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Biomedical subjects

A Mallat

Publications and source records attributed to A Mallat.

At least 37 records · Page 2Linked to original sources
PubMed1996

Preoperative marijuana inhalation--an airway concern.

PURPOSE: Cannabis Sativa (marijuana) may cause a variety of respiratory disorders including uvular oedema. This case illustrates that uvular oedema secondary to marijuana inhalation may cause a potentially serious postoperative clinical problem. CLINICAL FEATURES: A healthy 17-yr-old man who inhaled marijuana prior to general anaesthesia. In the recovery room, after an uneventful general anaesthetic, acute uvular oedema resulted in post operative airway obstruction and admission to hospital. The uvular oedema was treated successfully with dexamethasone. CONCLUSION: Recent inhalation of marijuana before general anaesthesia may cause acute uvular oedema and post operative airway obstruction. The uvular oedema can be easily diagnosed and treated.

Administration, Inhalation↗
PubMed1995

Significance of anti-hepatitis C virus core IgM antibodies in patients with chronic hepatitis C.

Antihepatitis C virus (HCV) IgM antibodies were found in patients with both acute and chronic hepatitis C. The aims of the study were to determine the significance, in terms of liver disease and virological parameters, of anti-HCV core IgM antibodies in the serum of patients with chronic hepatitis C, and the possible relationship between the presence of these antibodies before treatment and biochemical and virological responses to interferon therapy. Sixty-one patients with chronic hepatitis C were studied. Tests for serum anti-HCV core IgM antibodies were carried out before treatment. The patients received 3 mega units of interferon alpha-2a subcutaneously thrice weekly for at least 3 months (6 months when alanine aminotransferase activity was normal at month 3). A biochemical response to interferon therapy was defined as normal alanine aminotransferase activity at the end of treatment (month 6: biochemical response) and 6 months later (month 12: sustained biochemical response). A sustained virological response was defined as serum HCV RNA negativity by a polymerase chain reaction-based detection method (PCR) in patients with normal alanine aminotransferase at month 12. Anti-HCV core IgM antibodies were detected in 28 of the 61 patients (46%). The prevalence of these antibodies was significantly higher in patients infected with HCV genotype 1 (including subtypes 1a and 1b) than in patients infected with other genotypes (including 2a and 3a) (57% vs. 17%; P < 0.01). No significant difference was found between IgM-positive and IgM-negative patients as regards the mean age, sex ratio, serum alanine aminotransferase and gamma-glutamyl transpeptidase activities, the prevalence of cirrhosis in liver biopsy specimens, detection of HCV RNA by PCR, and quantitation by branched DNA assay. At month 6 of interferon therapy, normal alanine aminotransferase activity was significantly more frequent in IgM-negative than in IgM-positive patients (52% vs. 21%, respectively; P < 0.02). At month 12, normal alanine aminotransferase activity and PCR negativity were significantly more frequent in IgM-negative than in IgM-positive patients (18% vs. 0%, P < 0.04). It is concluded that anti-HCV core IgM antibodies in serum are significantly more frequent in patients infected by HCV type 1 than by other types. This suggests that their overall prevalence in patients with chronic hepatitis C in industrialized countries, where HCV type 1 accounts for the majority of infections, would be of the order of 50%, that anti-HCV core IgM antibodies are not associated with characteristic features of liver disease, and that their presence before treatment is associated with a failure of interferon alpha therapy to clear the virus.

Adolescent↗
PubMed1995

Fibroblast growth factor 2 and transforming growth factor beta 1 interactions in human liver myofibroblasts.

BACKGROUND & AIMS: During liver fibrogenesis, myofibroblastic liver cells proliferate and synthesize components of fibrosis. Fibroblast growth factor 2 (FGF-2) is expressed in vivo in myofibroblastic liver cells (MFLCs) during fibrogenesis, and exogenous FGF-2 is mitogenic for MFLCs. The aim of this study was to study the expression and role of endogenous FGF-2 in cultured human MFLCs. METHODS: FGF-2 and FGF-2 receptors were studied using immunoblotting. All RNA studies used ribonuclease protection. Growth of MFLCs was studied using [3H]thymidine incorporation and direct cell counting. RESULTS: MFLCs expressed FGF-2 and its receptors FGF receptor 1 and FGF receptor 2. An antibody to FGF-2 blocked the mitogenic effect of transforming growth factor beta 1 (TGF-beta 1) for MFLCs but not TGF-beta 1-induced increase in cellular fibronectin messenger RNA (mRNA). TGF-beta 1 increased levels of FGF-2 and FGF receptor mRNAs in MFLCs. We have previously shown that TGF-beta 1 also increased platelet-derived growth factor (PDGF) A chain mRNA in these cells and that anti-PDGF antibody blunted the mitogenic effect of TGF-beta 1. The present results show that anti-FGF-2 and anti-PDGF-AA are not additive and that FGF-2 and PDGF-AA are not sequentially induced by TGF-beta 1. CONCLUSIONS: FGF-2 mediates the mitogenic but not the profibrogenic effect of TGF-beta 1 for human MFLCs, and autocrine FGF-2 and PDGF-A interact in the mediation of the mitogenic effect of TGF-beta 1.

Analysis of Variance↗
PubMed1995

Growth inhibitory properties of endothelin-1 in human hepatic myofibroblastic Ito cells. An endothelin B receptor-mediated pathway.

Ito cells play a pivotal role in the development of liver fibrosis associated with chronic liver diseases. During this process, Ito cells acquire myofibroblastic features, proliferate, and synthesize fibrosis components. Considering the reported mitogenic properties of endothelin-1 (ET-1), we investigated its effects on the proliferation of human Ito cells in their myofibroblastic phenotype. Both ET receptor A (ETA: 20%) and ET receptor B (ETB: 80%) binding sites were identified, using a selective ETA antagonist, BQ 123, and a selective ETB agonist, sarafotoxin S6C (SRTX-C). ET-1 did not stimulate proliferation of myofibroblastic Ito cells. In contrast, ET-1 inhibited by 60% DNA synthesis and proliferation of cells stimulated with either human serum or platelet-derived growth factor -BB (PDGF-BB). PD 142893, a nonselective ETA/ETB antagonist totally blunted this effect. SRTX-C was as potent as ET-1, while BQ 123 did not affect ET-1-induced growth inhibition. Analysis of the intermediate steps leading to growth-inhibition by ET-1 revealed that activation of mitogen-activated protein kinase by serum or PDGF-BB was decreased by 50% in the presence of SRTX-C. In serum-stimulated cells, SRTX-C reduced c-jun mRNA expression by 50% whereas c-fos or krox 24 mRNA expression were not affected. We conclude that ET-1 binding to ETB receptors causes a potent growth inhibition of human myofibroblastic Ito cells, which suggests that this peptide could play a key role in the negative control of liver fibrogenesis. Our results also point out that, in addition to its well known promitogenic effects, ET-1 may also exert negative control of growth on specific cells.

Adipocytes↗
PubMed1995

Human myofibroblastlike cells obtained by outgrowth are representative of the fibrogenic cells in the liver.

During human fibrogenesis, myofibroblastlike cells proliferate and are the main source of fibrosis components. We have used cultured myofibroblastlike cells obtained by outgrowth from explants of human liver to study the expression of extracellular matrix (ECM) components and matrix-metalloproteinase-2 (MMP-2) These cells contained types I, III, IV, and V procollagen messenger RNAs (mRNAs). They also expressed mRNAs for laminin B1 chain and for cellular and plasma fibronectin. The corresponding proteins were detected by immunocytochemistry. MMP-2 expression was shown by Northern blot and gelatin zymography. Because transforming growth factor beta 1 (TGF beta 1) is considered an important mediator in liver fibrogenesis, we examined its effect on expression of ECM components by cultural human myofibroblastlike cells. TGF beta 1 increased collagen mRNAs steady-state levels and total collagen secretion in the culture medium. It also increased fibronectin mRNA levels but had no effect on laminin mRNA or MMP-2 expression. In summary, cultured human myofibroblastlike cells express those ECM components that accumulate during hepatic fibrogenesis, indicating the usefulness of this model to study mechanisms of human liver fibrogenesis. In addition to the mitogenic effect of TGF beta 1 on human myofibroblastlike cells, we now demonstrate its stimulation of ECM accumulation in these cells, thus emphasizing the central role of TGF beta 1 and myofibroblastlike cells in the pathophysiology of human hepatic fibrosis.

Cells, Cultured↗
PubMed1995

Interferon alfa and gamma inhibit proliferation and collagen synthesis of human Ito cells in culture.

During the course of ongoing liver fibrogenesis, Ito cells acquire myofibroblastic features, proliferate, and synthesize increased amounts of extracellular matrix components. Interferon (IFN) alfa and IFN gamma have been shown to elicit antiproliferative and/or antifibrogenic effects in various cell cultures of mesenchymal origin. The aim of this study was to investigate the effects of IFN-alpha and IFN-gamma on cultured human myofibroblastic Ito cells (MFBIC) proliferation and collagen synthesis and secretion. Serum-stimulated incorporation of [3H]-thymidine into DNA of MFBIC was dose-dependently decreased by both cytokines. IFN-alpha (10(4) U/mL) and IFN-gamma (10(3) U/mL) decreased DNA synthesis by 69% and 66%, respectively. Inhibition of cell proliferation was confirmed by cell counting. Similar results were observed when cell growth was stimulated with platelet-derived growth factor (PDGF-BB, PDGF-AA) or transforming growth factor (TGF)-beta 1. Collagen secretion per cell was inhibited by both cytokines, as assessed by [3H]-hydroxyproline incorporation. After a 6-day treatment, IFN-gamma showed a greater potency than IFN-alpha in inhibiting secretion of newly synthetized collagen (41% and 4% of control in the presence of 10(2) U/mL of IFN-gamma and 10(4) U/mL of IFN-alpha, respectively). Both IFN-alpha and IFN-gamma concurrently decreased steady-state expression of type I and type III procollagen messenger RNAs (mRNAs) in quiescent MFBIC. Viability assays ruled out cytotoxic effects of the two molecules. Finally, both IFNs decreased smooth muscle alpha-actin (SM alpha-actin) expression, whether assayed by immunoblotting or by Northern blot analysis. We conclude that IFN-alpha and IFN-gamma inhibit proliferation as well as collagen synthesis in human MFBIC.

Actins↗
PubMed1995

Antiproliferative effects of ET-1 in human liver Ito cells: an ETB- and a cyclic AMP-mediated pathway.

Ito cells play a key role in the development of liver fibrosis associated with chronic liver diseases. Both ETA (20%) and ETB (80%) receptors were identified in human Ito cells. ET-1 did not stimulate proliferation of Ito cells. In contrast, ET-1 inhibited DNA synthesis stimulated by serum or PDGF-BB, through an ETB-mediated pathway. The mechanism leading to growth inhibition involved elevation of cAMP leading to inhibition of serum-stimulated MAP kinase and selective reduction of c-jun expression. Finally, ET receptors were upregulated by cAMP, providing a positive feedback loop that would amplify ET-1-induced growth inhibition. We conclude that ET-1 is a potent growth inhibitory peptide and may exert positive or negative control of cell growth, depending on cell type. Moreover, this peptide may play a key role in the negative control of liver fibrogenesis.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1994

Coupling of endothelin B receptors to the calcium pump and phospholipase C via Gs and Gq in rat liver.

We have demonstrated in liver from male rats that both endothelin A (ETA) and ETB receptors coexist in equal proportion and that ETA receptors mediate a calcium-dependent activation of glycogenolysis. We describe here a sex difference in endothelin action in hepatocytes because, in female rats, 80% of the ET receptors are of ETB type and, accordingly, activation of glycogenolysis is an ETB-mediated process (EC50 = 0.03 pM). ET-1 stimulation of glycogenolysis in female rats was consecutive to activation of phosphatidylinositol 4,5-bisphosphate hydrolysis (EC50 = 0.03 pM) and to inhibition of the calcium extrusion pump (IC50 = 0.03 pM) in plasma membranes, with ET-1 approximately sarafotoxin S6C approximately ET-3. Endothelin regulation of each effector was potentiated by GTP gamma S. ET-1 did not stimulate adenylyl cyclase activity. To identify the nature of the guanine nucleotide regulatory proteins (G protein(s)) coupling ETB receptors to each effector, we used antibodies against the COOH terminus of different G protein alpha subunits. Antibodies reactive with Gs alpha (RM) blocked ET-1 inhibition of the calcium pump, while they did not affect ET-1 stimulation of phospholipase C. Antibodies reactive with Gq alpha (QL) dose-dependently antagonized stimulation of phospholipase C by ET-1 and vasopressin, without affecting ET-1 inhibition of the calcium pump. Antibodies reactive with Gi1 alpha/Gi2 alpha (AS) had no effect on either system. We conclude that the calcium signal provoked by endothelins in hepatocyte is not only consecutive to activation of phospholipase C but also to inhibition of the plasma membrane calcium pump, each effector being coupled to ETB receptors by different G proteins, Gq, and Gs.

Amino Acid Sequence↗
PubMed1994

Effect of simvastatin, an inhibitor of hydroxy-methylglutaryl coenzyme A reductase, on the growth of human Ito cells.

During hepatic fibrogenesis, Ito cells proliferate, acquire a myofibroblastlike phenotype and synthesize increased amounts of extracellular matrix components. In this study, we have assessed the effects of simvastatin, an inhibitor of hydroxy-methylglutaryl-coenzyme A reductase, on the growth of human myofibroblastlike Ito cells. Cells were grown from explants of normal human liver and characterized by a positive staining for desmin and smooth muscle alpha-actin. Simvastatin (0.1 to 10 mumol/L) induced a marked dose-dependent decrease of [3H]thymidine incorporation in human Ito cells, whether stimulated by human serum or by purified growth factors. Simvastatin-induced inhibition of DNA synthesis was confirmed by nuclear autoradiography and was not explained by a cytotoxic effect. The growth inhibitory effect of simvastatin was specifically due to inhibition of hydroxy-methylglutaryl-coenzyme A reductase because it was overcome by addition of mevalonic acid, the product of the enzymatic reaction. The reduction in [3H]thymidine incorporation was not affected by supplementation of culture medium with purified cholesterol-low-density lipoprotein or isopentenyl adenine. It was partially reversed by addition of farnesol. These results show that simvastatin decreases the growth of human Ito cells, independently of its effect on cholesterol synthesis. This decrease may be due in part either to reduced farnesylation of proteins involved in growth factor signaling pathway or to inhibition of N-linked protein glycosylation. Whether this effect exists in vivo and could thus lead to a parallel decrease of fibrosis deposition within the liver requires further study.

Actins↗
PubMed1994

Inhibition of gastric alcohol dehydrogenase activity by histamine H2-receptor antagonists has no influence on the pharmacokinetics of ethanol after a moderate dose.

Ethanol undergoes gastric first pass metabolism by alcohol dehydrogenase (ADH). We have shown that cimetidine and famotidine both cause competitive inhibition of human gastric ADH in vitro. However, in a randomized 4-way cross-over study in 12 healthy subjects a 7-day course of treatment with cimetidine (800 mg day-1), ranitidine (300 mg day-1) or famotidine (40 mg day-1), did not modify the pharmacokinetics of ethanol given as a post-prandial 0.3 g kg-1 dose. We conclude that gastric mucosal concentrations of histamine H2-receptor blockers achieved after oral dosing are probably too low to cause significant inhibition of gastric ADH in vivo.

Administration, Oral↗
PubMed1994

[Chronic lesion of the interlobular bile ducts induced by fenofibrate].

We report a case of chronic intra-hepatic cholestasis observed after 5 months treatment of fenofibrate, a drug extensively prescribed in the treatment of dyslipidemia. Clinically asymptomatic liver injury was revealed by a marked elevation of GGT activity, associated with a moderate increase in alkaline phosphatase and aminotransferases activities. GGT activity remained moderately increased 2 years after discontinuation of treatment. Examination of a liver biopsy showed a reduction in the number of interlobular bile ducts. This case emphasizes the need for systematic and repeated control of blood liver tests in patients receiving fenofibrate therapy.

Cholestasis, Intrahepatic↗
PubMed1993

[Chronic active hepatitis and cirrhosis induced by wild germander. 3 cases].

We report 3 cases of chronic liver injury that were observed after prolonged treatment with wild germander, a herbal medicine recently prohibited by French Ministry of Health, following several reports suggesting its hepatotoxicity. Chronic active hepatitis was found in 2 cases, and active cirrhosis in 1 case. The onset of hepatitis occurred after 6 to 7 months of treatment. Serum anti-nuclear and anti-smooth muscle antibodies were present in 2 patients. In 2 cases, wild-germander involvement was recognized several months after appearance of liver injury. Following treatment discontinuation, outcome was favorable in the 3 patients. These observations suggest that diagnosis of acute or chronic liver injury of unknown origin should always include the search for herbal medicine treatment.

Adult↗
PubMed1993

Mitogenic effect of transforming growth factor-beta 1 on human Ito cells in culture: evidence for mediation by endogenous platelet-derived growth factor.

We assessed the effect of transforming growth factor-beta 1 on the proliferation of human Ito cells. Ito cells in their myofibroblastlike phenotype were grown from explants of human liver and were characterized with electron microscopy and positive immunostaining for desmin and smooth muscle alpha-actin. Transforming growth factor-beta 1 was mitogenic for human Ito cells whatever the culture conditions, although it was, as previously described, inhibitory of growth for rat Ito cells. The mitogenic effect of transforming growth factor-beta 1 was likely due to induction of autocrine platelet-derived growth factor chain secretion by Ito cells themselves because (a) the mitogenic effect of transforming growth factor-beta 1 was blocked by specific platelet-derived growth factor antibodies, (b) transforming growth factor-beta 1 increased platelet-derived growth factor-A chain messenger RNA expression and platelet-derived growth factor-AA secretion by human Ito cells and (c) human Ito cells expressed the alpha-type platelet-derived growth factor-A receptor messenger RNA. Exogenous platelet-derived growth factor-AA was also mitogenic for human Ito cells, mimicking the effect of transforming growth factor-beta 1. Our data suggest that results obtained with rat Ito cells must be extrapolated with caution to human ones. The mitogenic effect of transforming growth factor-beta 1 on human Ito cells probably has pathophysiological relevance because transforming growth factor-beta 1 has been demonstrated in vivo at sites of active liver fibrogenesis.

Actins↗
PubMed1992

Role of G protein beta gamma subunits in the regulation of the plasma membrane Ca2+ pump.

In Zajdela hepatoma cells (ZHC) the plasma membrane Ca2+ pump displayed no sensitivity to glucagon (19-29) (mini-glucagon), whereas in hepatocyte this metabolite of glucagon evoked a biphasic regulation of the Ca2+ pump system via a cholera toxin-sensitive G protein. Analysis of G protein subunits in ZHC membranes indicated the presence of cholera toxin-sensitive Gs alpha and G beta gamma proteins, whose functionality was manifested by GTP and NaF stimulation of adenylylcyclase activity, and pertussis toxin-catalyzed ADP-ribosylation of Gi alpha, respectively. However, immunoblotting experiments suggested a lower content in beta gamma subunits in ZHC as compared with hepatocyte plasma membranes. Complementation of ZHC or hepatocyte plasma membranes with purified beta gamma subunits from transducin (T beta gamma) caused inhibition of the basal activity of the Ca2+ pump at 10 and 300 ng/ml, respectively, and revealed (in ZHC) or increased (in hepatocytes) sensitivity of the system to mini-glucagon. After cholera toxin treatment of ZHC, T beta gamma no longer reconstituted the response of the Ca2+ pump to mini-glucagon, suggesting that the mechanism of beta gamma action is dependent on an association with the alpha subunit of a cholera toxin-sensitive G protein. It is concluded that G beta gamma subunits control both the basal activity of the plasma membrane Ca2+ pump and its inhibition by mini-glucagon.

Adenosine Diphosphate Ribose↗