Regulation of ceramide generation during macrophage apoptosis by ASMase and de novo synthesis.

The survival of macrophages depends on the presence of specific cytokines that activate survival signaling events, as well as suppressing formation of apoptosis-inducing pathways. We have previously shown that macrophages deprived of macrophage colony stimulating factor (M-CSF) produce ceramide that contributes to apoptosis of these cells, a pathway that is suppressed by exposure to oxidized LDL. In this study we have examined macrophages derived from mice lacking acid sphingomyelinase (ASMase) to ask whether these events are altered due to the impaired ability of these cells to break down sphingomyelin and produce ceramide.

First successful treatment of post-liver transplant hepatitis C fibrosing cholestatic hepatitis with boceprevir, peginterferon and ribavirin in a pre-transplant null responder.

Fibrosing cholestatic hepatitis (FCH) is a less common but well-recognized severe complication of recurrent hepatitis C virus (HCV) infection post-liver transplant. This condition is fatal without successful treatment and to date; post-transplant antiviral interferon-based antiviral therapy has been associated with guarded success. The new era of protease inhibitors in the treatment of chronic HCV infection may alter the dismal outcome of this condition.

Familial hypobetalipoproteinemia-induced nonalcoholic steatohepatitis.

Familial hypobetalipoproteinemia (FHBL) is a rare genetic disorder of lipid metabolism that is associated with abnormally low serum levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein B. It is an autosomal co-dominant disorder, and depending on zygosity, the clinical manifestations may vary from none to neurological, endocrine, hematological or liver dysfunction. Nonalcoholic fatty liver disease is common in persons with FHBL, however progression to nonalcoholic steatohepatitis is unusual.

Fluorescent adducts formed by reaction of oxidized unsaturated fatty acids with amines increase macrophage viability.

Macrophages are prominent components of human atherosclerotic lesions and they are believed to accelerate the progression and/or complications of both early and advanced atherosclerotic lesions. We and others have shown that oxidized low-density lipoprotein (oxLDL) induces growth and inhibits apoptosis in murine bone marrow-derived macrophages. In this study, we sought to characterize the oxidative modification of LDL that is responsible for this prosurvival effect.

OxLDL-mediated survival of macrophages does not require LDL internalization or signalling by major pattern recognition receptors.

Macrophages play a key role in the pathogenesis of atherosclerosis, in part by destabilizing plaques. We and others have shown that low concentrations of oxidized LDL (oxLDL) inhibit macrophage apoptosis. As oxLDL is present in lesions, this may be a mechanism by which macrophage populations in the intima are expanded.

Spontaneous clearance of hepatitis C infection post-liver transplant: A rare but real phenomenon? A case report and review of the literature.

Recurrent hepatitis C virus (HCV) infection after liver transplantation is a significant cause of morbidity, mortality and graft loss. Spontaneous clearance of recurrent HCV after liver transplant is a rarely reported phenomenon. We report a case of a 66-year-old woman who underwent liver transplantation for HCV cirrhosis (treatment- naive genotype 2) under immunosuppression with tacrolimus, mycophenolate mofetil (MMF), and short-term corticosteroids.

Predictors of relapse to significant alcohol drinking after liver transplantation.

Background: End-stage alcoholic liver disease is common, with many of these patients referred for liver transplantation (LT). Alcohol relapse after LT can have detrimental outcomes such as graft loss and can contribute to a negative public perception of LT.

Objective: To identify factors that predict the recurrence of harmful alcohol consumption after LT.

Multimodal therapy for hepatocellular carcinoma: a complementary approach to liver transplantation.

Objective: To evaluate the survival benefit of multimodal therapy for the treatment of HCC.

Background: Orthotopic liver transplantation (OLT) is considered the treatment of choice for selected patients with hepatocellular carcinoma (HCC). However, donor organ shortages and patients whose HCCs exceed OLT criteria require consideration of alternate therapeutic options such as hepatic resection, radiofrequency ablation (RFA), ethanol injection (EI), transarterial chemoembolization (TACE), and chemotherapy (CTX).

Late acute celiac and hepatic artery thrombosis with portal vein thrombosis resulting in hepatic infarction 12 years post orthotopic liver transplantation.

Hepatic artery thrombosis (HAT) is relatively infrequent, but possibly a devastating complication of orthotopic liver transplantation (OLT). It often requires urgent retransplantation. Two main forms of HAT are recognized as early and late HAT (diagnosis within or after 30 days following LT).

Sphingosine kinase regulates oxidized low density lipoprotein-mediated calcium oscillations and macrophage survival.

We recently reported that oxidized LDL (oxLDL) induces an oscillatory increase in intracellular calcium ([Ca(2+)](i)) levels in macrophages. Furthermore, we have shown that these [Ca(2+)](i) oscillations mediate oxLDL's ability to inhibit macrophage apoptosis in response to growth factor deprivation. However, the signal transduction pathways by which oxLDL induces [Ca(2+)](i) oscillations have not been elucidated.

Parvovirus B19 induced hepatic failure in an adult requiring liver transplantation.

Parvovirus B19 induced acute hepatitis and hepatic failure have been previously reported, mainly in children. Very few cases of parvovirus induced hepatic failure have been reported in adults and fewer still have required liver transplantation. We report the case of a 55-year-old immunocompetent woman who developed fulminant hepatic failure after acute infection with Parvovirus B19 who subsequently underwent orthotopic liver transplantation.

LOX-1 augments oxLDL uptake by lysoPC-stimulated murine macrophages but is not required for oxLDL clearance from plasma.

Oxidized LDL (oxLDL) promotes lipid accumulation as well as growth and survival signaling in macrophages. OxLDL uptake is mainly due to scavenger receptors SR-AI/II and CD36. However, other scavenger receptors such as lectin-like oxLDL receptor-1 (LOX-1) may also play a role.

Surgical morbidity in severely obese liver transplant recipients - a single Canadian Centre Experience.

The prevalence of obesity is increasing globally, with nearly half of a billion of the world's population now considered to be overweight or obese. Obesity and overweight patients are one of the major health issues in Canada, resulting in approximately 57,000 deaths related to obesity over the last 15 years. The effect of obesity on outcomes following liver transplantation remains largely unclear.

Mycophenolate mofetil in liver transplant patients with calcineurin-inhibitor-induced renal impairment.

Background: Calcineurin inhibitors (CNIs) provide effective immunosuppression after orthotopic liver transplantation (OLTx), but the associated nephrotoxicity can cause substantial morbidity and mortality among transplant patients. In this study, we retrospectively investigated the efficacy and safety of mycophenolate mofetil (MMF) in OLTx patients with CNI-induced renal impairment.

Patients & Methods: A chart review was undertaken of all liver transplant recipients followed at the Vancouver General Hospital.

Oxidized LDL-mediated macrophage survival involves elongation factor-2 kinase.

Objective: Macrophage survival and proliferation is believed to be a contributing factor in the development of early atherosclerotic lesions. Oxidized low density lipoprotein (oxLDL), a key mediator in the pathogenesis of this disease, has been shown to block apoptosis in macrophages deprived of growth factor. In this report, we investigate the mechanism of oxLDL-mediated macrophage survival.

VEGF secretion by macrophages is stimulated by lipid and protein components of OxLDL via PI3-kinase and PKCzeta activation and is independent of OxLDL uptake.

Oxidized LDL (OxLDL) is thought to play a role in the pathogenesis of early as well as advanced stages of atherosclerosis. One possible mechanism involves local upregulation of pro-inflammatory cytokines such as vascular endothelial growth factor (VEGF). This study was done to define the mechanism by which OxLDL increases secretion of VEGF in macrophages.

Ceramide 1-phosphate stimulates macrophage proliferation through activation of the PI3-kinase/PKB, JNK and ERK1/2 pathways.

Ceramide 1-phosphate (C1P) was first shown to be mitogenic for fibroblasts, but the mechanisms whereby it stimulated cell proliferation have remained largely unknown. Here we demonstrate that C1P stimulates DNA synthesis and cell division in murine bone marrow-derived macrophages. C1P caused rapid phosphorylation of protein kinase B (PKB, also known as Akt), a downstream target of phosphatidylinositol 3-kinase (PI3-K).

Pertussis toxin promotes macrophage survival through inhibition of acid sphingomyelinase and activation of the phosphoinositide 3-kinase/protein kinase B pathway.

Apoptosis is an important mechanism involved in regulating the number of macrophages present at sites of inflammation. Several lines of evidence indicate that blocking macrophage apoptosis can increase atherosclerosis. We previously reported that oxidized LDL can inhibit apoptosis in cultured bone marrow-derived macrophages.

Spatulated end-to-end bile duct reconstruction in orthotopic liver transplantation.

Biliary complications continue to be a major source of morbidity following orthotopic liver transplantation. The aim of this study was to analyze the incidence and management of biliary complications related to the technique of bile duct reconstruction. The patients were stratified into two groups: group I (n = 39) had bile duct reconstruction performed by an end-to-end single interrupted suture choledochocholedochostomy (EE-CDCD) and group II (n = 38) had a spatulated end-to-end CDCD (spEE-CDCD) reconstruction; both groups had an intraductal stent.

Epithelioid angiosarcoma of the small bowel.

Background: Angiosarcoma is a rare soft-tissue neoplasm that occurs most often in the skin and the subcutaneous tissues but very rarely in the GI tract.

Design: We report a case of multifocal epithelioid angiosarcoma involving skin and bowel and review the 18 previously reported cases of epithelioid intestinal angiosarcoma.

Main Outcome Measurements: Our patient presented with weakness from anemia.

Subcutaneous administration of hepatitis B immune globulin in combination with lamivudine following orthotopic liver transplantation: effective prophylaxis against recurrence.

Prophylaxis against recurrent hepatitis B virus (HBV) infection with hepatitis B immune globulin (HBIG), in combination with antiviral agents such as lamivudine, has allowed transplantation for this condition to become feasible and accepted. Current protocols allow for HBIG administration either intravenously or intramuscularly. To date, there has been no reported experience with the subcutaneous route of post-transplant HBIG delivery.