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The evolution of managing short gut syndrome optimizes management and decision making of intestinal failure by way of a multidisciplinary team utilizing the latest advances in therapeutic options. Only the minority of patients referred for small bowel transplantation will actually need a transplant. Many of these patients can be rehabilitated without the need for transplant, by way of early referral, and thus the likelihood of medical therapy increases. On the other hand, in those patients with little likelihood of success with medical therapy, early referral decreases the morbidity and mortality associated with long-term total parenteral nutrition and associated complications and will improve their overall survival outcomes.

The survival of patients receiving transplanted lungs is poorer than that of patients receiving transplants of many other organs. In this trial, inhaled cyclosporine, in addition to systemic immunosuppression, did not improve rejection rates but was associated with better overall survival and chronic rejection–free survival. In this trial, inhaled cyclosporine, in addition to systemic immunosuppression, did not improve rejection rates but was associated with better overall survival and chronic rejection–free survival. Outcomes after lung transplantation are poor as compared with those after heart, kidney, or liver transplantation, with a three-year survival rate of only 55 percent for recipients of lung transplants. Death is commonly due to chronic rejection, 1 which presents histologically as bronchiolitis obliterans 2 – 7 ); the latter is thought to be a complex response to immunologic, ischemic, and infectious injury. 8 – 11 Preventive and therapeutic strategies for this process have been largely unsuccessful. 12 – 14 Since the immunosuppressive effect of cyclosporine is dose-dependent, targeted delivery of this drug might improve efficacy by increasing the concentration of cyclosporine in the allograft. In animal . . .

Zimislecel is an allogeneic stem cell–derived islet-cell therapy. This phase 1–2 study supports the hypothesis that zimislecel can restore physiologic islet function and thus treat persons with type 1 diabetes.

Father of modern transplantation Thomas E. Starzl, best known for his contributions to the field of organ transplantation, died on 4 March 2017 in Pittsburgh, Pennsylvania. He was 90 years old. Starzl pioneered many aspects of transplantation, including immunosuppressive drug development, organ preservation, tissue matching, and innovative transplant surgical procedures. He developed the team approach to organ transplantation, thus paving the way for the success and acceptance of heart, lung, pancreas, intestinal, liver, kidney, and composite tissue transplants. Thanks to Starzl's lifetime commitment to transplantation, close to 1 million patients around the world have received a life-saving organ transplant.

The role of transjugular intrahepatic portosystemic shunt (TIPS) for treating complications of portal hypertension after orthotopic liver transplantation (OLT) is unclear. In this review of 13 retrospective studies and 8 case reports comprising 213 patients, we assessed the indications, technical success, and clinical outcomes of TIPS procedures performed in patients who had undergone OLT. Indications for TIPS were refractory ascites ( n  = 168), variceal hemorrhage ( n  = 36), and hydrothorax ( n  = 9). Technical success was reported in 98 % of cases. Five procedures failed because of portal vein thrombosis, caval tear, technical inability, patient instability, and unknown reasons (one each). Clinical success of TIPS after OLT was 57 % in patients with refractory ascites, 69 % in those with variceal hemorrhage, and 56 % in those with hydrothorax. TIPS revision was required in 16 % of cases, while 19 % of patients underwent subsequent retransplantation. Postprocedural or worsening encephalopathy occurred in 33 % of patients. Survival analysis based on 122 cases with data available revealed a 30-day mortality rate of 11 %, a 1-year cumulative survival rate of 53 %, and a 1-year cumulative retransplantation-free survival rate of 41 %. Given the complexity of post-OLT cases with complications of recurrent portal hypertension, it is not surprising that the overall clinical success rate of TIPS was relatively low. Nevertheless, TIPS may remain a viable choice for the treatment of patients who have undergone OLT with recurrent portal hypertensive complications when medical therapy is unsuccessful.

Prevention of Diabetes in NOD Mice by Administration of Dendritic Cells Deficient in Nuclear Transcription Factor-κB Activity Linlin Ma 1 , Shiguang Qian 1 , Xiaoyan Liang 1 , Lianfu Wang 1 , Jennifer E. Woodward 1 , Nick Giannoukakis 2 , Paul D. Robbins 3 , Suzanne Bertera 4 , Massimo Trucco 4 , John J. Fung 1 and Lina Lu 1 1 Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 2 Diabetes Institute, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 3 Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 4 Division of Immunogenetics, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania Address correspondence and reprint requests to Lina Lu, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, W1556 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15261. E-mail: lul{at}msx.upmc.edu Abstract Abnormalities of dendritic cells (DCs) have been identified in type 1 diabetic patients and in nonobese diabetic (NOD) mice that are associated with augmented nuclear transcription factor (NF)-κB activity. An imbalance that favors development of the immunogenic DCs may predispose to the disease, and restoration of the balance by administration of DCs deficient in NF-κB activity may prevent diabetes. DCs propagated from NOD mouse bone marrow and treated with NF-κB–specific oligodeoxyribonucleotide (ODN) in vitro (NF-κB ODN DC) were assessed for efficacy in prevention of diabetes development in vivo. Gel shift assay with DC nuclear extracts confirmed specific inhibition of NF-κB DNA binding by NF-κB ODN. The costimulatory molecule expression, interleukin (IL)-12 production, and immunostimulatory capacity in presenting allo- and islet-associated antigens by NF-κB ODN DC were significantly suppressed. NF-κB ODN renders DCs resistant to lipopolysaccharide stimulation. Administration of 2 × 10 6 NF-κB ODN DCs into NOD mice aged 6–7 weeks effectively prevented the onset of diabetes. T-cells from pancreatic lymph nodes of NF-κB ODN DC–treated animals exhibited hyporesponsiveness to islet antigens with low production of interferon-γ and IL-2. These findings provide novel insights into the mechanisms of autoimmune diabetes and may lead to development of novel preventive strategies. APC, antigen-presenting cell CTL, cytotoxic T-lymphocyte DC, dendritic cell ELISA, enzyme-linked immunosorbent assay EMSA, electrophoretic mobility shift assay FITC, fluorescein isothiocyanate GM-CSF, granulocyte-macrophage colony-stimulating factor IFN, interferon IκB, inhibitor of κB IL, interleukin iNOS, inducible nitric oxide synthetase LPS, lipopolysaccharide mAb, monoclonal antibody MHC, major histocompatibility complex MLR, mixed leukocyte reaction NF-κB, nuclear transcription factor-κB ODN, oligodeoxyribonucleotide TNF, tumor necrosis factor TUNEL, transferase-mediated dUTP nick-end labeling Footnotes Accepted May 16, 2003. Received August 16, 2002. DIABETES

In an effort to understand the role of IL-6/gp130 signaling in chronic liver injury, IL-6 deficient (IL-6 −/−. and wild-type control (IL-6 +/+) mice were subjected to bile duct ligation (BDL) for 12 weeks. This maneuver causes chronic biomechanical stress and liver injury, fueling sustained biliary epithelial and hepatocyte proliferation. By 12 weeks after BDL, IL-6 −/− mice develop significantly higher total serum bilirubin levels (23.2 ± 2.3 versus 14.9 ± 2.1 mg/dl, P < 0.0001; delta bilirubin subfraction 16.7 ± 4.0% versus 9.2 ± 1.8%; P < 0.002), and the majority (15/18) show “black” gallbladder bile, compared to IL-6 +/+ mice (5/16; P < 0.003). The IL-6 −/− mice also cannot sustain the compensatory liver mass increase commonly seen with chronic obstructive cholangiopathy, because of less hepatocyte proliferation, despite a rate of hepatocyte apoptosis similar to that of IL-6 +/+ mice. Moreover, IL-6 −/− mice show a more advanced stage of biliary fibrosis and a higher mortality rate than the IL-6 +/+ controls (51% versus 23%; P < 0.02). These phenotypic changes in the IL-6 −/− mice are associated with decreased expression and phosphorylation of gp130 and the transcription factor STAT3, compared to IL-6 +/+ mice. Daily treatment with exogenous recombinant IL-6 for 3–6 weeks starting at 6 weeks after BDL significantly lowers the serum total bilirubin in both groups. In the IL-6 −/− mice, exogenous IL-6 treatment also increases the level of gp130 protein expression and completely reverses the loss of liver mass by increasing the hepatocyte proliferation. In conclusion, IL-6 appears to contribute to biliary tree integrity and maintenance of hepatocyte mass during chronic injury.

Insight into the mechanisms of organ engraftment and acquired tolerance has made it possible to facilitate these mechanisms, by tailoring the timing and dosage of immunosuppression in accordance with two therapeutic principles: recipient pretreatment, and minimum use of post-transplant immunosuppression. We aimed to apply these principles in recipients of renal and extrarenal organ transplants. 82 patients awaiting kidney, liver, pancreas, or intestinal transplantation were pretreated with about 5 mg/kg of a broadly reacting rabbit antithymocyte globulin during several hours. Post-transplant immunosuppression was restricted to tacrolimus unless additional drugs were needed to treat breakthrough rejection. After 4 months, patients on tacrolimus monotherapy were considered for dose-spacing to every other day or longer intervals. We frequently saw evidence of immune activation in graft biopsy samples, but unless this was associated with graft dysfunction or serious immune destruction, treatment usually was not intensified. Immunosuppression-related morbidity was virtually eliminated. 78 (95%) of 82 patients survived at 1 year and at 13–18 months. Graft survival was 73 (89%) of 82 at 1 year and 72 (88%) of 82 at 13–18 months. Of the 72 recipients with surviving grafts, 43 are on spaced doses of tacrolimus monotherapy: every other day (n=6), three times per week (11), twice per week (15), or once per week (11). The striking ability to wean immunosuppression in these recipients indicates variable induction of tolerance. The simple therapeutic principles are neither drug-specific nor organ-specific. Systematic application of these principles should allow improvements in quality of life and long-term survival after organ transplantation.

Introduction: Various studies have demonstrated that low-Model for End-Stage Liver Disease (MELD) living-donor liver transplant (LDLT) recipients have better outcomes with improved patient survival than deceased-donor liver transplantation (DDLT) recipients. LDLT recipients gain the most from being transplanted at MELD <25–30; however, some existing data have outlined that LDLT may provide equivalent outcomes in high-MELD and low-MELD patients, although the term “high” MELD is arbitrarily defined in the literature and various cut-off scores are outlined between 20 and 30, although most commonly, the dividing threshold is 25. The aim of this meta-analysis was to compare LDLT in high-MELD with that in low-MELD recipients to determine patient survival and graft survival, as well as perioperative and postoperative complications. Methods: Following PROSPERO registration CRD-42021261501, a systematic database search was conducted for the published literature between 1990 and 2021 and yielded a total of 10 studies with 2183 LT recipients; 490 were HM-LDLT recipients and 1693 were LM-LDLT recipients. Results: Both groups had comparable mortality at 1, 3 and 5 years post-transplant (5-year HR 1.19; 95% CI 0.79–1.79; p-value 0.40) and graft survival (HR 1.08; 95% CI 0.72, 1.63; p-value 0.71). No differences were observed in the rates of major morbidity, hepatic artery thrombosis, biliary complications, intra-abdominal bleeding, wound infection and rejection; however, the HM-LDLT group had higher risk for pulmonary infection, abdominal fluid collection and prolonged ICU stay. Conclusions: The high-MELD LDLT group had similar patient and graft survival and morbidities to the low-MELD LDLT group, despite being at higher risk for pulmonary infection, abdominal fluid collection and prolonged ICU stay. The data, primarily sourced from high-volume Asian centers, underscore the feasibility of living donations for liver allografts in high-MELD patients. Given the rising demand for liver allografts, it is sensible to incorporate these insights into U.S. transplant practices.

Invasive aspergillosis (IA) in liver transplant recipients is associated with poor response rates and a very high mortality rate, despite administration of therapy with conventional amphotericin B. We conducted a single-center, retrospective study to compare the outcome of liver transplant recipients with IA who received amphotericin B lipid complex (ABLC) or conventional amphotericin B. IA was present in 12 ABLC-treated patients (definite, 4; probable, 8) and 29 amphotericin B recipients (definite, 11; probable, 18) in the historical cohort. The 60-day mortality rate was lower in the ABLC cohort: 4 (33%) of 12 patients versus 24 (83%) of 29 patients (P =.006). Only 1 of 4 ABLC recipients with definite IA died, compared with all 11 in the amphotericin B group. Sixty-day survival probability curves was significantly lower in the amphotericin B cohort (P =.008). ABLC therapy was the only independent mortality-protective variable (odds ratio, 0.31; 95% confidence interval, 0.07–0.44; P =.02). First-line or early salvage therapy for IA with ABLC was associated with significantly improved survival relative to a comparable historical group treated with amphotericin B.