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Biomedical subjects

E Sutherland

Publications and source records attributed to E Sutherland.

34 records · Page 2Linked to original sources
PubMed1983

Metronidazole in the treatment of intra-abdominal sepsis.

A study of antibiotic treatment of intra-abdominal sepsis was conducted between May 1978 and May 1981. In the first phase, clindamycin (C) was compared with metronidazole (M), each combined with tobramycin (T), in a prospective, double-blind, randomized study. Twenty-three patients received C + T and 34 patients received M + T. The two groups were similar with respect to age, gender, underlying disease, presence of abscess, clinical condition, severity of illness, duration of illness before treatment and bacteriology. Anaerobic organisms outnumbered facultative and aerobic organisms. Bacteroides fragilis and Escherichia coli predominated. In the C + T group of patients, 74% had a good response. In the M + T group, 83% had good results. Adverse effects were few and minor in the two treatment groups. Three patients on C + T and one who received M + T followed by C + T died of infections; two patients died of underlying disease. In the second, open phase of the study, M + T was used to treat 45 patients with 46 courses. Twenty patients had intra-abdominal abscesses, which represented all grades of severity of illness. Five patients received long-term corticosteroid therapy. Almost half the patients had peritonitis complicating appendicitis. Good results were obtained in 81%. One patient died of the underlying disease and one died of infection complicating severe trauma and hypovolemic shock.

Abdomen↗
PubMed1980

Prospective, randomized, double-blind comparison of metronidazole and tobramycin with clindamycin and tobramycin in the treatment of intra-abdominal sepsis.

In a prospective, double-blind study, clindamycin was compared with metronidazole, each combined with tobramycin and all by the intravenous route in the treatment of intra-abdominal sepsis. Twenty-three patients received clindamycin and 34 patients received 35 courses of metronidazole. Analysis of the clinical responses of patients indicates that the two antibiotic regiments are of equal efficacy in that there was no difference between them in terms of defervescence or duration of infection. Few adverse effects were noted, and all appeared to be of a minor nature.

Abdomen↗
PubMed1980

Reversal of ethinyl estradiol-induced bile secretory failure with Triton WR-1339.

The effects of Triton WR-1339 and phenobarbital on ethinyl estradiol bile secretory failure were examined to determine the mechanism responsible for decreased bile salt excretion. When administered to ethinyl estradiol-treated rats, Triton WR-1339 restored bile salt independent bile flow and maximum taurocholate transport, whereas phenobarbital corrected bile flow only. Ethinyl estradiol decreased the activities of Na(+)-K(+)-ATPase, 5'-nucleotidase, while increasing the activities of Mg(++)-ATPase and alkaline phosphatase. In contrast to these heterogeneous changes in surface membrane enzyme activities, the number and affinity of [(14)C]cholic acid carriers were not altered. When administered in vivo or added directly to surface membrane fractions Triton WR-1339 restored the activities of Na(+)-K(+)-ATPase and Mg(++)-ATPase of rats treated with ethinyl estradiol through a process that did not require protein synthesis (unaffected by cycloheximide). Phenobarbital also restored the activity of Na(+)-K(+)-ATPase to control levels, but, unlike Triton WR-1339 it did not correct the defect responsible for reduced bile salt secretion. Ethinyl estradiol increased the concentration of cholesterol esters in surface membrane fractions. When administered to ethinyl estradiol-treated rats, Triton WR-1339 restored cholesterol ester concentrations to normal, whereas phenobarbital did not. These combined data suggest that decreased or altered bile salt carriers or reduced sodium driving forces resulting from impaired activity of Na(+)-K(+)-ATPase are not responsible for decreased bile salt excretion in ethinyl estradiol-treated rats. It is proposed that the diverse changes in surface membrane function, which are associated with ethinyl estradiol bile secretory failure, may be the result of a generalized alteration in membrane lipid structure.

Animals↗
PubMed1979

Rate limitation of (Na+ + K+)-stimulated adenosinetriphosphatase by membrane acyl chain ordering.

A somatic cell mutant (CR1) of the Chinese hamster ovary cell line (CHO-K1) that is defective in the regulation of cholesterol biosynthesis can be grown under conditions in which plasma membranes from these cells display various cholesterol contents and acyl chain order parameters. The (Na+ + K+)-stimulated adenosinetriphosphatase (ATP phosphohydrolase, EC 3.6.1.3) from these cells was shown to vary in activity by a factor of 10 as the order parameter was varied, and the activity exhibited an exponential dependence on this parameter. Under these conditions the number of Na+,K+-ATPase molecules was shown to remain constant by affinity labeling with [gamma-32P]ATP in the absence of Na+. Control experiments showed that alteration in cholesterol content without change in order parameter did not result in altered enzyme activity. It is concluded that, under our conditions, the rate of catalysis by the Na+,K+-ATPase is determined by the order parameter. These studies suggest a physical mechanism by which variation of membrane lipid composition or other factors that determine membrane lipid acyl chain order parameter can result in variation in membrane enzyme activity.

Acylation↗
PubMed1979

Regulation of hepatic transport of bile salt. Effect of protein synthesis inhibition on excretion of bile salts and their binding to liver surface membrane fractions.

The overall transport of bile salts across the hepatocyte is characterized as a carrier-mediated process whose rate-limiting step is biliary secretion. Specific bile salt binding proteins have been identified in liver surface membrane fractions and were postulated to represent the initial interaction in bile salt translocation across both the sinusoidal and canalicular membranes. To test this hypothesis, cycloheximide was administered to rats to inhibit hepatic protein synthesis. 16 h after cycloheximide administration [14C]leucine incorporation into hepatic protein was inhibited by 93% at 1 h and 47% at 12 h. However, values of liver function tests were not increased, although serum albumin, serum alanine amino-transferase, and alkaline phosphatase were significantly decreased. Light and electron microscopy did not demonstrate necrosis or fat accumulation. The latter demonstrated minimal disorganization of rough endoplasmic reticulum and occasional lamellar whorls. 16 h after cycloheximide administration bile salt independent bile flow, basal bile salt excretion, and basal bile flow were unaltered, but the maximum bile salt transport capacity was reduced to 62% of control and 24 h later to 38%. Decreased bile salt transport was reversible, for it returned to control values after 48 h, when hepatic protein synthesis was also normal. Maximum bromosulfophthalein (BSP) transport, on the other hand, was reduced after 16 h to only 85% of control. Both bile salt and BPS maximum transport capacities decreased with time during inhibition of protein synthesis, apparently following first order kinetics. It was estimated that their half-lives are 20 h for bile salt transport and 55 h for BSP transport. These different turnover rates suggest that cycloheximide does not decrease active transport through generalized hepatic dysfunction or alteration of high energy sources possibly required for transport. The maximum number of [14C]cholic acid binding sites in liver surface membrane fractions was determined by an ultrafiltration assay. They were reduced to 68% of control after 16 h of cycloheximide and to 25% after 24 h. This reduction in the number of binding sites is apparently selective, for the activities of the liver surface membrane enzymes (Na+-K+)ATPase, Mg++-ATPase, and 5'-nucleotidase were not significantly changed. The associated alterations in bile salt transport and the maximum number of binding sites after cycloheximide administration suggests that these receptors may be the bile salt carriers.

Animals↗
PubMed1978

Alterations of hepatic Na+,K+-atpase and bile flow by estrogen: effects on liver surface membrane lipid structure and function.

Administration of the synthetic estrogen ethinyl estradiol (17alpha-ethinyl-1,3,5-estratriene-3,17beta-diol) decreases hepatic Na(+),K(+)-ATPase (ATP phosphohydrolase; EC 3.6.1.3) activity and bile flow to 50% and alters the composition and structure of surface membrane lipid in rats. Although the content of phospholipids was not changed by treatment, free cholesterol (130%) and cholesterol esters (400%) were increased in liver surface membrane fractions. These observations correlate with changes in membrane viscosity, as shown by electron spin resonance probes. Both rotational correlation time, using the isotropic probe methyl (12-nitroxyl)stearate, and the order parameter, determined by the anisotropic probe 5-nitroxylstearic acid, were significantly increased in liver surface membrane fractions from rats treated with ethinyl estradiol. Administration of Triton WR-1339, a nonionic detergent that corrects hepatic and serum lipid changes caused by ethinyl estradiol treatment, restored toward normal elevated membrane lipids and viscosity as well as Na(+),K(+)-ATPase activity and bile flow. Although restoration of normal liver surface membrane structure and function may be due to reversal of abnormal lipid composition, detergents also may directly alter membrane enzyme activity. Addition of Triton WR-1339 in vitro increased Na(+),K(+)-ATPase activity and reduced membrane viscosity of surface membranes from rats treated with ethinyl estradiol. Triton had no effect on either parameter in normal membrane preparations. Studies of membrane structure and function both in vivo and in vitro suggest that alterations in lipid composition may alter Na(+),K(+)-ATPase function and bile flow.

Animals↗
PubMed1977

Hepatic alkaline phosphatase isoenzymes: isolation, characterization and differential alteration.

Although it is generally believed that hepatic alkaline phosphatase is localized to liver plasma membranes, 63% is present in the cytosol fraction after ultracentrifugation of rat liver homogenates. Divalent cation requirements, heat inactivation, pH optima, Km and chemical inhibition characteristics of partially purified alkaline phosphatase enzymes prepared from membrane and cytosol fractions suggested different structural forms. Furthermore, bile duct obstruction and ethinyl estradiol administration preferentially increased membrane-bound alkaline phosphatase activity, while cytosol activity was unaltered. In contrast, phenobarbital treatment decreased membrane-bound alkaline phosphatase and increased cytosol activity. These studies support the presence of two forms of hepatic alkaline phosphatase in rat liver which are regulated by different control mechanisms.

Alkaline Phosphatase↗
PubMed1977

Stimulation of hepatic sodium and potassium-activated adenosine triphosphatase activity by phenobarbital. Its possible role in regulation of bile flow.

Since phenobarbital administration produces a profound increase in bile flow without changing bile acid secretion, we examined whether this drug increases the activity of hepatic sodium-potassium-activated ATPase [Na+-K+)-ATPase], the postulated regulating enzyme in the secretion of bile salt independent bile flow. After freeze-thawing to increase substrate accessibility, (Na+-K+) ATPase activity was determined by ouabain inhibition of total ATPase activity. Its activity was highest in isolated liver surface membrane fractions enriched in bile canalicult. Phenobarbital administration significatly increased (Na+-K+)-ATPase activity in both liver surface membrane fractions as well as liver homogenates. This enhanced activity is apparently selective for other membrane phosphatases and the enzyme activity in other tissues is either unaltered or decreased. Kinetic analysis of (Ka+-K+)-ATPase indicates that phenobarbital treatment increased maximum velocity and half-maximum activation constant was unchanged, consistent with activation of latent molecules or an increased number of enzyme molecules. The latter process seems more likely because cycloheximide prevented phenobarbital induction and activators were not demonstrated in vitro. Examination of the full time course of phenobarbital induction to determine whether phenobarbital increased synthesis or decreased degradation was consistent with increased synthesis since the apparent degradation rates were similar with or without phenobarbital treatment. The apparent half-life for (Na+-K+)-ATPase was estimated to be approximately 2.5 days, consistent with liver surface membrane protein turnover. The correlation of changes in bile flow with (Na+-K+)-ATPase was examined under several experimental situations. Phenobarbital caused a parallel increase in each during the 1st 2 days of greatment: thereafter other factors become rate limiting for flow, since enzyme activity doesn't reach a new steady state until 4-days. Consistent with increased sodium-potassium exchange, bile sodium was unchanged while potasium concentrations were significantly reduced. Changes in both bile flow and (Na+-K+)-ATPase induced by phenobarbital are independent of thyroid hormone. These studies support the postulate that (Na+-K+)-ATPase is an important factor in regulation of bile flow. In addition, phenobarbital enhancement of both bile flow and (Na+-K+)-ATPase is dependent upon de novo protein synthesis.

Adenosine Triphosphatases↗
PubMed1977

Effects of ethinyl estradiol on hepatic microsomal proteins and the turnover of cytochrome P-450.

The effect of ethinyl estradiol, a steroid commonly used in birth control pills and possibly associated with impaired drug metabolism in humans, on the activity of and turnover of components of the hepatic microsomal mixed-function oxidase system was studied in male rats. After 5 days of ethinyl estradiol, 5 mg/kg/day, there was a significant decrease in the activity of ethylmorphine-N-demethylase and in cytochrome P-450, cytochrome b2, and NADPH cytochrome c reductase. Cytochrome P-450 apoproteins were identified within an SDS-polyacrylamide gel system, and the rate of turnover of cytochrome P-450 apoproteins was studied by double-isotope labeling techniques. After 5 days of ethinyl estradiol administration, the rate of degradation of cytochrome P-450 apoprotein was reduced (half-life of 50 hr compared to 24 hr in control), and their relative rate of synthesis was likewise reduced, indicating that a new steady state of protein turnover associated with reduced synthesis rate had been reached. This was confirmed by studies of the effect of ethinyl estradiol on the level of microsomal cytochrome P-450 over a 10-day period.

Animals↗
PubMed1971

Thermal denaturation in acidic solutions of double-helical ribonucleic acid from virus-like particles found in Penicillium chrysogenum. A spectrophotometric study.

1. Two species of double-helical RNA isolated from mycelium of Penicillium chrysogenum were titrated with acid at 25 degrees C and 95 degrees C (solvent 0.1m-sodium phosphate buffer). At 25 degrees C denaturation occurred at about pH3. At 95 degrees C in the denatured form cytosine residues titrated as a simple monobasic acid of pK3.9 compared with pK approximately 2.5 for the native form at 25 degrees C. 2. On thermal denaturation in neutral and acidic solutions one species of RNA (38% rG.rC) ;melted' in three distinct stages, equivalent to a mixture of three species, namely one of about 25% rG.rC, another of about 33% rG.rC and a third of about 46% rG.rC: the relative proportions were 0.25:0.35:0.40. 3. On thermal denaturation in acidic solutions the increase in the fraction of ionized cytosine residues concomitant with the ;melting' of rG.rC base pair also affects the spectrum especially at 280nm and serves to enhance the contribution of rG.rC base pairs at this wavelength. The increment in epsilon((P)) at 280nm on ;melting' an rG.rC base pair approaches 53501.mol(-1).cm(-1) depending on pH, compared with 33501.mol(-1).cm(-1) at pH7. In contrast epsilon((P)) at 280nm is scarcely affected by ;melting' rA.rU base pairs or by the protonization of adenine residues. 4. Changes in the spectrum of Escherichia coli rRNA on denaturation in acidic solutions were studied to yield the mole fractions of rA.rU and rG.rC base pairs ;melting' at particular pH values.

Acids↗