Phaeochromocytoma in Papu New Guinea.
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Adolescent↗
Biomedical subjects
G C Farrell
Publications and source records attributed to G C Farrell.
Plasma GABA, GABA-like activity and the brain GABA-benzodiazepine receptor complex in rats with chronic hepatic encephalopathy.
Plasma gamma-aminobutyric acid (GABA)-like activity, plasma GABA and the brain GABA-benzodiazepine receptor complex were studied in rats with chronic hepatic encephalopathy. Portal vein ligation (after prior subcutaneous transposition of the spleen) results in complete portal bypass of splanchnic blood. In addition, significant hepatocellular damage was superimposed on this model of portosystemic shunting by ligation of the common bile duct. Plasma GABA-like activity (determined by radioreceptor assay) and true plasma GABA concentrations (determined by high-performance liquid chromatography) were found to be significantly increased in both portal vein-ligated and portal vein and bile duct-ligated rats, compared with controls. However, plasma GABA-like activity was consistently greater than the concentration of true GABA in the plasma of all rats. This suggested the presence of a GABA-like factor in plasma that can inhibit [3H]GABA binding, but is not GABA itself. The concentration of this GABA-like factor was significantly increased in the plasma of rats with chronic hepatic encephalopathy. Despite the significant increase in plasma GABA-like activity and plasma GABA concentrations, there was no alteration in the affinity or density of the physiologically relevant, low-affinity brain GABA binding site in the rats with portal vein ligation, with or without bile duct ligation. There was also no significant alteration in brain benzodiazepine binding in these rats. GABA enhancement of benzodiazepine binding was unchanged in the portal vein-ligated rats. However, the maximal enhancement of benzodiazepine binding was decreased in the rats with portal vein and bile duct ligation. There appears to be no substantial evidence that brain GABAergic neurotransmission is increased in these models of chronic hepatic encephalopathy.
Animals↗
Investigation of focal hepatic lesions: is tomographic red blood cell imaging useful?
Noninvasive diagnosis of cavernous hemangioma of the liver is an important step in the investigation of patients with focal hepatic lesions since biopsy may result in life-threatening hemorrhage. To determine the diagnostic accuracy of 99m-technetium red blood cell (99mTc-RBC) imaging with tomography, 50 patients with various types of focal liver lesions were studied. Thirty-two patients had 45 hemangiomas and 7 other benign lesions while 18 patients had either primary (n = 8) or secondary (n = 10) hepatic malignancies. Tomographic imaging identified 12 more hemangiomas than planar imaging, improving sensitivity from 53% to 80%, and was found most useful for detection of smaller lesions (mean size, 2.1 cm). Specificity for hemangiomas was 100% with all lesions greater than 1.9 cm showing the characteristic scintigraphic pattern of blood-pooling on delayed images. There was excellent agreement between 2 independent observers concerning interpretation of tomographic images (89% for the hemangioma group and 100% for other patients). Therefore 99mTc-RBC scintigraphy with tomography is an accurate diagnostic technique in the investigation of cavernous hemangiomas. Its major value resides in its ability to distinguish hemangiomas from other types of hepatic pathology.
Carcinoma, Hepatocellular↗
The effects of cell density, attachment substratum and dexamethasone on spontaneous apoptosis of rat hepatocytes in primary culture.
The rates of spontaneous cell detachment, cell viability, and apoptosis in primary cultures of rat hepatocytes plated at high and low density were compared. Apoptosis was frequent in detached cells, and the rates of cell detachment and apoptosis were greater in high-density than in low-density cultures. Among attached cells, more cells had condensed or fragmented nuclei in high-density than in low-density cultures. Further, ladder-like DNA fragmentation was not seen in low-cell-density cultures but was clearly evident in high-density cultures. Bax was more highly expressed in cells cultured at high density, and on collagen vs. matrigel, whereas changes of Bcl-2 and Fas expression observed in culture appeared unrelated to the rate of apoptosis. The rate of hepatocyte apoptosis appeared to be identical in low-density cultures on collagen 1 and matrigel, but when cells were cultured at high density, matrigel suppressed apoptosis by more than 50% at 36 h. In hepatocytes cultured on collagen 1, dexamethasone (0.1 microM) suppressed apoptosis in both low- and high-density cultures; higher doses had no further effects. In high density cultures, aurintricarboxylic acid (10 microM) suppressed apoptosis and this improved cell attachment at 48 h. It is concluded that cell viability in primary cultures of rat hepatocytes grown on collagen I is dependent on optimal culture density and that the cell population is regulated, at least in part, by apoptosis. Corticosteroids suppress spontaneous apoptosis of cultured hepatocytes in a non-dose-dependent manner, whereas matrigel abolishes apoptosis induced by increasing cell density. Bax may be an important protein in the cell density and cell matrix-dependent regulation of apoptosis in cultured hepatocytes.
Animals↗
The interaction of cigarette smoking and chronic drug ingestion on human drug metabolism.
1. Drug metabolism was assessed by the disappearance rate of antipyrine as measured in saliva. Results were expressed in terms of both clearance and half life. 2. Basal measurements of antipyrine disappearance rate were performed in seven non-smokers and six smokers. After administration of glutethimide 250 mg daily for 7 days a second measurement of antipyrine disappearance rate was made. 3. Glutethimide enhanced antipyrine metabolism in both smokers and non-smokers. The degree of change in both groups was similar. 4. A similar study was carried out with a smaller dose (125 mg) of glutethimide. There was no significant difference between smokers and non-smokers.5. The data are consistent with smoking and chronic drug ingestion having additive effects on enhancement of hepatic drug metabolism.
Adult↗
Effect of genetic obesity and experimental diabetes on hepatic microsomal mixed function oxidase activities.
In male rats, genetic obesity and experimental diabetes are associated with altered activities of several of the hepatic microsomal P-450 isozymes concerned with steroid and xenobiotic oxidation. The present study examined the roles of insulin and ketonaemia in effecting these changes. In obese male Zucker rats, androstenedione 6 beta-, 16 alpha- and 16 beta-hydroxylase activities (mediated by P450PCN-E, P-450UT-A and P450PB-B, respectively) were significantly decreased to 21%, 20% and 43% of lean control. Obesity was also associated with a significant decrease in the activities of N-nitrosodimethylamine demethylase (P-450j) and aniline p-hydroxylase to about 70%. A similar decrease in total microsomal P-450 was also observed. Androstenedione 7 alpha-hydroxylase activity (mediated by P-450UT-F) was unchanged in these animals. In streptozotocin-induced diabetic male Wistar rats, androstenedione 7 alpha- and 16 beta-hydroxylase activities were significantly elevated to 230% and 270% of control, respectively. Significant increases in the rates of N-nitrosodimethylamine demethylase and aniline p-hydroxylase were also noted in diabetic rat liver. In contrast, the activity of P-450UT-A was reduced to 30% of control and P-450PCN-E-specific 6 beta-hydroxylation was unchanged. Control of the diabetic state with insulin treatment reversed all the changes in P-450-mediated activities. Significant correlations were found between serum concentrations of insulin and catalytic activities of P-450PB-B (rho = -0.46), P-450UT-F (rho = -0.65) and P-450j (rho = -0.71). Positive correlations of the same magnitude were also found between these mixed function oxidase activities and beta-hydroxybutyrate.(ABSTRACT TRUNCATED AT 250 WORDS)
Aniline Hydroxylase↗
The Journal of Gastroenterology and Hepatology: the first five years ... and the next.
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Forecasting↗
Non-alcoholic steatohepatitis: impaired antipyrine metabolism and hypertriglyceridaemia may be clues to its pathogenesis.
Non-alcoholic steatohepatitis resembles alcoholic liver disease in hepatic morphology but appears to have a different natural history. We sought to assess the nature of non-alcoholic steatohepatitis by a prospective study of its clinical progression and the relationship of biochemical abnormalities to changes in serum lipids among 15 patients with this disorder. In addition, antipyrine clearance (Cl-AP), which reflects hepatic microsomal oxidative capacity, was measured serially. Although initial liver histology included micronodular cirrhosis in five cases and bridging fibrosis in another three, only one patient developed a hepatic complication during 1-10 years (median: 3.7) of follow up. This confirms the relatively benign nature of non-alcoholic steatohepatitis. Moreover, Cl-AP, which was below the normal range in 13 patients, did not change significantly during 10-40 months of follow up. However, compared with other chronic liver diseases, the reduced Cl-AP was disproportionately low relative to the uniformly normal serum albumin concentration and other indices of hepatic metabolic function. This is consistent with selective impairment of endoplasmic reticular drug oxidizing enzymes. Hyperlipidaemia was present in 11 patients. In three of these, diet-induced correction of serum triglyceride elevation was associated with reduction of hepatocellular damage as indicated by serum enzyme levels. A hypothesis that unites these and earlier findings is that release of cytokines may occur in non-alcoholic steatohepatitis and produce accumulation of free fatty acids in the liver, leading to focal necro-inflammatory lesions and the destruction or down-regulation of cytochrome P450.
Adult↗
Hepatitis C as the cause of chronic non-A, non-B hepatitis: high sensitivity of simultaneous measurement of core and non-structural antibodies.
First generation serologic tests (ELISA-1) for hepatitis C virus infection measure antibodies directed against a short non-structural segment of the virus (anti-c100-3). A major disadvantage of this test is that it lacks sensitivity in the identification of hepatitis C virus among patients at risk of infection. Thus, only 70-90% of chronic non-A, non-B cases are ELISA-1 positive. The present study set out to determine whether antibodies directed against the core region would be a more sensitive indicator of hepatitis C virus infection in patients with chronic non-A, non-B hepatitis. Sera were studied from 97 patients with raised serum alanine aminotransferase levels for more than 6 months in whom other causes of abnormal alanine aminotransferase were excluded. Using ELISA-1, 85 sera (87%) were anti-c100-3 positive. Sera were then tested for presence of antibody directed against Po, a core peptide of a Japanese strain of hepatitis C virus, using an ELISA method. Eighty-eight sera (91%) were anti-Po positive. Among the 12 anti-c100-3 negative patients, six were anti-Po positive. A second generation ELISA for anti-HCV (ELISA-2) incorporates a different antibody to the core region (c22-3) in addition to an expanded non-structural region, c200, which consists of c100-3 plus c33c. With these tests, all sera but one were positive, including 11 of 12 ELISA-1 negative and eight of nine anti-Po negative sera.(ABSTRACT TRUNCATED AT 250 WORDS)
Chronic Disease↗
Portal vein thrombosis associated with prolonged ingestion of oral contraceptive steroids.
The case is described of a 38 year old woman who developed severe right upper quadrant abdominal pain that was associated with partial portal vein occlusion, as confirmed by flow Doppler ultrasonography and dynamic contrast computed tomography. The patient was a cigarette smoker and had taken combined oestrogen/progestagen oral contraceptive steroids (OCS) continuously for 24 years. There were no other risk factors for portal vein thrombosis or for thromboembolic disease. Following anticoagulant therapy and discontinuation of OCS complete recovery occurred. The case is reported to draw attention to portal vein thrombosis as an extremely rare complication of OCS.
Adult↗
Role of the oestrogen receptor in liver regeneration in the male rat.
Partial hepatectomy in male rats results in raised serum oestrogen levels, nuclear binding of oestrogen receptor (ER) and feminization of certain aspects of hepatic metabolism. It has been proposed that these changes may have an important role in liver regeneration. The present study was performed to ascertain the effects of the oestrogen agonist diethylstilbestrol (DES), 2 mg/kg, and the oestrogen antagonist tamoxifen (TAM), 2 mg/kg, on liver regeneration induced by partial hepatectomy in the male rat. Regenerative activity was determined by incorporation of [3H]-thymidine into hepatic DNA as well as by measurement of liver remnant weight. Following partial hepatectomy, there was a trend towards an increase in liver remnant weight at 24 h in rats treated with DES (DES, 5.95 +/- 1.52 g; vehicle, 4.87 +/- 0.66 g; P = 0.06) though by 48 h no effect was found. Tamoxifen treatment did not significantly affect liver weight at 24 h but by 48 h there was a highly significant reduction in liver remnant weight (TAM, 5.41 +/- 0.85 g; vehicle, 7.31 +/- 1.43 g; P < 0.001). Neither DES nor TAM treatment influenced liver regeneration as determined by [3H]-thymidine incorporation into hepatic DNA. We conclude that pharmacologic manipulation of oestrogens does not influence the initiation of the regenerative process but that oestrogen may facilitate later phases of hepatic growth.
Animals↗
Reciprocal control of apoptosis and proliferation in cultured rat hepatoma arl-6 cells: roles of nutrient supply, serum, and oxidative stress.
In order to understand how cancer cells accumulate, rat hepatoma ARL-6 cells were cultured for 8 d to identify factors involved in spontaneous cell proliferation and apoptosis. With increasing time in culture, the proportion of cells in the proliferative phases of the cell cycle and the rate of deoxyribonucleic acid (DNA) synthesis decreased. The waning of proliferation was associated with a gradual reduction of cell viability, and this was temporally related to the appearance of typical apoptotic morphology and DNA laddering. Medium replacement or supplementation with fetal calf serum (FCS) suppressed apoptosis, while medium change, but not fetal calf serum alone, enhanced cell proliferation. Apoptosis was also suppressed by dimethyl sulfoxide (DMSO), but supplementary glutathione was without effect. Expression of poly(adenosine diphosphate[ADP]-ribose)polymerase peaked on days 34 of culture, and was followed by a progressive decrease thereafter, consistent with proteolytic cleavage. This decrease was prevented to varying extents by complete medium replacement, FCS and DMSO, indicating a close temporal relationship between poly(ADP-ribose)polymerase activation and apoptosis. Expression of Fas and Bcl-2 did not change appreciably over the 8-d culture, but there was a gradual increase in Bax expression; medium change, FCS and DMSO all partly inhibited Bax expression. These data indicate that spontaneous apoptosis in cultured ARL-6 cells is inversely related to cell proliferation, and that nutrient supply, and to a lesser extent, serum-derived factors and oxidative stress modulate apoptosis in this system. Proteolytic cleavage of poly(ADP-ribose)polymerase and expression of Bax are likely to be mechanistically involved with the control of spontaneous apoptosis in ARL-6 cells, whereas changes in the levels of Fas and Bcl-2 do not play a role.
Animals↗
The hepatic side-effects of drugs.
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Acetaminophen↗