Short-term high-fat feeding induces islet macrophage infiltration and ß-cell replication independently of insulin resistance in mice.

Short-term high-fat consumption stimulates mouse islet ß-cell replication through unknown mechanisms. Resident macrophages (MΦs) are capable of secreting various factors involved in islet development and tissue remodeling. We hypothesized that a short-term high-fat diet (HFD) promotes MΦ infiltration in pancreatic islets and that MΦs serve as a regulator of ß-cell replication. To test these hypotheses and dissect mechanisms involved in HFD-induced ß-cell replication, adult C57BL/6J mice were fed a HFD for 7 days with or without administration of clodronate-containing liposomes, an MΦ-depleting agent. Mouse body and epididymal fat pad weights, and nonfasting blood glucose and fasting serum insulin levels were measured, and pancreatic islet ß-cell replication, oxidative stress, and MΦ infiltration were examined. Short-term HFD promoted an increase in body and epididymal fat pad weight and blood glucose levels, along with an increased fasting serum insulin concentration. ß-Cell replication, islet MΦ infiltration, and the percentage of inducible NO synthase positive MΦs in the islets increased significantly in mice fed the HFD. Immunofluorescence staining for 8-oxo-2'-deoxyguanosine or activated caspase-3 revealed no significant induction of DNA damage or apoptosis, respectively. In addition, no change in stromal-derived factor 1-expressing cells was found induced by HFD. Despite continuous elevation of nonfasting blood glucose and fasting serum insulin levels, depletion of MΦs through treatments of clodronate abrogated HFD-induced ß-cell replication. These findings demonstrated that HFD-induced MΦ infiltration is responsible for ß-cell replication. This study suggests the existence of MΦ-mediated mechanisms in ß-cell replication that are independent of insulin resistance.

Transient-mixed Chimerism With Nonmyeloablative Conditioning Does Not Induce Liver Allograft Tolerance in Nonhuman Primates.

BACKGROUND: Although short-term outcomes for liver transplantation have improved, patient and graft survival are limited by infection, cancer, and other complications of immunosuppression. Rapid induction of tolerance after liver transplantation would decrease these complications, improving survival and quality of life. Tolerance to kidneys, but not thoracic organs or islets, has been achieved in nonhuman primates and humans through the induction of transient donor chimerism. Since the liver is considered to be tolerogenic, we tested the hypothesis that the renal transplant transient chimerism protocol would induce liver tolerance. METHODS: Seven cynomolgus macaques received immune conditioning followed by simultaneous donor bone marrow and liver transplantation. The more extensive liver surgery required minor adaptations of the kidney protocol to decrease complications. All immunosuppression was discontinued on postoperative day (POD) 28. Peripheral blood chimerism, recipient immune reconstitution, liver function tests, and graft survival were determined. RESULTS: The level and duration of chimerism in liver recipients were comparable to those previously reported in renal transplant recipients. However, unlike in the kidney model, the liver was rejected soon after immunosuppression withdrawal. Rejection was associated with proliferation of recipient CD8 T effector cells in the periphery and liver, increased serum interleukin (IL)-6 and IL-2, but peripheral regulatory T cell (Treg) numbers did not increase. Antidonor antibody was also detected. CONCLUSIONS: These data show the transient chimerism protocol does not induce tolerance to livers, likely due to greater CD8 T cell responses than in the kidney model. Successful tolerance induction may depend on greater control or deletion of CD8 T cells in this model.

Negative impact of neutrophil-lymphocyte ratio on outcome after liver transplantation for hepatocellular carcinoma.

BACKGROUND: The Milan criteria have been adopted by United Network for Organ Sharing (UNOS) to preoperatively assess outcome in patients with hepatocellular carcinoma (HCC) who receive orthotopic liver transplantation (OLT). These criteria rely solely on radiographic appearances of the tumor, providing no measure of tumor biology. Recurrence rates, therefore, remain around 20% for patients within the criteria. The neutrophil-lymphocyte ratio (NLR) is an indicator of inflammatory status previously established as a prognostic indicator in colorectal liver metastases. We aimed to determine whether NLR predicts outcome in patients undergoing OLT for HCC. DESIGN: Analysis of patients undergoing OLT for HCC between 2001 and 2007 at our institution. A NLR > or =5 was considered to be elevated. RESULTS: : A total of 150 patients were identified, with 13 patients having an elevated NLR. Of these, 62% developed recurrence compared with 14% with normal NLR (P < 0.0001). The disease-free survival for patients with high NLR was significantly worse than that for patients with normal NLR (1-, 3-, and 5-year survivals of 38%, 25%, and 25% vs. 92%, 85%, and 75%, P < 0.0001). Patients with high NLR also had poorer overall survival (5-year survival, 28% vs. 64%, P = 0.001). Patients within Milan with an elevated NLR had significantly poorer disease-free survival than those with normal NLR within Milan (5-year survival, 30% vs. 81%, P < 0.0001). On univariate analysis, 9 factors including an NLR > or =5 were significant predictors of poor disease-free survival. However, only a raised NLR remained significant on multivariate analysis (P = 0.005, HR: 19.98). CONCLUSION: Elevated NLR significantly increases the risk for tumor recurrence and recipient death. Preoperative NLR measurement may provide a simple method of identifying patients with poorer prognosis and act as an adjunct to Milan in determining, which patients benefit most from OLT.

The combined organ effect: protection against rejection?

OBJECTIVES: To further our understanding of the potential protective effects of one organ allograft for another in combined organ transplants by comparing rejection-free survival and the 1-year rejection rate of each type of combined organ transplant. SUMMARY BACKGROUND DATA: Liver allografts have been thought to be immunoprotective of other donor-specific allografts. Recent observations have extended this property to other organs. METHODS: Analysis of data from the United Network of Organ Sharing included recipients 18 years or older (except those receiving intestinal transplants) transplanted between January 1, 1994, and October 6, 2005, and excluded those with a previous transplant (n = 45,306), live-donor transplant (n = 80,850), or insufficient follow-up (n = 4304). Patients were followed from transplant until death (n = 41,524), retransplantation (n = 4649), or last follow-up (n = 87,243). RESULTS: A total of 133,416 patients were analyzed. Rejection rates for allografts co-transplanted with donor-specific primary liver, kidney, and heart allografts are significantly lower than rejection rates for allografts transplanted alone. Allografts accompanying primary intestinal or pancreatic allografts did not have reduced rejection rates. A decreased rate of rejection was seen in interval kidney-heart transplants when allografts shared partial antigenic identity. Decreased rates of rejection were also seen in transplants of 2 donor-specific organs of the same type. CONCLUSIONS: In combined simultaneous transplants, heart, liver, and kidney allografts are themselves protected and protect the other organ from rejection. Analysis of interval heart-kidney allografts suggests the need for partial antigenic identity between organs for the immunoprotection to take effect. This was not demonstrated in interval liver-kidney transplants. Increased antigen load of identical antigens, as seen in double-lung and double-kidney transplants, also offers immunologic protection against rejection.

Routine chest X-ray is unnecessary after ultrasound-guided central venous line placement in the operating room.

BACKGROUND: Central venous catheters (CVC) can be useful for perioperative monitoring and insertion has low complication rates. However, routine post insertion chest X-rays have become standard of care and contribute to health care costs with limited impact on patient management. METHODS: 200 patient charts who underwent pancreaticoduodenectomy with central line placement and early line removal were reviewed for clinical complications related to central line placement as well as radiographic evidence of malpositioning. A cost analysis was performed to estimate savings if CXR had not been performed across routine surgical procedures requiring central access. RESULTS: In 200 central line placements for Whipple procedures, 198 lines were placed in the right internal jugular and 2 were placed in the subclavian. No cases of pneumothorax or hemothorax were identified and 30 (15.3%) of CVCs were improperly positioned. Only 1 (0.5%) of these was deemed clinically significant and repositioned after the CXR was performed. CONCLUSION: Routine CXR consumes valuable time and resources (≅$155,000 annually) and rarely affects management. Selection should be guided by clinical factors.

Islet grafting and imaging in a bioengineered intramuscular space.

BACKGROUND: Because the hepatic portal system may not be the optimal site for islet transplantation, several extrahepatic sites have been studied. Here, we examine an intramuscular transplantation site, bioengineered to better support islet neovascularization, engraftment, and survival, and we demonstrate that at this novel site, grafted beta cell mass may be quantitated in a real-time noninvasive manner by positron emission tomography (PET) imaging. METHODS: Streptozotocin-induced rats were pretreated intramuscularly with a biocompatible angiogenic scaffold received syngeneic islet transplants 2 weeks later. The recipients were monitored serially by blood glucose and glucose tolerance measurements and by PET imaging of the transplant site with [11C] dihydrotetrabenazine. Parallel histopathologic evaluation of the grafts was performed using insulin staining and evaluation of microvasularity. RESULTS: Reversal of hyperglycemia by islet transplantation was most successful in recipients pretreated with bioscaffolds containing angiogenic factors when compared with those who received no bioscaffolds or bioscaffolds not treated with angiogenic factors. PET imaging with [11C] dihydrotetrabenazine, insulin staining, and microvascular density patterns were consistent with islet survival, increased levels of angiogenesis, and with reversal of hyperglycemia. CONCLUSIONS: Induction of increased neovascularization at an intramuscular site significantly improves islet transplant engraftment and survival compared with controls. The use of a nonhepatic transplant site may avoid intrahepatic complications and permit the use of PET imaging to measure and follow transplanted beta cell mass in real time. These findings have important implications for effective islet implantation outside of the liver and offer promising possibilities for improving islet survival, monitoring, and even prevention of islet loss.

A case of portal venous gas after extracorporeal shockwave lithotripsy and obstructive pyelonephritis.

The presence of gas in the portal venous system is considered an ominous sign often mandating immediate exploratory laparotomy; however, there are numerous reports of benign incidences of this finding. This report describes a case of portal venous gas after extracorporeal shockwave lithotripsy. The patient had the rare complication of obstructive pyleonephritis that progressed to sepsis and subsequently underwent a negative exploratory laparotomy. It is suggested that the radiographic finding of portal venous gas should be correlated with the likely cause and overall clinical picture.