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Biomedical subjects

Bruce R Bacon

Publications and source records attributed to Bruce R Bacon.

At least 19 recordsLinked to original sources
PubMed2006

Coordinate activation of intracellular signaling pathways by insulin-like growth factor-1 and platelet-derived growth factor in rat hepatic stellate cells.

Proliferation of activated hepatic stellate cells (HSC) is an important event in the development of hepatic fibrosis. Insulin-like growth factor-1 (IGF-1) has been shown to be mitogenic for HSC, but the intracellular signaling pathways involved have not been fully characterized. Thus, the aims of the current study were to examine the roles of the extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3-K) and p70-S6 kinase (p70-S6-K) signaling pathways in IGF-1- and platelet-derived growth factor (PDGF)-induced mitogenic signaling of HSC and to examine the potential crosstalk between these pathways. Both IGF-1 and PDGF increased ERK, PI3-K and p70-S6-K activity. When evaluating potential crosstalk between these signaling pathways, we observed that PI3-K is required for p70-S6-K activation by IGF-1 and PDGF, and is partially responsible for PDGF-induced ERK activation. PDGF and IGF-1 also increased the levels of cyclin D1 and phospho-glycogen synthase kinase-3beta. Coordinate activation of ERK, PI3-K and p70-S6-K is important for perpetuating the activated state of HSC during fibrogenesis.

Animals↗
PubMed2006

Splenectomy for thrombocytopenia in patients with hepatitis C cirrhosis.

BACKGROUND: Many patients with hepatitis C cirrhosis and low Model for End-Stage Liver Disease scores are too early for transplant but too thrombocytopenic to treat with interferon. GOAL: To report a case series of splenectomy to raise platelet counts so that pegylated interferon and ribavirin can be given in patients with hepatitis C cirrhosis. METHODS: Retrospective chart and computer record review. RESULTS: Seven patients with hepatitis C cirrhosis (mean age=45.4+/-11.1 y, 4 men) had elective splenectomy for thrombocytopenia before pegylated interferon-alpha 2b therapy. All had thrombocytopenia contraindicating antiviral therapy. Five were Child's-Pugh Class A; 2 were B. All 7 had increases in platelet count (mean 32,400 to 222,140 /mL, P<0.01) at 221+/-151 days postsurgery. Median hospital stay and blood loss were 9 days (4 to 25) and 750 mL (100 to 2500 mL). Median platelet packs, units of packed red blood cells and fresh frozen plasma given were 1 (0 to 7), 0 (0 to 14) and 0 (0 to 2), respectively. There were no deaths or portal vein thrombosis. One patient who was status-post liver transplantation had significant morbidity. Five completed pegylated interferon-alpha 2b and ribavirin therapy; 1 is on therapy and 1 awaits initiation. Of the 5 who completed therapy, there were 2 with sustained virologic response, 1 nonresponse, 1 breakthrough, and 1 relapse. CONCLUSIONS: Splenectomy in patients with hepatitis C cirrhosis can be done safely to allow application of antiviral treatment and potentially avoid transplantation. It may be considered in patients with Child's-Pugh A cirrhosis, no prior abdominal surgeries and with non-1 HCV viral genotype.

Adult↗
PubMed2006

Differential findings for CD14-positive hepatic monocytes/macrophages in primary biliary cirrhosis, chronic hepatitis C and nonalcoholic steatohepatitis.

BACKGROUND AND AIMS: Endotoxin-responsive monocytes/macrophages (CD14-positive) are potential sources of profibrogenic factors. The aims of this study were to determine (1) whether hepatic CD14-positive cells are present in various forms of chronic liver disease, and (2) the relationship between CD14-positive cells, myofibroblasts, and fibrosis in these diseases. METHODS: Liver specimens from control subjects (n = 12) and those with primary biliary cirrhosis (n = 18), chronic hepatitis C (n = 13), or nonalcoholic steatohepatitis (n = 13) were immunostained for CD14, CD68, and alpha-smooth muscle actin (SMA) and the number of cells expressing these antigens was determined. Fibrosis and inflammation were also assessed. RESULTS: The total number of hepatic CD68-positive cells was similar in diseased and control livers. The number of CD14-positive cells was increased in advanced fibrosis in primary biliary cirrhosis and hepatitis C but not in nonalcoholic steatohepatitis. The number of CD14-positive cells was also increased in hepatitis C specimens with high inflammatory activity. CD14-positive cells were often associated with alpha-SMA-positive myofibroblasts in fibrous septa. CONCLUSIONS: The number of hepatic CD14-positive cells is increased in advanced fibrosis in subjects with primary biliary cirrhosis and hepatitis C but not in nonalcoholic steatohepatitis. In primary biliary cirrhosis and hepatitis C, CD14-positive macrophages are found in close proximity to fibrous septa and myofibroblasts. In hepatitis C, an increased number of CD14-positive cells are associated with high inflammatory activity.

Biopsy↗
PubMed2005

Survival after liver transplantation in patients with hepatic iron overload: the national hemochromatosis transplant registry.

BACKGROUND & AIMS: Previous uncontrolled studies have suggested that patients with hepatic iron overload have a poor outcome after liver transplantation. We examined the effect of HFE mutations on posttransplantation survival in patients with hepatic iron overload. METHODS: Two hundred sixty patients with end-stage liver disease and hepatic iron overload were enrolled from 12 liver transplantation centers. Hepatic iron concentration (HIC), hepatic iron index (HII), HFE mutation status, and survival after liver transplantation were recorded. RESULTS: HFE-associated hemochromatosis (HH) defined as homozygosity for the C282Y (n = 14, 7.2%) mutation or compound heterozygosity for the C282Y/H63D (n = 11, 5.6%) mutation was identified in 12.8% of patients. Survival postliver transplantation was significantly lower among patients with HH (1-, 3-, and 5-year survival rates of 64%, 48%, 34%, respectively) compared with simple heterozygotes (C282Y/wt or H63D/wt) or wild-type patients. Patients with HH had a hazard ratio for death of 2.6 (P = .002) after adjustment for age, United Network for Organ Sharing status, year of transplantation, and either elevated HII or HIC. Non-HH patients with hepatic iron overload also had significantly decreased survival when compared with the overall population undergoing liver transplantation (OR = 1.4, 95% CI: 1.15-1.61, P < .001). CONCLUSIONS: One- and 5-year survivals after liver transplantation are significantly lower among patients with HFE-associated HH. Our data also suggest that hepatic iron overload may be associated with decreased survival after liver transplantation, even in patients without HH. Early diagnosis of hepatic iron overload using HFE gene testing and iron depletion prior to liver transplantation may improve posttransplantation survival, particularly among patients with HH.

Adult↗
PubMed2005

Relation of hemochromatosis with hepatocellular carcinoma: epidemiology, natural history, pathophysiology, screening, treatment, and prevention.

HH is a common inherited disorder of iron metabolism affecting about 1 out of 250 individuals of Northern European decent. Many of these patients do not have evident phenotypic expression and do not develop significant iron loading. Some patients, however, develop progressive iron overload and cirrhosis. These individuals are at risk of developing HCC. Cirrhotics with hemochromatosis should undergo regular screening for HCC. If HCC is identified early, treatment with either resection or liver transplantation is optimal. Palliative measures, including ablative therapy and chemoembolization, can be used. With increasing clinical recognition,hemochromatosis should be diagnosed earlier and progression to cirrhosis and HCC should be minimized.

Carcinoma, Hepatocellular↗
PubMed2005

Effect of significant histologic steatosis or steatohepatitis on response to antiviral therapy in patients with chronic hepatitis C.

BACKGROUND & AIMS: Treatment of chronic hepatitis C (CHC) results in an average sustained viral response (SVR) rate of 54%-63%. Most previous studies have not separately reported SVR rates for patients who have CHC and concomitant significant hepatic steatosis (>33%) or histologic evidence of steatohepatitis (SH). The aim of this study was to evaluate SVR in patients with CHC plus steatosis or SH on biopsy examination, compared with a group of controls with CHC and no significant steatosis or SH. METHODS: Our surgical pathology database and clinical files were queried for CHC between 1997 to 2002. Biopsy specimens with both CHC and significant steatosis (>33%) or SH were categorized as group 1. Of the patients treated with antiviral therapy, information on either SVR (hepatitis C virus [HCV] RNA negative at 6 months posttreatment) or lack of SVR (nonresponse as early as 12 weeks into therapy and relapsers) with either interferon (IFN)/ribavirin or pegylated IFN/ribavirin was found in 84 patients. A control group (group 2) of 231 CHC patients was identified by using a 2-year database (January 2000-June 2001) of patients without evidence of greater than 33% steatosis or SH. RESULTS: The overall SVR was 28% in group 1, compared with 44% for group 2 ( P = .001). For HCV genotype 1, the SVR was 23% vs 34% for group 2 ( P = .19). For HCV genotypes 2 and 3, the SVR was 42% vs 78% for groups 1 and 2 ( P = .008), respectively. CONCLUSIONS: Overall SVR for patients with HCV and significant steatosis or SH is considerably lower than for HCV and steatosis less than 33% and no SH.

Antiviral Agents↗
PubMed2005

A dose-ranging study of the efficacy and tolerability of entecavir in Lamivudine-refractory chronic hepatitis B patients.

BACKGROUND & AIMS: Entecavir is a nucleoside analogue with potent in vitro activity against lamivudine-resistant hepatitis B virus (HBV). This randomized, dose-ranging, phase 2 study compared the efficacy and safety of entecavir with lamivudine in lamivudine-refractory patients. METHODS: Hepatitis B e antigen (HBeAg)-positive and -negative patients (n = 182), viremic despite lamivudine treatment for > or =24 weeks or having documented lamivudine resistance substitutions, were switched directly to entecavir (1.0, 0.5, or 0.1 mg daily) or continued on lamivudine (100 mg daily) for up to 76 weeks. RESULTS: At week 24, significantly more patients receiving entecavir 1.0 mg (79%) or 0.5 mg (51%) had undetectable HBV DNA levels by branched chain DNA assay compared with lamivudine (13%; P < .0001). Entecavir 1.0 mg was superior to entecavir 0.5 mg for this end point (P < .01). After 48 weeks, mean reductions in HBV DNA levels were 5.06, 4.46, and 2.85 log(10) copies/mL on entecavir 1.0, 0.5, and 0.1 mg, respectively, significantly higher than 1.37 log(10) copies/mL on lamivudine. Significantly higher proportions of patients achieved normalization of alanine aminotransferase levels on entecavir 1.0, 0.5, and 0.1 mg (68%, 59%, and 47%, respectively) than on lamivudine (6%). One virologic rebound due to resistance occurred (in the 0.5-mg group). CONCLUSIONS: In HBeAg-positive and HBeAg-negative lamivudine-refractory patients, treatment with entecavir 1.0 and 0.5 mg daily was well tolerated and resulted in significant reductions in HBV DNA levels and normalization of alanine aminotransferase levels. One milligram of entecavir was more effective than 0.5 mg in this population.

Adult↗
PubMed2005

Pathophysiology of hereditary hemochromatosis.

Hereditary hemochromatosis (HH) encompasses several inherited disorders of iron homeostasis characterized by increased gastrointestinal iron absorption and tissue iron deposition. The most common form of this disorder is HFE-related HH, nearly always caused by homozygosity for the C282Y mutation. A substantial proportion of C282Y homozygotes do not develop clinically significant iron overload, suggesting roles for environmental factors and modifier genes in determining the phenotype. Recent studies have demonstrated that the pathogenesis of nearly all forms of HH involves inappropriately decreased expression of the iron-regulatory hormone hepcidin. Hepcidin serves to decrease the export of iron from reticuloendothelial cells and absorptive enterocytes. Thus, HH patients demonstrate increased iron release from these cell types, elevated circulating iron, and iron deposition in vulnerable tissues. The mechanism by which HFE influences hepcidin expression is an area of current investigation and may offer insights into the phenotypic variability observed in persons with mutations in HFE.

Absorption↗
PubMed2005

Duration of hepatic iron exposure increases the risk of significant fibrosis in hereditary hemochromatosis: a new role for magnetic resonance imaging.

OBJECTIVES: Hepatic fibrosis is a complication of hereditary hemochromatosis. The aim of this study was to determine whether the product of the magnitude and duration of hepatic iron exposure is related to the risk of significant fibrosis. METHODS: Receiver-operating characteristic curve analysis to determine the utility of hepatic iron concentration (HIC) and age in the diagnosis of low- or high-grade fibrosis was undertaken retrospectively in 60 subjects who had undergone liver biopsy for assessment of hereditary hemochromatosis. A prospective pilot study was then conducted in 10 additional subjects to evaluate utility of magnetic resonance imaging (MRI) measurements of HIC to predict fibrosis. RESULTS: Eighteen subjects had high-grade fibrosis while 42 subjects had low-grade fibrosis. Hepatic iron concentration alone was highly sensitive (100%) but of limited specificity (67%) in diagnosis of high-grade fibrosis. The product of [HIC x age] had a sensitivity and specificity of 100% and 86%, respectively, for diagnosis of high-grade fibrosis. Magnetic resonance imaging measurements also provided accurate assignment of subjects into fibrosis severity groups. CONCLUSIONS: Duration of exposure to iron is important in the development of hepatic fibrosis in hereditary hemochromatosis. The product of HIC and age is highly sensitive and specific for diagnosis of high-grade fibrosis and can be obtained using MRI.

Adult↗