Urs P Steinbrecher

Government of British Columbia, Canada, Vancouver, British Columbia, Canada

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Publications (101)495.02 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Endoscopic therapy has been successful in the management of biliary complications after both deceased donor liver transplantation (DDLT) and living donor liver transplantation (LDLT). LDLT is thought to be associated with higher rates of biliary complications, but there are few studies comparing the success of endoscopic management of anastomotic strictures between the two groups. This study aims to compare our experience in the endoscopic management of anastomotic strictures in DDLT versus LDLT. This is a retrospective database review of all liver transplant patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) after liver transplantation. The frequency of anastomotic stricture and the time to develop and to resolve anastomotic stricture were compared between DDLT and LDLT. The response of anastomotic stricture to endoscopic therapy was also analyzed. A total of 362 patients underwent liver transplantation between 2003 and 2011, with 125 requiring ERCP to manage biliary complications. Thirty-three (9.9%) cases of DDLT and 8 (27.6%) of LDLT (P=0.01) were found to have anastomotic stricture. When comparing DDLT and LDLT, there was no difference in the mean time to the development of anastomotic strictures (98+/-17 vs 172+/-65 days, P=0.11), likelihood of response to ERCP [22 (66.7%) vs 6 (75.0%), P=0.69], mean time to the resolution of anastomotic strictures (268+/-77 vs 125+/-37 days, P=0.34), and the number of ERCPs required to achieve resolution (3.9+/-0.4 vs 4.7+/-0.9, P=0.38). Endoscopic therapy is effective in the majority of biliary complications relating to liver transplantation. Anastomotic strictures occur more frequently in LDLT compared with DDLT, with equivalent endoscopic treatment response and outcomes for both groups.
    Hepatobiliary & pancreatic diseases international: HBPD INT 10/2013; 12(5):488-493. · 1.17 Impact Factor
  • John C T Wong, Urs P Steinbrecher
    Gastroenterology 07/2013; · 12.82 Impact Factor
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    ABSTRACT: 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. To date, however, the experience with protease inhibitors in this condition is unreported. We report a post-liver transplant recipient with HCV associated FCH treated successfully with boceprevir, peginteferon and ribavirin for severe FCH. The patient was young woman who was a null responder pre-transplant to peginterferon and ribavirin. The peak serum bilirubin 391 μmol/L normalized to 15 μmol/L by week 8 of therapy. The pre-treatment HCV viral load of > 78 million IU/mL, decreased to 78 IU/mL at week 8 of therapy and was undetectable by week 12 and at the end of 48 week of treatment. 12 weeks post treatment, the HCV viral load remains undetectable. Significant anemia and neutropenia were encountered. Tacrolimus dosage titrated to trough levels, required marked reduction to 0.5 mg three times weekly. Despite the suboptimal peginterferon and ribavirin dosing, limited by adverse effects, full boceprevir dosing was maintained, with resolution of liver dysfunction. Boceprevir was obtained on compassionate grounds from the manufacturer before its licensure in Canada and this was the first use of boceprevir in the world for post-transplant FCH.
    Annals of hepatology: official journal of the Mexican Association of Hepatology 01/2013; 12(1):156-60. · 2.19 Impact Factor
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    ABSTRACT: 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. We describe here a patient with a novel APOB mutation, V703I, which appears to contribute to the severity of the FHBL phenotype. He had liver enzyme abnormalities, increased echogenicity of the liver consistent with steatosis, very low LDL cholesterol at 0.24 mmol/l (normal 1.8-3.5 mmol/l) and an extremely low apolipoprotein B level of 0.16 g/l (normal 0.6-1.2 g/l). APOB gene sequencing revealed him to be a compound heterozygote with two mutations (R463W and V703I). APOB R463W has previously been reported to cause FHBL. Genetic sequencing of his first-degree relatives identified the APOB V703I mutation in his normolipidemic brother and father and the APOB R463W mutation in his mother and sister, both of whom have very low LDL cholesterol levels. These results suggest that the APOB V703I mutation alone does not cause the FHBL phenotype. However, it is possible that it has a contributory role to a more aggressive phenotype in the presence of APOB R463W.
    Case Reports in Gastroenterology 01/2012; 6(2):429-37.
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    ABSTRACT: 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. We found that both the modified lipid and the modified protein components of oxLDL can increase the viability of macrophages. The key modification appeared to involve derivatization of amino groups in apoB or in phosphatidylethanolamine by lipid peroxidation products. These reactive oxidation products were primarily unfragmented hydroperoxide- or endoperoxide-containing oxidation products of linoleic acid or arachidonic acid. LC-MS/MS studies showed that some of the arachidonic acid-derived lysine adducts were isolevuglandins that contain lactam and hydroxylactam rings. MS/MS analysis of linoleic acid autoxidation adducts was consistent with 5- or 6-membered nitrogen-containing heterocycles derived from unfragmented oxidation products. The amine modification by oxidation products generated a fluorescence pattern with an excitation maximum at 350nm and emission maximum at 430nm. This is very similar to the fluorescence spectrum of copper-oxidized LDL.
    Free Radical Biology and Medicine 09/2011; 51(10):1926-36. · 5.27 Impact Factor
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    ABSTRACT: 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. We have previously shown that oxLDL activates prosurvival signalling pathways such as the phosphoinositide 3-kinase (PI3K) pathway in bone marrow derived macrophages (BMDMs). However, little is known about more upstream signalling events especially at the receptor level. The endocytic pattern recognition receptors (PRRs), scavenger receptor A (SR-A) and CD36, are the main receptors on macrophages for uptake of oxLDL and are therefore important in foam cell formation. The signalling PRRs such as toll-like receptor (TLR) 2 and 4 also bind some types of oxLDL. This study was done to determine if any of the known PRRs are required for the anti-apoptotic effects of oxLDL in BMDMs. To do this, we tested the effect of oxLDL on viability of BMDMs lacking both SR-A and CD36 or lacking TLR2, TLR4, CD14, FcγRIIb, or RAGE. Our results indicate that none of these receptors are essential for activating the oxLDL prosurvival pathway. Furthermore, we show that the anti-apoptotic effect is not dependent on the uptake of oxLDL.
    Biochemistry and Cell Biology 08/2011; 89(4):387-95. · 2.35 Impact Factor
  • Ellick Pau, Yi He, Marilee Lougheed, Urs P. Steinbrecher
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    ABSTRACT: It is believed that the major mechanisms by which hydroxymethylglutaryl coenzyme A reductase inhibitors lower plasma cholesterol levels are by inducing hepatic low-density lipoprotein (LDL) receptor activity and by decreasing apolipoprotein B (apoB) secretion by the liver. However, the intestine is also an important cholesterogenic organ and the possibility that this class of drugs may alter lipoprotein secretion by the intestine has not been fully studied. The purpose of the present study was to examine the possible role of cholesterol in regulating apoB secretion by the intestine by testing if the suppression of cholesterol synthesis by the reductase inhibitor lovastatin affected the secretion of apoB by CaCo-2 human intestinal cells. Differentiated post-confluent CaCo-2 cells were incubated for 24-72 h in serum-free medium in the presence or absence of 5 microM lovastatin, and the secretion rate of lipids, as well as apoB and apolipoprotein AI (apoAI) into the medium, was measured. Lovastatin markedly inhibited the incorporation of [1-14C]acetate into cholesterol for at least 48 h, lowered the content of esterified cholesterol in cells, and reduced their rate of cholesterol secretion. However, under basal conditions lovastatin had no effect on the secretion rate of apoB. After stimulation of apoB secretion by addition of 0.8 mM oleic acid to the medium, lovastatin did not alter apoB secretion in the first 2 days of incubation, but reduced the content of apoB in media from the 3rd day by 30%. This could not be explained by an increase in the rate of LDL degradation. Furthermore, supplementation with mevalonic acid only reversed about one-half of the effect of lovastatin, suggesting that this effect was at least parly nonspecific or unrelated to inhibition of cholesterol biosynthesis. There was also no specific effect of lovastatin on apoAI secretion. When cells were cultured with [1-14C]acetate for 24 or 72 h, the specific activity of cholesterol in medium at the end of the incubation was the same as in cells, suggesting that cholesterol used for lipoprotein secretion was in equilibrium with bulk cellular cholesterol and was not from a segregated compartment derived from newly synthesized cholesterol. This may explain why apoB secretion by CaCo-2 cells was unaffected by inhibition of cholesterol synthesis with lovastatin.
    Biochemistry and Cell Biology 01/2011; 73(1-2):81-90. · 2.35 Impact Factor
  • Chemistry and Physics of Lipids 08/2010; 163:S13–S14. · 2.59 Impact Factor
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    ABSTRACT: 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. To identify factors that predict the recurrence of harmful alcohol consumption after LT. A total of 80 patients who underwent LT for alcoholic cirrhosis or had significant alcohol consumption in association with another primary liver disease, from July 1992 to June 2006 in British Columbia, were retrospectively evaluated by chart review. Several demographic-, psychosocial- and addiction-related variables were studied. Univariate and multivariate logistic regression analyses were used to test possible associations among the variables studied and a return to harmful drinking after LT. The relapse rate of harmful alcohol consumption post-liver transplant was 10%, with two patient deaths occurring directly as a result of alcohol relapse. Univariate analysis revealed relapse was significantly associated with pretransplant abstinence of less than six months (P=0.003), presence of psychiatric comorbidities (P=0.016), female sex (P=0.019) and increased personal stressors (P=0.044), while age at transplant of younger than 50 years approached significance (P=0.054). Multivariate logistic regression analysis revealed the following independent factors for relapse: pretransplant abstinence of less than six months (OR 77.07; standard error 1.743; P=0.013) and female sex (OR 18.80; standard error 1.451; P=0.043). The findings of the present study strongly support a required minimum of six months of abstinence before LT because duration of abstinence was found to be the strongest predictor of recidivism. Female sex, younger age at transplant and psychiatric comorbidities were also associated with relapse to harmful drinking.
    Canadian journal of gastroenterology = Journal canadien de gastroenterologie 04/2010; 24(4):245-50. · 1.97 Impact Factor
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    ABSTRACT: To evaluate the survival benefit of multimodal therapy for the treatment of HCC. 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). This study was performed to evaluate the survival benefit of multimodal therapy for treatment of HCC as complementary therapy to OLT. A retrospective review was conducted of HCC patients undergoing therapy following multidisciplinary review at our institution from 1996 . 2006 with a minimum of a 2 year patient follow-up. Data were available on 247/252 patients evaluated. Relevant factors at time of diagnosis included symptoms, hepatitis B (HBV) and C (HCV) status, antiviral therapy, Child-Pugh classification, portal vein patency, and TNM staging. Patients underwent primary treatment by hepatic resection, RFA, EI, TACE, CTX, or were observed (best medical management). Patients with persistent or recurrent disease following initial therapy were assessed for salvage therapy. Survival curves and pairwise multiple comparisons were calculated using standard statistical methods. Mean overall survival was 76.8 months. Pairwise comparisons revealed significant mean survival benefits with hepatic resection (93.2 months), RFA (66.2 months), and EI (81.1 months), compared with TACE (47.4 months), CTX (24.9 months), or observation (31.4 months). Shorter survival was associated with symptoms, portal vein thrombus, or Child-Pugh class B or C. HCV infection was associated with significantly shorter survival compared with HBV infection. Antiviral therapy was associated with significantly improved survival in chronic HBV and HCV patients only with earlier stage disease. Multimodal therapy is effective therapy for HCC and may be used as complementary treatment to OLT.
    Annals of hepatology: official journal of the Mexican Association of Hepatology 01/2010; 9(1):23-32. · 2.19 Impact Factor
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    ABSTRACT: 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. In this study, we show that these oscillations are mediated in part by intracellular mechanisms, as depleting extracellular Ca(2+) did not completely abolish the effect. Inhibiting sarco-endoplasmic reticulum ATPase (SERCA) completely blocked [Ca(2+)](i) oscillations, suggesting a role for Ca(2+) reuptake by the ER. The addition of oxLDL resulted in an almost immediate activation of sphingosine kinase (SK), which can increase sphingosine-1-phosphate (S1P) levels by phosphorylating sphingosine. Moreover, S1P was shown to be as effective as oxLDL in blocking macrophage apoptosis and producing [Ca(2+)](i) oscillations. This suggests that the mechanism in which oxLDL generates [Ca(2+)](i) oscillations may be 1) activation of SK, 2) SK-mediated increase in S1P levels, 3) S1P-mediated Ca(2+) release from intracellular stores, and 4) SERCA-mediated Ca(2+) reuptake back into the ER.
    The Journal of Lipid Research 11/2009; 51(5):991-8. · 4.73 Impact Factor
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    ABSTRACT: 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. This is believed to be the first reported case in the literature in which an adult patient with fulminant hepatic failure associated with acute parvovirus B19 infection and without hematologic abnormalities has been identified prior to undergoing liver transplantation. This case suggests that Parvovirus B19 induced liver disease can affect adults, can occur in the absence of hematologic abnormalities and can be severe enough to require liver transplantation.
    World Journal of Gastroenterology 09/2009; 15(32):4067-9. · 2.43 Impact Factor
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    ABSTRACT: 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. We used mice with targeted inactivation of the LOX-1 gene to define the role of this receptor in the uptake of oxLDL and in activation of survival pathways. There was no difference in uptake or degradation of 125I-oxLDL in unstimulated macrophages from wild-type and LOX-1 knockout mice and no difference in the rate of clearance of oxLDL from plasma in vivo. However, when expression of LOX-1 was induced with lysophosphatidylcholine, oxLDL uptake and degradation increased 2-fold in wild-type macrophages but did not change in LOX-1 knockout macrophages. Macrophages lacking LOX-1 showed the same stimulation of PKB phosphorylation and enhancement of survival by oxLDL as wild-type cells. These data show that LOX-1 does not alter the uptake of oxLDL in unstimulated macrophages and is not essential for the pro-survival effect of oxLDL in these cells. However, LOX-1 expression is highly inducible by lysophosphatidylcholine and pro-inflammatory cytokines, and if that occurred in macrophages within atheromas, LOX-1 could substantially increase oxLDL uptake by lesion macrophages.
    The Journal of Lipid Research 05/2009; 50(8):1676-84. · 4.73 Impact Factor
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    ABSTRACT: 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. To determine the effect of obesity on outcome we reviewed 167 liver transplants, performed at the Vancouver General Hospital, between February 1999 and October 2003. Severe obesity was defined as body mass index (BMI) > 35 kg/m2 and moderate obesity as BMI of 30 - 34 kg/m2. One hundred forty three transplants were performed in patients with a body mass index (BMI) < 30 kg/m2, 14 in patients with a BMI of 30 - 34 kg/m2, and 10 in patients with a BMI > 35 kg/m2. Non-weight related patient demographics were similar between the groups. A very high proportion of Hepatitic C patients (7/10) were observed in the severely obese group. In the early postoperative course severely obese patients had a higher rate of wound infection (20% vs. 4%, p = 0.0001) and wound dehiscence (40% vs. 1.2%, p = 0.0001). Within the first twelve postoperative months severely obese liver transplant recipients had a higher rate of ventral wound herniation (30% vs. 2.8%, p = 0.0001) when compared to obese or non-obese recipients. The one-year graft and patient survival were similar to non-obese patients. An increased BMI in liver transplant recipients in our centre did not increase the risk of early postoperative mortality, but did increase surgical complications, such as wound infection and wound dehiscence. The 1-year patient and graft survival however was indistinguishable from those of non-obese patients.
    Annals of hepatology: official journal of the Mexican Association of Hepatology 01/2009; 8(1):38-40. · 2.19 Impact Factor
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    ABSTRACT: 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. OxLDL, but not native LDL (nLDL), induces an immediate and oscillatory increase in intracellular calcium ([Ca(2+)](i)). We also show that the calcium/calmodulin dependent kinase, eukaryotic elongation factor-2 kinase (eEF2 kinase), is activated in response to oxLDL, an effect that can be blocked by inhibiting calcium mobilization. Furthermore, selective inhibition of eEF2 kinase reverses the prosurvival effect of oxLDL and results in cellular apoptosis. p38 MAP kinase, a negative regulator of eEF2 kinase, is activated on growth factor withdrawal, a response that can be inhibited by oxLDL. Finally, we show that oxLDL, by activating eEF2 kinase, phosphorylates and therefore inhibits eEF2, resulting in an overall decrease in protein synthesis. These results indicate a novel signaling pathway in which oxLDL can block macrophage apoptosis by mobilizing calcium and activating eEF2 kinase.
    Arteriosclerosis Thrombosis and Vascular Biology 12/2008; 29(1):92-8. · 6.34 Impact Factor
  • Maziar Riazy, Johnny H Chen, Urs P Steinbrecher
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    ABSTRACT: 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. The murine leukemia-derived RAW 264.7 macrophage cell line as well as mouse peritoneal macrophages and human monocyte-derived macrophages were used in these studies. Cells were exposed to native low-density lipoprotein (LDL), acetylated LDL, and LDL that had been modified by oxidation with copper or ferrous ions or by exposure to auto-oxidation products of arachidonic acid for 16h, and VEGF was then assayed in medium. Pharmacological inhibitors of phosphatidylinositol 3-kinase (PI3K) or PKCzeta blocked VEGF secretion by OxLDL. Inhibitors of other protein kinase C (PKC) subtypes had no effect, and neither did inhibitors of mitogen activated protein kinase kinase (MAPKK). We found that LDL with oxidative modification of either its lipid or protein component can induce VEGF expression. Higher degrees of oxidation of LDL conferred higher potency to induce VEGF. Macrophages from mice lacking both scavenger receptors A (SR-A) and CD36 were fully responsive to OxLDL with regard to VEGF secretion. These macrophages show an 85% reduction in OxLDL uptake compared to macrophages from wild-type mice. Macrophages from mice lacking LOX-1 were also fully responsive to oxLDL with regard to VEGF secretion. We conclude that VEGF upregulation is mediated through PI3K and PKCzeta, and does not involve the above three scavenger receptors or require uptake of oxidized LDL.
    Atherosclerosis 09/2008; 204(1):47-54. · 3.71 Impact Factor
  • Annals of hepatology: official journal of the Mexican Association of Hepatology 08/2008; 7(3):257. · 2.19 Impact Factor
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    ABSTRACT: 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). Selective inhibition of PI3-K blocked both DNA synthesis and cell growth. C1P induced phosphorylation of GSK-3beta, which is a major target of PKB, and this effect was also abolished by inhibition of PI3-K. In addition, C1P upregulated the expression of cyclin D1 and c-Myc, two major targets of GSK-3beta, which are important regulators of cell proliferation. C1P stimulated the activity of NF-kappaB, and inhibitors of this transcription factor completely blocked macrophage proliferation. Lastly, C1P induced phosphorylation of the mitogen activated protein kinases (MAPK) extracellularly regulated kinases 1 and 2 (ERK1/2), and c-Jun N-terminal kinase (JNK). Inhibition of ERK1/2 and JNK also blocked C1P-induced macrophage proliferation. It can be concluded that C1P stimulates macrophage proliferation through activation of the PI3-K/PKB, ERK and JNK pathways, and that GSK-3beta, c-Myc, cyclin D1, and NF-kappaB are important downstream effectors in this action.
    Cellular Signalling 05/2008; 20(4):726-36. · 4.47 Impact Factor
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    P T Kim, J E Davis, S R Erb, E M Yoshida, U P Steinbrecher
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    ABSTRACT: Malakoplakia is a rare inflammatory condition seen in transplant patients. There are two previously reported cases of malakoplakia involving the gastrointestinal tract in liver transplant patients. The present paper reports a case of colonic malakoplakia in a 58-year-old woman, a liver transplant recipient who was receiving immunosuppressive drugs. She presented with chronic diarrhea while on tacrolimus. There was no history of antecedent infection. Colonoscopy showed patchy mucosal edema, but no discrete yellow plaques or nodules. The diagnosis was made by colon biopsies, which showed chronic inflammation with many histiocytes containing Michaelis-Gutmann bodies. Although rare, malakoplakia is one of many potential causes of diarrhea in a transplant patient. The present case indicates that malakoplakia may be associated with chronic diarrhea, even if there are no macroscopic lesions seen during colonoscopy.
    Canadian journal of gastroenterology = Journal canadien de gastroenterologie 12/2007; 21(11):753-5. · 1.97 Impact Factor
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    ABSTRACT: 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. We used pertussis toxin (PTX) to test whether G protein coupled receptors are activated by oxLDL. PTX is a bacterial toxin that inhibits Gi activation by ADP-ribosylating the alpha subunit of Gi, preventing the subunit from interacting with receptors. Unexpectedly, we found that PTX by itself selectively blocks macrophage apoptosis in a dose-dependent manner. PTX acts in part by inhibiting acid sphingomyelinase activity which in turn prevents generation of ceramide, which is required for macrophage apoptosis. A Gi activator peptide, mastoparan, increased ceramide levels in macrophage and induced apoptosis, but pre-treatment with PTX partially overrode mastoparan-induced apoptosis. The anti-apoptotic effect of PTX was found to require ADP-ribosylation. PTX failed to prevent A-SMase activation or apoptosis in macrophages lacking TLR4. The anti-apoptotic effect of PTX involved the same signaling pathways as those of oxidized LDL, in that both inhibited acid sphingomyelinase, and activated the phosphoinositide 3 kinase (PI3K)/protein kinase B (PKB) pathway which leads to nuclear localization of the transcription factor NFkappaB and up-regulation of Bcl-XL. These results indicate that Gi proteins, TLR4, A-SMase and the PI3K/PKB pathway are crucial components for regulation of macrophage apoptosis.
    Cellular Signalling 09/2007; 19(8):1772-83. · 4.47 Impact Factor

Publication Stats

6k Citations
495.02 Total Impact Points


  • 2013
    • Government of British Columbia, Canada
      Vancouver, British Columbia, Canada
  • 2005–2013
    • Vancouver General Hospital
      • Division of Gastroenterology (UBC)
      Vancouver, British Columbia, Canada
  • 1989–2012
    • University of British Columbia - Vancouver
      • • Division of Gastroenterology
      • • Department of Medicine
      • • Department of Anesthesiology, Pharmacology and Therapeutics
      Vancouver, British Columbia, Canada
  • 2006–2010
    • Columbia University
      • Department of Medicine
      New York City, NY, United States
  • 2001–2005
    • Universidad del País Vasco / Euskal Herriko Unibertsitatea
      • • Biochemistry and Molecular Biology
      • • Medicine
      Leioa, Basque Country, Spain
  • 1984–1985
    • University of California, San Diego
      • • Department of Medicine
      • • Division of Endocrinology & Metabolism
      San Diego, CA, United States