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Normothermic machine perfusion (NMP) enables pretransplant assessment of high-risk donor livers. The VITTAL trial demonstrated that 71% of the currently discarded organs could be transplanted with 100% 90-day patient and graft survivals. Here, we report secondary end points and 5-year outcomes of this prospective, open-label, phase 2 adaptive single-arm study. The patient and graft survivals at 60 months were 82% and 72%, respectively. Four patients lost their graft due to nonanastomotic biliary strictures, one caused by hepatic artery thrombosis in a liver donated following brain death, and 3 in elderly livers donated after circulatory death (DCD), which all clinically manifested within 6 months after transplantation. There were no late graft losses for other reasons. All the 4 patients who died during the study follow-up had functioning grafts. Nonanastomotic biliary strictures developed in donated after circulatory death livers that failed to produce bile with pH >7.65 and bicarbonate levels >25 mmol/L. Histological assessment in these livers revealed high bile duct injury scores characterized by arterial medial necrosis. The quality of life at 6 months significantly improved in all but 4 patients suffering from nonanastomotic biliary strictures. This first report of long-term outcomes of high-risk livers assessed by normothermic machine perfusion demonstrated excellent 5-year survival without adverse effects in all organs functioning beyond 1 year (ClinicalTrials.gov number NCT02740608).
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Trasplante de Hígado , Anciano , Humanos , Constricción Patológica/etiología , Hígado/cirugía , Trasplante de Hígado/efectos adversos , Preservación de Órganos , Perfusión , Estudios Prospectivos , Calidad de VidaRESUMEN
Skin development and patterning is dependent on factors that regulate the stepwise differentiation of dermal fibroblasts concomitant with dermal-epidermal reciprocal signaling, two processes that are poorly understood. Here we show that dermal EZH2, the methyltransferase enzyme of the epigenetic Polycomb Repressive Complex 2 (PRC2), is a new coordinator of both these processes. Dermal EZH2 activity is present during dermal fibroblast differentiation and is required for spatially restricting Wnt/ß-catenin signaling to reinforce dermal fibroblast cell fate. Later in development, dermal EZH2 regulates the expression of reticular dermal markers and initiation of secondary hair follicles. Embryos lacking dermal Ezh2 have elevated epidermal proliferation and differentiation that can be rescued by small molecule inhibition of retinoic acid (RA) signaling. Together, our study reveals that dermal EZH2 is acting like a rheostat to control the levels of Wnt/ß-catenin and RA signaling to impact fibroblast differentiation cell autonomously and epidermal keratinocyte development non-cell autonomously, respectively.
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Dermis/citología , Dermis/embriología , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Epidermis/embriología , Fibroblastos/citología , Queratinocitos/citología , Complejo Represivo Polycomb 2/metabolismo , Animales , Diferenciación Celular , Proliferación Celular , Dermis/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Epidermis/metabolismo , Fibroblastos/metabolismo , Hiperplasia , Queratinocitos/metabolismo , Ratones , Organogénesis , Retinoides/farmacología , Transducción de Señal , Células Madre/citología , Células Madre/metabolismo , Tretinoina/metabolismo , Vía de Señalización Wnt , beta Catenina/metabolismoRESUMEN
PURPOSE OF REVIEW: Epigenetic regulation is a distinct mechanism of gene regulation that functions by modulating chromatin structure and accessibility. Polycomb Repressive Complex 2 (PRC2) is a conserved chromatin regulator that is required in the developing embryo to control the expression of key developmental genes. An emerging feature of PRC2 is that it not only allows for binary ON/OFF states of gene expression but can also modulate gene expression in feed-forward loops to change the outcome of gene regulatory networks. This striking feature of epigenetic modulation has improved our understanding of musculoskeletal development. RECENT FINDINGS: Recent advances in mouse embryos unravel a range of phenotypes that demonstrate the tissue-specific, temporal, and spatial role of PRC2 during organogenesis and cell fate decisions in vivo. Here, we take a detailed view of how PRC2 functions during the development of calvarial bone and skin. Based on the emerging evidence, we propose that PRC2 serves as a "dimmer switch" to modulate gene expression of target genes by altering the expression of activators and inhibitors. This review highlights the findings from contemporary research that allow us to investigate the unique developmental potential of intramembranous calvarial bones.
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Desarrollo Óseo/genética , Epidermis/embriología , Regulación del Desarrollo de la Expresión Génica/genética , Complejo Represivo Polycomb 2/genética , Cráneo/embriología , Animales , Humanos , RatonesRESUMEN
The skull bones must grow in a coordinated, three-dimensional manner to coalesce and form the head and face. Mammalian skull bones have a dual embryonic origin from cranial neural crest cells (CNCC) and paraxial mesoderm (PM) and ossify through intramembranous ossification. The calvarial bones, the bones of the cranium which cover the brain, are derived from the supraorbital arch (SOA) region mesenchyme. The SOA is the site of frontal and parietal bone morphogenesis and primary center of ossification. The objective of this review is to frame our current in vivo understanding of the morphogenesis of the calvarial bones and the gene networks regulating calvarial bone initiation in the SOA mesenchyme.
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Desarrollo Óseo , Regulación del Desarrollo de la Expresión Génica , Cráneo/embriología , Animales , Epigénesis Genética , Humanos , Cráneo/metabolismoRESUMEN
Development of the skull bones requires the coordination of two stem progenitor populations, the cranial neural crest cells (CNCC) and head paraxial mesoderm (PM), to ensure cell fate selection and morphogenesis. The epigenetic methyltransferase, Ezh2, plays a role in skull bone formation, but the spatiotemporal function of Ezh2 between the CNCC- and PM-derived bone formation in vivo remains undefined. Here, using a temporally-inducible conditional deletion of Ezh2 in both the CNCC- and PM- derived cranial mesenchyme between E8.5 and E9.5, we find a reduction of the CNCC-derived calvarial bones and a near complete loss of the PM-derived calvarial bones due to an arrest in calvarial bone fate commitment. In contrast, deletion of Ezh2 after E9.5 permits PM-derived skull bone development, suggesting that Ezh2 is required early to guide calvarial bone progenitor commitment. Furthermore, exposure to all-trans Retinoic acid at E10.0 can mimic the Ezh2 mutant calvarial phenotype, and administration of the pan retinoic acid receptor (RAR) antagonist, BMS-453, to Ezh2 mutants partially restores the commitment to the calvarial bone lineage and PM-derived bone development in vivo. Exogenous RA signaling activation in the Ezh2 mutants leads to synergistic activation of the anti-osteogenic factors in the cranial mesenchyme in vivo. Thus, RA signaling and EZH2 can function in parallel to guide calvarial bone progenitor commitment by balancing the suppression of anti-osteogenic factors.
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Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Cráneo/embriología , Tretinoina/metabolismo , Animales , Diferenciación Celular/genética , Linaje de la Célula/genética , Proteína Potenciadora del Homólogo Zeste 2/fisiología , Regulación del Desarrollo de la Expresión Génica/genética , Edad Gestacional , Mesodermo/embriología , Mesodermo/metabolismo , Ratones , Cresta Neural/embriología , Cresta Neural/metabolismo , Transducción de Señal , Cráneo/metabolismo , Tretinoina/fisiologíaRESUMEN
In the United States, distance from liver transplant center correlates with worsened outcomes; the effects of geography elsewhere are unassessed. We performed a national registry analysis of United Kingdom listings for liver transplantation (1995-2014) and assessed whether travel time to transplant center correlates with outcome. There were 11 188 listings assessed (8490 transplanted), with a median travel time to center of 60 minutes (range 36-86). Of the national population, 3.38 × 107 (55.1%) reside ≥60 minutes from a center, and 7.65 × 106 (12.5%) >119 minutes. After competing risk analysis, increasing travel time was associated with an increased risk of death after listing (subdistribution hazard ratios relative to <60 minutes of 1.33 for 60-119 and 1.27 for >119 minutes; P < 0.001) and reduced likelihood of transplantation or recovery (0.94 and 0.86; P < 0.001). Among those transplanted, travel time was not associated with retransplant-free survival (P = 0.532). We used our model to examine optimal placement of a new center and identify a single site with a total travel time reduction of ≈10%. Our findings of disparities in accessibility of liver transplantation showed worse outcomes following listing in those distant from their transplant center, and our description of a method to model a new center complement existing data and support similar analyses of other networks.
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Enfermedad Hepática en Estado Terminal/mortalidad , Enfermedad Hepática en Estado Terminal/cirugía , Accesibilidad a los Servicios de Salud , Trasplante de Hígado/métodos , Características de la Residencia , Obtención de Tejidos y Órganos/métodos , Adulto , Supervivencia sin Enfermedad , Femenino , Geografía Médica , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Sistema de Registros , Factores de Riesgo , Tiempo de Tratamiento , Viaje , Resultado del Tratamiento , Reino UnidoRESUMEN
In this paper we demonstrate a simple and new fibre optic technique for measuring detonation velocities using uniform fibre Bragg gratings. We compare this new system with chirped fibre Bragg grating diagnostics and show how coherent source illumination can yield spatial uncertainties below ±10 µm - a percentage error that is an order of magnitude lower than the broadband ASE methods we have tested.
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In this paper, a simple detonation velocity measurement scheme is presented, which exploits the length-dependent amplified spontaneous emission (ASE) power emitted by off-the-shelf Er-doped fibres. This measurement scheme is first calibrated using cutback tests, so that minimal processing is required between data collection and velocity readout. We then demonstrate the use of this method in an explosive cylinder test and achieve a spatial resolution of approximately ±2 mm, owing to its implementation in a helical geometry. Alongside the standard Er fibres, a specially made, high-concentration Er/Yb-doped fibre is also calibrated, which demonstrates a potential spatial resolution approaching ±20 µ m.
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Over the last decade, the use of chirped fibre Bragg gratings (CFBGs) in detonation velocity experiments has been steadily increasing. In this paper, we show how CFBG design parameters-chirp-rate, reflectivity and apodisation-affect linearity in detonation velocity tests. It is found that the optimal CFBG detonation velocity probe should have a high chirp-rate, a low reflectivity and no apodisation. As a further demonstration of these findings, we measure detonation velocity with a 24 cm optimised CFBG; the longest CFBG test of this kind so far.
RESUMEN
The cranial bones and dermis differentiate from mesenchyme beneath the surface ectoderm. Fate selection in cranial mesenchyme requires the canonical Wnt effector molecule ß-catenin, but the relative contribution of Wnt ligand sources in this process remains unknown. Here we show Wnt ligands are expressed in cranial surface ectoderm and underlying supraorbital mesenchyme during dermal and osteoblast fate selection. Using conditional genetics, we eliminate secretion of all Wnt ligands from cranial surface ectoderm or undifferentiated mesenchyme, to uncover distinct roles for ectoderm- and mesenchyme-derived Wnts. Ectoderm Wnt ligands induce osteoblast and dermal fibroblast progenitor specification while initiating expression of a subset of mesenchymal Wnts. Mesenchyme Wnt ligands are subsequently essential during differentiation of dermal and osteoblast progenitors. Finally, ectoderm-derived Wnt ligands provide an inductive cue to the cranial mesenchyme for the fate selection of dermal fibroblast and osteoblast lineages. Thus two sources of Wnt ligands perform distinct functions during osteoblast and dermal fibroblast formation.
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Diferenciación Celular/genética , Cráneo/crecimiento & desarrollo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animales , Ectodermo/crecimiento & desarrollo , Ectodermo/metabolismo , Regulación del Desarrollo de la Expresión Génica , Ligandos , Mesodermo/citología , Mesodermo/crecimiento & desarrollo , Ratones , Osteoblastos/citología , Osteoblastos/metabolismo , Transducción de Señal , Cráneo/metabolismo , Células Madre/citología , Células Madre/metabolismoRESUMEN
Liver transplantation (LT) in patients with portopulmonary hypertension (PoPH) has historically resulted in unpredictable and often poor outcomes. The United Kingdom experience for the period 1992-2012 is reported in this article. A retrospective analysis of patients, preoperatively fulfilling the PoPH European Respiratory Society Task Force on Pulmonary-Hepatic Vascular Disorders diagnostic criteria was conducted across all UK LT centers. Data collection included comorbidities, use of preoperative and postoperative pharmacotherapy, patient survival, and cause of death. To enable survival stratification, PoPH was classified as mild, moderate, or severe based on mean pulmonary pressure of <35 mm Hg, 35-49 mm Hg, and ≥50 mm Hg, respectively. Of 127 patients reported to have PoPH, just 28 fulfilled the diagnostic criteria (14 mild, 9 moderate, 5 severe). Twenty (71.4%) patients were male with median age and Model for End-Stage Liver Disease of 50 years (range, 23-62 years) and 18 (range, 6-43), respectively. Twelve (42.9%) patients died within 5 years of LT. The majority of deaths (10 of 12; 83%) occurred within the first 6 months after LT, aetiologies of which included right heart failure (n = 3), progressive PoPH (n = 2), and sepsis (n = 2). Of those receiving preoperative pharmacotherapy (n = 8), 5 are currently alive and were classified as mild to moderate PoPH. Both severe PoPH patients optimized preoperatively with pharmacotherapy died within a year of LT. Development of effective vasodilatory therapies in the setting of pulmonary arterial hypertension has led to a dramatic improvement in patient survival. The available data indicate that in this era of pharmacotherapy, PoPH in isolation no longer represents a valid consideration to transplant. Liver Transplantation 22 1637-1642 2016 AASLD.
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Enfermedad Hepática en Estado Terminal/complicaciones , Hipertensión Portal/cirugía , Hipertensión Pulmonar/cirugía , Trasplante de Hígado/efectos adversos , Vasodilatadores/uso terapéutico , Adulto , Enfermedad Hepática en Estado Terminal/cirugía , Femenino , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/mortalidad , Humanos , Hipertensión Portal/tratamiento farmacológico , Hipertensión Portal/etiología , Hipertensión Portal/mortalidad , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/mortalidad , Trasplante de Hígado/mortalidad , Trasplante de Hígado/normas , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , Presión Esfenoidal Pulmonar , Estudios Retrospectivos , Sepsis/etiología , Sepsis/mortalidad , Tasa de Supervivencia , Resultado del Tratamiento , Reino Unido/epidemiología , Adulto JovenRESUMEN
OBJECTIVE: Recent data have suggested that non-selective ß-blockers (NSBB) are associated with increased mortality in patients with cirrhosis and refractory ascites. However, other evidence implies that NSBB may be beneficial in this setting by reducing bacterial translocation. Our aim was to determine whether NSBB use was a risk factor for mortality in patients with end-stage chronic liver disease and ascites awaiting liver transplantation. DESIGN: This was a single-centre retrospective study of 322 patients with ascites listed January 2007 to July 2011. RESULTS: NSBB patients (n=159) and non-NSBB patients (n=163) were comparable with regards to listing model for end-stage liver disease score (p=0.168), frequency of hepatocellular carcinoma (p=0.193) and refractory ascites (35.2% vs. 37.4%, p=0.681). 82 patients died, 221 patients were transplanted and 19 patients were removed from the list during a median follow-up duration of 72 days; the median time to death was 150 and 54 days in the NSBB and non-NSBB groups, respectively. In a multivariate competing risk Cox model, patients on NSBB had reduced mortality compared with propensity risk score-matched non-NSBB patients (HR 0.55; 95% CI 0.32 to 0.95, p=0.032). Similarly, in the subgroup of patients with refractory ascites (n=117), NSBB remained independently associated with less waitlist death (adjusted HR 0.35; 95% CI 0.14 to 0.86, p=0.022). CONCLUSIONS: NSBB in patients with ascites and refractory ascites listed for liver transplantation are not detrimental, and instead are associated with reduced waitlist death. Our findings argue that NSBB are safe and may confer benefit in patients with ascites complicating end-stage liver disease.
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Ascitis/mortalidad , Enfermedad Hepática en Estado Terminal/mortalidad , Antagonistas de Receptores Adrenérgicos beta 1 , Adulto , Anciano , Enfermedad Hepática en Estado Terminal/cirugía , Femenino , Humanos , Trasplante de Hígado , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Estudios RetrospectivosRESUMEN
These updated guidelines on the management of variceal haemorrhage have been commissioned by the Clinical Services and Standards Committee (CSSC) of the British Society of Gastroenterology (BSG) under the auspices of the liver section of the BSG. The original guidelines which this document supersedes were written in 2000 and have undergone extensive revision by 13 members of the Guidelines Development Group (GDG). The GDG comprises elected members of the BSG liver section, representation from British Association for the Study of the Liver (BASL) and Liver QuEST, a nursing representative and a patient representative. The quality of evidence and grading of recommendations was appraised using the AGREE II tool.The nature of variceal haemorrhage in cirrhotic patients with its complex range of complications makes rigid guidelines inappropriate. These guidelines deal specifically with the management of varices in patients with cirrhosis under the following subheadings: (1) primary prophylaxis; (2) acute variceal haemorrhage; (3) secondary prophylaxis of variceal haemorrhage; and (4) gastric varices. They are not designed to deal with (1) the management of the underlying liver disease; (2) the management of variceal haemorrhage in children; or (3) variceal haemorrhage from other aetiological conditions.
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Várices Esofágicas y Gástricas/terapia , Hemorragia Gastrointestinal/terapia , Algoritmos , Várices Esofágicas y Gástricas/etiología , Hemorragia Gastrointestinal/etiología , Humanos , Cirrosis Hepática/complicacionesRESUMEN
BACKGROUND & AIMS: In the absence of overt infection, the systemic inflammatory response is increasingly recognised as a pathogenetic factor in the circulatory dysfunction of advanced cirrhosis. Our aim was to determine whether the neutrophil-to-lymphocyte ratio, a marker of systemic inflammation, is predictive of mortality in patients with end-stage cirrhosis listed for liver transplantation. METHODS: A single centre study of 570 patients listed for first elective single-organ liver transplantation January 2007-June 2011. RESULTS: The median listing neutrophil-to-lymphocyte ratio was 2.9 (IQR 1.9-4.7). Neutrophil-to-lymphocyte ratio demonstrated a positive correlation with listing serum bilirubin (P < 0.001), negative correlation with serum sodium (P < 0.001), and positive correlation with the MELD score (P < 0.001). Neutrophil-to-lymphocyte ratio increased with increasing severity of ascites (P < 0.001). A higher neutrophil count (P < 0.001) and lower lymphocyte count (P = 0.001) were predictors of wait-list death. In a multivariate competing risk Cox model, neutrophil-to-lymphocyte ratio remained independently associated with mortality (HR 1.10; 95% CI 1.05-1.15, P < 0.001). The proportion of patients with a neutrophil-to-lymphocyte ratio <2, 2-4.9, and ≥5 who had died by 3 months of listing was 3%, 13.8% and 37.3% respectively (P < 0.001). After adjusting for MELD, increasing increments of neutrophil-to-lymphocyte ratio were predictive of death by 3 months (P = 0.043). CONCLUSIONS: The blood neutrophil-to-lymphocyte ratio, a simple and readily available marker of systemic inflammation, is an independent predictor of mortality in patients with liver failure listed for liver transplantation.
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Biomarcadores , Cirrosis Hepática/mortalidad , Linfocitos/citología , Neutrófilos/citología , Síndrome de Respuesta Inflamatoria Sistémica/mortalidad , Listas de Espera/mortalidad , Femenino , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/patología , Trasplante de Hígado , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Síndrome de Respuesta Inflamatoria Sistémica/etiologíaRESUMEN
BACKGROUND & AIMS: The growing discrepancy between supply and demand for liver transplantation has necessitated a greater use of higher risk grafts. Donation after Circulatory Death (DCD) liver transplant recipients have an increased frequency of acute kidney injury (AKI). We hypothesised that other higher risk grafts might also impact negatively on renal function. Our aim was to examine the effect of the evolving use of higher risk grafts on the incidence of post liver transplant AKI. METHODS: Single-centre study of 1152 patients undergoing first-single-organ liver transplantation for chronic liver disease 01/2000-12/2011. To assess the impact of the evolution of graft quality over time; donor/graft/recipient variables were compared over three 4-year periods. RESULTS: Pretransplant recipient renal function improved during follow-up (p<0.001), and the median postoperative day-1 (p<0.001), -2 (p<0.001), and -3 (p<0.001) tacrolimus trough levels fell. The proportion of patients receiving a higher risk graft was 31.8% in 2000-2003, 40.9% in 2004-2007, and 59.1% in 2008-2011 (p<0.001). There was a progressive increase in AKI (2000-2003, OR 1.00; 2004-2007, OR 1.43; 2008-2011, OR 2.40, p<0.001). After adjusting for recipient variables increasing recipient warm ischaemic time (p=0.019), DCD transplantation (p<0.001), donor age ≥60 years (p=0.020), and donor body mass index ≥30 kg/m(2) (p<0.001) were independent predictors of AKI. CONCLUSIONS: The increasing use of higher risk liver grafts is associated with an increased incidence of AKI. These findings support the need for therapies that minimise the hepatic ischaemia-reperfusion injury.
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Lesión Renal Aguda/etiología , Enfermedad Hepática en Estado Terminal/cirugía , Trasplante de Hígado/efectos adversos , Lesión Renal Aguda/mortalidad , Adulto , Índice de Masa Corporal , Enfermedad Hepática en Estado Terminal/mortalidad , Femenino , Estudios de Seguimiento , Supervivencia de Injerto , Humanos , Incidencia , Trasplante de Hígado/mortalidad , Modelos Logísticos , Masculino , Persona de Mediana Edad , Morbilidad , Obesidad/mortalidad , Daño por Reperfusión/mortalidad , Factores de Riesgo , Donantes de Tejidos , Resultado del Tratamiento , Isquemia Tibia/mortalidadRESUMEN
Small series have suggested that split liver transplantation (SLT) has an increased frequency of peri-operative acute kidney injury (AKI). However, the optimal donor selection in this setting could have a favourable impact on renal outcomes. This was a retrospective single-centre study of 76 adults who underwent SLT (right extended lobe) and 301 adults who underwent elective full-size donation after brain death liver transplantation (FSLT). SLT recipients were less likely than unmatched FSLT recipients to develop AKI (≥stage 1 KDIGO criteria) (40.3% vs. 56.1%, P = 0.016) and had a reduced frequency of renal replacement therapy (11.8% vs. 21.9%, P = 0.049). In 72 pairs of SLT patients and propensity risk score-matched FSLT controls the incidence of AKI was not significantly different (40.3% vs. 47.2%, P = 0.473). However, SLT patients were less likely to require renal replacement therapy (11.1% vs. 23.6%, P = 0.078; adjusted OR 0.32; 95% CI 0.11-0.87, P = 0.026). There was no association between SLT and the development of chronic kidney disease (eGFR<60 ml/min/1.73 m(2) , log rank P = 0.534). In conclusion, SLT is not associated with an increased frequency of AKI. These observations support the postulation that the optimal donor status of SLT may result in less graft injury with renal sparing effects.
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Cirugía General/educación , Trasplante de Hígado/educación , HumanosRESUMEN
Microtubule doublets (MTDs) comprise an incomplete microtubule (B-tubule) attached to the side of a complete cylindrical microtubule. These compound microtubules are conserved in cilia across the tree of life; however, the mechanisms by which MTDs form and are maintained in vivo remain poorly understood. Here, we identify microtubule-associated protein 9 (MAP9) as an MTD-associated protein. We demonstrate that C. elegans MAPH-9, a MAP9 homolog, is present during MTD assembly and localizes exclusively to MTDs, a preference that is in part mediated by tubulin polyglutamylation. We find that loss of MAPH-9 causes ultrastructural MTD defects, including shortened and/or squashed B-tubules with reduced numbers of protofilaments, dysregulated axonemal motor velocity, and perturbed cilia function. Because we find that the mammalian ortholog MAP9 localizes to axonemes in cultured mammalian cells and mouse tissues, we propose that MAP9/MAPH-9 plays a conserved role in regulating ciliary motors and supporting the structure of axonemal MTDs.