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Biomedical subjects

Bruce R Bacon

Publications and source records attributed to Bruce R Bacon.

At least 55 records · Page 3Linked to original sources
PubMed2003

Effect of protein kinase C activation and inhibition on rat hepatic stellate cell activation.

Protein kinase C (PKC) may play a role in the intracellular signaling pathways responsible for transforming hepatic stellate cells into myofibroblasts. This study examined the effects of inhibitors and activators of PKC on hepatic stellate cell activation. Stellate cells isolated from normal rats were incubated with either 10(-5) M chelerythrine, 10(-7) M bisindolylmaleimide I hydrochloride (BIM), or 10(-6) M staurosporine (PKC inhibitors), or 10(-7) M phorbol myristate acetate (PMA) or 10(-6) M thymeleatoxin (PKC activators). Chelerythrine suppressed alpha-smooth muscle actin expression and proliferation by 49% and 33%, respectively. BIM inhibited alpha-smooth muscle actin expression by 60%, but had no significant effect on proliferation. Staurosporine decreased proliferation by 86% and completely prevented alpha-smooth muscle actin expression. PKC activators had divergent effects on proliferation and alpha-smooth muscle actin expression. PMA and thymeleatoxin caused a 2.8- to 3.2-fold increase in proliferation, while suppressing alpha-smooth muscle actin expression by 50-70%. The demonstration that hepatic stellate cell activation can be suppressed by PKC inhibitors suggests a role for PKC in the regulation of hepatic stellate cell activation.

Actins↗
PubMed2003

Human platelets express hemochromatosis protein (HFE) and transferrin receptor 2.

OBJECTIVES: While body iron status may influence platelets, little information is available about platelet expression of proteins regulating iron homeostasis. HFE, the protein defective in hereditary hemochromatosis, and transferrin receptor 2 (TfR2) are two novel protein candidates that could be involved in mechanisms of iron transport across the platelet plasma membrane. METHODS: The expression and localization of HFE, TfR1 and TfR2 proteins in human platelets were examined using Western blotting and immunocytochemistry. RESULTS: Human platelets expressed HFE and TfR2, whereas no signal for TfR1 was found. The positive reactions for HFE and TfR2 were mainly confined to the platelet plasma membrane. CONCLUSIONS: Expression of HFE and TfR2 proteins in human platelets may indicate that the mutations in the corresponding genes could influence platelet count, size and/or activation. The presence of TfR2 and absence of TfR1 suggests that HFE may serve a different function in platelets compared with the other HFE-positive cell types, e.g. enterocytes, macrophages and syncytiotrophoblasts.

Blood Platelets↗
PubMed2003

Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone.

Insulin resistance (IR) commonly is associated with nonalcoholic steatohepatitis (NASH). To establish whether IR causes NASH, this study was undertaken to determine if improving IR would improve the histologic features that define NASH. Thirty adults with prior biopsy evidence of NASH were enrolled to receive rosiglitazone, 4 mg twice daily for 48 weeks. All patients were overweight (body mass index [BMI] > 25 kg/m(2)) and 23% were severely obese (BMI > 35 kg/m(2)); 50% had impaired glucose tolerance or diabetes. Liver biopsy specimens were obtained before beginning treatment and at treatment completion. Twenty-six patients had posttreatment biopsies; of these, 22 had initial protocol liver biopsies that met published criteria for NASH on subsequent blinded evaluation. Within this initial NASH group, the mean global necroinflammatory score significantly improved with treatment and biopsies of 10 patients (45%) no longer met published criteria for NASH after treatment. Significant improvement in hepatocellular ballooning and zone 3 perisinusoidal fibrosis also occurred. Five patients withdrew early; the 25 patients completing 48 weeks of treatment had significantly improved insulin sensitivity and mean serum alanine aminotransferase (ALT) levels (104 initially, 42 U/L at the end of treatment). Adverse effects led to withdrawal of 3 patients (10%). Weight gain occurred in 67% of patients and the median weight increase was 7.3%. Within 6 months of completing treatment, liver enzyme levels had increased to near pretreatment levels. In conclusion, improving insulin sensitivity with rosiglitazone resulted in improved histologic markers of NASH, an observation suggesting that insulin resistance contributes to its development and that improving insulin sensitivity may be important in treating this liver disease.

Adult↗
PubMed2003

Concurrence of histologic features of steatohepatitis with other forms of chronic liver disease.

Steatohepatitis, of either alcoholic or nonalcoholic etiologies, is ultimately diagnosed by clinical-pathologic correlation and is characterized histologically by lesions that differ from the portal-based chronic inflammation and fibrosis of most other forms of chronic liver disease. With the increasing prevalence of steatohepatitis in our society, it is likely that some patients will have coexistent clinical and/or histopathologic findings of steatohepatitis concurrently with another form of liver disease. The aim of this study was to document clinical and histologic findings in biopsies in an academic referral center. Ninety-three non-allograft liver biopsies with lesions of both steatohepatitis and another liver disease were retrospectively identified in 85 patients. The finding of coexisting disease represented 5.5% of all hepatitis C biopsies and 4.0% of other forms of chronic liver disease in the 34 month time period. Clinical chart review of patients with concurrent disease showed the following: Group 1, patients with hepatitis C (n = 54); Group 2, patients with hepatitis C and prior or current history of more than 80 g/d alcohol consumption (n = 20); Group 3, patients with other forms of chronic liver disease (n = 11). Groups 1 and 3 had <10 g/d alcohol use. Obesity (body mass index >30) was noted in 75%, 60%, and 33% respectively, while 94%, 87% and 100% of patients were considered overweight (body mass index > or = 25). Diabetes was reported in 35%, 25%, and 9%. The concurrence of clinical and histologic features of steatohepatitis with another chronic liver disease may be a reflection of the frequency of steatohepatitis in the population at large.

Adult↗
PubMed2003

Budd-Chiari syndrome and hepatocellular carcinoma: a case report and review of the literature.

Acid suppression medications have become A 62-yr-old woman with a long-standing history of presumed cryptogenic cirrhosis was referred for evaluation of an elevated bilirubin level. Workup showed an elevated alpha-fetoprotein level, and a mass in the liver was detected by imaging studies; this was confirmed as hepatocellular carcinoma by biopsy. Her past medical history was significant for a portocaval shunt procedure 30 yr prior; a wedge biopsy obtained at that time had been interpreted as postnecrotic cirrhosis, but upon current review, lesions of acute and chronic venous outflow obstruction consistent with Budd-Chiari syndrome were noted. This case is unusual in two aspects: the patient survived 30 yr after shunt surgery with undiagnosed Budd-Chiari syndrome; and the association of Budd-Chiari syndrome with subsequent hepatocellular carcinoma is uncommon.

Budd-Chiari Syndrome↗
PubMed2003

Orlistat in the treatment of NASH: a case series.

Nonalcoholic steatohepatitis is now recognized as a common chronic liver disorder. Up to 16% of affected patients may progress to cirrhosis. The incidence and prevalence of this disease are noted to be increasing, in parallel with the nationwide increase in obesity and diabetes. Treatment options for these patients remain quite limited, however. Weight reduction has been advocated, but there are little data to support this practice, as most patients are unable to comply with the proper dietary modifications. We report three obese patients with biopsy-proven nonalcoholic steatohepatitis treated for 6-12 months with a weight reduction medication, orlistat, who lost between 22-42 lb, and had significant clinical and histopathological improvement on follow-up.

Adult↗
PubMed2003

Insurance, employment, and psychosocial consequences of a diagnosis of hereditary hemochromatosis in subjects without end organ damage.

OBJECTIVES: Asymptomatic individuals with hereditary hemochromatosis (HH) may experience difficulties in obtaining employment or insurance, despite their good health. The extent to which these difficulties occur is unclear. The aim of this study was to assess the insurance, employment, and psychosocial consequences of a diagnosis of HH in subjects with no end organ damage. METHODS: In three outpatient clinics specializing in the treatment of HH, we performed a survey of individuals diagnosed with HH who were without end organ damage secondary to iron overload, along with their unaffected siblings. A review of the medical records of subjects with HH was performed. Main outcomes were attaining and keeping employment; health, disability and life insurance; and scores on the SF-36, a quality of life measure, and the SCL-90-R, a measure of psychological well-being. RESULTS: Of 130 eligible subjects with HH, 126 (97%) responded. Of the 55 eligible controls, 46 (84%) responded. Of the 126 subjects with HH, 25 (20%) described 28 incidents of insurance denial or increased premium rates, which they attributed to their diagnosis HH. Of the 28 incidents, 16 (57%) involved life insurance, eight (29%) involved health insurance, and four (14%) involved disability insurance. One subject reported an employment refusal. Five of the 25 subjects (20%) reporting insurance denial or increased premiums had significant comorbid conditions. One of 46 sibling controls (2%) reported an increased rate for life insurance (p = 0.003). No differences were noted in either the SF-36 or the SCL-90-R scores between subjects with HH and unaffected siblings. Overall rates of active health, disability, and life insurance were similar between the groups. CONCLUSIONS: Insurance denial and increased premium rates are reported commonly among individuals with HH without end organ damage. However, the overall proportion of those with active insurance, the quality of life, and the psychological well-being of these subjects were similar to those of unaffected siblings.

Adult↗
PubMed2002

Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis.

Hereditary hemochromatosis (HH) is a common genetic disorder characterized by excess absorption of dietary iron and progressive iron deposition in several tissues, particularly liver. The vast majority of individuals with HH are homozygous for mutations in the HFE gene. Recently a second transferrin receptor (TFR2) was discovered, and a previously uncharacterized type of hemochromatosis (HH type 3) was identified in humans carrying mutations in the TFR2 gene. To characterize the role for TFR2 in iron homeostasis, we generated mice in which a premature stop codon (Y245X) was introduced by targeted mutagenesis in the murine Tfr2 coding sequence. This mutation is orthologous to the Y250X mutation identified in some patients with HH type 3. The homozygous Tfr2(Y245X) mutant mice showed profound abnormalities in parameters of iron homeostasis. Even on a standard diet, hepatic iron concentration was several-fold higher in the homozygous Tfr2(Y245X) mutant mice than in wild-type littermates by 4 weeks of age. The iron deposition in the mutant mice was predominantly hepatocellular and periportal. The mean splenic iron concentration in the homozygous Tfr2(Y245X) mutant mice was significantly less than that observed in the wild-type mice. The homozygous Tfr2(Y245X) mutant mice also demonstrated elevated transferrin saturations. There were no significant differences in parameters of erythrocyte production including hemoglobin levels, hematocrits, erythrocyte indices, and reticulocyte counts. Heterozygous Tfr2(Y245X) mice did not differ in any measured parameter from wild-type mice. This study confirms the important role for TFR2 in iron homeostasis and provides a tool for investigating the excess iron absorption and abnormal iron distribution in iron-overload disorders.

Alleles↗
PubMed2002

Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis.

The protein defective in hereditary hemochromatosis, called HFE, is similar to MHC class I-type proteins and associates with beta2-microglobulin (beta2M). Its association with beta2M was previously shown to be necessary for its stability, normal intracellular processing, and cell surface expression in transfected COS cells. Here we use stably transfected Chinese hamster ovary cell lines expressing both HFE and beta2M or HFE alone to study the effects of beta2M on the stability and maturation of the HFE protein and on the role of HFE in transferrin receptor 1 (TfR1)-mediated iron uptake. In agreement with prior studies on other cell lines, we found that overexpression of HFE, without overexpressing beta2M, resulted in a decrease in TfR1dependent iron uptake and in lower iron levels in the cells, as evidenced by ferritin and TfR1 levels measured at steady state. However, overexpression of both HFE and beta2M had the reverse effect and resulted in an increase in TfR1-dependent iron uptake and increased iron levels in the cells. The HFE-beta2M complex did not affect the affinity of TfR1 for transferrin or the internalization rate of transferrin-bound TfR1. Instead, HFE-beta2M enhanced the rate of recycling of TfR1 and resulted in an increase in the steady-state level of TfR1 at the cell surface of stably transfected cells. We propose that Chinese hamster ovary cells provide a model to explain the effect of the HFE-beta2M complex in duodenal crypt cells, where the HFE-beta2M complex appears to facilitate the uptake of transferrin-bound iron to sense the level of body iron stores. Impairment of this process in duodenal crypt cells leads them to be iron poor and to signal the differentiating enterocytes to take up iron excessively after they mature into villus cells in the duodenum of hereditary hemochromatosis patients.

Animals↗
PubMed2002

Iron toxicity and chelation therapy.

Iron is an essential mineral for normal cellular physiology, but an excess can result in cell injury. Iron in low-molecular-weight forms may play a catalytic role in the initiation of free radical reactions. The resulting oxyradicals have the potential to damage cellular lipids, nucleic acids, proteins, and carbohydrates; the result is wide-ranging impairment in cellular function and integrity. The rate of free radical production must overwhelm the cytoprotective defenses of cells before injury occurs. There is substantial evidence that iron overload in experimental animals can result in oxidative damage to lipids in vivo, once the concentration of iron exceeds a threshold level. In the liver, this lipid peroxidation is associated with impairment of membrane-dependent functions of mitochondria and lysosomes. Iron overload impairs hepatic mitochondrial respiration primarily through a decrease in cytochrome C oxidase activity, and hepatocellular calcium homeostasis may be compromised through damage to mitochondrial and microsomal calcium sequestration. DNA has also been reported to be a target of iron-induced damage, and this may have consequences in regard to malignant transformation. Mitochondrial respiratory enzymes and plasma membrane enzymes such as sodium-potassium-adenosine triphosphatase (Na(+) + K(+)-ATPase) may be key targets of damage by non-transferrin-bound iron in cardiac myocytes. Levels of some antioxidants are decreased during iron overload, a finding suggestive of ongoing oxidative stress. Reduced cellular levels of ATP, lysosomal fragility, impaired cellular calcium homeostasis, and damage to DNA all may contribute to cellular injury in iron overload. Evidence is accumulating that free-radical production is increased in patients with iron overload. Iron-loaded patients have elevated plasma levels of thiobarbituric acid reactants and increased hepatic levels of aldehyde-protein adducts, indicating lipid peroxidation. Hepatic DNA of iron-loaded patients shows evidence of damage, including mutations of the tumor suppressor gene p53. Although phlebotomy therapy is effective in removing excess iron in hereditary hemochromatosis, chelation therapy is required in the treatment of many patients who have combined secondary and transfusional iron overload due to disorders in erythropoiesis. In patients with beta-thalassemia who undergo regular transfusions, deferoxamine treatment has been shown to be effective in preventing iron-induced tissue injury and in prolonging life expectancy. The use of the oral chelator deferiprone remains controversial, and work is continuing on the development of new orally effective iron chelators.

Cell Membrane↗
PubMed2002

Accelerated hepatic fibrosis in patients with combined hereditary hemochromatosis and chronic hepatitis C infection.

BACKGROUND/AIMS: Hereditary hemochromatosis (HH) and chronic hepatitis C virus (HCV) infection can both result in hepatic fibrosis and cirrhosis. It has been proposed that iron overload and HCV may have potentiating effects on hepatic fibrogenesis. This study determined if HH patients with HCV would present with hepatic fibrosis/cirrhosis at a younger age and at a lower hepatic iron concentration compared to patients with HH or HCV alone. METHODS: Ten patients with combined HCV and HH were compared to 13 patients who had HH alone and 24 patients who had HCV alone. All patients had advanced fibrosis/cirrhosis on liver biopsy. All HH patients were homozygous for the C282Y mutation. RESULTS: At presentation with advanced fibrosis/cirrhosis, the mean age of the HH/HCV group was significantly lower than that of the HH group and the HCV group. The mean hepatic iron concentration was lower in the combined HH/HCV group compared to that of the HH group. CONCLUSIONS: HH patients with HCV present with advanced fibrosis/cirrhosis at a younger age and at a lower hepatic iron concentration compared to HH patients without HCV. These findings support the concept that the combination of HH-induced iron overload and HCV has a potentiating effect on hepatic fibrogenesis.

Adult↗
PubMed2002

Macro-aspartate aminotransferase in a female with antibodies to hepatitis C virus.

Persistent elevation of aspartate aminotransferase (AST) activity in serum due to the presence of a macroenzyme form of AST (macro-AST) may lead to diagnostic confusion in many clinical conditions, particularly those associated with chronic liver disease. We describe a case of macro-AST arising in an adult female with a false-positive hepatitis C virus (HCV) RNA test result that was not accompanied by other biochemical or histologic evidence of liver disease. The presence of macro-AST in serum was confirmed utilizing size-exclusion, high performance liquid chromatography (HPLC) and Protein G-agarose beads to precipitate immune complexes of AST and immunoglobulin G followed by centrifugation and AST activity measurements in the supernatant. A brief review of the clinical enzymology of AST and methods used to quantify serum macro-AST activity is provided.

Adult↗
PubMed2002

Aldehydic products of lipid peroxidation do not directly activate rat hepatic stellate cells.

BACKGROUND AND AIM: Activation of hepatic stellate cells (HSC) results in the transdifferentiation of the resting (quiescent) phenotype to one characterized by loss of vitamin A droplets, increased alpha-smooth muscle actin (SMA) expression and increased collagen production. Aldehydic products of lipid peroxidation have been shown to increase collagen production by cultured fibroblasts and by passaged HSC, but it is unclear whether these products of lipid peroxidation can initiate the activation of HSC. In the present study the effects were examined of two aldehydic products of lipid peroxidation, malondialdehyde (MDA) and 4-hydroxynonenal (HNE), on activation of rat HSC in early culture as measured by SMA and desmin expression, and collagen production. METHODS: The HSC from normal rat liver were plated in plastic wells and exposed to either MDA (5-200 micromol/L), HNE (0.1-20 micromol/L) or vehicle for either 3 or 7 days. The cells were then harvested; SMA and desmin levels were measured by western blotting. Collagen production was measured by radiolabeled proline incorporation after 6 h of aldehyde exposure. RESULTS: Malondialdehyde (100 and 200 micromol/L) decreased SMA expression during the 3-day and 7-day exposures compared with controls. 4-Hydroxynonenal (20 micromol/L) decreased SMA expression significantly while no effects were observed with lower concentrations compared with controls during the 3-day exposure. Seven-day exposure to HNE (0.1-20 micromol/L) failed to alter SMA expression compared with controls. Exposure to MDA or HNE did not influence desmin expression or collagen production. CONCLUSIONS: Aldehydic products of lipid peroxidation do not directly activate HSC in early culture and alternative pathways may be responsible for HSC activation during oxidative stress.

Actins↗
PubMed2002

Treatment of patients with hepatitis C and normal serum aminotransferase levels.

Approximately 30% of patients with chronic hepatitis C have normal serum alanine aminotransferase (ALT) levels and another 40% have ALT levels that are less than twice the upper limit of the normal range. Most patients with normal ALT levels have mild degrees of inflammation with mild or no fibrosis, and the rate of disease progression is reduced compared with that in patients with elevated ALT levels. Some patients with normal ALT levels have advanced fibrosis and cirrhosis on liver biopsy. Treatment of patients with normal ALT levels with either interferon monotherapy or interferon/ribavirin combination therapy has shown sustained virological response (SVR) rates that are equivalent to those achieved for patients with elevated ALT levels. Thus, patients with chronic hepatitis C should not be excluded from therapy based on ALT levels alone. The decision to initiate therapy with interferon and ribavirin should be based on a combination of factors independent of ALT levels including amount of fibrosis on liver biopsy, hepatitis C virus (HCV) genotype and viral level, patient age and motivation, and co-morbid illness, and the presence of other complicating conditions.

Antiviral Agents↗
PubMed2002

Hepatic iron concentration does not influence response to therapy with interferon plus ribavirin in chronic HCV infection.

In patients with chronic hepatitis C, prior studies have suggested that increased hepatic iron concentration (HIC) is predictive of a poor response to interferon (IFN) monotherapy. The aim of this study was to assess the importance of HIC on the virologic response to therapy with IFN alone or when combined with ribavirin. Records of 91 patients were reviewed for inclusion in this study. Fifty-one received IFN alone, and 40 received IFN plus ribavirin. HIC and serum iron studies, alanine aminotransferase (ALT) values, hepatitis C virus (HCV) genotype, and HCV RNA were determined prior to therapy. Sustained response was defined as the absence of HCV RNA 6 months after the end of therapy. In the IFN monotherapy group, mean HIC was higher for nonresponders (803 + 89 microg/g, range 130-2808 microg/g) compared with sustained responders (241 + 54 micro g/g, range 187-295 microg/g) (p < 0.01). In contrast, in the combination therapy group, the mean HIC was similar for both groups (533 + 86 microg/g, range 79-1338 microg/g in the nonresponders, and 662 + 95 microg/g, range 94-2031 microg/g, in the sustained responders). No difference between transferrin saturation and serum ferritin level was observed in sustained responder or nonresponder patients treated with IFN plus ribavirin. IFN monotherapy nonresponder patients tended to have a higher HIC. With IFN plus ribavirin, the sustained virologic response rate was not affected by the HIC.

Antiviral Agents↗
PubMed2002

Use of complementary and alternative medicine in patients with liver disease.

OBJECTIVES: Complementary and alternative medicine (CAM) is used by 42% of the U.S. population. Its use among patients with chronic liver disease has not been well defined. Toward that end, we surveyed patients in six geographically diverse liver disease clinics in the United States for use of CAM. METHODS: Patients attending six liver disease clinics were polled via a common questionnaire regarding their use of CAM. Demographic information was obtained to identify predictors of CAM use. Statistical analysis included univariate and multivariate analysis using logistic regression. RESULTS: A total of 989 patients completed the questionnaire. Of these, 389 (39%) admitted to using some form of CAM at least once during the preceding month; 21% admitted to using herbal preparations, and 13% used herbs to treat their liver disease. Five variables were found to be predictive of alternative therapy use: female sex, young age, level of education, annual income, and geographic location. In all, 74% of patients reported using CAM in addition to the medications prescribed by their physician, but 26% did not inform their physician of their CAM use. CONCLUSIONS: CAM use is as common among patients visiting liver disease clinics in the United States as in the general population (39% vs 42%). Many patients are using herbs to treat their liver disease but are declining to discuss this use with their physician.

Adolescent↗