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B R Bacon

Publications and source records attributed to B R Bacon.

At least 73 records · Page 4Linked to original sources
PubMed1997

Fibronectin and cytokines increase JNK, ERK, AP-1 activity, and transin gene expression in rat hepatic stellate cells.

Cytokines, growth factors, and alterations in the extracellular matrix composition may play a role in maintaining hepatic stellate cells (HSC) in the activated state that is responsible for hepatic fibrogenesis. However, the signal transduction pathways that are stimulated by these factors in HSC remain to be fully elucidated. Recent evidence indicates that the mitogen-activated protein kinase (MAPK) family, including c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), plays an important role in the cellular response to stress. The aims of this study were to investigate whether fibronectin (FN) or the inflammatory cytokines interleukin-1alpha (IL-1alpha) and tumor necrosis factor-alpha (TNF-alpha) activate JNK, ERK, and AP-1 activity in HSC and induce the gene expression of the matrix metalloproteinase transin. Treatment of HSC with FN resulted in an up to 4.5-fold increase in ERK activity and a 2.1-fold increase in JNK activity. IL-1alpha and TNF-alpha produced up to a fourfold increase in JNK activity and a twofold increase in ERK activity. We then compared the effects of FN, IL-1alpha, and TNF-alpha on AP-1 activity and metalloproteinase mRNA induction. All three compounds increased AP-1 binding and promoter activity, and transin mRNA levels were increased 1.8-fold by FN, 2.2-fold by IL-1alpha, and 2.8-fold by TNF-alpha. Therefore, FN and inflammatory cytokines increase MAPK activity, stimulate AP-1 activity, and increase transin gene expression in HSC. Signal transduction pathways involving the MAPK family may play an important role in the regulation of matrix metalloproteinase expression by cytokines and FN in HSC.

Animals↗
PubMed1997

Hereditary hemochromatosis: presentation and diagnosis in the 1990s.

OBJECTIVES: In the past, patients with hereditary hemochromatosis have been identified predominantly from symptomatic presentation or from family studies. In the 1990s, iron studies on routine screening chemistry panels have become more commonplace. The purpose of this paper is to describe the clinical, laboratory, and presenting features of a series of patients with hereditary hemochromatosis, diagnosed from 1990 to 1995. METHODS: Clinical information, serum and liver iron studies, liver histology, and phlebotomy requirements were evaluated in 40 patients with newly diagnosed hereditary hemochromatosis prospectively referred to a tertiary university-based hepatology clinic. RESULTS: Eighty-three percent of patients came to medical attention as a result of screening blood work: 73% were asymptomatic and 78% had normal physical examinations. Only three patients had cirrhosis from hemochromatosis alone, only two were diabetic, and only two had increased skin pigmentation. These findings are in contrast to previous reports of hemochromatosis probands in which patients with symptoms and more advanced disease were identified. The hepatic iron concentration, hepatic iron index, and age at diagnosis were similar for men and women. CONCLUSIONS: With the use of screening iron studies on routine serum chemistry panels, patients with hemochromatosis can be identified and subsequently treated before they have symptoms or organ damage.

Adult↗
PubMed1996

Thiol regulation of endotoxin-induced release of tumour necrosis factor alpha from isolated rat Kupffer cells.

Proinflammatory cytokines released by hepatic macrophages (Kupffer cells) have a central role in the pathogenesis of liver injury and the cardiovascular abnormalities of sepsis. Because cytokine release is controlled primarily at the level of gene expression, intracellular signalling mechanisms that control the transcription of cytokine genes are critical links to organ injury. Oxidant stress up-regulates and antioxidants down-regulate the pleiotropic transcription factor NF-kappa B, a DNA-binding protein that induces the expression of cytokines and vascular adhesion molecules. Thiol-bearing molecules are also important inhibitors of NF-kappa B activation, but whether this inhibition represents an antioxidant effect is unknown. This study was undertaken to determine whether important endogenous and pharmacological thiols modulate the activation of NF-kappa B and the release of tumour necrosis factor alpha (TNF-alpha) from Kupffer cells and to ascertain whether these effects are mediated through glutathione. Exposure of rat Kupffer cells to a physiologically relevant concentration of lipopolysaccharide (10 ng/ml) activated NF-kappa B within 1 h and induced the release of TNF-alpha over 5 h. Cellular glutathione content remained unchanged after lipopolysaccharide exposure, but both glutathione monoethyl ester and N-acetyl-L-cysteine increased cellular glutathione levels, blocked NF-kappa B activation and inhibited the release of TNF-alpha. Inhibition of glutathione synthesis prevented the NAC-induced increase in Kupffer cell glutathione, yet it did not prevent the inhibition of TNF-alpha release by NAC. Thus the inhibition of NF-kappa B activation by pharmacological thiols such as NAC might reflect a more general role of the intracellular thiol redox status in NF-kappa B regulation rather than the antioxidant properties of these agents.

Acetylcysteine↗
PubMed1996

An update on iron metabolism: summary of the Fifth International Conference on Disorders of Iron Metabolism.

HHC is the most common inherited metabolic disease among the white population worldwide, with a gene frequency of about 10% and a frequency of homozygosity of about 1 of 250. Many patients harbor a common haplotype of informative markers on chromosome 6p2l.23, suggesting a strong founder effect exerted by a common Celtic ancestor. With the advent of screening tests (serum Tf saturation, fe), many subjects with HHC are being identified before development of cirrhosis or diabetes mellitus, and early detection is important because prompt and vigorous iron reduction prevents development of such complications and assures normal life expectancy. The HIC can be estimated as accurately by specialized magnetic resonance imaging or susceptometric measurements as by chemical measurements on liver biopsy specimens. However, biopsy specimens retain value for showing fibrosis/cirrhosis and dysplastic hepatocytes, both of which increase risks of HCC development. There is growing evidence that iron in the liver plays an important role in non-HHC diseases, such as alcoholic liver disease, chronic viral hepatitis, and porphyria cutanea tarda. The complicated, manifold roles of iron in pathogenesis of the latter disorder include enhancement of production and irreversible oxidation of uroporphyrinogen, as well as formation of an inhibitor targeted specifically at hepatic uroporphyrinogen decarboxylase. The nature of the gene and gene product that are abnormal in HHC remain elusive, despite the intense efforts of several investigative groups. The search has been hampered by a dearth of informative markers in HHC patients in the relevant region of chromosome 6p. Note added in proof: The cloning of a candidate gene, the mutation of which may perhaps cause HLA-linked hemochromatosis, has just been reported (Feder et al: A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature (Genetics) 1996;399-408). These workers identified a 250-kb region move than three megabases telomeric of the MHC that was identical in 85% of chromosomes of HHC patients. Within this region, they identified a gene related to the MHC class I family, termed HLA-H, containing two missense alterations one of which is predicted to inactivate this class of proteins. 83% of 178 patients were homozygous for this mutation (Cys 282Tyr). This variant was also found on 3.2% of control chromosomes, as would be expected for such a common disorder. Functional studies are awaited with great interest.

Congresses as Topic↗
PubMed1996

Performance characteristics and results of a large-scale screening program for viral hepatitis and risk factors associated with exposure to viral hepatitis B and C: results of the National Hepatitis Screening Survey. National Hepatitis Surveillance Group.

Chronic viral hepatitis frequently goes undetected until cirrhosis develops. Although the effect of interferon on the natural history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection in asymptomatic persons is unknown, treatment may modify the course of the infection, producing cures in some. In September 1992, screening for HBV and HCV was offered in 40 centers throughout the United States. Demographic features, potential risk factors, and symptoms were studied. Blood samples were obtained for the determination of serum alanine aminotransferase levels and for markers of HBV and HCV infection. Thirteen thousand nine hundred ninety seven subjects were screened. The prevalence of infection with HBV or HCV was 24.8% (HBV 17.8%; HCV 7.0%; and both 2.8%). Hepatitis B and C disease was present in 0.7% and 4.4% of the population, respectively. Risk factors for HBV and HCV infection were similar in: blood transfusions, hemodialysis, IV drug use, and sex with an IV drug user. For HBV infection, sex with multiple partners, increasing age, and birth in South East Asia or Africa were additional risk factors. The cost to find a case of HCV infection is less than the costs for finding many other treatable diseases. Screening for HBV, though more costly, is reasonably efficient, and simultaneous screening for HBV and HCV provides greater efficiency. It is practical to consider screening for HBV and HCV in the United States, particularly if any risk factor is present. Improved treatment strategies will make screening even more cost effective.

Adult↗
PubMed1996

Nonalcoholic steatohepatitis.

NASH is a form of chronic liver disease that is defined by biopsy findings and has the appearance of alcoholic hepatitis. Although this disease was once thought to be a problem of women, diabetics, and the obese, more recent studies have identified a significant proportion of patients who do not fit these risk factors. In a fraction of patients, the disease can progress to various stages of fibrosis leading ultimately to cirrhosis and death from end-stage liver disease. For this reason, recognition of NASH is important and provides a further impetus for performing a liver biopsy as part of the evaluation of unexplained liver biochemical abnormalities. The mainstay of treatment is weight reduction in the obese. For those individuals who are not obese, continued observation is the only available option at this point. With increasing knowledge about the pathophysiology of hepatic steatosis, perhaps more specific diagnostic tests for the cause of the disease in specific patients will be available and will guide appropriate therapy.

Biopsy↗
PubMed1996

A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.

Hereditary haemochromatosis (HH), which affects some 1 in 400 and has an estimated carrier frequency of 1 in 10 individuals of Northern European descent, results in multi-organ dysfunction caused by increased iron deposition, and is treatable if detected early. Using linkage-disequilibrium and full haplotype analysis, we have identified a 250-kilobase region more than 3 megabases telomeric of the major histocompatibility complex (MHC) that is identical-by-descent in 85% of patient chromosomes. Within this region, we have identified a gene related to the MHC class I family, termed HLA-H, containing two missense alterations. One of these is predicted to inactivate this class of proteins and was found homozygous in 83% of 178 patients. A role of this gene in haemochromatosis is supported by the frequency and nature of the major mutation and prior studies implicating MHC class I-like proteins in iron metabolism.

Alleles↗
PubMed1996

Ascorbate-stimulated lipid peroxidation in human brain is dependent on iron but not on hydroxyl radical.

Lipid peroxidation has been postulated as a cause of neuronal damage in both aging and neurodegenerative disease. In studies of neurodegenerative disease, iron, iron plus ascorbate, or ascorbate alone has been used to stimulate lipid peroxidation. The mechanism by which ascorbate stimulates lipid peroxidation in human brain is unclear. The studies reported here were performed to determine whether ascorbate-stimulated lipid peroxidation in human brain membrane fragments was dependent on iron, superoxide radical, hydrogen peroxide, or hydroxyl radical. Our findings indicate that although ascorbate-stimulated lipid peroxidation in brain is iron dependent, it apparently does not require hydrogen peroxide or hydroxyl radical, but rather is dependent on superoxide radical formation.

Adult↗
PubMed1996

Rat liver ferritin selectively inhibits expression of alpha-smooth muscle actin in cultured rat lipocytes.

The role of ferritin in lipocyte activation is unknown. This study examined the effect of rat liver ferritin (RLF), human recombinant H-ferritin (HrHF), human recombinant L-ferritin (HrLF), apo-ferritin (apo-RLF), and hemin on lipocyte activation. Lipocytes were cultured on uncoated plastic and were incubated with these agents for 7 days, at concentrations ranging from 10(-14) to 10(-7) M (0.5 to 50 microM for hemin). Collagen/noncollagen protein production and lipocyte proliferation were determined by [3H]proline and [3H]thymidine incorporation, respectively, and the expression of alpha-smooth muscle actin (alpha-SMA) and desmin was determined by Western blot. RLF, at concentrations ranging from 10(-10) to 10(-7) M, decreased alpha-SMA expression by 65-88%. Apo-RLF, HrHF, and HrLF decreased alpha-SMA by 17-45% at 10(-7) and 10(-8) M. Hemin (10 or 50 microM) inhibited alpha-SMA by 37 and 54%, respectively. Desmin expression was not altered by ferritin or hemin. Collagen and noncollagen protein production were not altered by either RLF or apo-RLF. Lipocyte proliferation was decreased by 54, 32, and 40%, by 10(-7) M RLF, HrHF, and HrLF, respectively, whereas apo-RLF had no effect. Thus RLF inhibited lipocyte alpha-SMA expression, which may be due to an effect of sequestered iron, since neither apo-RLF, HrHF, nor HrLF had a potent effect on alpha-SMA expression and all are essentially iron-free. The inhibitory effect of iron-loaded RLF on alpha-SMA expression suggests that tissue ferritin does not initiate lipocyte activation in iron overload, but rather may have a suppressive action on this process.

Actins↗
PubMed1996

Vitamin E decreases hepatic levels of aldehyde-derived peroxidation products in rats with iron overload.

Hepatic iron overload can cause lipid peroxidation with the formation of aldehydic products, hepatocellular injury, and fibrosis. Vitamin E (alpha-tocopherol) may prevent peroxidation-induced hepatic damage. We used confocal laser scanning microscopy, digital image analysis, and immunohistochemical methods to quantitate aldehyde-derived peroxidation products in the liver of rats with experimental iron overload with or without supplemental vitamin E. A strong autofluorescent reaction colocalizing with iron deposits was present in the livers of iron-loaded rats. Fluorescent granules were unevenly distributed in the cytosol of both hepatocytes and Kupffer cells in the periportal regions. Immunohistochemical studies revealed the presence of malon-dialdehyde adducts in the periportal regions of the ironloaded rats. Vitamin E supplementation markedly reduced the fluorescence intensity and the amount of aldehyde-derived peroxidation products and changed the distribution of stainable iron and iron-associated peroxidation products such that their levels were much decreased in Kupffer cells. These results indicate that aldehyde-derived covalent chemical addition products are formed in the liver in iron overload. Vitamin E supplementation markedly reduces the amount of these compounds and changes their cellular distribution. These findings should be implicated in the role of antioxidant therapy in conditions causing iron overload and lipid peroxidation.

Aldehydes↗
PubMed1996

LPS-mediated NF-kappa beta activation in rat Kupffer cells can be induced independently of CD14.

Lipopolysaccharide (LPS) activation of macrophages occurs after LPS complexed with serum LPS-binding protein (LBP) binds CD14. Activation of the nuclear transcription factor NF-kappa B is directly related to this event. Since the role of CD14 in LPS signaling has not been evaluated in Kupffer cells, the resident hepatic macrophage, the purpose of this study was to characterize LPS-mediated NF-kappa B activation under CD14-dependent (1% serum, as a source of LBP) and CD14-independent (serum-free) conditions. Classic CD14-dependent signaling was seen in peritoneal macrophages where serum potentiated NF-kappa B activation. However, in Kupffer cells, NF-kappa B was activated by LPS under CD14-independent conditions, and this response was not potentiated by serum. The activation of NF-kappa B in Kupffer cells, by 1 ng/ml LPS, reached a maximum within 60 min of stimulation. However, peritoneal macrophage NF-kappa B activation occurred only in serum and increased progressively through 240 min of stimulation. These results suggest a novel mechanism of LPS-mediated activation in Kupffer cells that may represent an adaptation to their role in clearance and detoxification of gut-derived endotoxin.

Animals↗
PubMed1996

Interpreting serologic tests for hepatitis C virus infection: balancing cost and clarity.

Although progress has been made toward developing a cheap and accurate method to diagnose hepatitis C virus (HCV) infection, current screening tests have an unacceptably high false-positive rate. Newer tests are more accurate, but also more costly. This paper outlines an approach for interpreting and using these different tests. The second-generation enzyme-linked immunosorbent assay (ELISA) for HCV antibodies, the current screening test for HCV infection, has a sensitivity of approximately 90% but a low specificity. Persons with risk factors for HCV infection, elevated aminotransferase levels, and a positive ELISA result most likely have HCV infection. Confirmatory testing with a recombinant immunoblot assay adds considerably to the cost of diagnosis and should only be used to confirm HCV infection in ELISA-positive patients at low risk or with conditions such as hyperglobulinemia that promote false-positive reactivity. Polymerase chain reaction (PCR) testing is the most sensitive and accurate method of diagnosing HCV infection, but its cost limits its use. PCR testing should be reserved for cases of diagnostic uncertainty, evaluation of possible acute hepatitis C, patients with normal serum aminotransferase levels and anti-HCV antibodies, and patients about to undergo interferon therapy.

Adult↗
PubMed1995

Primary liver cancer and survival in patients undergoing liver transplantation for hemochromatosis.

Cirrhotic patients with hereditary hemochromatosis (HHC) have an increased risk of primary liver cancer (PLC). The purpose of this study was to determine the prevalence of primary liver cancer in patients with HHC undergoing orthotopic liver transplantation (OLT). Five liver transplant centers were surveyed; clinical and pathological data on 37 patients with HHC undergoing OLT were retrospectively collected and analyzed. The diagnosis of HHC was established by a combination of serum transferrin-iron saturation, hepatic iron index (HII), and/or pattern of liver iron staining. The diagnosis of HHC had been unsuspected before OLT in 13 of 37 (35%). Primary liver cancer was found in the explants of 10 of 37 patients (27%) and was unsuspected in 7 of 10 (70%); 8 were hepatocellular carcinoma, and 2 were cholangiocarcinoma; foci of hepatocyte dysplasia were found in 6 additional patients. Mean (+/- SEM) hepatic iron content and HII in 20 patients without prior phlebotomy or bleeding were 17.2 mg/g dry weight (+/- 2.9) and 5.5 (+/- 0.8), respectively. The overall 1-year survival rate after OLT in the 37 HHC patients was 58% (v 55% for HHC patients with PLC). We draw the following conclusions: (1) the diagnosis of HHC is often unsuspected before OLT, and HHC should be evaluated pretransplantation by direct and indirect markers; (2) HHC patients undergoing OLT have a high prevalence of primary liver cancer, the majority being unsuspected; and (3) HHC patients have poorer than average survival after OLT, which cannot be explained solely by the presence of concomitant PLC.

Female↗
PubMed1995

Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C.

BACKGROUND/AIMS: It has been reported that hepatic iron concentration (HIC) may influence response to therapy in chronic viral hepatitis. The aim of this study was to determine the relationship between HIC and response to interferon alfa therapy in patients with chronic hepatitis C. METHODS: HIC was measured in liver biopsy specimens from 58 patients with chronic hepatitis C treated at three centers. Three patients had mild chronic hepatitis C, 35 had moderate to severe chronic hepatitis C, and 20 had active cirrhosis. Serum ferritin levels were measured in 51 of these 58 patients. Response to therapy was defined as normalization of alanine aminotransferase levels at the end of treatment. RESULTS: Twenty-four patients (41%) responded to therapy. HICs were generally within the normal range (< 1500 micrograms/g). The mean HIC in nonresponders (860 +/- 100 micrograms/g; range, 116-2296 micrograms/g) was significantly higher than in responders (548 +/- 85 micrograms/g; range, 29-1870 micrograms/g) (P < 0.05). Eighty-eight percent of patients with an HIC of > 1100 micrograms/g and 87% of patients with an elevated serum ferritin concentration did not respond to interferon alfa therapy. CONCLUSIONS: HIC seems to influence response to interferon alfa therapy among patients with chronic hepatitis C. A subgroup of patients with chronic hepatitis C has been identified for which an HIC of > 1100 micrograms/g predicted nonresponse in 88% of patients.

Adult↗
PubMed1995

Chronic iron overload causes activation of rat lipocytes in vivo.

Chronic iron overload can result in hepatic fibrosis and cirrhosis. Activated lipocytes, through increased production of collagen and extracellular matrix, play an important role in hepatic fibrogenesis in several types of experimental liver injury, but their contribution to hepatic injury after iron overload is unknown. This study examines the effect of iron overload on lipocyte activation, in vivo. Male Sprague-Dawley rats were fed a chow diet supplemented with 1% carbonyl iron for up to 20 mo. Controls were fed the chow diet alone. Lipocytes were prepared by sequential pronase and collagenase perfusion of the livers, followed by density-gradient centrifugation. Lipocyte activation was assessed by immunohistochemistry of liver sections and by Western blot analysis of alpha-smooth muscle actin expression in freshly isolated lipocytes. In addition, to measure the biosynthetic capability of these lipocytes, collagen and noncollagen protein production was determined after 3 days in culture, using [3H]proline incorporation. The hepatic iron concentration was increased by eightfold in the iron-loaded rats, and lipocytes from these animals expressed alpha-smooth muscle actin. Collagen production was increased by 2.5-fold, and noncollagen protein production was elevated by twofold in lipocytes isolated from iron-loaded rats. In the iron-loaded livers, autofluorescent material with the characteristics of lipofusion was present in periportal zones. Chronic iron overload expression results in the activation of lipocytes, as determined by increased expression of alpha-smooth muscle actin and by increased production of both collagen and noncollagen protein. This activation may contribute to iron-induced hepatic fibrogenesis.

Actins↗
PubMed1995

Vitamin A-poor lipocytes: a novel desmin-negative lipocyte subpopulation, which can be activated to myofibroblasts.

Lipocytes have been classified as vitamin A-storing, desmin-positive cells. In hepatic fibrogenesis, lipocytes transform into myofibroblasts, which express alpha-smooth muscle actin (alpha-SMA) and produce increased amounts of collagen. We isolated a population of vitamin A-poor lipocytes (VAPL) from normal rat liver and examined the morphological and biochemical differences between VAPL and vitamin A-replete lipocytes (VARL). Desmin and alpha-SMA expression were determined by Western blot in quiescent cells and in cells activated by culture on uncoated plastic. Both cell types were alpha-SMA-negative; however, in contrast to VARL, freshly isolated VAPL did not contain desmin. Desmin expression was induced in VAPL on activation. With time in culture, both VAPL and VARL expressed alpha-SMA and produced collagen, indicative of transformation to myofibroblasts. Ferritin receptor expression was demonstrated in cultured VARL after 1 day and in VAPL after 5 days, indicating that this is an early marker of lipocyte activation. After 7 days, VARL and VAPL were indistinguishable in terms of desmin, ferritin receptor expression, and collagen production. This study demonstrates the first isolation and characterization of two distinct quiescent subpopulations of lipocytes from normal rat liver: desmin-negative VAPL and desmin-positive VARL. Both populations of cells can be activated to myofibroblasts, the phenotype associated with hepatic fibrogenesis.

Adipocytes↗
PubMed1995

Hepatic mitochondrial oxidative metabolism and lipid peroxidation in iron-loaded rats fed ethanol.

The aims of this study were to determine whether chronic ethanol consumption potentiates mitochondrial lipid peroxidation or impairment of mitochondrial oxidative metabolism in rats with chronic iron overload. Experimental iron overload was induced by feeding rats a chow diet supplemented with 2.5% carbonyl iron. After 8 to 12 weeks, half of the iron-loaded and control animals were changed to a liquid diet containing ethanol for 4 to 5 weeks. The remaining animals were fed an isocaloric amount of diet containing dextrin-maltose instead of ethanol for 4 to 5 weeks. Iron-supplemented animals had a 20-fold increase in hepatic iron concentration as compared with controls. Iron and ethanol independently increased plasma alanine aminotransferase (ALT) levels (p < 0.05) while the combination resulted in an additive increase in ALT levels (p < 0.01). Although iron overload increased the levels of mitochondrial conjugated dienes and significantly reduced the mitochondrial respiratory control ratio, ethanol administration did not affect these parameters in animals with or without iron overload. Livers from iron-loaded rats that received ethanol showed mild to moderate steatosis with scattered necroinflammatory foci. There was no significant increase in necroinflammatory foci in the livers of the iron plus ethanol group as compared with the iron group. In conclusion, we have demonstrated an additive increase in hepatocellular injury when ethanol is fed to iron-loaded rats, as evidenced by an increase in plasma ALT level. However, there were no additive or synergistic effects of iron and ethanol on either mitochondrial lipid peroxidation or mitochondrial oxidative metabolism.

Alanine Transaminase↗