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Biomedical subjects

C D Gove

Publications and source records attributed to C D Gove.

33 records · Page 2Linked to original sources
PubMed1989

Immunohistochemical demonstration of the asialoglycoprotein receptor in rat liver by a sensitive avidin-biotin technique.

An immunohistochemical technique for the detection of the hepatic asialoglycoprotein receptor (ASGP-R) in cryostat sections of liver by polyclonal and monoclonal anti-ASGP-R antibodies is described. The procedure is based on the alkaline-phosphatase-avidin-biotin complex (ABC-AP) system and important features include fixation of the sections with periodate-lysine-paraformaldehyde (with or without dichromate) and an absolute requirement for blocking of endogenous biotin activity. The sensitivity of the technique is such that binding to ASGP-R can be detected with femtomolar concentrations of monoclonal anti-ASGP-R antibodies and, with polyclonal antisera, approaches that of a radioimmunoassay.

Animals↗
PubMed1988

Inhibition of bile secretion in the rat by serum ultrafiltrates and fractions from patients with fulminant hepatic failure.

The effects of serum ultrafiltrates and fractions from patients with fulminant hepatic failure (FHF) on bile production in the rat were investigated. When serum ultrafiltrates (mol. wt less than 10,000) were infused into the portal vein bile flow showed a significant decrease with FHF ultrafiltrate (90.4 +/- s.e. 2.0% of baseline at the end of infusion, n = 4) compared with a small increase on infusion of normal ultrafiltrate (107.9 +/- 3.4%, n = 6, P less than 0.025). Bile acid output was significantly decreased by FHF ultrafiltrate (62.0 +/- 2.3%., P less than 0.005). Chromatography of the ultrafiltrates on Sephadex G-25 gave two fractions from FHF serum which produced similar changes as with whole ultrafiltrate on bile secretion. Thus, toxic substances accumulating in the circulation of patients with FHF could reduce bile flow and impair the recovery of hepatic function.

Adult↗
PubMed1987

Reduced brain Na+, K+-ATPase activity in rats with galactosamine-induced hepatic failure: relationship to encephalopathy and cerebral oedema.

Previously we have shown that sera from patients with fulminant hepatic failure (FHF) will inhibit partially purified rat brain Na+, K+-ATPase and sodium efflux from human leucocytes in vitro. Similar inhibition may be involved in the pathogenesis of encephalopathy and cerebral oedema in these patients. In the present study we have attempted to establish whether the activity of brain Na+, K+-ATPase is decreased in vivo in rats with D-galactosamine induced hepatic failure using homogenates of snap-frozen brains. Na+, K+-ATPase activity was significantly reduced in the forebrain region at the stage of mild encephalopathy (43 h after injection), while at the deeper stage of coma (43-53 h after injection) enzyme activity was further reduced in the forebrain region and was also significantly reduced in the hindbrain region. Ouabain insensitive ATPase activity was not significantly altered at any time. While a significant increase in the water content (0.5%) of the hindbrain region was found 43 h after galactosamine, there was no clear correlation between the development of cerebral oedema and the reduction of Na+, K+-ATPase activity. The activity of partially purified normal rat brain Na+, K+-ATPase was 15% lower when incubated with sera from rats in the deep stage of coma compared with control sera. These data support other evidence that the reduction in brain Na+, K+-ATPase is likely to be due to toxic substance circulating in serum which have been shown to inhibit this enzyme in vitro and to cause coma when administered to normal animals.

Acute Disease↗
PubMed1985

Fibronectin and Kupffer cell function in fulminant hepatic failure.

The relationship between plasma fibronectin, in vitro plasma opsonic activity, which measures the biological activity of fibronectin, and in vivo Kupffer cell function, as assessed by the systemic clearance of microaggregated [125I]albumin, were determined simultaneously in 15 patients with fulminant hepatic failure and 12 normal subjects. Both the plasma fibronectin and plasma opsonic activity were significantly reduced in patients with fulminant hepatic failure, while the systemic clearance of microaggregated albumin was decreased. There was a significant correlation between plasma fibronectin and the plasma opsonic activity on admission, but no correlation could be detected between either parameter and the clearance of microaggregated albumin. A gelatin-derived plasma expander was shown to block the plasma opsonic activity both in vitro and in vivo. The low plasma fibronectin and decreased clearance of microaggregated albumin in fulminant hepatic failure reflect different aspects of the overall impairment of Kupffer cell function.

Adolescent↗
PubMed1984

Inhibition of partially purified rat brain Na+, K+-dependent ATPase by bile acids, phenolic acids and endotoxin.

Sera from patients with fulminant hepatic failure (FHF) has previously been shown to contain substance(s) which inhibit leucocyte ouabain-sensitive sodium efflux and rat brain Na+, K+-dependent ATPase in vitro. Similar effects in the patients could be an important mechanism in the development of encephalopathy and cerebral oedema. In previous studies, bilirubin, free fatty acids and mercaptans have been shown to inhibit Na+, K+-ATPase in vitro. The present report is concerned with the effects of a number of other potentially toxic substances present in the serum of patients with FHF. Chenodeoxycholic acid, p-hydroxyphenyllactic acid, p-hydroxyphenylpyruvic acid and endotoxin caused 30-45% inhibition of partially purified rat brain Na+, K+-ATPase at concentrations known to occur in the serum of patients with FHF. At low concentrations the inhibitory effects of these substances were additive, but at higher concentrations a maximum level of inhibition was reached. These further substances are likely, therefore, to be of importance in the disturbances of brain function found in FHF.

Animals↗
PubMed1984

Removal of inhibitors of brain Na+, K+-ATPase by hemoperfusion in fulminant hepatic failure.

Serum from patients with fulminant hepatic failure inhibits rat brain Na+, K+-ATPase activity in vitro. The effect of hemoperfusion on the level of inhibition was investigated with both resin and charcoal columns in clinical use. In the patient perfusions, the mean inhibitory activity of serum fell from 34.7 +/- 1.6 (SE) to 20.9 +/- 1.5% compared with pooled control serum when a resin column was used for the first time and from 26.9 +/- 2.2 to 20.4 +/- 1.7% with charcoal hemoperfusion, a statistically significant (p less than 0.01) removal in both groups. Column chromatography on Sephadex G-25 of material eluted from the resin column post-hemoperfusion and of serum ultrafiltrates before and after in vitro adsorption with charcoal showed considerable overlap in the profile of the substances removed, but with some peaks removed by only one adsorbent. Combinations of resin and charcoal in one hemoperfusion should remove a wider range of potentially toxic substances.

Adsorption↗
PubMed1982

Reticuloendothelial system and hepatocytic function in fulminant hepatic failure.

Kupffer cell and hepatocyte function were studied in 36 patients with fulminant hepatic failure by measurement of clearance of 125I microaggregated albumin (125IMAA) and galactose, respectively. Both were impaired but there was no correlation with final outcome, although on sequential testing 48 hours later, those patients who survived had a significantly greater improvement in Kupffer cell and hepatocyte function. In six other patients with similar hepatocyte dysfunction but no encephalopathy, Kupffer cell function was not significantly different from that of controls. This is additional support for a possible relation between encephalopathy and damage to Kupffer cell function. The latter was also shown to correlate with renal failure; this is consistent with the suggestion that endotoxaemia is important in the pathogenesis of this complication.

Adolescent↗
PubMed1982

Rapid inhibition of DNA synthesis in hepatocytes from regenerating rat liver by serum from patients with fulminant hepatic failure.

The acute effects of serum from patients with fulminant hepatic failure (FHF) on isolated hepatocytes from normal and regenerating rat livers were investigated. DNA and protein synthesis monitored by following the incorporation of [6-3H]-thymidine and [U-14C]-1-leucine into acid-precipitable material was accelerated in hepatocytes from regenerating livers. A specific inhibitory effect of FHF serum on DNA synthesis in hepatocytes from regenerating livers was found. DNA and protein synthesis was inhibited in normal rat hepatocytes by normal serum, the inhibition being less with FHF serum. Cell integrity assessed by leakage of lactate dehydrogenase was not affected by normal or FHF serum. These findings may explain the reduced rate of hepatic regrowth in patients with FHF. Identification of the substances involved will assist in the design of artificial liver support systems and may improve prognosis in this condition.

Animals↗
PubMed1981

Circulating lysosomal enzymes and acute hepatic necrosis.

The activities of the lysosomal enzymes acid and neutral protease, N-acetylglucosaminidase, and acid phosphatase were measured in the serum of patients with fulminant hepatic failure. Acid protease (cathepsin D) activity was increased about tenfold in patients who died and nearly fourfold in those who survived fulminant hepatic failure after paracetamol overdose, whereas activities were increased equally in patients with fulminant hepatic failure due to viral hepatitis whether or not they survived. A correlation was found between serum acid protease activity and prothrombin time, and the increase in cathepsin D activity was sustained over several days compared with aspartate aminotransferase, which showed a sharp early peak and then a fall. Circulating lysosomal proteases can damage other organs, and measurement of their activity may therefore be of added value in assessing prognosis in this condition.

Acetylglucosaminidase↗
PubMed1979

Catabolic effects of adrenaline and angiotensin II in the perfused liver of normal and genetically obese (ob/ob) mice.

1. Rapid effects of hormones on the metabolism of glycogen and fatty acids were studied in the perfused liver of normal and genetically obese (ob/ob) mice. 2. In livers from normal and obese mice adrenaline and angiotensin II stimulated glycogenolysis. 3. These hormones inhibited the synthesis de novo of long-chain fatty acids in livers from normal mice, but not in livers from obese mice. 4. The proportion of acetyl-CoA carboxylase in the active form was decreased by adrenaline but not by angiotensin II in livers from obese mice. 5. The potency of hormone effects on liver suggests that they could occur in the intact animal. 6. The results add to the evidence that hepatic fatty acid synthesis in genetically obese (ob/ob) mice is irreversibly resistant to inhibition by a range of hormones. Such resistance could be of primary significance in the pathogenesis of the obesity.

Acetyl-CoA Carboxylase↗
PubMed1978

Effects of glucagon and insulin on fatty acid synthesis and glycogen degradation in the perfused liver of normal and genetically obese (ob/ob) mice.

1. Rapid effects of hormones on glycogen metabolism and fatty acid synthesis in the perfused liver of the mouse were studied. 2. In perfusions lasting 2h, of livers from normal mice, glucagon in successive doses, each producing concentrations of 10(-10) or 10(-9)M, inhibited fatty acid and cholesterol synthesis. In perfusions lasting 40--50 min, in which medium was not recycled, inhibition of fatty acid synthesis was only observed with glucagon at concentrations greater than 10(-9)M. This concentration was about two orders of magnitude higher than that required for the stimulation of glycogen breakdown. Glucagon did not inhibit the activity of acetyl-CoA carboxylase, assayed 10 or 20 min after addition of glucagon (10(-9) or 10(-10)M). It is proposed that the action of glucagon on hepatic fatty acid biosynthesis could be secondary in time to depletion of glycogen. Insulin prevented the effect of glucagon (10(-10)M) on glycogenolysis, but not that of vasopressin. 3. Livers of genetically obese (ob/ob) mice did not show significant inhibition of lipid biosynthesis in response to glucagon, although there was normal acceleration of glycogen breakdown. This resistance to glucagon action was not reversed by food deprivation. Livers of obese mice exhibited resistance to the counteraction by insulin of glucagon-stimulated glycogenolysis, which was reversible by partial food deprivation.

Acetyl-CoA Carboxylase↗
PubMed1978

Fatty acid synthesis in the regenerating liver of the rat.

1. Synthesis de novo of fatty acids in the rat liver, measured per g wet wt. of tissue, was increased by a factor of about two, between 1 and 4 days after partial hepatectomy, compared with rates in sham-operated control rat livers. 2. There were no associated changes in the rates of liver cholesterol synthesis or of adipose-tissue fatty acid synthesis in rats after partial hepatectomy, compared with rates in sham-operated rats. 3. In regenerating livers, perfused under three different conditions, there was no alteration in the capacity for fatty acid synthesis compared with that of control rats. 4. The increased synthesis of fatty acids in regenerating liver was associated with insignificant increases in plasma concentrations of tricylglycerols and free fatty acids, with a decrease in content of liver glycogen, and with no change in hepatic activity of acetyl-CoA carboxylase. 5. The accelerated rate of synthesis of fatty adids in regenerating liver appears not to be due to any intrinsic alteration in hepatic capacity for fatty acid synthesis, but it may be caused by the continuous action on liver of unidentified circulating factors.

Acetyl-CoA Carboxylase↗
PubMedDate not supplied

Inhibition of rat brain Na+,K+-ATPase activity by serum from patients with fulminant hepatic failure.

Among the toxins accumulating in the circulation of patients with fulminant hepatic failure (FHF) are substances which inhibit leucocyte ouabain-sensitive sodium transport. A similar inhibition of brain Na+,K+-ATPase could lead to both coma and cerebral edema found in these patients which are associated with high mortality. In this study, we have investigated the effect of sera from FHF on normal rat brain Na+,K+-ATPase activity in vitro. Serum from patients with FHF significantly decreased the ouabain-sensitive Na+,K+-ATPase activity (13.58 +/- S.D. 2.60 mumoles Pi mg protein-1 hr-1) in the rat brain membrane preparation in vitro as compared to normal serum (20.33 +/- 3.24 mumoles Pi mg protein-1 hr-1, p less than 0.001). A final serum dilution of 1 in 40 was required to abolish the inhibition of Na+,K+-ATPase activity. Cerebrospinal fluid obtained at postmortem from FHF patients also contained the inhibitory substances. Serum from patients in coma due to decompensated chronic liver disease inhibited the Na+,K+-ATPase activity (17.25 +/- 1.37 mumoles Pi mg protein-1 hr-1), but this was less marked than with FHF serum. Hence, the inhibition of brain Na+,K+-ATPase by substances accumulating in the serum in FHF may be important in the pathogenesis of hepatic coma.

Adult↗