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Preoperative fasting induces robust protection against renal ischemia/reperfusion (I/R) injury in mice but is considered overcautious and possibly detrimental for postoperative recovery in humans. Furthermore, fasting seems to conflict with reported benefits of preoperative nutritional enhancement with carbohydrate-rich drinks. Here, we investigated whether preoperative ingestion of a glucose solution interferes with fasting-induced protection against renal I/R injury.

Ischemic‐type biliary lesions (ITBL) are the most frequent cause of nonanastomotic biliary strictures after liver transplantation. This complication develops in up to 25% of patients, with a 50% retransplantation rate in affected patients. Traditionally, ischemia‐reperfusion injury to the biliary system is considered to be the major risk factor for ITBL. Several other risk factors for ITBL have been identified, including the use of liver grafts donated after cardiac death, prolonged cold and warm ischemic times and use of University of Wisconsin preservation solution. In recent years however, impaired microcirculation of the peribiliary plexus (PBP) has been implicated as a possible risk factor. It is widely accepted that the PBP is exclusively provided by blood from the hepatic artery, and therefore, the role of the portal venous blood supply has not been considered as a possible cause for the development of ITBL. In this short report, we present three patients with segmental portal vein thrombosis and subsequent development of ITBL in the affected segments in the presence of normal arterial blood flow. This suggests that portal blood flow may have an important contribution to the biliary microcirculation and that a compromised portal venous blood supply can predispose to the development of ITBL.

Barrett’s esophagus (BE) affects approximately 2% of the Western population and progresses to esophageal adenocarcinoma (EAC) in 0.5% of these patients each year. In BE, the stratified epithelium is replaced by an intestinal-type epithelium owing to chronic gastroduodenal reflux. Since self-renewal of intestinal crypts is driven by Notch signaling, we investigated whether this pathway was active in the proliferative crypts of BE. Immunohistochemistry confirmed the presence of an intact and activated Notch signaling pathway in metaplastic BE epithelium, but not in the normal human esophagus. Similar observations were made in two well-known human Barrett’s-derived EAC cell lines, OE33 and SKGT-5. We then sought to investigate the effects of Notch inhibition by systemic treatment with a γ-secretase inhibitor in a well-validated rodent model for BE. As we have shown previously in normal intestinal epithelium, Notch inhibition converted the proliferative Barrett’s epithelial cells into terminally differentiated goblet cells, whereas the squamous epithelium remained intact. These data imply that local application of γ-secretase inhibitors may present a simple therapeutic strategy for this increasingly common pre-malignant condition.

In mycophenolate mofetil (MMF)-treated organ transplant recipients, lower mycophenolic acid (MPA) plasma concentrations have been found in cyclosporine (CsA) compared with tacrolimus (Tac)-based immunosuppressive regimens. We previously demonstrated that CsA decreases exposure to MPA and increases exposure to its metabolite MPA-glucuronide (MPAG), possibly by interfering with the biliary excretion of MPAG. To elucidate the role of the multidrug resistance-associated protein (Mrp)-2 in the interaction between MMF and CsA, we treated three groups of 10 Mrp2-deficient rats (TR− rat) for 6 days with either vehicle, CsA (8 mg/kg) or Tac (4 mg/kg) by oral gavage. Hereafter, co-administration with MMF (20 mg/kg) was started in all groups and continued through day 14. The 24-h MPA/MPAG area under the concentration-time curve (AUC) was determined after single (day 7) and multiple MMF doses (day 14). On both study days, there were no significant differences in the mean MPA and MPAG AUC between CsA and Tac-treated animals. We conclude that the pharmacokinetics of MMF are comparable in Mrp2-deficient rats receiving either CsA or Tac as co-medication. This finding suggests that CsA-mediated inhibition of the biliary excretion of MPAG by the Mrp2 transporter is the mechanism responsible for the interaction between CsA and MMF.

Abstract: In unraveling the pathogenesis of chronic transplant dysfunction (CTD), non-alloantigen specific factors, as ischemia/reperfusion and renal mass have been suggested to play a role in the process. The aim of the present study was to investigate the effect of the transplantation procedure per se on the development of CTD in a syngeneic kidney transplant model in the rat. Kidney transplantation was performed with the BN rat as donor and recipient, the recipient kidneys having been removed. Unilaterally nephrectomized (UNx) and native BN rats served as controls. Renal function was determined monthly (proteinuria and glomerular filtration rate/100 g body weight; GFR). The follow-up period was until 52 weeks post-transplantation. Histomorphological analysis of CTD according to the BANFF criteria was carried out. Immunohistochemical staining was performed to identify infiltrating cells (CD4, CD8, and ED1) and the expression of MHC class II and ICAM-1. Isografts had a minor, constant proteinuria during follow-up, which did not differ from that of UNx: 27 ± 10 vs. 29 ± 2 mg/24 h at week 52. Unilateral nephrectomy led to a significant reduction of the GFR, which was about 80 % of that of native rats. The GFR of isografts did not differ from that of UNx rats. Histomorphology of renal isografts was comparable to UNx and native kidneys; some glomerulopathy and tubular atrophy leading to a total BANFF-score of 2.6 ± 0.5. In native BN kidneys, few CD4+ cells and ED-1+macrophages (mΦ) were found; MHC class II was constitutively expressed on the proximal tubules and ICAM-1 on the glomeruli and peritubular capillaries. UNx-kidneys showed a similar pattern. Isografts had significantly more CD4+cells and MΦ, mainly localized in the glomeruli, and a more intense ICAM-1 expression in the glomeruli and interstitium. Transplantation of one kidney in itself does not lead to CTD.

Although clinical small-bowel transplantation is still severely hindered by rejection of the graft, prolonged graft survival can be achieved by using cyclosporin A in several experimental models of small-bowel transplantation. In an immunologically quiescent phase after transplantation, the important question arises whether a small-bowel allograft has enough functional capacity to maintain a normal nutritional status. We investigated the functional capacity of orthotopic small-bowel transplants and evaluated the ability of the total small-bowel transplant to absorb orally given cyclosporin in the early postoperative period and the effect of this oral cyclosporin treatment on allograft survival as compared with intramuscular administration. Between 3 and 7 months postoperatively, recipients of syngeneic and allogeneic total small-bowel transplants and syngeneic jejunal segmental grafts had significantly decreased serum triglyceride levels. Total serum protein and albumin concentrations, serum cholesterol values, fecal fat excretion, and percentage of split fatty acids were normal. One year after transplantation the weight in the groups transplanted with a total small-bowel graft was not different from age-matched untreated controls. Animals grafted with a segmental graft, however, showed a significantly impaired growth and had not reached a normal weight 1 year after transplantation. Growth was also significantly impaired after near-total small-bowel resection. These animals had to be killed because of their poor condition. Cyclosporin absorption after small-bowel transplantation equalled that in normal controls. Graft survival after intramuscular treatment, however, was significantly better than after oral treatment.

Previous studies have shown that lung metastases from a non-immunogenic sarcoma (LS175) in BN (homozygous for RT1n) rats were stimulated by blood transfusions. Enhanced growth was also observed after abdominal surgery combined with allogeneic blood transfusions while syngeneic blood transfusions had no effect. These experimental findings have been confirmed in retrospective clinical studies. The allogeneic blood transfusion effect may be avoided in cancer patients by autologous blood transfusions although this implies blood donation before surgery. The aim of the present study was to investigate the effect of blood loss before surgery on formation (‘take’) of lung colonies, and on the outgrowth of established metastases in the BN rat model. These aspects of tumour behaviour were also investigated in rats undergoing surgery, or receiving blood transfusion, or both, after blood loss. The results indicate that blood loss has a profound stimulating effect on the growth of established metastases, but not on the ‘take’ of tumour cells. This stimulating effect was also present when blood loss was combined with surgery, while previously surgery alone was found to have no effect. Allogeneic and syngeneic transfusions in combination with blood loss both had a strong stimulating effect on growth of established lung metastases. The results indicate that blood loss may be an important factor in determining the outcome of metastatic growth.