in patients with lower MFI (1000-10 000). METHODS: All patients who underwent liver transplantation from January 2000 to April 2009, had DSA (MFI ≥1000) in serum 10 to 14 months postliver transplantation, and had a protocolized liver biopsy were evaluated (n = 230). The previously proposed chronic AMR (cAMR) score was used to risk-stratify putative chronic AMR in DSA+ patients with MFI from 1000 to 10 000. RESULTS: The MFI distribution of DSA+ recipients were as follows: 66% had MFI 1000 to 4999, 14% had MFI 5000 to 10 000, and 20% had MFI greater than 10 000. The cAMR score distribution on 1-year protocol liver biopsy found that 41% had a score less than 13; 27% a score of 13 to 27.5, and 32% a score greater than 27.5. MFI correlated with 1-year cAMR category (<13, 46% vs 21% and >27.5, 29% vs 42% when MFI was 1000-10 000 vs MFI >10 000; P = 0.047). In patients with a cAMR score less than 13, 10-year death-censored allograft survival was 96% to 100% regardless of MFI (P = NS). The risk of allograft loss increased in patients with a cAMR score greater than 13 (P = 0.004) in DSA+ patients with MFI 1000 to 10 000. DSA MFI greater than 10 000 versus MFI 1000 to 10 000 at 1 year was also more likely to persist at 5 years (95% vs 68%; P < 0.0001). CONCLUSIONS: Validation of the previously proposed cAMR score in a separate cohort predicts death-censored long-term allograft failure in DSA+ patients regardless of MFI, and higher MFI at 1 year predicts DSA persistence at 5 years.
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Técnicas de Apoyo para la Decisión , Rechazo de Injerto/diagnóstico , Supervivencia de Injerto , Isoanticuerpos/inmunología , Trasplante de Hígado/efectos adversos , Aloinjertos , Biopsia , Enfermedad Crónica , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/mortalidad , Rechazo de Injerto/terapia , Humanos , Inmunohistoquímica , Isoanticuerpos/sangre , Estimación de Kaplan-Meier , Pruebas de Función Hepática , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
UNLABELLED: STAT3-driven expression of small proline rich protein 2a (SPRR2a), which acts as an src homology 3 (SH3) domain ligand, induces biliary epithelial cell (BEC) epithelial-mesenchymal transition (EMT), which, in turn, promotes wound healing. SPRR2a also quenches free radicals and protects against oxidative stress and DNA damage in nonneoplastic BEC. Sprr2a-induced EMT also increases local invasiveness of cholangiocarcinomas (CC), but prevents metastases. Understanding SPRR2a regulation of EMT has potential for therapeutic targeting in both benign and malignant liver disease. Molecular mechanisms responsible for SPRR2a-induced EMT were characterized, in vitro, and then evidence for utilization of these pathways was sought in human intrahepatic CC, in vivo, using multiplex labeling and software-assisted morphometric analysis. SPRR2a complexes with ZEB1 and CtBP on the microRNA (miR)-200c/141 promoter resulting in synergic suppression of miR-200c/141 transcription, which is required for maintenance of the BEC epithelial phenotype. SPRR2a induction promotes dephosphorylation and nuclear translocation of the SH3-domain containing protein GRB2 and an SH3-domain ligand in ZEB1 is required for SPRR2a-induced synergic suppression of miR-200c/141. Multiplex protein labeling of CC and morphometric analyses showed: 1) up-regulation of ZEB-1, and 2) down-regulation of CK19 in intrahepatic CC compared to nonneoplastic BEC, consistent with previous CC proteomic studies showing EMT during cholangiocarcinogenesis. CONCLUSION: SPRR2a modulates ZEB-1 signaling by way of miR-200c/141-associated EMT through SH3-domain networks and contributes to benign and malignant BEC wound-healing responses.
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Neoplasias de los Conductos Biliares/fisiopatología , Conductos Biliares Intrahepáticos/fisiopatología , Colangiocarcinoma/fisiopatología , Proteínas Ricas en Prolina del Estrato Córneo/metabolismo , Transición Epitelial-Mesenquimal/fisiología , Hepatopatías/fisiopatología , Oxidorreductasas de Alcohol/genética , Oxidorreductasas de Alcohol/metabolismo , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/metabolismo , Conductos Biliares Intrahepáticos/metabolismo , Línea Celular Tumoral , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Proteínas Ricas en Prolina del Estrato Córneo/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Células Epiteliales/citología , Células Epiteliales/fisiología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Hepatopatías/genética , Hepatopatías/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Cicatrización de Heridas/fisiología , Homeobox 1 de Unión a la E-Box con Dedos de Zinc , Dominios Homologos src/fisiologíaRESUMEN
The scarcity of organ donors requires consideration of marginal organs. The aim of this study was to evaluate the impact of anti HB core positive ( anti HBc +) graft donor status on patients transplanted for Hepatitis B HBV related cirrhosis. Recipients of first hepatic allograft from donor with antibiodies to HBV were identified retrospectively. All patients who had positive serology for HBV and were nwgative for Hepatitis C and D were included in the analysis. Kaplan meier methods were used to asses the actuarial recurrence free survival on patients with graft survival longer than 1,5 months. The Stepwise Cox Regression Model was used to identify independent predictors of HBV recurrence. 1717 first liver transplant were perfomed in our institution from September 1, 1990 to December 31, 1999. HBV was the cause of cirrhosis in 112 patients (6.5 per cents). 69 patients survived over 1,5 months. 33 patients had coexistent viral infection (23 HCB and 10 HDV). 14 donors (17.2 per cents) were positive for HBV markers, 9 anti-HBc + and 5 anti-HBc + and anti HBs +. 13 anti HBc + organ recipients met inclusion criteria. Nine (69.2 per cents) of these cases were re-infected vs. 20 (35.7 per cents) in the group that received graft from HBV negative donors (p<0.05, Fischer's Exact). The time to re-infection was briefer in the anti HBc + group (2.9 yr v 6,4 yr, p= 0.05). There were no diggerences in graft or patients survival between the two groups. HBV prophylaxis with combined lamivudine and HBIG significantly reduced the re-infection rate (p<0.03). hBeAg + recipients trenled to faster re infection (N.S). Cox Regression analysis revealed that both anti HBc graft donor status (HR 2,796, p=0.0020) and combination of lamivudine/HBIG (HR 0.249, p=0.021 are independently associated with re infection. The use of anti-HBc + liver graft does not affect graft or patient survival. However, patients who receive these organs are 2.5 times more likely to develop HBV recurrence. Lamivudine/HBIG combination decreases HBV recurrence fourfold