Daily distracted consumption patterns and their relationship with BMI.

The rapidly increasing prevalence of overweight and obesity has heightened the need for a better understanding of obesity-related eating patterns and dietary behaviours. Recent work suggests that distracted eating is causally related to increased immediate and later food, pushing the need for a better understanding of the prevalence of distracted consumption and how this relates to body weight. To extract insights in the relationship between demographics, daily consumption settings, and BMI, we performed secondary data analyses on data from 1011 individuals representative of the Dutch population (adults, 507F, BMI 17-50 kg/m2). The most commonly reported distractions were talking to others (32.7%) and watching television (21.7%). Only 18.4% of respondents reported no distractions during meals. To examine how different distractions related to BMI, we performed OLS regression which showed, among other things, that watching tv while eating lunch (η2 = 0.37) and working during dinner were associated with a higher BMI (η2 = 1.63). To examine the robustness of these findings, machine learning techniques were used. A random forest analysis (RMSE = 4.09) showed that next to age and education level, distraction during lunch and snack was amongst the largest predictors of BMI. Multiple linear regression with lasso penalty (RMSE = 4.13) showed that specifically watching tv while eating lunch or snacks was associated with a higher BMI. In conclusion, our analyses confirmed the assumption that people are regularly distracted during their daily meals, with distinct distractors relating to BMI. These findings provide a starting point for evidence-based recommendations on which consumption settings are associated with healthier eating patterns and body weight.

Presenting and sharing clinical data using the eTRIKS Standards Master Tree for tranSMART.

MOTIVATION: Standardization and semantic alignment have been considered one of the major challenges for data integration in clinical research. The inclusion of the CDISC SDTM clinical data standard into the tranSMART i2b2 via a guiding master ontology tree positively impacts and supports the efficacy of data sharing, visualization and exploration across datasets. RESULTS: We present here a schema for the organization of SDTM variables into the tranSMART i2b2 tree along with a script and test dataset to exemplify the mapping strategy. The eTRIKS master tree concept is demonstrated by making use of fictitious data generated for four patients, including 16 SDTM clinical domains. We describe how the usage of correct visit names and data labels can help to integrate multiple readouts per patient and avoid ETL crashes when running a tranSMART loading routine. AVAILABILITY AND IMPLEMENTATION: The eTRIKS Master Tree package and test datasets are publicly available at https://doi.org/10.5281/zenodo.1009098 and a functional demo installation at https://public.etriks.org/transmart/datasetExplorer/ under eTRIKS-Master Tree branch, where the discussed examples can be visualized.

Crystalline silica alters Sulfatase-1 expression in rat lungs which influences hyper-proliferative and fibrogenic effects in human lung epithelial cells.

Lung epithelial cells are the first cell-type to come in contact with hazardous dust materials. Upon deposition, they invoke complex reactions in attempt to eradicate particles from the airways, and repair damage. The cell surface is composed of a heterogeneous network of matrix proteins and proteoglycans, which act as scaffold and control cell-signaling networks. These functions are controlled, in part, by the sulfation patterns of heparin-sulfate proteoglycans (HSPGs), which are enzymatically regulated. Although there is evidence of altered HSPG-sulfation in idiopathic pulmonary fibrosis (IPF), this is not investigated in silicosis. Our previous studies revealed down-regulation of Sulfatase-1 (SULF1) in human bronchial epithelial cells (BECs) by crystalline silica (CS). In this study, CS-induced down-regulation of SULF1, and increases in Sulfated-HSPGs, were determined in human BECs, and in rat lungs. By siRNA and plasmid transfection techniques the effects of SULF1 expression on silica-induced fibrogenic and proliferative gene expression were determined. These studies confirmed down-regulation of SULF1 and subsequent increases in sulfated-HSPGs in vitro. Moreover, short-term exposure of rats to CS resulted in similar changes in vivo. Conversely, effects were reversed after long term CS exposure of rats. SULF1 knockdown, and overexpression alleviated and exacerbated silica-induced decrease in cell viability, respectively. Furthermore, overexpression of SULF1 promoted silica-induced proliferative and fibrogenic gene expression, and collagen production. These findings demonstrate that the HSPG modification enzyme SULF1 and HSPG sulfation are altered by CS in vitro and in vivo. Furthermore, these changes may contribute to CS-induced lung pathogenicity by affecting injury tolerance, hyperproliferation, and fibrotic effects.

Indications for distinct pathogenic mechanisms of asbestos and silica through gene expression profiling of the response of lung epithelial cells.

Occupational and environmental exposures to airborne asbestos and silica are associated with the development of lung fibrosis in the forms of asbestosis and silicosis, respectively. However, both diseases display distinct pathologic presentations, likely associated with differences in gene expression induced by different mineral structures, composition and bio-persistent properties. We hypothesized that effects of mineral exposure in the airway epithelium may dictate deviating molecular events that may explain the different pathologies of asbestosis versus silicosis. Using robust gene expression-profiling in conjunction with in-depth pathway analysis, we assessed early (24 h) alterations in gene expression associated with crocidolite asbestos or cristobalite silica exposures in primary human bronchial epithelial cells (NHBEs). Observations were confirmed in an immortalized line (BEAS-2B) by QRT-PCR and protein assays. Utilization of overall gene expression, unsupervised hierarchical cluster analysis and integrated pathway analysis revealed gene alterations that were common to both minerals or unique to either mineral. Our findings reveal that both minerals had potent effects on genes governing cell adhesion/migration, inflammation, and cellular stress, key features of fibrosis. Asbestos exposure was most specifically associated with aberrant cell proliferation and carcinogenesis, whereas silica exposure was highly associated with additional inflammatory responses, as well as pattern recognition, and fibrogenesis. These findings illustrate the use of gene-profiling as a means to determine early molecular events that may dictate pathological processes induced by exogenous cellular insults. In addition, it is a useful approach for predicting the pathogenicity of potentially harmful materials.

Unique clinical conditions associated with different acinar regions of fibrosis in long-term surviving pediatric liver grafts.

In the majority of long-term survivors after PLTx, graft fibrosis has been identified. Recently, subtypes of graft fibrosis have been described based on their predominant acinar localization. We aimed to evaluate whether the development of portal, perisinusoidal, and centrilobular distribution of graft fibrosis is related to patient or transplantation-related parameters. We reviewed the histological features in protocol liver biopsies taken at 1 and 5 years after PLTx of 47 children on a tacrolimus-based immunosuppressive regimen. Fibrosis was assessed according to the LAFSc. The prevalence of portal fibrosis increased from 31% to 62%, sinusoidal from 68% to 79%, and centrilobular from 76% to 85%. The presence of portal fibrosis was associated with total bilirubin and γGT levels (each P<.02) and tended to be associated with biliary complications (P=.06). Sinusoidal fibrosis was associated with prior rejection episodes (P<.02) and centrilobular fibrosis with the presence of HLA mismatches (P=.02). In conclusion, using the LAFSc, we found a high incidence of progressive fibrosis in the 1-year and 5-year protocol biopsies after PLTx. Progression of fibrosis was observed in all acinar compartments, and each of the three locations is associated with different clinical conditions.

Choledochal Malformation in Children: Lessons Learned from a Dutch National Study.

INTRODUCTION: A choledochal malformation (CM) is a rare entity, especially in the Western world. We aimed to determine the incidence of CM in the Netherlands and the outcome of surgery for CM in childhood. METHODS: All pediatric patients who underwent a surgical procedure for type I-IV CM between 1989 and 2014 were entered into the Netherlands Study group on choledochal cyst/malformation. Patients with type V CM were excluded from the present analysis. Symptoms, surgical details, short-term (<30 days) and long-term (>30 days) complications were studied retrospectively. RESULTS: Between January 1989 and December 2014, 91 pediatric patients underwent surgery for CM at a median age of 2.1 years (0.0-17.7 years). All patients underwent resection of the extrahepatic biliary tree with restoration of the continuity via Roux-en-Y hepaticojejunostomy. Twelve patients (12%) were operated laparoscopically. Short-term complications, mainly biliary leakage and cholangitis, occurred in 20 patients (22%), without significant correlations with weight or age at surgery or surgical approach. Long-term postoperative complications were mainly cholangitis (13%) and anastomotic stricture (4%). Eight patients (9%) required radiological intervention or additional surgery. Surgery before 1 year of age (OR 9.3) and laparoscopic surgery (OR 4.4) were associated with more postoperative long-term complications. We did not observe biliary malignancies during treatment or follow-up. CONCLUSION: Surgery for CM carries a significant short- and long-term morbidity. Given the low incidence, we would suggest that (laparoscopic) hepatobiliary surgery for CM should be performed in specialized pediatric surgical centers with a wide experience in laparoscopy and hepatobiliary surgery.

Insulin glargine use and breast cancer risk: Associations with cumulative exposure.

BACKGROUND: This study was aimed to assess the risk of breast cancer associated with exposure to insulin glargine in women with type 2 diabetes and evaluate whether the pattern of risk concurs with the hypothesized trend of an increase in risk with longer duration of use, taking into account previous cumulative exposure to other types of insulin. METHODS: We performed a restrospective cohort study (2002-2013) in the Clinical Practice Research Datalink among adult female patients with a first ever insulin prescription (n = 12 468). Time-dependent exposure measures were used to assess associations with duration of use of: (1) other insulin types before glargine was first prescribed (i.e. among switchers); and (2) of glargine during follow-up. Analyses were performed separately for insulin-naïve glargine users and patients switched to glargine. Cox proportional hazards models were used to derive p-trends, hazard ratios (HR) and 95% confidence intervals (CI) for breast cancer associated with glargine use. RESULTS: During 66 151 person years, 186 breast cancer cases occurred; 76 in glargine users (3.0/1000 years) and 110 in users of other insulins (2.7/1000 years). Among insulin-naïve women, no association with cumulative glargine use was observed (p-trend = 0.91), even after ≥5 years (HR = 1.06, 95% CI 0.48-2.33). Among switchers, a linear trend with years of prior exposure to other insulins was found (p-trend = 0.02). An increased risk was observed in glargine users with extensive (>3 years) past exposure to other insulins (HR = 3.17, 95% CI 1.28-7.84). A non-significant trend with cumulative glargine exposure was found among switchers (p-trend = 0.24). CONCLUSIONS: Exposure to glargine was not associated with an increased breast cancer risk in insulin-naïve patients. Exposure to other insulins prior to the start of glargine appears to be relevant when studying breast cancer risk associated with glargine use.

Achievement of developmental milestones in young adults after liver transplantation in childhood.

Little is known about the achievement of developmental milestones (i.e., COL) after pediatric liver transplantation. The aim of this study was to examine the COL of young adults who underwent a liver transplantation during childhood and to compare it to healthy peers. Furthermore, we studied factors possibly related to their COL. COL was assessed using the CLQ, which assesses the achievement of developmental milestones (autonomy, psychosexual, social, and antisocial development) and risk behavior (substance abuse and gambling). Sociodemographic characteristics and clinical data were collected using the prospective institutional liver transplantation database. A total of 39 young adults who underwent a liver transplantation at the UMCG in their childhood completed the CLQ. They achieved fewer milestones with regard to autonomy, psychosexual, and social development compared to healthy peers, and they reported less risk behavior. Neither age at the time of study nor age at the time of transplantation was significantly correlated with any of the COL subscales. Young adults show delay in reaching developmental milestones in every dimension after a liver transplantation during their childhood.

Silica-induced NLRP3 inflammasome activation in vitro and in rat lungs.

RATIONALE: Mineral particles in the lung cause inflammation and silicosis. In myeloid and bronchial epithelial cells the inflammasome plays a role in responses to crystalline silica. Thioredoxin (TRX) and its inhibitory protein TRX-interacting protein link oxidative stress with inflammasome activation. We investigated inflammasome activation by crystalline silica polymorphs and modulation by TRX in vitro, as well as its localization and the importance of silica surface reactivity in rats. METHODS: We exposed bronchial epithelial cells and differentiated macrophages to silica polymorphs quartz and cristobalite and measured caspase-1 activity as well as the release of IL-1ß, bFGF and HMGB1; including after TRX overexpression or treatment with recombinant TRX. Rats were intratracheally instilled with vehicle control, Dörentruper quartz (DQ12) or DQ12 coated with polyvinylpyridine N-oxide. At days 3, 7, 28, 90, 180 and 360 five animals per treatment group were sacrificed. Hallmarks of silicosis were assessed with Haematoxylin-eosin and Sirius Red stainings. Caspase-1 activity in the bronchoalveolar lavage and caspase-1 and IL-1ß localization in lung tissue were determined using Western blot and immunohistochemistry (IHC). RESULTS: Silica polymorphs triggered secretion of IL-1ß, bFGF and HMGB1 in a surface reactivity dependent manner. Inflammasome readouts linked with caspase-1 enzymatic activity were attenuated by TRX overexpression or treatment. At day 3 and 7 increased caspase-1 activity was detected in BALF of the DQ12 group and increased levels of caspase-1 and IL-1ß were observed with IHC in the DQ12 group compared to controls. DQ12 exposure revealed silicotic nodules at 180 and 360 days. Particle surface modification markedly attenuated the grade of inflammation and lymphocyte influx and attenuated the level of inflammasome activation, indicating that the development of silicosis and inflammasome activation is determined by crystalline silica surface reactivity. CONCLUSION: Our novel data indicate the pivotal role of surface reactivity of crystalline silica to activate the inflammasome in cultures of both epithelial cells and macrophages. Inhibitory capacity of the antioxidant TRX to inflammasome activation was evidenced. DQ12 quartz exposure induced acute and chronic functional activation of the inflammasome in the heterogeneous cell populations of the lung in associated with its crystalline surface reactivity.

Silica induces NLRP3 inflammasome activation in human lung epithelial cells.

BACKGROUND: In myeloid cells the inflammasome plays a crucial role in innate immune defenses against pathogen- and danger-associated patterns such as crystalline silica. Respirable mineral particles impinge upon the lung epithelium causing irreversible damage, sustained inflammation and silicosis. In this study we investigated lung epithelial cells as a target for silica-induced inflammasome activation. METHODS: A human bronchial epithelial cell line (BEAS-2B) and primary normal human bronchial epithelial cells (NHBE) were exposed to toxic but nonlethal doses of crystalline silica over time to perform functional characterization of NLRP3, caspase-1, IL-1ß, bFGF and HMGB1. Quantitative RT-PCR, caspase-1 enzyme activity assay, Western blot techniques, cytokine-specific ELISA and fibroblast (MRC-5 cells) proliferation assays were performed. RESULTS: We were able to show transcriptional and translational upregulation of the components of the NLRP3 intracellular platform, as well as activation of caspase-1. NLRP3 activation led to maturation of pro-IL-1ß to secreted IL-1ß, and a significant increase in the unconventional release of the alarmins bFGF and HMGB1. Moreover, release of bFGF and HMGB1 was shown to be dependent on particle uptake. Small interfering RNA experiments using siNLRP3 revealed the pivotal role of the inflammasome in diminished release of pro-inflammatory cytokines, danger molecules and growth factors, and fibroblast proliferation. CONCLUSION: Our novel data indicate the presence and functional activation of the NLRP3 inflammasome by crystalline silica in human lung epithelial cells, which prolongs an inflammatory signal and affects fibroblast proliferation, mediating a cadre of lung diseases.

The FAIR Cookbook - the essential resource for and by FAIR doers.

The notion that data should be Findable, Accessible, Interoperable and Reusable, according to the FAIR Principles, has become a global norm for good data stewardship and a prerequisite for reproducibility. Nowadays, FAIR guides data policy actions and professional practices in the public and private sectors. Despite such global endorsements, however, the FAIR Principles are aspirational, remaining elusive at best, and intimidating at worst. To address the lack of practical guidance, and help with capability gaps, we developed the FAIR Cookbook, an open, online resource of hands-on recipes for "FAIR doers" in the Life Sciences. Created by researchers and data managers professionals in academia, (bio)pharmaceutical companies and information service industries, the FAIR Cookbook covers the key steps in a FAIRification journey, the levels and indicators of FAIRness, the maturity model, the technologies, the tools and the standards available, as well as the skills required, and the challenges to achieve and improve data FAIRness. Part of the ELIXIR ecosystem, and recommended by funders, the FAIR Cookbook is open to contributions of new recipes.

Biliary atresia in the Netherlands: outcome of patients diagnosed between 1987 and 2008.

OBJECTIVE: To examine the outcome of biliary atresia (BA) and to identify prognostic factors using a national database. STUDY DESIGN: All children born between January 1987 and December 2008 who underwent the Kasai surgical procedure for BA were retrieved from the Netherlands Study Group on Biliary Atresia Registry database. Outcomes were measured in terms of clearance of jaundice (bilirubin <1.17 g/dL, or 20 µmol/L, within 6 months after surgery) and 4-year transplant-free survival. Two cohorts, one from 1987-1997 and the other from 1998-2008, were compared. Survival rates were determined using Kaplan-Meier analysis, and prognostic factors were tested with univariate and multivariate analyses. RESULTS: Between January 1987 and December 2008, 214 patients underwent Kasai surgery for BA. In this series, the 4-year transplant-free survival was 46%±4%, and 4-year overall survival was 73%±3%. Clearance of jaundice, surgery within 60 days, and postoperative antibiotic prophylaxis use were independently associated with increased transplant-free survival. The yearly caseload per center (range, 0.5-2.1) was not correlated with transplant-free survival (r=0.024; P=.73). CONCLUSION: During the past 2 decades, outcome parameters have remained constant and are comparable with those reported from other Western countries, despite a relatively low annual caseload per center. Timely surgical correction and postoperative antibiotic therapy were associated with a higher transplant-free survival rate.

Differences in gene expression and cytokine production by crystalline vs. amorphous silica in human lung epithelial cells.

BACKGROUND: Exposure to respirable crystalline silica particles, as opposed to amorphous silica, is associated with lung inflammation, pulmonary fibrosis (silicosis), and potentially with lung cancer. We used Affymetrix/GeneSifter microarray analysis to determine whether gene expression profiles differed in a human bronchial epithelial cell line (BEAS 2B) exposed to cristobalite vs. amorphous silica particles at non-toxic and equal surface areas (75 and 150 × 106µm2/cm2). Bio-Plex analysis was also used to determine profiles of secreted cytokines and chemokines in response to both particles. Finally, primary human bronchial epithelial cells (NHBE) were used to comparatively assess silica particle-induced alterations in gene expression. RESULTS: Microarray analysis at 24 hours in BEAS 2B revealed 333 and 631 significant alterations in gene expression induced by cristobalite at low (75) and high (150 × 106µm2/cm2) amounts, respectively (p < 0.05/cut off ≥ 2.0-fold change). Exposure to amorphous silica micro-particles at high amounts (150 × 106µm2/cm2) induced 108 significant gene changes. Bio-Plex analysis of 27 human cytokines and chemokines revealed 9 secreted mediators (p < 0.05) induced by crystalline silica, but none were induced by amorphous silica. QRT-PCR revealed that cristobalite selectively up-regulated stress-related genes and cytokines (FOS, ATF3, IL6 and IL8) early and over time (2, 4, 8, and 24 h). Patterns of gene expression in NHBE cells were similar overall to BEAS 2B cells. At 75 × 106µm2/cm2, there were 339 significant alterations in gene expression induced by cristobalite and 42 by amorphous silica. Comparison of genes in response to cristobalite (75 × 106µm2/cm2) revealed 60 common, significant gene alterations in NHBE and BEAS 2B cells. CONCLUSIONS: Cristobalite silica, as compared to synthetic amorphous silica particles at equal surface area concentrations, had comparable effects on the viability of human bronchial epithelial cells. However, effects on gene expression, as well as secretion of cytokines and chemokines, drastically differed, as the crystalline silica induced more intense responses. Our studies indicate that toxicological testing of particulates by surveying viability and/or metabolic activity is insufficient to predict their pathogenicity. Moreover, they show that acute responses of the lung epithelium, including up-regulation of genes linked to inflammation, oxidative stress, and proliferation, as well as secretion of inflammatory and proliferative mediators, can be indicative of pathologic potential using either immortalized lines (BEAS 2B) or primary cells (NHBE). Assessment of the degree and magnitude of these responses in vitro are suggested as predictive in determining the pathogenicity of potentially harmful particulates.

Mortality of biliary atresia in children not undergoing liver transplantation in the Netherlands.

In order to further improve the outcome of BA, we characterized the mortality of BA patients who did not undergo OLT in the Netherlands, and compared our results with international data. For this purpose, we analyzed the causes of mortality of non-transplanted BA patients before the age of five yr, using the NeSBAR database. To evaluate trends in mortality, we compared the cohort 1987-1996 (n=99) with 1997-2008 (n=111). We compared clinical condition at OLT assessment with available international data, using the PELD-score. Mortality of non-transplanted BA children was 26% (26/99) in 1987-1996 and 16% (18/111) in 1997-2008 (p=0.09). Sepsis was the prevailing direct cause of death (30%; 13/44). PELD-scores at the time of assessment were higher in non-transplanted BA patients (median 20.5; range 13-40) compared with international data (mean/median between 11.7 and 13.3). Based on our national data, we conclude that pretransplant mortality of BA patients is still considerable, and that sepsis is a predominant contributor. Our results strongly indicate that the prognosis of patients with BA in the Netherlands can be improved by earlier listing of patients for OLT and by improving pretransplant care.

Immediate postoperative low platelet count is associated with delayed liver function recovery after partial liver resection.

OBJECTIVE: To evaluate whether a low postoperative platelet count is associated with a poor recovery of liver function in patients after partial liver resection. BACKGROUND: Experimental studies in rodents have recently suggested that blood platelets play a critical role in the initiation of liver regeneration. It remains unclear whether platelets are also involved in liver regeneration in humans. METHODS: In a series of 216 consecutive patients who underwent partial liver resection for colorectal liver metastases, we studied postoperative mortality and liver dysfunction in relation to the immediate postoperative platelet count. All patients had normal preoperative liver function and none of them had liver fibrosis or cirrhosis. Delayed postoperative recovery of liver function was defined as serum bilirubin >50 micromol/L or prothrombin time >20 seconds at any time point between postoperative day 1 and 5. RESULTS: Patients with a low (<100 x10(9)/L) immediate postoperative platelet count had worse postoperative liver function, higher serum markers of liver injury, and increased mortality compared with patients with normal platelet counts (>100/L). A low immediate postoperative platelet count was identified as an independent risk factor of delayed postoperative recovery of liver function (OR, 11.5; 95% CI, 1.1-122.4; P = 0.04 in multivariate analysis). CONCLUSION: After partial liver resection, a low platelet count is an independent predictor of delayed postoperative liver function recovery and is associated with increased risk of postoperative mortality. These clinical findings are in accordance with the accumulating evidence from experimental studies, indicating that platelets play a critical role in liver regeneration.

Long-term results of urgent revascularization for hepatic artery thrombosis after pediatric liver transplantation.

Hepatic artery thrombosis (HAT) after pediatric orthotopic liver transplantation (OLT) is a serious complication resulting in bile duct necrosis and often requiring retransplantation. Immediate surgical thrombectomy/thrombolysis has been reported to be a potentially successful treatment for restoring blood flow and avoiding urgent retransplantation. The long-term results of this strategy remain to be determined. In 232 pediatric liver transplants, we analyzed long-term outcomes after urgent revascularization for early HAT. HAT developed in 32 patients (13.7%). In 16 children (50%), immediate surgical thrombectomy was performed in an attempt to salvage the graft. Fourteen patients (44%) underwent urgent retransplantation, and 2 (6%) died before further intervention. Immediate thrombectomy resulted in long-term restoration of the hepatic artery flow in 6 of 16 patients (38%) and in 1- and 5-year graft and patient survival rates of 83% and 67%, respectively. In 10 patients, revascularization was unsuccessful, and retransplantation was inevitable. The 1- and 5-year patient survival rates in this group decreased to 50% and 40%, respectively. After immediate retransplantation, the 5-year patient survival rate was 71%. In conclusion, immediate surgical thrombectomy for HAT after pediatric OLT results in long-term graft salvage in about one-third of patients. However, when thrombectomy is unsuccessful, long-term patient survival is lower than the survival of patients who underwent immediate retransplantation.

Graft fibrosis after pediatric liver transplantation: ten years of follow-up.

UNLABELLED: Previously we reported the presence of portal fibrosis in 31% (n = 84) of the grafts in protocol biopsies 1 year after pediatric liver transplantation (LTx). To assess the natural history of graft fibrosis after pediatric liver transplantation, we extended the analysis of graft histology in follow-up protocol biopsy specimens obtained 5 and 10 years after transplantation. We correlated histological results with clinical parameters at the time of LTx and during follow-up, to allow identification of risk factors for the development of fibrosis. From 1 year to 5 years after LTx, the prevalence of fibrosis increased from 31% to 65% (n = 66) but remained stable thereafter (at 10 years, 69%, n = 55). At 10 years after LTx, however, the percentage of patients with severe fibrosis had increased from 10% (at 5 years) to 29%. Of the 69% of children without fibrosis at 1 year post-transplantation, 64% (n = 39) had developed some degree of fibrosis at 10 years. Fibrosis was strongly related to transplant-related factors such as prolonged cold ischemia time, young age at the time of transplantation, high donor/recipient age ratio, and the use of partial grafts (P < 0.05). Fibrosis was not significantly related to rejection, chronic hepatitis, or the nature of the immunosuppressive therapy. CONCLUSION: Biopsies after pediatric LTx show that most grafts developed fibrosis within 5 years. At 10 years after LTx, the graft fibrosis had progressed to severe fibrosis in at least 25% of the patients. Development of fibrosis, starting either before or after the first year post-LTx, was strongly related to transplant-related factors, indicating the importance of these factors to long-term graft prognosis.

The clinical relevance of the anhepatic phase during liver transplantation.

This study assesses the relation between the anhepatic phase duration and the outcome after liver transplantation. Of 645 patients who underwent transplantation between 1994 and 2006, 194 were recipients of consecutive adult primary piggyback liver transplants using heart-beating donors. The anhepatic phase was defined as the time from the physical removal of the liver from the recipient to recirculation of the graft. Other noted study variables were the cold and warm ischemia times, donor and recipient age, donor and recipient body mass index, perioperative red blood cell (RBC) transfusion, indication for transplantation, and Model for End-Stage Liver Disease score. The primary outcome parameter was graft dysfunction, which was defined as either primary nonfunction or initial poor function according to the Ploeg-Maring criteria. The median anhepatic phase was 71 minutes (37-321 minutes). Graft dysfunction occurred in 27 patients (14%). Logistic regression analysis showed an anhepatic phase over 100 minutes [odds ratio (OR), 4.28], a recipient body mass index over 25 kg/m(2) (OR, 3.21), and perioperative RBC transfusion (OR, 3.04) to be independently significant predictive factors for graft dysfunction. One-year patient survival in patients with graft dysfunction was 67% versus 92% in patients without graft dysfunction (P < 0.001). A direct relation between the anhepatic phase duration and patient survival could, however, not be established. In conclusion, this study shows that liver transplant patients with an anhepatic phase over 100 minutes have a higher incidence of graft dysfunction. Patients with graft dysfunction have significantly worse 1-year patient survival.

The evolution of surgical techniques in clinical liver transplantation. A review.

Currently, liver transplantation (LT) is an accepted method of treatment of end-stage liver disease, metabolic diseases with their primary defect in the liver and unresectable primary liver tumors. Surgical techniques in LT have evolved considerably over the past 40 yr. The developments have led to a safer procedure for the recipient reflected by continuously improving survival figures after LT. Also the new techniques offer the possibility of tailoring the operation to the needs and condition of the recipient as in partial grafting or in different revascularization techniques, or in techniques of biliary reconstructions. In addition, the new techniques such as split LT, domino transplantation and living donor LT have brought about an increase in the available grafts. In this review the evolution of surgical techniques in LT over the past 40 yr and their contribution to the current results are discussed.

Results of pancreaticoduodenectomy in patients with periampullary adenocarcinoma: perineural growth more important prognostic factor than tumor localization.

OBJECTIVE: To study the impact of perineural growth as a prognostic factor in periampullary adenocarcinoma (pancreatic head, ampulla of Vater, distal bile duct, and duodenal carcinoma). SUMMARY BACKGROUND DATA: Pancreatic head carcinoma is considered to have the worst prognosis of the periampullary carcinomas. Several other prognostic factors for periampullary tumors have been identified, eg, lymph node status, free resection margins, tumor size and differentiation, and vascular invasion. The impact of perineural growth as a prognostic factor in relation to the site of origin of periampullary carcinomas is unknown. METHODS: Data of 205 patients with periampullary carcinomas were retrieved from our prospective database. Pancreaticoduodenectomy was performed in 121 patients. Their clinicopathological data were reviewed and analyzed in a multivariate analysis. RESULTS: Perineural growth was present in 49% of the cases (37 of the 51 patients with pancreatic head carcinoma; 7 of the 30 patients with ampulla of Vater carcinoma; 7 of the 19 with distal bile duct carcinoma; and 8 of the 21 with duodenal carcinoma). Overall 5-year survival was 32.6% with a median survival of 20.7 months. Median survival in tumors with perineural growth was 13.1 months compared with 36.0 months in tumors without perineural growth (P < 0.0001) Using multivariate analysis, the following unfavorable prognostic factors were identified: perineural growth (RR = 2.90, 95% CI 1.62-5.22), nonradical resection (RR = 2.28, 95% CI 1.19-4.36), positive lymph nodes (RR = 1.96, 95% CI 1.11-3.45), and angioinvasion (RR = 1.79, 95% CI 1.05-3.06). Portal or superior mesenteric vein reconstruction and tumor localization were not of statistical significance. CONCLUSION: Perineural growth is a more important risk factor for survival than the primary site of periampullary carcinomas.