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Biomedical subjects

W G Cooksley

Publications and source records attributed to W G Cooksley.

At least 73 records · Page 4Linked to original sources
PubMed1982

Altered body composition and muscle protein degradation in nutritionally growth-retarded children with cystic fibrosis.

To investigate nutritional growth retardation and the adaptive response to malnutrition in cystic fibrosis (CF), body composition and muscle protein catabolism were studied in nine malnourished CF children and eight healthy controls by anthropometry, measurement of whole body potassium, urinary creatinine excretion, creatinine height index, and urinary 3-methylhistidine excretion, an index of myofibrillar protein catabolism. CF children had a significant deficit of body mass (p less than 0.001), derived from both the body fat and the fat-free compartments, including a deficit in muscle mass (p less than 0.005). A deficit of muscle mass in CF was also reflected by a lower creatinine height index (mean +/- 1 SEM = 0.66 +/- 0.04 in CF, versus 0.85 +/- 0.5 in controls, p less than 0.02). Urinary 3-methylhistidine excretion was elevated in CF children and the mean (+/- 1 SEM) rate of muscle protein catabolism was 0.82 +/- 0.06 versus 0.53 +/- 0.04 kg-1 24 h-1 in CF and controls, respectively (p less than 0.01). 3-Methylhistidine excretion rates did not correlate with severity of disease as assessed by clinical score. We conclude that nutritional growth retardation in CF is characterized by a protein energy deficit resembling that of protein-energy malnutrition, but that in contrast to the normal adaptive response to protein-energy malnutrition, muscle protein catabolism is markedly increased. These data may have important implications regarding the clinical course and prognosis of CF and the design of optimal therapy.

Adipose Tissue↗
PubMed1981

Regulation of plasma ferritin by the isolated perfused rat liver.

The isolated perfused rat liver has been used to investigate the regulation of plasma ferritin in normal, iron-deficient and iron-overloaded states. Both 125I-labelled and non-labelled rat liver ferritins were rapidly cleared from the perfusion circuit with a half-life of approximately 30 min. Perfusion of livers from normal, iron-loaded or iron-deficient rats with blood obtained from normal, iron-loaded or iron-deficient rats showed that the liver takes up plasma ferritin, and releases ferritin into the perfusate to achieve a perfusate ferritin level appropriate to the iron stores of the animal from which the liver was taken. It is concluded that the liver is capable of both uptake and release of ferritin and that within the liver there resides a mechanism which maintains circulating ferritin concentrations at a level appropriate to body iron stores.

Animals↗
PubMed1980

Improved growth and clinical, nutritional, and respiratory changes in response to nutritional therapy in cystic fibrosis.

To investigate the role of nutritional factors in growth and in the clinical, nurtitional, and respiratory status in cystic fibrosis, we studied 12 problem CF patients from six months before to six months after a period of supplemental parenteral nutrition. During the initial six months' observation period on appropriate conventional therapy, the patients (aged 0.5 to 11 years) had inadequate growth and weight gain, a total of 21 active pulmonary infections, and, despite dietary supplements, inadequate ad libitum nutrient intakes. After nutritional therapy, providing a balanced consistent hypercaloric intake for 21 days, catch-up weight gain occurred by one month and continued at six months; catch-up in linear growth was observed by three months and continued at six months. In addition, significantly fewer pulmonary infections were observed in the six months' post-therapy (n = 3), sustained and significant improvements were noted in clinical score and plumonary function, and there was a marked improvement in well-being and ad libitum nutrient intake. We conclude that adequate nutritional support can favorably affect growth, clinical status, and the course of chronic pulmonary disease in problem cases of CF.

Body Weight↗
PubMed1980

Alterations of drug metabolism in rats exposed to cigarette smoke.

In male rats exposed to cigarette smoke, antipyrine clearance was enhanced to the same extent as has been observed in human cigarette smokers. The activity of aryl hydrocarbon hydroxylase, a representative microsomal mixed function oxidase, was increased significantly in lung and kidney of smoke-exposed rats compared with controls. The activity of this enzyme in the liver, however, was not altered by cigarette smoke. Although aryl hydrocarbon hydroxylase activity in extrahepatic tissues was significantly enhanced after cigarette smoke exposures, the total drug metabolizing capacity of these tissues remained trivial compared with that of the liver. Hence, extrahepatic drug metabolism is unlikely to account for enhanced antipyrine elimination in cigarette smokers. The present study has established an animal model for studying the changes produced by cigarette smoke which result in enhanced drug metabolism in man.

Animals↗
PubMed1980

Cell-mediated immunity to liver antigen in toxic liver injury. II. Role in pathogenesis of liver damage.

The possible pathogenetic role of lymphocytes sensitized to liver antigens was investigated in CBA mice in which sublethal hepatic necrosis had been induced by carbon tetrachloride (CCl4). Sensitized lymphocytes from CCl4-treated mice were administered to syngeneic recipients. The recipients developed sensitivity to liver antigens but showed no evidence of liver damage. The cell mediating the immune response both in the donor and the recipient was a T cell. This was demonstrated further by studies involving mice rendered T cell deficient. These mice did not develop sensitized lymphocytes when they were treated with CCl4 but the extent of liver damage was similar in both T cell-depleted and intact animals. These findings suggest that T cell sensitization to liver antigens occurs as a result of toxic liver damage and does not play a role in the pathogenesis of the hepatic necrosis.

Animals↗
PubMed1980

Cell-mediated immunity to liver antigen in toxic liver injury. I. Occurrence and specificity.

To investigate the possible role of cell-mediated immunity in the pathogenesis of liver disease lymphocyte function was studied in CBA mice in which predictable sublethal liver necrosis had been included by the administration of the hepatotoxin carbon tetrachloride (CCl4). Non-specific lymphocyte function, as assessed by the response to the mitogen phytohaemagglutinin (PHA) was normal in over 90 percent of the animals. Forty-three per cent of the treated mice demonstrated specific lymphocyte sensitivity to liver antigen preparations. Such specific sensitivity was transient and apparent in only one case for more than 2 weeks after the CCl4 treatment. The lymphocyte sensitization was not reproduced by the addition of CCl4 to the lymphocyte cultures. There was no correlation between the severity of the liver disease and the detection of sensitized lymphocytes. Although these data may not be extrapolated directly to human liver disease, they demonstrate that cell-mediated immune reactivity to liver-derived antigens can occur as a result of non-immunological toxic liver injury.

Animals↗
PubMed1979

The nature of piecemeal necrosis in chronic active hepatitis.

On the basis of histological studies, it is proposed that the type of liver-cell death in piecemeal necrosis is apoptosis. The characteristic inconspicuousness of apoptosis explains why the mode of hepatocyte elimination in piecemeal necrosis has hitherto remained obscure. Cell-mediated immune attack induces apoptosis, not classical necrosis, and the occurrence of apoptosis in piecemeal necrosis links the observed morphological changes in chronic active hepatitis with the other evidence for an autoimmune pathogenesis. It is significant that apoptosis does not evoke inflammation or fibroplasia. In attempting to elucidate the cause of the fibrosis that accompanies progression to cirrhosis in chronic hepatitis, it may thus be more relevant to study the effect on fibroblasts of substances liberated during lymphocyte-hepatocyte interactions than the death of the hepatocytes.

Autoimmune Diseases↗
PubMed1979

Drug metabolism in liver disease: activity of hepatic microsomal metabolizing enzymes.

The concentration of cytochrome P-450 and activities of the microsomal enzymes aryl hydrocarbon hydroxylase and ethylmorphine demethylase were measured in hepatic tissue obtained at biopsy from 69 patients. Antipyrine half-life (AP t1/2) was measured simultaneously as an in vivo marker of drug metabolism. Values for each index of the drug-metabolizing system varied greatly, but the mean values in groups of patients with mild hepatitis or inactive cirrhosis did not differ significantly from those of controls. Hepatic cytochrome P-450 content and aryl hydrocarbon hydroxylase activity were lower in patients with severe hepatitis or active cirrhosis than in controls, but ethylmorphine demethylase activity was unchanged in the patients. Drug ingestion was associated with enhancement of drug-metabolizing enzymes in all patients but those with severe liver disease; ethylmorphine demethylase activity was enhanced proportionately more than aryl hydrocarbon hydroxylase activity or cytochrome P-450 concentration. The observation that aryl hydrocarbon hydroxylase and ethylmorphine demethylase activities are influenced to a different extent by liver disease and also by drug ingestion indicates functional heterogeneity of the hepatic microsomal drug-metabolizing system in man. Correlations between t1/2 and hepatic drug oxidases were weak, even when allowance was made for variation in liver size. Thus, the rate of drug metabolism in vivo assessed by measuring AP t1/2 does not appear to be closely related to the activity of some hepatic drug-metabolizing enzymes.

Antipyrine↗
PubMed1979

Enhancement of hepatic drug metabolism by glutethimide in patients with liver disease.

A controlled study of the effects of glutethimide on antipyrine metabolism was performed to ascertain how patients with varying degrees of liver damage responded to microsomal enzyme inducing agents. The administration of 250mg glutethimide daily for one week resulted in significant enhancement of antipyrine metabolism in 4 patients with compensated cirrhosis and 5 patients with features of hepatic failure as well as 7 control subjects without liver disease. Even patients with very severe liver disease did undergo microsomal enzyme induction. Changes in antipyrine half-life after glutethimide were directly proportional to the original antipyrine half-life so that the greatest absolute alterations due to enzyme induction occurred in patients with the most severely impaired hepatic function. These results indicate that not only is antipyrine metabolism severely impaired in patients with liver failure, but elimination rates are markedly altered by enzyme inducing agents. Thus, although these results cannot be extrapolated to all inducers of hepatic microsomal enzymes nor to all drugs metabolized by microsomal oxidases, it is suggested that safe and effective management of drug therapy in these patients requires measurement of plasma levels.

Adult↗
PubMed1978

Drug metabolism in liver disease. Identification of patients with impaired hepatic drug metabolism.

Antipyrine half-life (AP t1/2) was measured in 62 patients with, and 10 control patients without, liver disease to ascertain possible factors which may be useful in identifying patients with abnormal drug metabolism. Antipyrine metabolism was normal or marginally impaired in patients with compensated cirrhosis or acute hepatitis, whereas it was frequently abnormal in those with chronic active hepatitis or advanced alcoholic liver disease. A high degree of correlation was found among AP t1/2 and prothrombin time, hepatic encephalopathy, and ascites. Of patients with severely impaired drug metabolism, 80% had one or more of these features. The severity of histological changes in liver biopsies was of additional help in predicting impaired drug metabolism. Concurrent drug ingestion enhanced antipyrine metabolism in most patients with liver disease as well as in control patients. Inadequate diet was associated with prolongation of AP t1/2, but other environmental factors such as alcohol ingestion, cigarette smoking, and coffee consumption did not affect rates of drug metabolism in patients with liver disease. Consideration of all of the above factors allows qualitative predictions of the rate of hepatic drug metabolism in patients with liver disease, as assessed by the AP t1/2.

Acute Disease↗