No abstract

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has a drastic impact on national health care systems. Given the overwhelming demand on facility capacity, the impact on all health care sectors has to be addressed.Solid organ transplantation represents a field with a high demand on staff, intensive care units, and follow-up facilities. The great therapeutic value of organ transplantation has to be weighed against mandatory constraints of health care capacities. In addition, the management of immunosuppressed recipients has to be reassessed during the ongoing coronavirus disease 2019 (COVID-19) pandemic. In addressing these crucial questions, transplant physicians are facing a total lack of scientific evidence.Therefore, the aim of this study was to offer an approach of consensus-based guidance, derived from individual information of 22 transplant societies. Key recommendations were extracted and the degree of consensus among different organizations was calculated. A high degree of consensus was found for temporarily suspending nonurgent transplant procedures and living donation programs. Systematic polymerase chain reaction-based testing of donors and recipients was broadly recommended.Additionally, more specific aspects (eg, screening of surgical explant teams and restricted use of marginal donor organs) were included in our analysis. This study offers a novel approach to informed guidance for health care management when a priori no scientific evidence is available.

Heme oxygenase-1 (HO-1) degrades heme into iron, biliverdin, and carbon monoxide (CO). HO-1 expression can be used therapeutically to ameliorate undesirable consequences of ischemia reperfusion injury (IRI), but the mechanism by which this occurs, remains to be established. Rat hearts, exposed to a prolonged period (24 h) of cold (4 degrees C) ischemia, failed to function upon transplantation into syngeneic recipients. Induction of HO-1 expression by administration of cobalt protoporphyrin IX (CoPPIX) to the graft donor restored graft function. Inhibition of HO-1 enzymatic activity, by administration of zinc protoporphyrin (ZnPPIX) at the time of transplantation, reversed the protective effect of HO-1. Exposure of the graft donor as well as the graft (during ischemia) to exogenous CO mimicked the protective effect of HO-1. This was associated with a significant reduction in the number of cells undergoing apoptosis in the graft with no apparent decrease of intravascular fibrin polymerization, platelet aggregation, or P-selectin expression. In conclusion, HO-1-derived CO prevents IRI associated with cardiac transplantation based on its antiapoptotic action. The observation that exposure of the donor and the graft to CO is sufficient to afford this protective effect should have important clinical implications in terms of preventing IRI associated with heart transplantation in humans.

Background-Bilirubin, a natural product of heme catabolism by heme oxygenases, was considered a toxic waste product until 1987, when its antioxidant potential was recognized. On the basis of observations that oxidative stress is a potent trigger in vascular proliferative responses, that heme oxygenase-1 is antiatherogenic, and that several studies now show that individuals with high-normal or supranormal levels of plasma bilirubin have a lesser incidence of atherosclerosisrelated diseases, we hypothesized that bilirubin would have salutary effects on preventing intimal hyperplasia after balloon injury. Methods and Results-We found less balloon injury-induced neointima formation in hyperbilirubinemic Gunn rats and in wild-type rats treated with biliverdin, the precursor of bilirubin, than in controls. In vitro, bilirubin and biliverdin inhibited serum-driven smooth muscle cell cycle progression at the G 1 phase via inhibition of the mitogen-activated protein kinase signal transduction pathways and inhibition of phosphorylation of the retinoblastoma tumor suppressor protein. Conclusions-Bilirubin and biliverdin might be potential therapeutics in vascular proliferative disorders. (Circulation.

We have recently shown that the natural bile pigment bilirubin has antiproliferative effects on vascular smooth muscle cells (VSMCs). Bilirubin is the end product of heme catabolism mediated by heme oxygenases and has for decades been considered a toxic waste product of our bodies. However, 14 separate studies and a meta-analysis have documented an inverse correlation between atherosclerosis and the levels of bilirubin in normal individuals. Having high normal or supranormal levels of bilirubin is associated with less atherosclerotic-type disease as compared with that in individuals with low normal levels of bilirubin. This combined with experimental data showing anti-atherosclerotic properties of the enzyme heme oxygenase-1 encouraged us to hypothesize that bilirubin and its precursor biliverdin, would act to ameliorate components of atherosclerosis, in a manner similar to what has been shown with HO-1. Both did so in an animal model of restenosis in which vascular smooth muscle cell proliferation leads to intimal proliferation and causes narrowing of the vessels. We also analyzed the antiproliferative effects of the bile pigments in an in vitro system where bilirubin/biliverdin caused p53 dependent cell cycle arrest by hypophosphorylation of the retinoblastoma tumor suppressor protein in growth factor stimulated VSMCs.

No abstract

Co-stimulatory blockade of CD28-B7 interaction with CTLA4Ig is a well-established strategy to induce transplantation tolerance. Although previous in vitro studies suggest that CTLA4Ig up-regulates expression of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in dendritic cells, the relationship of CTLA4Ig and IDO in in vivo organ transplantation remains unclear. Here we studied if concerted immunomodulation in vivo by CTLA4Ig depends on IDO. C57BL/6 recipients receiving a fully MHC-mismatched BALB/c heart graft treated with CTLA4Ig + donor specific transfusion (DST) showed indefinite graft survival [>100 days] without signs of chronic rejection or donor specific antibody formation. Recipients with long-term surviving grafts had significantly higher systemic IDO activity as compared to rejectors, which markedly correlated with intragraft IDO and Foxp3 levels. IDO inhibition with 1-methyl-DL-tryptophan, either at transplant or at POD 50, abrogated CTLA4Ig+DST-induced long-term graft survival. Importantly, IDO1 knock-out recipients experienced acute rejection and graft survival comparable to controls. In addition, αCD25 mAb-mediated depletion of Tregs resulted in decreased IDO activity and again prevented CTLA4Ig+DST induced indefinite graft survival. Our results suggest that CTLA4Ig-induced tolerance to murine cardiac allografts is critically dependent on synergistic cross-linked interplay of IDO and Tregs. These results have important implications for the clinical development of this co-stimulatory blocker.

Purpose Extended right hepatectomy is associated with wide surgical margins in PHC and often favored for oncological considerations. However, it remains uncertain whether established surgical principles also apply to the subgroup of node-positive patients. The aim of the present study was to define a tailored surgical approach for patients with perihilar cholangiocarcinoma (PHC) and lymph node metastases. Methods We reviewed the course of all consecutive patients undergoing major hepatectomy for PHC between 2005 and 2015 at the Department of Surgery, Charité – Universitätsmedizin Berlin. Results Two hundred and thirty-one patients underwent major hepatectomy for PHC with 1-, 3-, and 5-year overall (OS) and disease-free survival (DFS) rates of 72%, 48%, and 36%, and 60%, 22%, and 12%, respectively. In lymph node-positive patients (n = 109, 47%), extended left hepatectomy was associated with improved OS and DFS, respectively, when compared to extended right hepatectomy (p = 0.008 and p = 0.003). Interestingly, OS and DFS did not differ between R0 and R1 resections in those patients (both p = ns). Patients undergoing extended left hepatectomy were more likely to receive adjuvant chemotherapy (p = 0.022). This is of note as adjuvant chemotherapy, besides grading (p = 0.041), was the only independent prognostic factor in node-positive patients (p=0.002). Conclusion Patients with node-positive PHC might benefit from less aggressive approaches being associated with lower morbidity and a higher chance for adjuvant chemotherapy. Lymph node sampling might help to guide patients to the appropriate surgical approach according to their lymph node status.