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Background Caroli disease (CD) is characterized by dilation of the intrahepatic biliary tree, which may result in malignancy. Treatments include management of symptoms and hepatic resection to decrease disease burden. In patients with CD not amenable to these treatments, orthotopic liver transplantation (OLT) has been used. This study examines if OLT is a reasonable treatment for patients with CD. Materials and methods The United Network of Organ Sharing/Organ Procurement and Transplantation Network database between September 30, 1987 and March 31, 2011 was queried. Cases without patient or allograft survival time or without a diagnosis were excluded from analysis. Patients with CD were compared to patients with primary biliary cirrhosis (PBC), secondary biliary cirrhosis (BC), primary sclerosing cholangitis (PSC), and all indications for OLT. Survival analysis was performed by log-rank test and Kaplan-Meier. Results One hundred forty patients with CD were compared to 4797 patients with PBC, 489 patients with secondary BC, 6033 patients with PSC, and 92,210 patients post-OLT. Patient and allograft survivals of CD patients at 1, 3, 5, and 10 y are, respectively, 88.5%, 83.4%, 80.9%, and 77.8%; and 81.2%, 74.8%, 70.6%, and 67.9%. CD patients have significantly improved patient and allograft survivals after OLT compared to patients with secondary BC ( P = 0.003, P = 0.015) and all other patients undergoing OLT ( P = 0.003, P = 0.026). There is a trend towards long-term improved patient and allograft survival in transplanted patients with CD compared to patients with PBC and PSC. Conclusions These results suggest that OLT should be considered an effective treatment modality for patients with CD resulting in excellent long-term outcomes.

Though robust clinical data are available within transplantation, these data are not used for broad-based, multicentered quality improvement initiates. This article describes a targeted quality improvement initiative within the Studies of Pediatric Liver Transplantation (SPLIT) Registry. Using standard statistical techniques and clinical expertise to adjust for data and statistical reliability, we identified the pediatric liver transplant centers in North America with the lowest hepatic artery thrombosis rate and biliary complication rates. A survey was completed to establish current practices within the entire SPLIT group. Surgeons from the highest performing centers presented a detailed, technically oriented overview of their current practices. The presentations and discussion that followed were recorded and form the basis of the best practices described herein. We frame this work as a unique six-step approach roadmap that may serve as an efficient and cost effective model for novel broad-based quality improvement initiatives within transplantation.

Purpose: Despite growing concerns toward maintaining participants' privacy, individual investigators collecting tissue and other biological specimens for genomic analysis are encouraged to obtain informed consent for broad data sharing. Our purpose was to assess the effect on research enrollment and data sharing decisions of three different consent types (traditional, binary, or tiered) with varying levels of control and choices regarding data sharing. Methods: A single-blinded, randomized controlled trial was conducted with 323 eligible adult participants being recruited into one of six genome studies at Baylor College of Medicine in Houston, Texas, between January 2008 and August 2009. Participants were randomly assigned to one of three experimental consent documents (traditional, n = 110; binary, n = 103; and tiered, n = 110). Debriefing in follow-up visits provided participants a detailed review of all consent types and the chance to change data sharing choices or decline genome study participation. Results: Before debriefing, 83.9% of participants chose public data release. After debriefing, 53.1% chose public data release, 33.1% chose restricted (controlled access database) release, and 13.7% opted out of data sharing. Only one participant declined genome study participation due to data sharing concerns. Conclusion: Our findings indicate that most participants are willing to publicly release their genomic data; however, a significant portion prefers restricted release. These results suggest discordance between existing data sharing policies and participants' judgments and desires.

Incorporating a scalable parametric measurement (SPM) macro in semiconductor products enables N to P ratio screening at wafer test where each die can be tested. While in line scribe line measurements provide valuable feedback to correct manufacturing problems, in line test sample sizes and the need to disposition entire wafers limit the usefulness of this technique as a product screen. Functional patterns applied at module test provide a measure of protection against escapes to system level, but module yield loss results in higher cost than wafer yield loss because of the added loss of package and module test costs. Use of a SPM macro for N to P ratio disposition maximizes yield and minimizes false rejects and false accepts.

Personalized genomic medicine and surgery (PGMS) represents a new approach to health care that customizes patients’ medical treatment according to their own genetic information. This new approach is the result of increased knowledge of the human genome and ways this information can be applied by physicians in the medical and surgical management of their patients. A patient’s genotype can yield important information concerning disease susceptibility and the effectiveness of medications, therefore guiding specific, targeted imaging and treatment therapies. This review summarizes major achievements of human genomic studies and applications of genomics in health care. Five years ago we developed a model for the development of PGMS in which genomic profile guides choice of therapy. In this article we discussed our progress, including an updating of the model, and a future vision of PGMS.

Background: Percutaneous coronary intervention (PCI) is used with increasing frequency in patients with diabetes and multivessel disease. This study investigated evolving revascularization strategies in the State of Washington. Methods: The Clinical Outcomes Assessment Program captures all revascularization in the State of Washington and was used to compare diabetic patients with multivessel disease undergoing first-time revascularization from 1999 to 2007. Categorical variables were compared with the chi-squared test and continuous variables were compared with the student's t-test. Results were risk-adjusted using a logistic regression. Results: A total of 11,602 patients with diabetes and multivessel disease underwent revascularization from 1999 to 2007 and were nearly equally divided between coronary artery bypass grafting (CABG) (51%) and PCI (49%). Patients undergoing CABG had a higher (p < 0.0001) prevalence of congestive heart failure, cerebrovascular disease, peripheral vascular disease, three-vessel coronary artery disease (CAD), and intraaortic balloon pump insertion, but a lower prevalence of female gender, cardiogenic shock, and emergency procedures. Patients undergoing CABG had more (p < 0.0001) three-vessel CAD and more complete revascularization (3.7 vs. 1.5 lesions treated). Short-term risk-adjusted mortality was equivalent. The prevalence of PCI increased from 34.1% in 1999 to 59.4% in 2007. Conclusions: PCI is applied with increasing frequency to patients with diabetes mellitus (DM) and multivessel disease. PCI is used most commonly in two-vessel CAD or with acute coronary syndromes with more limited and targeted revascularization. CABG is more commonly applied to extensive disease with more complete revascularization. Both the prevalence and percentage of patients undergoing PCI as primary therapy for multivessel disease with DM is increasing. A multidisciplinary approach may be warranted to ensure optimal outcomes. (J Card Surg 2011;26:1-8)

Background Severe geographic inequities in liver transplantation have persisted for years. Previous investigators have demonstrated 90-day transplant rates varying from 14% to 82% and death rates varying from 18% to 86%. The aim of this analysis was to utilize a robust multivariate analysis to investigate whether geographic inequities affected the length of stay after liver transplantation. Methods We conducted a unique Kaplan-Meier analysis with the event being discharge from the hospital and length of stay as the time to the event, using a cohort of 66 674 recipients listed in the UNOS database from 2002 to 2016. Multivariate Cox regression using 43 covariates was used for time-to-event analysis. Results Region 9 (0.82; CI 0.79-0.85), Region 2 (0.85; CI 0.83-0.88), and Region 10 (0.96; CI 0.93-0.99) were statistically significant factors for prolonged hospital stay. The following covariates were the most significant factors for prolonged hospital stay: serum sodium >150 mEq/L (0.70; CI 0.62-0.78), ICU admission (0.77; CI 0.74-0.80), hospital admission (0.81; 0.79-0.83), region 9 (0.82; CI 0.79-0.85), and ventilator dependence (0.82; CI 0.76-0.88). Conclusion In this analysis, we demonstrate regional disparities in hospital length of stay that are significant in robust multivariable Cox regression analysis. We hope the transplant community will take immediate measures to correct geographic inequities.

The Milan criteria (MC) have historically determined eligibility for transplantation for hepatocellular carcinoma (HCC). The United Network for Organ Sharing (UNOS) Region 4 expanded the criteria for transplantation in HCC to include a single tumor ≤6 cm or up to 3 tumors with the largest diameter ≤5 cm and total additive diameter ≤9 cm (R4C). The aim of this study was to report the 10-year outcomes of this expanded criteria compared to MC. Transplants performed for HCC in Region 4 between October 2007 and December 2016 were reviewed using the UNOS database. Recipients were categorized based on imaging findings at initial evaluation. A total of 2068 patients were included in the study. There was no significant difference in 10-year patient survival between the groups (53% MC vs 48% R4C, P = .23). There was also no significant difference in recurrence-free survival (54% MC vs 47% R4C, P = .15) or allograft survival (53% MC vs 48% R4C, P = .16). Finally, there was no significant difference in outcomes between the MC and R4C groups when stratifying patients by locoregional therapy. This study demonstrates promising data that the criteria for liver transplantation in HCC can be safely expanded to the R4C without compromising outcomes.

We describe a male with a large abdominal mass, most likely originating from the liver, with capsule rupture and tumor dissemination into the abdominal cavity. Adherence of the tumor to the diaphragm and lower right colon also were noted. A comprehensive evaluation of the mass revealed no tumor-defining histopathologic, immunocytochemical, ultrastructural, cytogenetic, or translocation features. The malignant tumor was found to have a novel translocation (X;19)(q13;13.3), which has not been reported in small round cell tumors of childhood or adults. The final diagnosis rendered was an undifferentiated small round cell tumor of uncertain cell of origin.

An index to predict hospital length of stay after liver transplantation could address unmet clinical needs. Length of stay is an important surrogate for hospital costs and efforts to limit stays can preserve our healthcare resources. Here, we devised a scoring system that predicts hospital length of stay following liver transplantation. We used univariate and multivariate analyses on 73,635 adult liver transplant recipient data and identified independent recipient and donor risk factors for prolonged hospital stay (> 30 days). Multiple imputation was used to account for missing variables. We identified 22 factors as significant predictors of prolonged hospital stay, including the most significant risk factors: Intensive Care Unit (ICU) admission (OR 1.75, CI 1.58-1.95) and previous transplant (OR 1.60, CI 1.47-1.75). The Length of Stay (LOS) index assigns weighted risk points to each significant factors in a scoring system to predict prolonged hospital stay after liver transplantation with a c-statistic of 0.75. The LOS index demonstrated good discrimination across the entire population, dividing the cohort into tertiles, which had odds ratios of 2.25 (CI 2.06-2.46) and 7.90 (7.29-8.56) for prolonged hospital stay (> 30 days). The LOS index utilizes 22 significant donor and recipient factors to accurately predict hospital length of stay following liver transplantation. The index further demonstrates the basis for a clear clinical recommendation to mitigate risk of long hospitalization by minimizing cold ischemia time. This article is protected by copyright. All rights reserved.

Conservation objectives for non-breeding coastal birds (shorebirds and wildfowl) are determined from their population size at coastal sites. To advise coastal managers, models must predict quantitatively the effects of environmental change on population size or the demographic rates (mortality and reproduction) that determine it. As habitat association models and depletion models are not able to do this, we developed an approach that has produced such predictions thereby enabling policy makers to make evidence-based decisions. Our conceptual framework is individual-based ecology, in which populations are viewed as having properties (e.g. size) that arise from the traits (e.g. behaviour, physiology) and interactions of their constituent individuals. The link between individuals and populations is made through individual-based models (IBMs) that follow the fitness-maximising decisions of individuals and predict population-level consequences (e.g. mortality rate) from the fates of these individuals. Our first IBM was for oystercatchers Haematopus ostralegus and accurately predicted their density-dependent mortality. Subsequently, IBMs were developed for several shorebird and wildfowl species at several European sites, and were shown to predict accurately overwinter mortality, and the foraging behaviour from which predictions are derived. They have been used to predict the effect on survival in coastal birds of sea level rise, habitat loss, wind farm development, shellfishing and human disturbance. This review emphasises the wider applicability of the approach, and identifies other systems to which it could be applied. We view the IBM approach as a very useful contribution to the general problem of how to advance ecology to the point where we can routinely make meaningful predictions of how populations respond to environmental change.

Phosphatase and tensin homolog (PTEN) is a tumor-suppressor gene that is mutated in cancer of the liver, pancreas, endometrium, and prostate. PTEN-dependent pathways are involved in mediating cell growth and invasion. To sequence the whole gene (including introns and exons), we have taken advantage of new technologies that allow for rapid, inexpensive sequencing to great depth.DNA from 15 HCC specimens were pooled, and long-range PCR was performed by using the GeneAmp XL PCR kit. Primer parameters included: length of 20-30 base pairs (bp), melting temperature of -68 degrees C, and G/C content of 50-60%. PCR products were then column-purified and pooled, and DNA libraries were prepared for "shotgun sequencing" on both the 454 GS and Illumina GA sequencing platforms.We successfully amplified approximately 98.9% of the PTEN gene by using one long-range PCR protocol applied to 24 primer sets, resulting in 20 amplicons approximately 6.5 kilobases (kb) in length, 2 amplicons approximately 10 kb in length, and 2 amplicons approximately 2.5 kb in length. Sequencing of fragmented PCR products on both sequencing platforms identified six high-frequency SNPs that were catalogued in dbSNP as known variants.Shotgun sequencing based on a single long-range PCR protocol in pooled samples is an efficient and relatively inexpensive way to sequence an entire gene.

Mammalian cells are frequently at risk of DNA damage from multiple sources. Accordingly, cells have evolved the DNA damage response (DDR) pathways to monitor the integrity of their genome. Conceptually, DDR pathways contain three major components (some with overlapping functions): sensors, signal transducers, and effectors. At the level of sensors, ATM (ataxia telangiectasia mutated) and ATR (ATM-Rad3-related) are proximal kinases that act as the core sensors of and are central to the entire DDR. These two kinases function to detect various forms of damaged DNA and trigger DNA damage response cascades. If cells harbor DDR defects and fail to repair the damaged DNA, it would cause genomic instability and, as a result, lead to cellular transformation. Indeed, deficiencies of DDR frequently occur in human cancers. Interestingly, this property of cancer also provides a great opportunity for cancer therapy. For example, by using a synthetic lethality model to search for the effective drugs, ChK1 inhibitors have been shown to selectively target the tumor cells with p53 mutations. In addition, the inhibitors of poly(ADP-ribose) polymerase (PARP-1) showed selectively killing effects on the cells with defects of homologous recombination (HR), particularly in the context of BRCA1/2 mutations. Since Brit1 is a key regulator in DDR and HR repair, we believe that we can develop a similar strategy to target cancers with Brit1 deficiency. Currently, we are conducting a high-throughput screening to identify novel compounds that specifically target the Brit1-deficient cancer which will lead to development of effective personalized drugs to cure cancer in clinic.

Liver tumors in childhood are rare and are typically not detected clinically until they reach a large size and often spread within the organ or metastasize. This can make surgical resection problematic, and almost all of them require extirpation for cure. With very effective chemotherapy for hepatoblastoma and to some extent for sarcomas, many cancers can be shrunk to permit partial hepatectomy, but for most hepatocarcinomas, some of the other malignancies, and even some benign proliferations, their location at the hilum and multiplicity of masses in multiple lobes make transplantation the treatment of choice. Major advances in diagnostic imaging, especially enhanced computed tomography and magnetic resonance imaging, permit a preoperative choice of resection versus transplantation to be achieved in almost all instances, and for the remainder, intraoperative ultrasonography can further help to determine the most desirable approach. The outcome is very much better in the case of hepatoblastoma when transplantation is a primary modality rather than following unsuccessful attempts at resection. In this review, transplantation for liver tumors in children is considered from all aspects, including the importance of screening for tumors whenever possible to avoid the need for transplantation.

Two strategies to increase the donor allograft pool for pediatric orthotopic liver transplantation (OLT) are deceased donor segmental liver transplantation (DDSLT) and living donor liver transplantation (LDLT). The purpose of this study is to evaluate outcomes after use of these alternative allograft types. Data on all OLT recipients between February 2002 and December 2004 less than 12 years of age were obtained from the United Network for Organ Sharing database. The impact of allograft type on posttransplant survivals was assessed. The number of recipients was 1260. Of these, 52% underwent whole liver transplantation (WLT), 33% underwent DDSLT, and 15% underwent LDLT. There was no difference in retransplantation rates. Immediate posttransplant survivals differed, with WLT patients having improved 30-day patient survivals compared to DDSLT and LDLT patients (P = 0.004). Although unadjusted 1-year patient survivals were better for WLT versus DDSLT (P = 0.01), after risk adjustment, 1-year patient survivals for WLT (94%), DDSLT (91%), and LDLT (93%) were similar (P values0.05). Unadjusted allograft survivals were better for WLT and LDLT in comparison with DDSLT (P = 0.009 and 0.018, respectively); however, after adjustment, these differences became nonsignificant (all P values0.05). For patientsor = 2 years of age (n = 833), the adjusted 1-year patient and allograft survivals were also similar (all P values0.05). In conclusion, in the current era of pediatric liver transplantation, WLT recipients have better immediate postoperative survivals. By 1 year, adjusted patient and allograft survivals are similar, regardless of the allograft type.

Population models show that the response of migratory bird populations to a reduction in the area, or change in the quality, of their winter feeding areas depends critically on the shape (linear or non-linear) and strength (slope) of the relationship describing how the proportion dying from starvation changes with population density. Yet the parameters that define such density-dependent functions are extremely difficult to estimate from direct measurements of mortality at different population sizes. Even if they could be estimated, there would be uncertainty as to whether or not the relationship would remain the same, and thus provide reliable predictions, in the new circumstances for which forecasts are required. This paper summarizes studies of the Oystercatcher Haematopus ostralegus which aim to derive the shape and strength of the winter density-dependent mortality and emigration function for one estuary, under existing and new circumstances, from the responses of individual birds to each other and to their spatially and seasonally varying food supply. Based on these studies, an individuals-based, physiologically structured game theoretic distribution model has been built which predicts the carrying capacity and numbers of birds dying at different population sizes. The model also can be applied to Oyster-catchers occupying several estuaries distributed throughout their wintering range and can thus be extended to the entire biogeographical or global population. In addition, it can be used to identify some easily measured behavioural and ecological parameters that identify those species, from a wide range of taxa, that are most likely to be affected by habitat loss and change.

Since 1976, the numbers of Oystercatchers Haematopus ostralegus wintering on the Exeestuary have fluctuated independently of the substantial increase over the same period in the numbers wintering in Britain as a whole. While this might imply that the carrying capacity of the Exe has been reached, closer examination suggests not. Over a sample of the years studied, Oystercatcher numbers on the main Mussel Mytilus edulis feeding areas increased even though the mussel bed quality remained unchanged, food abundance decreased and disturbance on some important beds increased. There was some redistribution of birds between mussel beds, apparently linked to the increased bird numbers and to a relative improvement in the food supply on two preferred mussel beds. The increase in Oystercatcher numbers on the main feeding areas over a period in which the feeding conditions did not improve suggests that carrying capacity was not reached on the mussel beds themselves and, therefore, on the estuary as a whole.

Numbers of Oystercatchers Haematopus ostralegus overwintering on the Exe estuary, south Devon, increased over the period 1976 to 1991. Mortality of colour-ringed adults also increased over this period. In this study, we tested for density-dependence in adult Oystercatcher annual and winter mortality. We examined mortality in all adults, using estuary-wide bird counts, and in mussel feeders only, using bird densities on the mussel beds. Results for annual mortality were equivocal, but suggested that mortality was density-dependent, both for all adults and for mussel feeders only. No density-dependence was detected in the winter mortality of all adults, but strong density-dependent mortality was found amongst mussel-feeders. By modelling mussel feeder mortality at different times of year, we also predict that strong density-dependent mortality occurs on spring migration.

Oystercatchers Haematopus ostralegus periodically pause while handling mussels Mytilus edulis to make visual scans. This paper presents evidence that scanning is associated with the high incidence of intra-specific food stealing among mussel-eating Oystercatchers. Scanning increased in frequency as bird density - and the risk of being attacked for mussels increased and the duration of attacks decreased. Additionally, among a sample of individually marked adults, the aggressive dominant birds spent half as much time scanning as the less aggressive subdominants and were also less likely to be attacked. Whereas detecting an attack made no difference to the success with which the dominants defended their mussels, subdominants increased their chances of retaining the mussel if they detected and carried the mussel away from the approaching attacker. The extra time which the less aggressive birds spent in vigilance seems best understood as a tactic for reducing food loss to kleptoparasites.

Individual-based models (IBMs) predict how animal populations will be affected by changes in their environment by modeling the responses of fitness-maximizing individuals to environmental change and by calculating how their aggregate responses change the average fitness of individuals and thus the demographic rates, and therefore size of the population. This paper describes how the need to develop a new approach to make such predictions was identified in the mid-1970s following work done to predict the effect of building a freshwater reservoir on part of the intertidal feeding areas of the shorebirds Charadrii that overwinter on the Wash, a large embayment on the east coast of England. The paper describes how the approach was developed and tested over 20 years (1976–1995) on a population of European oystercatchers Haematopus ostralegus eating mussels Mytilus edulis on the Exe estuary in Devon, England. The paper goes on to describe how individual-based modeling has been applied over the last 10 years to a wide range of environmental issues and to many species of shorebirds and wildfowl in a number of European countries. Although it took 20 years to develop the approach for 1 bird species on 1 estuary, ways have been found by which it can now be applied quite rapidly to a wide range of species, at spatial scales ranging from 1 estuary to the whole continent of Europe. This can now be done within the time period typically allotted to environmental impact assessments involving coastal bird populations in Europe. The models are being used routinely to predict the impact on the fitness of coastal shorebirds and wildfowl of habitat loss from (i) development, such as building a port over intertidal flats; (ii) disturbance from people, raptors, and aircraft; (iii) harvesting shellfish; and (iv) climate change and any associated rise in sea level. The model has also been used to evaluate the probable effectiveness of mitigation measures aimed at ameliorating the impact of such environmental changes on the birds. The first steps are now being taken to extend the approach to diving sea ducks and farmland birds during the nonbreeding season. The models have been successful in predicting the observed behavior and mortality rates in winter of shorebirds on a number of European estuaries, and some of the most important of these tests are described. These successful tests of model predictions raise confidence that the model can be used to advise policy makers concerned with the management of the coast and its important bird populations.

Ca2+ influx through plasma membrane lesions triggers a rapid repair process that was previously shown to require the exocytosis of lysosomal organelles (Reddy, A., E. Caler, and N. Andrews. 2001. Cell. 106:157–169). However, how exocytosis leads to membrane resealing has remained obscure, particularly for stable lesions caused by pore-forming proteins. In this study, we show that Ca2+-dependent resealing after permeabilization with the bacterial toxin streptolysin O (SLO) requires endocytosis via a novel pathway that removes SLO-containing pores from the plasma membrane. We also find that endocytosis is similarly required to repair lesions formed in mechanically wounded cells. Inhibition of lesion endocytosis (by sterol depletion) inhibits repair, whereas enhancement of endocytosis through disruption of the actin cytoskeleton facilitates resealing. Thus, endocytosis promotes wound resealing by removing lesions from the plasma membrane. These findings provide an important new insight into how cells protect themselves not only from mechanical injury but also from microbial toxins and pore-forming proteins produced by the immune system.

Both Atp7b (Wilson disease gene) and Atp7a (Menkes disease gene) have been reported to be trafficked by copper. Atp7b is trafficked to the bile duct canaliculi and Atp7a to the plasma membrane. Whether or not liver ischemia or ischemia-reperfusion modulates Atp7b expression and trafficking has not been reported. In this study, we report for the first time that the multi-specific metal transporter Atp7b is significantly induced and trafficked by both liver ischemia alone and liver ischemia-reperfusion, as judged by immunohistochemistry and Western blot analyses. Although hepatocytes also stained for Atp7b, localized intense staining of Atp7b was found on bile duct canaliculi. Inductive coupled plasma-mass spectrometry analysis of bile copper, iron, zinc, and manganese found a corresponding significant increase in biliary iron. In our attempt to determine if the increased biliary iron transport observed may be a result of altered bile flow, lysosomal trafficking, or glutathione biliary transport, we measured bile flow, bile acid phosphatase activity, and glutathione content. No significant difference was found in bile flow, bile acid phosphatase activity, and glutathione, between control livers and livers subjected to ischemia-reperfusion. Thus, we conclude that liver ischemia and ischemia-reperfusion induction and trafficking Atp7b to the bile duct canaliculi may contribute to preferential iron transport into bile.

Late graft loss (LGL) and late mortality (LM) following liver transplantation (LT) in children were analyzed from the studies of pediatric liver transplantation (SPLIT) database. Univariate and multivariate associations between pre- and postoperative factors and LGL and LM in 872 patients alive with their primary allografts 1 year after LT were reviewed. Thirty-four patients subsequently died (LM) and 35 patients underwent re-LT (LGL). Patients who survive the first posttransplant year had 5-year patient and graft survival rates of 94.2% and 89.2%, respectively. Graft loss after the first year was caused by rejection in 49% of the cases with sequelae of technical complications accounting for an additional 20% of LGL. LT for tumor, steroid resistant rejection, reoperation in the first 30 days and >5 admissions during the first posttransplant year were independently associated with LGL in multivariate analysis. Malignancy, infection, multiple system organ failure and posttransplant lymphoproliferative disease accounted for 61.8% of all late deaths after LT. LT performed for FHF and tumor were associated with LM. Patients who are at or below the mean for weight at the time of transplant were also at an increased risk of dying. Frequent readmission was also found to be associated with LM.

To examine the outcome of technical variant liver transplant techniques relative to whole organ liver transplantation in pediatric liver transplant recipients.Technical variant liver transplant techniques comprising split, reduced, and live-donor liver transplantation evolved to address the need for timely and size appropriate grafts for pediatric recipients.Analysis of data from the Studies of Pediatric Liver Transplantation (SPLIT) registry, a multicenter database of 44 North American pediatric liver transplant programs. The outcome (morbidity and mortality) of each of the technical variants were compared with that of whole organ recipients.Data were available on 2192 transplant recipients (1183 whole, 261 split, 388 reduced, and 360 live donor). Recipients of all technical variant graft type were significantly younger than whole organ recipients, but on average spent 2.3 months less on the waiting list. Thirty-day post-transplant morbidity was increased for each type of technical variant relative to whole organ (45.1% whole, 66.7% split, 65.5% reduced, 51.9% live-donor). Biliary complications (30 day: 7.5% whole, 18.8% split, 16% reduced, 17.5% live-donor) and portal vein thrombosis (30 day: 3.6% whole, 8% split, 8% reduced, 7.5% live-donor) were more common in all technical variant types. Graft type was an independent predictor of graft loss (death or retransplantation) in a multivariate analysis. Split and reduced (relative risk = 1.74 and 1.77, respectively) grafts had a worse outcome when compared with whole organ recipients.Technical variant techniques expand the pediatric donor pool and reduce time from listing to transplant, but they are associated with increased morbidity and mortality.

The aim of this study was to determine whether prolonged expression of neurotrophin-3 (NT-3) in mice, achieved by herpes simplex virus (HSV)-mediated gene transfer with gene expression under the control of an HSV latency promoter, can provide protection against the progression of diabetic neuropathy over a 6 month period.Mice with diabetes induced by streptozotocin were inoculated s.c. into both hind feet with a non-replicating HSV vector containing the coding sequence for NT-3 under the control of the HSV latency-associated promoter 2 (LAP2) elements or with a control vector. Nerve function was evaluated by electrophysiological and behavioural measures over the course of 6 months after the onset of diabetes.Animals inoculated with the NT-3-expressing vector, but not animals inoculated with control vector, showed preservation of sensory and motor nerve amplitude and conduction velocity measured electrophysiologically, small fibre sensory function assessed by withdrawal from heat, autonomic function measured by pilocarpine-induced sweating, skin innervation assessed by protein gene product 9.5 staining of axons, and density of calcitonin gene-related peptide terminals in the spinal cord measured by immunohistochemistry 5.5 months after vector inoculation.These results indicate that the continuous production of NT-3 by LAP2-driven expression of the transgene from an HSV vector over a 6 month period protects against progression of diabetic neuropathy in mice, and provide a proof-of-principle demonstration for the development of a novel therapy for preventing the progression of diabetic neuropathy.

Extended criteria donor (ECD) liver allografts are often allocated to less severely ill liver transplant (LT) candidates who are at a relatively lower risk of pretransplant mortality, but it is not clear that the use of ECD allografts will decrease center waitlist mortality (WLM). Individual patient data from the UNOS OPTN database (2002-2005) were aggregated to obtain center-specific data. Deceased donor allografts with any of the following characteristics were defined as ECDs: from a donor with any of the criteria described by the New York State Department of Health Workgroup; or 12+ h of cold ischemia. Multivariate regression was used to examine the relationship between WLM and ECD, non-ECD and LDLT use after adjusting for candidate severity of illness. A total of 3555 ECD transplants, 11,660 standard criteria donor (SCD) transplants, and 717 LDLTs were performed at 100 centers during this period. The model demonstrated that SCD and ECD LTs were inversely correlated with a center's WLM (beta=-0.242 and -0.221, respectively; p

Introductions of non-native species are seen as major threats to ecosystem function and biodiversity. However, invasions of aquatic habitats by non-native species are known to benefit generalist consumers that exhibit dietary switches and prey upon the exotic species in addition to or in preference to native ones. There is, however, little knowledge concerning the population-level implications of such dietary changes. Here, we show that the introduction of the Manila clam Tapes philippinarum into European coastal waters has presented the Eurasian oystercatcher Haematopus ostralegus ostralegus with a new food resource and resulted in a previously unknown predator–prey interaction between these species. We demonstrate, with an individuals-based simulation model, that the presence of this non-native shellfish, even at the current low density, has reduced the predicted over-winter mortality of oystercatchers at one recently invaded site. Further increases in clam population density are predicted to have even more pronounced effects on the density dependence of oystercatcher over-winter mortality. These results suggest that if the Manila clam were to spread around European coastal waters, a process which is likely to be facilitated by global warming, this could have considerable benefits for many shellfish-eating shorebird populations.

The use of regional human islet cell processing centers (ICPC) supporting distant clinical islet transplantation programs (CITP) has proven successful in recent clinical trials. Standardization of islet shipping protocols is needed to preserve cell product identity, quantity, quality and sterility, and to meet criteria for transplantation. We evaluated the use of gas-permeable bags for human islet preparation shipment from a single ICPC to two remote CITPs. Product release tests (counts, purity, viability, sterility and potency) were performed at both centers using identical protocols to determine adequacy for transplantation.Thirty-five islet preparations were shipped either immediately after isolation (n = 20) or following culture (n = 15). Islet recovery rate after shipment was higher in cultured preparations, when compared to those not cultured (91.2 +/- 4.9% vs. 72.9 +/- 4.7%, respectively; p0.05), though the overall recovery rate based on isolation and pre-transplant counts was comparable (72.9 +/- 4.7% vs. 70.4 +/- 3.5%, respectively; p = N.S.). All preparations met product release criteria for transplantation. Additional experiments showed that gas-permeable bags led to improved recovery and potency, when compared to 50-mL conical tubes or to non-gas-permeable bags for shipment.Collectively, our data demonstrate that the use of gas-permeable bags is efficient for clinical-grade and should be preferred also for the shipment of research-grade islet preparations.

Diseases of lipid metabolism are a major cause of human morbidity, but no animal model entirely recapitulates human lipoprotein metabolism. Here we develop a xenograft mouse model using hepatocytes from a patient with familial hypercholesterolaemia caused by loss-of-function mutations in the low-density lipoprotein receptor (LDLR). Like familial hypercholesterolaemia patients, our familial hypercholesterolaemia liver chimeric mice develop hypercholesterolaemia and a ’humanized‘ serum profile, including expression of the emerging drug targets cholesteryl ester transfer protein and apolipoprotein (a), for which no genes exist in mice. We go on to replace the missing LDLR in familial hypercholesterolaemia liver chimeric mice using an adeno-associated virus 9-based gene therapy and restore normal lipoprotein profiles after administration of a single dose. Our study marks the first time a human metabolic disease is induced in an experimental animal model by human hepatocyte transplantation and treated by gene therapy. Such xenograft platforms offer the ability to validate human experimental therapies and may foster their rapid translation into the clinic.

Primary hepatic neoplasms in children are rare tumors. All malignant and medically refractive benign primary pediatric liver tumors ultimately require surgical resection for cure. Accurate preoperative imaging including multidetector helical computerized tomography or magnetic resonance imaging (MRI) is necessary to determine resectability. In the literature intraoperative ultrasound (IOUS) has proven to be a vital adjunct to liver surgery in adults, but this is not well established in children.Between April 2003 and November 2014, children (18-y-old) with a primary liver neoplasm, preoperatively evaluated with multidetector helical computerized tomography or MRI, who had IOUS used at the time of surgery were retrospectively reviewed.Preoperative evaluation with high-resolution MRI and IOUS were discordant in 4 of 19 patients (21%). In one case, right hepatic vein involvement was not accurately assessed with MRI. Two cases showed tumor involvement in segment IV by MRI; however, IOUS revealed no medial segment involvement. The final patient had a large (5 cm), solitary hepatic adenoma on MRI, but IOUS in this case revealed diffuse adenomatosis. The operative management was altered in three of these cases.Although MRI can provide a detailed view of the hepatic anatomy and is an invaluable tool for preoperative planning for the pediatric patient with a primary liver neoplasm, IOUS may provide further and more up to date delineation of tumor extent and should be considered a crucial element in operative planning for hepatectomy in children.

With the advent of segmental liver allografts from liver donors, reduced-size cadaveric allografts, and split cadaveric allografts, pediatric pre-transplantation patient mortality has reduced. However, this expansion of the donor pool for size-appropriate allografts for patients with end-stage liver disease has led to an increased incidence of biliary complications. We performed a retrospective review of our series of 242 pediatric patients who received a liver transplantation. Biliary complications at our institution are presented, with a review of the current literature identifying risk factors that predispose pediatric liver transplant patients to biliary complications. We present the protocol used at our institution to minimize risk of biliary complications in our pediatric post-operative patient population.

In behavior-based individual-based models (IBMs), demographic functions are emergent properties of the model and are not built into the model structure itself, as is the case with the more widely used demography-based IBMs. Our behavior-based IBM represents the physiology and behavioral decision making of individual animals and, from that, predicts how many survive the winter nonbreeding season, an important component of fitness. This paper provides the first test of such a model by predicting the change in winter mortality of a charadriid shorebird following removal of intertidal feeding habitat, the main effect of which was to increase bird density. After adjusting one calibration parameter to the level required to replicate the observed mortality rate before habitat loss, the model predicted that mortality would increase by 3.65%, which compares well with the observed increase of 3.17%. The implication that mortality was density-dependent was confirmed by predicting mortality over a range of bird densities. Further simulations showed that the density dependence was due to an increase in both interference and depletion competition as bird density increased. Other simulations suggested that an additional area of mudflat, equivalent to only 10% of the area that had been lost, would be needed by way of mitigation to return mortality to its original level. Being situated at a high shore level with the flow of water in and out impeded by inlet pipes, the mitigating mudflat would be accessible to birds when all mudflats in the estuary were covered at high tide, thus providing the birds with extra feeding time and not just a small replacement mudflat. Apart from providing the first, and confidence-raising, test of a behavior-based IBM, the results suggest (1) that the chosen calibration procedure was effective; (2) that where no new fieldwork is required, and despite being parameter rich, a behavior-based IBM can be parameterized quickly (few weeks), and thus cheaply, because so many of the parameter values can be obtained from the literature and are embedded in the model; and (3) that behavior-based IBMs can be used to explore system behavior (e.g., the role of depletion competition and interference competition in density-dependent mortality).

We have investigated the in vivo safety, efficacy, and persistence of autologous Epstein Barr virus (EBV)–specific cytotoxic T lymphocytes (CTLs) for the treatment of solid organ transplant (SOT) recipients at high risk for EBV-associated posttransplantation lymphoproliferative disease (PTLD). EBV-CTLs generated from 35 patients expanded with normal kinetics contained both CD8 and CD4 lymphocytes and produced significant specific killing of autologous EBV-transformed B lymphoblastoid cell lines (LCLs). Twelve SOT recipients at high risk for PTLD, or with active disease, received autologous CTL infusions without toxicity. Real-time polymerase chain reaction (PCR) monitoring of EBV-DNA showed a transient increase in plasma EBV-DNA suggestive of lysis of EBV-infected cells, although there was no consistent decrease in virus load in peripheral-blood mononuclear cells. Interferon-γ enzyme-linked immunospot (ELISPOT) assay and tetramer analysis showed an increase in the frequency of EBV-responsive T cells, which returned to preinfusion levels after 2 to 6 months. None of the treated patients developed PTLD. One patient with liver PTLD showed a complete response, and one with ocular disease has had a partial response stable for over one year. These data are consistent with an expansion and persistence of adoptively transferred EBV-CTLs that is limited in the presence of continued immunosuppression but that nonetheless produces clinically useful antiviral activity.

Propionic acidemia is a rare metabolic disorder that often results in episodic hyperammonemia, basal ganglia infarction, mental retardation, and cardiomyopathy. OLT has been used as a treatment for propionic acidemia, but its benefit in patients with this disease is unclear. The current study was undertaken to clarify the role of OLT in the management of this disease. The medical literature, a national registry of US OLT recipients, and a single institution liver transplant experience were reviewed for cases of OLT for propionic acidemia. Accumulated cases demonstrate that OLT has resulted in clear evidence of clinical improvement in several patients, often obviating the need for dietary restriction or other forms of medical management. OLT appears to halt the decline in neurocognitive function often associated with propionic acidemia. In total, 12 patients with propionic acidemia have undergone a total of 14 OLTs. A quantitative analysis of outcomes shows an overall patient survival rate of 72.2% at one year after OLT. In conclusion, OLT should be considered a treatment option for patients with propionic acidemia who continue to experience episodes of hyperammonemia in spite of maximal medical therapy. Early OLT may limit the development of mental retardation and/or cardiomyopathy.

We investigated the effects of nicotinamide (NA) supplementation of the processing medium during islet isolation. One hundred and two human pancreata were processed for clinical transplantation after preservation either in the University of Wisconsin (UW) or using the two-layer method (TLM). Pancreata were then divided into four groups and retrospectively analyzed. Group I: UW preservation followed by processing without NA, Group II: UW preservation and processing with NA, Group III: TLM preservation without NA, Group IV: TLM preservation with NA. We observed a significant increase in islet yield in Group II (4343 ± 348 IEQ/g) [mean ± SEM], compared to Group I (2789 ± 348 IEQ/g) (p = 0.005). Similarly, a significant increase in islet yield was observed when NA was used in the processing of organs preserved with TLM (Group IV: 5538 ± 413 vs. Group III: 3500 ± 629; p = 0.02). Furthermore islet yield was higher in Group IV than in Group II (p < 0.05). The percentages of preparations that qualified for transplantation were 25, 47, 45, 69% in Groups I, II, III, IV, respectively. Addition of NA to the processing medium significantly improved islet yields in both the UW and TLM preservation protocols, allowing for a higher percentage of islet preparations to qualify for clinical transplantation.

Simulation models that describe autonomous individual organisms (individual based models, IBM) or agents (agent-based models, ABM) have become a widely used tool, not only in ecology, but also in many other disciplines dealing with complex systems made up of autonomous entities. However, there is no standard protocol for describing such simulation models, which can make them difficult to understand and to duplicate. This paper presents a proposed standard protocol, ODD, for describing IBMs and ABMs, developed and tested by 28 modellers who cover a wide range of fields within ecology. This protocol consists of three blocks (Overview, Design concepts, and Details), which are subdivided into seven elements: Purpose, State variables and scales, Process overview and scheduling, Design concepts, Initialization, Input, and Submodels. We explain which aspects of a model should be described in each element, and we present an example to illustrate the protocol in use. In addition, 19 examples are available in an Online Appendix. We consider ODD as a first step for establishing a more detailed common format of the description of IBMs and ABMs. Once initiated, the protocol will hopefully evolve as it becomes used by a sufficiently large proportion of modellers.

Background. Polymorphisms of the solute carrier family 11 member 1 (Slc11a1) gene have previously been associated with susceptibility to infectious disease, anti-tumor defenses, and autoimmune diseases. We postulated that polymorphisms of the gene may also be associated with susceptibility to post-transplant lymphoproliferative disease (PTLD), a disease thought to be related to an impaired immune response to Epstein–Barr virus (EBV) in immunosuppressed patients. Methods. Whole blood samples were obtained from 45 pediatric patients who underwent liver transplantation. Polymerase chain reaction (PCR) was used to amplify a 3′ region of the gene that includes an exon 15 single-nucleotide substitution (referred to as D543N) and a 4-bp deletion polymorphism (referred to as 3′-UTR). PCR products were digested using AvaII and FokI restriction enzymes for the D543N and 3′-UTR polymorphisms, respectively. PTLD disease status and EBV virus serum titers of all patients were obtained from hospital records. Results. Six of the 45 pediatric transplant recipients developed PTLD. An association was found between 3′-UTR polymorphisms of Slc11a1 and incidence of PTLD after liver transplantation (P=0.005). In addition, post-transplant serum EBV titers were higher (P=0.009) for recipients with certain Slc11a1 polymorphisms. No association was found between the D543N polymorphism and incidence of PTLD. Conclusion. 3′-UTR polymorphisms of the Slc11a1 gene appear to be associated with susceptibility to PTLD and the immune response to EBV in pediatric liver transplant recipients. Genotyping of pediatric patients undergoing liver transplantation may enable early identification of patients at high risk for developing high EBV titers and/or PTLD.

Objective Currently there are no tests to accurately identify paediatric liver transplant patients at risk for post-transplant lymphoproliferative disorder (PTLD). Herein we describe the use of cytokine polymorphisms and real-time quantitative polymerase chain reaction (qPCR) Epstein-Barr virus (EBV) viral load to identify patients at risk for PTLD development. Methods Between 2001 and 2004, approximately 1047 patient samples were collected for qPCR for EBV in 59 patients. EBV viral load was reported in three groups: low EBV ( 4000 copies/microg DNA) and biopsy-proven PTLD. All 59 patients also had cytokine polymorphism genotyping performed for six cytokine polymorphisms (transforming growth factor (TGF)-beta, tumor necrosis factor (TNF)-alpha, interleukins (IL)-6, IL-10, IL-2, and interferon (IFN)-gamma) from DNA isolated from peripheral blood mononuclear cells. Positive predictive value (PPV) and negative predictive value (NPV) were calculated using qPCR and cytokine polymorphism results. Data are reported as a mean +/- standard error of the mean. Results There were 35 males and 24 females with a mean follow-up of 34.9 months. EBV viral load had a PPV and NPV of 29 and 95%, respectively. The low IFN-gamma (A/A) polymorphism was found to be present in 4/6 PTLD patients (67%) and only 17/53 (33%) non-PTLD patients. When the low A/A IFN-gamma polymorphism was combined with EBV viral load for prediction of PTLD, PPV and NPV were 57 and 93%, respectively. Discussion Use of cytokine genotyping in conjunction with qPCR for EBV viral load can significantly improve the predictive value of diagnostic tests for identification of patients at high risk for PTLD.

The pediatric end-stage liver disease (PELD) model accurately estimates 90-day waitlist mortality for pediatric liver transplant candidates, but it has been unclear if PELD can identify patients who will derive survival benefit from undergoing liver transplantation (LT), if it correlates with posttransplant survival, or if it can identify patients for whom LT would be futile. Pediatric patients who underwent LT between 2001 and 2004 were enrolled through the United Network for Organ Sharing Organ Procurement and Transplant Network database. Survival benefit was measured in terms of life-years gained during the first year after LT. Complete data were available for 1,247 patients: 53% were listed as Status 1 at the time of orthotopic liver transplantation (OLT), while the remaining 47% had PELD scores. Only in patients with a PELD of 17+ or those designated as United Network for Organ Sharing Status 1 derived a survival benefit within 1 year of LT; patients with a PELD score of < or = 16 did not. In addition, a statistically significant association was seen between 1-year post-OLT survival and PELD at LT (P = 0.03). No "threshold" PELD score, beyond which risk of post-LT mortality increased dramatically, was apparent. In conclusion, pediatric patients with a PELD score of 17+ derive survival benefit early after LT, and increasing PELD scores are associated with increasing transplant benefit after liver transplantation. PELD does correlate with posttransplant survival but should not be used as a marker for futility.

The use of split-liver (SL) allografts continues to be an excellent option for many pediatric recipients. Patient and graft survival with this graft type are comparable to patient and graft survival with whole organ grafts. Quality-of-life issues, specifically growth, for SL recipients have not been compared to those of recipients of more conventional whole-organ recipients. Pediatric recipients of SL and whole allografts at 2 institutions were identified. Height, z score, and delta z score were calculated for all recipients for each year after transplant. Between 1995 and 2004, 201 pediatric liver transplants were analyzed. Data were collected on 39 split-graft recipients and 36 whole-size recipients. Only subjects 3 years or younger were included in the study. Growth retardation was present in all recipients at transplant. Height z score post split and whole-size transplant were not statistically different at 1- (P = 0.65), 2- (P = 0.13), and 3-year (P = 0.32) anniversaries, respectively. Catch-up growth was present only in recipients of split grafts. In conclusion, the use of split grafts as opposed to whole-size grafts revealed no significant differences in terms of linear growth. Our report indicates that split-liver transplantation does not impair recipient growth.

Although rare in the pediatric population, the natural history of hepatitis C virus (HCV) recurrence in pediatric patients undergoing orthotopic liver transplantation (OLT) for end-stage liver disease secondary to HCV has not been well described. We performed an analysis of all 67 pediatric patients (< 17 years old) who have undergone OLT for HCV in the United States between 1/1988 and 6/2005. The 67 pediatric patients received a total of 83 OLTs for HCV. Following initial OLTs performed for HCV, the patient and allograft survival rates were 71.6% and 55.0%, respectively, at 5 years. Following retransplantation these rates decreased to 55.0% and 33.8%, respectively, following retransplantation. Recipients were listed for retransplantation after 31.3% of all OLTs, and overall recipients were retransplanted after 19.3% of OLTs. The overwhelming majority of retransplants were performed for HCV recurrence. A mean of 1.2 OLTs were performed per patient for HCV. The median time between OLTs for HCV was 290 days. In conclusion, the risk of HCV recurrence in pediatric OLT recipients is high and is associated with a high rate of retransplantation. Still, OLT represents the only treatment option that may achieve long-term survival in pediatric patients with end-stage liver disease secondary to HCV that is recalcitrant to medical management.

The intent of regional sharing for status 1 candidates is to promote timely access to donor livers. Presumably this decreases waitlist mortality. Little published data exists that supports this policy. Organ Procurement and Transplantation Network data was used to calculate region 4 and national adult waitlist death and transplant rates 4 yr prior to (period A) and after (period B) implementation of the sharing agreement in July 1999. Death and transplant rates were calculated using a competing risk analysis. Regional sharing resulted in a reduction in adult status 1 waitlist death rate and an increase in transplant rate for region 4 candidates at 7 and 14 days (P > 0.05) without a change in the death rate at 90 days for the non-status 1 candidates. National data showed a significant increase in transplant rate at 7 days and reduction in waitlist death rate at 14 days after listing (P < 0.05). Status 1 waiting time was decreased from 10 to 3 days (P < 0.05). Adult patient survival was not significantly different between the periods. In conclusion, regional sharing for status 1 candidates results in an increased transplant rate and a reduction in waitlist mortality. Sharing did not impact waitlist mortality for non-status 1 candidates.

The toxicities associated with the chronic use of tacrolimus are well described in the literature; however, little is known about the management during an acute overdose. Phenobarbital is a long-acting barbiturate metabolized in the liver by the cytochrome p450 3a4 system. It is known to enhance the rate of metabolism of itself and the clearance of drugs metabolized by p450 3a4. Because tacrolimus is a substrate of this particular isoenzyme, phenobarbital can be considered a potential option when rapid decreases in tacrolimus whole-blood levels are desired. We hereby report our experience using intravenous phenobarbital in the management of two infants with acute elevations in their tacrolimus whole-blood concentration following liver transplantation. Phenobarbital, through its up-regulation of hepatic cytochrome p450 system increases the elimination of whole-blood tacrolimus concentration in acute overdose situations.

Background Combined transplantation of the lungs and liver is indicated for patients who would not be expected to survive transplantation of either organ alone. No single center has accumulated a significant experience, and as a result the expectations for this operation in the current era are unknown. Methods Patients that have undergone combined lung-liver transplantation in the United States were enrolled through the United Network for Organ Sharing Organ Procurement and Transplantation Network database. In addition, the English-language literature was searched for additional cases of combined lung-liver transplantation. Results Eleven patients have undergone combined lung and liver transplantation in the United States at different centers. The 1- and 5-year patient survival rates are of 79% and 63%, respectively, and no patient has required retransplantation. These patient survival rates are equivalent to similar a combined lung-liver case series from the United Kingdom (P=0.37, log-rank test) and isolated orthotopic liver transplantation in the United States (P=0.59, log-rank test), and are comparable to patient survival rates following isolated lung transplantation in the United States. Conclusions Patient survival of combined lung-liver transplantation is comparable to that of isolated liver and isolated bilateral lung transplantation. This option should be considered for patients with end-stage lung disease and liver disease when transplantation of a single organ transplantation is precluded by severe disease in the other organ system.

Split-liver transplantation (SLT) effectively expands the cadaveric donor pool for children. The remaining right trisegmental (RTS) graft can be transplanted into adults. Limited information exists regarding the outcomes of RTS allografts. Sixty-five RTS graft recipients from five adult transplant programs in Texas were identified. Donor and recipient information were analyzed retrospectively. Most livers (75%) were originally allocated to pediatric recipients. Liver splitting occurred via the in situ (72%) and ex situ (28%) techniques. Arterial reconstruction of RTS grafts was common (52%). Patient and graft survival at 3 months were comparable for the in situ and ex situ techniques (p = 0.2). Cox regression showed only in situ splitting to be a predictor of outcome longer than 3 months posttransplant. Sharing of grafts between centers was frequent (37% of total). One-year patient and allograft survival (87.1% and 85.4%) were excellent with no cases of primary nonfunction. SLT consistently generates two functional liver allografts with excellent recipient survival. In situ splitting of the liver is the preferred technique. Decreased survival is observed with RTS graft use in higher risk recipients. Broader application of SLT with increased sharing is feasible and safely expands the number of liver allografts that can be transplanted.

The recently identified acute-phase response antimicrobial peptide hepcidin has been postulated to maintain iron homeostasis by modulating iron absorption at both the intestinal and macrophage levels. Hepcidin has also been reported to be responsible for anemia associated with chronic inflammatory diseases, and in anemia in patients with hepatic adenomas. Since Kupffer cells are known to be the primary contributor to early-phase ischemia-reperfusion injury in the liver and iron is known to modulate Kupffer cell production of proinflammatory cytokine and reactive oxygen species, we investigated hepcidin in vivo expression in the well-established rat partial-liver ischemia-reperfusion model. We found that both liver ischemia alone and liver ischemia-reperfusion significantly induced serum and liver hepcidin levels. Furthermore, currently proposed mediators of in vivo hepcidin expression, such as interleukin-6, signal transducers and activators of transcription-family transducers, and CCAAT/enhancing binding protein-alpha do not appear to modulate hepcidin expression in the liver ischemia-reperfusion acute inflammatory model. In this study we report the first in vivo evidence of liver ischemia and liver ischemia-reperfusion modulation of hepcidin expression. In conclusion, in the well-characterized liver ischemia-reperfusion model of acute inflammation, mechanism(s) other than interleukin-6 signal transduction via signal transducers and activators of transcription-3 may be responsible for hepcidin induction.