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Biomedical subjects

W G Cooksley

Publications and source records attributed to W G Cooksley.

At least 55 records · Page 3Linked to original sources
PubMed1988

The effect of smoking on caffeine elimination: implications for its use as a semiquantitative test of liver function.

1. The effects of caffeine ingestion and cigarette smoking on caffeine and antipyrine pharmacokinetics were studied using normal subjects as their own controls before and after cessation of smoking in an attempt to minimize genetic and other environmental influences. 2. Moderate caffeine ingestion had no inducing effect on caffeine or antipyrine clearance. 3. Cessation of cigarette smoking significantly reduced clearance of caffeine and antipyrine. 4. These results demonstrate that cigarette smoking significantly affects caffeine pharmacokinetics and this may contribute to the variable results for caffeine kinetics found in patients with liver disease.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Influence of alcohol and caffeine consumption on caffeine elimination.

Ten healthy male volunteers were each studied on four separate occasions to assess the role of regular caffeine and alcohol intake on caffeine elimination. Antipyrine disappearance was also studied as an established quantitative test of hepatic microsomal function. Regular caffeine intake in high doses for 1 week failed to alter either antipyrine or caffeine pharmacokinetics. In contrast, alcohol intake of 50 g/day significantly prolonged caffeine half-life by 72% (P less than 0.005) and diminished caffeine clearance by 36% (P less than 0.0005). However, antipyrine kinetics were unaltered. These results demonstrate that alcohol, in amounts commonly consumed, is a strong inhibitor of caffeine metabolism.

Adult↗
PubMed1985

Inhibition by ethanol of cardiac protein synthesis in the rat.

Protein synthesis and degradation were measured in the hearts of rats fed on diets containing 27% of calories as ethanol. Feeding of ethanol decreased the rate of synthesis of mixed cardiac proteins but was without effect on the rate of breakdown of myofibrillar and sarcoplasmic proteins. Concentrations of RNA in the hearts were not altered by ethanol feeding, indicating a decrease in RNA activity for protein synthesis.

Animals↗
PubMed1985

A comparison of cobalamin binding by liver and kidney in rat and man.

Binding of cobalamin (Cbl) was compared in liver and kidney plasma membranes prepared from rat and human tissues. Single, high-affinity, saturable (200 pmol/l), binding sites for TC II-Cbl were found in all tissues; by contrast no receptors were present for free cobalamin, for which only non-specific adsorption occurred. Binding constants for TC II-CNCbl determined for liver and kidney plasma membranes were of a similar magnitude. Mean values for Ka (litre/nmol) were 16.7 (rat liver), 18.8 (rat kidney), 8.0 (human liver) and 7.5 (human kidney). Results for binding TC II-OHCbl instead of TC II-CNCbl showed no difference in Ka and Bmax. values, although the non-specific adsorption was decreased to a third. Competitive inhibition results showed that the receptors are specific for the TC II molecule and that binding is unaffected either by the cobalamin moiety or by the presence of free cobalamin. Degradation of the receptor protein molecules by trypsin (10 micrograms/ml) resulted in 90% inhibition of binding. It is concluded that differences between liver and kidney in cobalamin uptake and accumulation cannot be attributed to differences in their TC II receptors.

Animals↗
PubMed1985

The retention of cobalamin by the liver in the cobalamin-deficient rat.

The effect of cobalamin deficiency on whole body cobalamin content and its turnover was examined in the rat. Quantitative and qualitative changes in hepatic cobalamin were also followed and the effect of deficiency on the turnover of this cobalamin was determined in the isolated perfused liver. As cobalamin deficiency developed after total gastrectomy, whole body cobalamin content declined at a constant rate, indicating no attempt to conserve total body cobalamin stores even when depleted (5% of normal). In contrast, the cobalamin concentration of liver declined more slowly, indicating conservation of hepatic cobalamin. Furthermore, the methylcobalamin (MeCbl) content of liver was maintained or even increased. Measurement of the rate of release of cobalamin by the isolated perfused liver at varying times after gastrectomy showed that as depletion of whole body and hepatic cobalamin stores proceeded, the rates of release of hepatic cobalamin into plasma and bile decreased. Regression analysis showed that the fractional rates of release of hepatic cobalamin into plasma (r = 0.9, P less than 0.001, n = 15) and bile (r = 0.65, P less than 0.01, n = 15) were significantly correlated with hepatic cobalamin content. It is concluded that conservation of hepatic cobalamin in deficiency is achieved, at least in part, by a specific decrease in the rate of release of hepatic cobalamin.

Animals↗
PubMed1985

Whole body protein turnover in malnourished cystic fibrosis patients and its relationship to pulmonary disease.

To investigate the effect of pulmonary disease in cystic fibrosis (CF), total body protein synthesis and catabolism were determined in eight CF children with acute exacerbations of pulmonary infection at the time of study (CF I), a group of CF children (n = 7) with chronic but stable pulmonary disease (CF II) and a group (n = 8) of healthy children. Protein synthesis was determined by the method of Waterlow et al (1978) using a single oral dose of 15N glycine and protein catabolism derived from nitrogen balance. Protein synthesis was markedly decreased (p less than 0.001) in the CF I group (1.01 +/- 0.10 g kg-1 10 h-1) compared with that of controls (2.02 +/- 0.08) and with CF children with chronic but stable pulmonary disease (CF II) (2.36 +/- 0.17). Protein catabolism was increased (p less than 0.01) in the CF II group compared with both controls and CF I. These findings contrast strongly to studies in normal children and those with mild protein-energy malnutrition (PEM) and infection, where infection increased protein synthesis, but are consistent with the observed decrease in protein turnover where severe PEM is accompanied by infection. We conclude that repeated pulmonary infection can adversely affect protein-energy balance and that adequate nutritional support should be considered in management during and after each episode.

Adolescent↗
PubMed1985

Apoptosis as the mode of cell death in antibody-dependent lymphocytotoxicity.

A light and electron microscopic study of antibody-dependent lymphocytotoxicity was carried out with the object of elucidating the mechanisms responsible for the cell killing, the basis for the research being the relationship that has recently been shown to exist between the morphology of cell death and its pathogenesis. Chang liver cells coated with a rabbit anti-human antibody were used as targets and normal human peripheral-blood lymphocytes as effector cells. Cytotoxicity assays using release of 51Cr demonstrated extensive K-cell killing, thus validating the suitability of the model for morphological studies. Cell death displaying the features of apoptosis correlated with K-cell activity. A small amount of cell death by classical necrosis was observed, but its extent appeared to be unrelated to the presence of lymphocytes, to pre-treatment of the target cells with antibody, or to the magnitude of 51Cr release. The results support evidence indicating that lymphocytotoxicity depends on activation of a self-destruct program within the target cell. They do not favour a mechanism involving the production of plasma membrane lesions analogous to those responsible for complement-mediated immune cytolysis.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1985

Hepatitis B transmission within families: potential importance of saliva as a vehicle of spread.

We report a family, extensively affected by hepatitis B virus (HBV), in whom sexual or vertical transmission is unlikely to account entirely for the intra-family clustering of the virus. HBV-DNA was detected in saliva in one family member and we suggest that spread by salivary transmission could account for at least some of the intra-family infection and could contribute to the "inapparent parenteral" spread of hepatitis B.

Adult↗
PubMed1985

The effect of acute liver damage on circulating ferritin levels in vivo and in the isolated perfused rat liver.

The effects of minimal acute liver injury on circulating ferritin levels have been examined in the rat both in vivo and in the isolated perfused liver. Liver damage produced by 6 mmol/kg of D-galactosamine (GalN) in vivo resulted in a marked rise in plasma ferritin levels 4 h after administration, 2 h before any significant increase in plasma aspartate transaminase. In the isolated perfused liver, damage produced by 5mM GalN introduced into the perfusate also produced an early increase in circulating ferritin before any evidence of release of intracellular enzymes, or alteration in liver histology as assessed by light microscopy was apparent. It is concluded that minimal acute liver damage results in a pronounced increase in circulating ferritin levels before other evidence of liver dysfunction. This is unlikely to be due solely to increased release from damaged cells but may rather result from an alteration in the mechanism responsible for ferritin homeostasis.

Animals↗
PubMed1984

The regulatory roles of liver and kidney in cobalamin (vitamin B12) metabolism in the rat: the uptake and intracellular binding of cobalamin and the activity of the cobalamin-dependent enzymes in response to varying cobalamin supply.

To examine possible regulatory roles of liver and kidney in cobalamin metabolism, specific activities of the two cobalamin-dependent enzymes, uptake in vivo of cyano [57Co]cobalamin [( 57Co]CNCbl) and the binding of [57Co]Cbl to intracellular proteins were measured in normal, cobalamin-loaded and cobalamin-deficient rats. Cobalamin deficiency and cobalamin loading produced greater changes in cobalamin concentration in the kidney than in the liver. Although cobalamin deficiency resulted in a decrease in total methylmalonyl-coenzyme A mutase (methylmalonyl-CoA mutase) in both organs, cobalamin loading had no effect. Neither deficiency nor loading altered total methyltransferase activity. The holoenzyme activities of both enzymes correlated with changes in tissue cobalamin levels. Uptake of [57Co]Cbl indicated that the kidney, in contrast to the liver, increased its uptake during loading and reduced it during deficiency, suggesting a possible regulatory role for this organ. In the normal rat, 24 h after injection of [57Co]CNCbl, 0.3% of the administered [57Co]Cbl was present in the liver as free cobalamin. By contrast, in the kidney, over 13% of the [57Co]Cbl was present in the free form. During deficiency free renal [57Co]Cbl was reduced to 0.6% of the administered [57Co]Cbl whereas in cobalamin-loaded rats it was increased to more than 27%. It is concluded that alterations in tissue cobalamin levels resulting from differences in cobalamin supply are due to changes in the large pool of free cobalamin present in the kidney and not to changes in the intracellular binding.

Animals↗
PubMed1984

Chronic hepatitis. Aetiology and current management.

The entity of chronic hepatitis has long been an enigma, and its treatment confusing. Recent studies have indicated the importance of excluding causes such as drugs, Wilson's disease and alpha 1-antitrypsin deficiency. After excluding such causes, there are 3 major groups--'autoimmune', hepatitis B, and non-A, non-B (NANB) in all of which an immunological basis for pathogenesis exists. The autoimmune group has been subdivided into a milder type (chronic persistent hepatitis) and a more severe type (chronic active hepatitis) on histological grounds. Corticosteroids are indicated in chronic active hepatitis if cirrhosis or bridging necrosis is present. However, corticosteroids are contraindicated in disease due to the hepatitis B virus where chronic active hepatitis correlates with the presence of replicating virus (serum positive for e antigen, DNA polymerase and HBV-DNA), and in such cases antiviral agents and immunomodulation are being studied. Very little is known about NANB hepatitis in the absence of an assay and there may be more than a single agent. In hepatitis B, the development of serological markers, molecular probes (HBV-DNA), natural animal hepatitis with near-identical viruses, and delta antigen (a virus requiring co-infection with hepatitis B) have all extended our knowledge so dramatically that it is hoped that the enigma of chronic hepatitis will be solved when an assay for NANB hepatitis becomes available.

Adrenal Cortex Hormones↗
PubMed1984

Are the causes and presentation of chronic hepatitis changing? An analysis of 104 cases over 15 years.

We describe the features at presentation of 104 patients with biopsy-proven chronic hepatitis who presented in Brisbane in the period 1968-32. The mean period of follow-up was 59 months. Sex ratio (female : male) was 70 : 34 and the mean age was 37 years (range 3-83). Eighty-five (82 per cent) were born in Australia. Serological evidence of hepatitis B (HBV) infection was present in 24 (23 per cent). Analysis of the HBV marker positive and negative (non-B) groups revealed that the clinical and laboratory features of HBsAg positive chronic hepatitis were much less florid than those of non-B patients. However, the disturbances seen in hepatic histopathology were similar in severity, and the mortality in the HBsAg positive group exceeded that in the non-B group. The relative risk calculated on an actuarial basis was higher in HBsAg positive patients. In contrast to the experience of others, severe chronic active hepatitis remains an important problem in Brisbane but some features of the disease are altering. Several changes may be attributable to the increasing incidence of HBV-associated disease, and in addition, patients aged under 20 with non-B chronic hepatitis are now rarely seen. This is of interest in view of recent reports of decreased incidence of another disease of disordered immune response, rheumatoid arthritis.

Adolescent↗
PubMed1983

Changes in body composition and muscle protein degradation during nutritional supplementation in nutritionally growth-retarded children with cystic fibrosis.

Changes in body composition and muscle protein degradation were studied in seven nutritionally growth-retarded children with cystic fibrosis (CF) before and after nutritional supplementation and in eight healthy children who served as controls. Supplemental feedings consisted of a peptide formula that increased dietary protein and energy intakes approximately 20-40% over a 6-month period, delivered either as oral supplement or overnight intragastric feeding. Body composition was assessed by anthropometric data and measurements of whole body potassium (40K) and creatinine excretion. Muscle protein degradation was measured by urinary 3-methylhistidine excretion, an index of myofibrillar protein catabolism. Compared with controls, CF children had significantly reduced body mass, body fat, and muscle mass, and a significantly increased rate of myofibrillar protein degradation. With nutritional supplementation, significant catch-up weight gain and improved linear growth were observed with evidence of accretion of lean body mass and muscle mass, and in all but one severely malnourished patient with progressive disease, there was normalization of the high rate of muscle protein degradation. Thus, this form of nutritional therapy has significant benefits in terms of body protein accretion and myofibrillar protein degradation.

Adolescent↗
PubMed1983

Mononuclear cell factors that inhibit fibroblast collagen synthesis. I. In vitro conditions determining their production and expression.

Peripheral blood mononuclear cells (PBMC) incubated either with phytohaemagglutinin-P (PHA) under serum-free conditions or with tuberculin purified protein derivative in the presence of 5% human blood group AB serum released into the culture medium factors that decreased collagen synthesis by dermal fibroblasts. These factors were first detected after incubation of PBMC with PHA for 24 h and were produced by non-adherent cells. The decrease in collagen synthesis was observed despite changes in conditions of fibroblast culture, the addition of a cross-linking inhibitor, and the use of different fibroblast cell lines.

Aminopropionitrile↗
PubMed1983

Mononuclear cell factors that inhibit fibroblast collagen synthesis. II. Properties of the factors.

Supernatants harvested from peripheral blood mononuclear cells (PBMC) incubated either with the non-specific mitogen phytohaemagglutinin-P (PHA) or with the specific antigen tuberculin purified protein derivative for 72 h decreased collagen synthesis by dermal fibroblasts. PHA-induced mononuclear cell factors (PHA-MCF) responsible for decreases in collagen synthesis by dermal fibroblasts were localized by column chromatography on Sephacryl S-200 to fractions of 30,000-60,000 daltons. Proteolytic enzymes destroyed the activity of PHA-MCF, but after incubation with neuraminidase some activity of these factors remained. The activity of PHA-MCF was not inhibited by incubation with the monosaccharides L-fucose, L-rhamnose, N-acetylglucosamine, and alpha-methyl-D-mannoside but was partially destroyed by heating at 80 degrees C for 10 min. The factors were not mitogenic to PBMC. These factors did not appear to resemble any previously characterized factors produced by non-adherent mononuclear cells. The mechanism by which these factors decreased fibroblast collagen synthesis appeared complex. There was no detectable increase in the release of collagenase by fibroblasts, nor was a cytotoxic effect apparent. Increased PGE2 production by fibroblasts could not be related to the factor-induced decrease in fibroblast collagen synthesis.

Collagen↗
PubMed1983

Synthesis of antibodies to hepatitis B virus by cultured lymphocytes from chronic hepatitis B surface antigen carriers.

It has been postulated that host immune defects are responsible for the development and persistence of the hepatitis B surface antigen (HBsAg) carrier state. The nature of these defects is unknown, but the absence of a readily detectable antibody response to HBsAg (anti-HBs) may be important. The synthesis of both anti-HBs and antibody to hepatitis B core antigen (anti-HBc) in cultures containing peripheral blood mononuclear cells from chronic HBsAg carriers and from control (antibody-positive) patients was measured in the presence of pokeweed mitogen. Similar amounts of polyclonal IgG and IgM were synthesized by cultures containing lymphocytes from chronic carriers and controls. Anti-HBc was detectable in lymphocyte supernatants from 2 of 20 controls and from 21 of 29 carriers. The presence of anti-HBc synthesis in vitro correlated with high serum titers of anti-HBc. In contrast, anti-HBs was detected in lymphocyte supernatants from 6 of 20 controls (predominantly in those who had high serum titers of anti-HBs) but in none of the supernatants from 29 HBsAg carriers. In order to identify the mechanisms for the lack of detectable anti-HBs synthesis by chronic HBsAg carrier lymphocytes, co-culture experiments were performed using T and B lymphocyte fractions that had been purified by affinity chromatography. B lymphocytes from carriers co-cultured with allogeneic irradiated ("helper") T lymphocytes from controls synthesized normal amounts of IgG, IgM, and anti-HBc but still did not synthesize detectable amounts of anti-HBs. In the converse experiments, B lymphocytes from controls were co-cultured with irradiated T lymphocytes from carriers. The T lymphocytes from 16 of 24 carriers augmented anti-HBs production by control B cells normally, the remaining eight did not. Finally, mixtures of control B cells and control irradiated T lymphocytes were co-cultured with T lymphocytes from chronic HBsAg carriers. 5 of 12 carriers demonstrated active suppression of anti-HBs production, and in three this suppression was specific, as IgG and IgM production remained normal. We conclude that chronic HBsAg carriers have a specific B lymphocyte defect in anti-HBs production. In addition, defects in the function of regulatory T lymphocytes may contribute to the absence of anti-HBs synthesis in some HBsAg carriers.

Adult↗