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Biomedical subjects

S Ewerth

Publications and source records attributed to S Ewerth.

At least 19 recordsLinked to original sources
PubMed1995

[Problem-based learning during surgery courses--good experiences with combination curriculum].

Problem solving and critical thinking are important components of problem based learning (PBL). The driving forces are the students' interest, involvement and sense of responsibility. A curriculum comprising a combination of PBL and conventional instruction was introduced during the surgery course at Huddinge Hospital in the autumn term 1993. The results showed the level of knowledge attained by the students to be comparable with that attained under conventional instruction. The authors of the article conclude that good results can be obtained by introducing PBL in isolated sections of medical education within the framework of an otherwise traditional curriculum.

Attitude↗
PubMed1992

Hepatic cholesterol metabolism in estrogen-treated men.

Operative liver biopsies were obtained from two male patients who developed gallstone disease during estrogen treatment of metastatic prostatic carcinoma. The heparin-sensitive binding of 125I-low-density lipoprotein (LDL) to liver homogenates (reflecting the expression of the LDL receptor) was determined, together with the activities of the rate-limiting enzymes in cholesterol synthesis [3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase], bile acid production (cholesterol 7 alpha-hydroxylase), and cholesterol esterification (acyl CoA:cholesterol acyl transferase). The results were related to data available in 18 patients (5 male, 13 female) who underwent cholecystectomy because of gallstone disease. The hepatic 125I-LDL-binding activity was increased threefold compared with five controls, and the activity of HMG-CoA reductase was increased twofold. There was no major difference in the activities of cholesterol 7 alpha-hydroxylase or acyl CoA:cholesterol acyl transferase. The concentration of free and total cholesterol in liver microsomes was approximately 30% lower in the estrogen-treated men than in 11 controls. The results indicate that estrogen at pharmacological doses stimulates hepatic LDL-receptor expression and HMG-CoA reductase activity in men. The increased LDL-receptor expression could in part explain the enhanced plasma clearance of injected 125I-LDL and hence the reduction in plasma LDL cholesterol previously shown to occur in estrogen-treated men.

Aged↗
PubMed1991

[Effect of pravastatin on hepatic cholesterol metabolism].

BACKGROUND: Inhibitors of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are now used frequently to treat hypercholesterolemia. We studied the effects of specific inhibition of cholesterol synthesis by one of these agents (pravastatin) on the hepatic metabolism of cholesterol in patients with gallstone disease who were scheduled to undergo cholecystectomy. METHODS: Ten patients were treated with pravastatin (20 mg twice a day) for three weeks before cholecystectomy; 20 patients not treated served as controls. A liver specimen was obtained from each patient at operation, and the activities of rate-determining enzymes in cholesterol metabolism as well as low-density-lipoprotein (LDL)-receptor binding activity were determined. RESULTS: Pravastatin therapy reduced plasma total cholesterol by 26 percent and LDL cholesterol by 39 percent (p less than 0.005). Serum levels of free lathosterol, a precursor of cholesterol whose concentration reflects the rate of cholesterol synthesis in vivo, decreased by 63 percent (p less than 0.005), indicating reduced de novo biosynthesis of cholesterol. Microsomal HMG-CoA reductase activity, when analyzed in vitro in the absence of the inhibitor, was increased 11.8-fold (1344 +/- 311 vs. 105 +/- 14 pmol per minute per milligram of protein in the controls; p less than 0.001). The expression of LDL receptors was increased by 180 percent (p less than 0.005), whereas the activities of cholesterol 7 alpha-hydroxylase (which governs bile acid synthesis) and of acyl-coenzyme A: cholesterol O-acyltransferase (which regulates cholesterol esterification) were unaffected by treatment. CONCLUSIONS: Inhibition of hepatic HMG-CoA reductase by pravastatin results in an increased expression of hepatic LDL receptors, which explains the lowered plasma levels of LDL cholesterol.

Adult↗
PubMed1991

Effects of bezafibrate on hepatic cholesterol metabolism.

The influence of bezafibrate treatment on hepatic cholesterol metabolism was studied in rats and in humans. The activities of the three key enzymes involved in cholesterol metabolism [3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol 7 alpha-hydroxylase, and acyl-coenzyme A: cholesterol acyltransferase (ACAT)] were suppressed by bezafibrate treatment in rats, but only the ACAT activity was significantly decreased when the activity was related to total liver weight. In humans, HMG-CoA reductase activity was increased about twice in the treated normolipidemic gallstone patients. In contrast, the concentration of lathosterol in serum decreased, indicating depression of the cholesterol synthesis. The increase in HMG-CoA reductase activity may be a compensatory effect of an inhibition of some other enzymes in the synthesis of cholesterol, as in vitro study on liver microsomes excluded a direct inhibitory effect of bezafibrate on HMG-CoA reductase. The ACAT activity was not significantly changed, and the cholesterol 7 alpha-hydroxylase activity was decreased by 55-60% compared with controls. The LDL-receptor-binding activity was unaffected by bezafibrate treatment.

Animals↗
PubMed1991

Hepatic metabolism of cholesterol in Crohn's disease. Effect of partial resection of ileum.

To study cholesterol metabolism in Crohn's disease and especially the effect of ileum resection, liver biopsy specimens were obtained from patients undergoing partial ileal resection because of Crohn's disease (n = 17) and patients with Crohn's colitis undergoing colectomy (n = 3). Gallstone-free patients (n = 16) undergoing cholecystectomy because of adenomyomas or polyps of the gallbladder served as controls. The mean levels of cholesterol 7 alpha-hydroxylase activity and 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, rate-determining enzymes in bile acid, and cholesterol synthesis, respectively, were twofold to threefold higher in the ileum-resected patients than in the controls. Significant positive correlations were obtained between length of resected ileum and cholesterol 7 alpha-hydroxylase activity. Provided patients who had received total parenteral nutrition preoperatively were excluded from analysis, a significant correlation was also observed between length of resected ileum and 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Significant positive correlations were also obtained between length of resected ileum and serum levels of 7 alpha-hydroxycholesterol (a marker for bile acid biosynthesis) and lathosterol (a marker for cholesterol synthesis). The plasma levels of total and low-density lipoprotein cholesterol were negatively correlated to the length of resected ileum. The expression of hepatic low-density lipoprotein-receptor binding activity was determined in five of the patients and in three of the controls. A significant positive correlation was observed between 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and low-density lipoprotein-receptor binding activity. The results show that malabsorption of bile acids leads to parallel stimulation of cholesterol synthesis, cholesterol degradation, and low-density lipoprotein-receptor expression in human liver. The resulting effect in the present patients was a significant reduction in low-density lipoprotein cholesterol.

Adult↗
PubMed1991

Bile acid sequestrants: mechanisms of action on bile acid and cholesterol metabolism.

Interruption of the enterohepatic circulation of bile acids by cholestyramine or colestipol influences the hepatic metabolism of cholesterol in many ways. The synthesis of bile acids is increased, as reflected by a several-fold increase in the activity of the cholesterol 7 alpha hydroxylase, the rate-determining enzyme in bile acid synthesis. The increased metabolism of cholesterol to bile acids causes an enhanced demand of cholesterol in the hepatocytes which respond with both new synthesis of cholesterol, as reflected in a several-fold increase of the HMG-CoA reductase activity, and increased expression of LDL receptors. As a consequence, the plasma level of LDL-cholesterol is lowered. The hepatic secretion rate of VLDL particles is increased. Cholestyramine therapy does not affect the output of biliary lipids or the cholesterol saturation of bile, indicating that treatment with bile acid sequestrants should not be associated with any increased risk of gallstone formation.

Bile↗
PubMed1990

Influence of pravastatin, a specific inhibitor of HMG-CoA reductase, on hepatic metabolism of cholesterol.

BACKGROUND: Inhibitors of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, are now used frequently to treat hypercholesterolemia. We studied the effects of specific inhibition of cholesterol synthesis by one of these agents (pravastatin) on the hepatic metabolism of cholesterol in patients with gallstone disease who were scheduled to undergo cholecystectomy. METHODS: Ten patients were treated with pravastatin (20 mg twice a day) for three weeks before cholecystectomy; 20 patients not treated served as controls. A liver specimen was obtained from each patient at operation, and the activities of rate-determining enzymes in cholesterol metabolism as well as low-density-lipoprotein (LDL)-receptor binding activity were determined. RESULTS: Pravastatin therapy reduced plasma total cholesterol by 26 percent and LDL cholesterol by 39 percent (P less than 0.005). Serum levels of free lathosterol, a precursor of cholesterol whose concentration reflects the rate of cholesterol synthesis in vivo, decreased by 63 percent (P less than 0.005), indicating reduced de novo biosynthesis of cholesterol. Microsomal HMG-CoA reductase activity, when analyzed in vitro in the absence of the inhibitor, was increased 11.8-fold (1344 +/- 311 vs. 105 +/- 14 pmol per minute per milligram of protein in the controls; P less than 0.001). The expression of LDL receptors was increased by 180 percent (P less than 0.005), whereas the activities of cholesterol 7 alpha-hydroxylase (which governs bile acid synthesis) and of acyl-coenzyme A:cholesterol O-acyltransferase (which regulates cholesterol esterification) were unaffected by treatment. CONCLUSIONS: Inhibition of hepatic HMG-CoA reductase by pravastatin results in an increased expression of hepatic LDL receptors, which explains the lowered plasma levels of LDL cholesterol.

Aged↗
PubMed1990

Low density lipoprotein receptor-binding activity in human tissues: quantitative importance of hepatic receptors and evidence for regulation of their expression in vivo.

The heparin-sensitive binding of 125I-labeled low-density lipoprotein (LDL) to homogenates from 18 different normal human tissues and some solid tumors was determined. The binding to adrenal and liver homogenates fulfilled criteria established for the binding of LDL to its receptor--namely, (i) saturability, (ii) sensitivity to proteolytic destruction, (iii) inhibition by EDTA, and (iv) heat sensitivity. When the binding of 125I-labeled LDL was assayed at a constant concentration (50 micrograms/ml), the adrenal gland and the ovary had the highest binding of normal tissues. The highest binding per g of tissue overall was obtained in homogenates of a gastric carcinoma and a parotid adenoma. When the weights of the parenchymatous organs were considered, the major amount of LDL receptors was contained in the liver. To study the possible regulation of hepatic LDL-receptor expression, 11 patients were pretreated with cholestyramine (8 g twice a day for 3 weeks). Increased binding activity (+105%, P less than 0.001) was obtained in homogenates from liver biopsies from the cholestyramine-treated patients as compared with 12 untreated controls. It is concluded that the liver is the most important organ for LDL catabolism in humans and that the receptor activity in this organ can be regulated upon pharmacologic intervention. Further studies are needed to confirm the possibility that certain solid tumors can exhibit high numbers of LDL receptors.

Adrenal Cortex↗
PubMed1990

Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients.

To characterize the metabolic regulatory response to interruption of the enterohepatic circulation of bile acids, we examined the effects of cholestyramine treatment on the rate-limiting steps in cholesterol biosynthesis (HMG-CoA reductase) and bile acid production (cholesterol 7 alpha-hydroxylase) as well as on the heparin-sensitive binding of low density lipoproteins (LDL) (reflecting LDL receptor expression) in human liver. Altogether, 18 normolipidemic patients with uncomplicated cholesterol gallstone disease were treated with cholestyramine (8 g b.i.d.) for 2-3 weeks prior to cholecystectomy, and another 34 cholesterol gallstone patients served as untreated controls. Cholestyramine treatment stimulated cholesterol 7 alpha-hydroxylase more than sixfold, and increased both HMG-CoA reductase activity (552 +/- 60 pmol/min per mg protein vs 103 +/- 9 pmol/min per mg protein) and LDL receptor expression (6.1 +/- 0.8 ng/mg protein; n = 6 vs 2.2 +/- 0.3 ng/mg protein; n = 7). Moreover, there was a good correlation between HMG-CoA reductase activity and LDL receptor binding (rs = +0.71; n = 13), suggesting a simultaneous stimulatory effect to compensate for the increased hepatic cholesterol catabolism due to bile acid depletion caused by cholestyramine. Further evidence for this assumption was the finding of a significant relationship between cholesterol 7 alpha-hydroxylase activity and both LDL receptor expression (rs = +0.77; n = 13) and HMG-CoA reductase activity (rs = +0.76; n = 46). We conclude that in human liver a parallel stimulation of cholesterol synthesis and LDL receptor expression occurs in response to stimulation of bile acid synthesis.

Adult↗
PubMed1989

Bile acid synthesis in humans: regulation of hepatic microsomal cholesterol 7 alpha-hydroxylase activity.

The present work tested the hypothesis that portal venous bile acids regulate the activity of the cholesterol 7 alpha-hydroxylase and studied the influence of hepatic microsomal free cholesterol concentration on the enzyme activity. Operative liver biopsies and samples of portal venous blood were obtained from a total of 61 patients with gallstones who were undergoing cholecystectomy. Fifteen of the patients were treated with cholestyramine (16 g/day) for 2-3 wk before operation and 23 patients with chenodeoxycholic acid (15 mg/kg.day) or ursodeoxycholic acid (15 mg/kg.day) for 3-4 wk before operation. Highly accurate methods based on isotope dilution-mass spectrometry were used for assay of the cholesterol 7 alpha-hydroxylase activity, the concentration of free cholesterol in the microsomes, and the levels of individual bile acids in portal venous blood. Cholestyramine treatment increased the cholesterol 7 alpha-hydroxylase activity about sixfold, from 7.6 +/- 1.1 (mean +/- SEM) to 45.7 +/- 6.7 pmol/min.mg protein. Administration of chenodeoxycholic acid reduced the enzyme activity considerably to 1.0 +/- 0.3 pmol/min.mg protein, whereas ursodeoxycholic acid did not significantly affect the enzyme activity (7.9 +/- 2.2 pmol/min.mg protein). The concentration of microsomal free cholesterol remained essentially unchanged in spite of a 45-fold variation in enzyme activity. There was a negative correlation between the absolute as well as the relative concentration of chenodeoxycholic acid in portal blood and the activity of the cholesterol 7 alpha-hydroxylase, whereas there was no correlation between the total concentration of bile acids and the enzyme activity. It is concluded that the composition of individual bile acids may be more important than the total concentration of bile acids in the portal vein for the regulation of the cholesterol 7 alpha-hydroxylase activity in humans. It is further concluded that chenodeoxycholic acid is a considerably stronger suppressor of bile acid synthesis than ursodeoxycholic acid.

Adult↗
PubMed1989

Biliary excretion of iron and ferritin in idiopathic hemochromatosis.

The role of biliary excretion of iron and ferritin in iron overload was studied and evaluated. Ten patients with idiopathic hemochromatosis and two groups of controls (14 gallstone patients and 16 healthy subjects) were included. Liver tissue (obtained by percutaneous or operative biopsy) was investigated with light microscopy and transmission electron microscopy in combination with x-ray microanalysis. Fasting bile samples were obtained through duodenal aspiration or at cholecystectomy. Iron was determined in liver tissue and bile using atomic absorption spectroscopy, and ferritin was determined in serum and bile with a radioimmunoassay technique. All patients with hemochromatosis had iron-positive staining as seen in light microscopy. Electron microscopy showed iron-containing proteins in the lysosomes and cytosol of liver parenchymal cells, and this observation was supported by x-ray microanalysis. Hepatic iron concentration was increased about eightfold in the patients with hemochromatosis (p less than 0.001). Biliary iron concentration, expressed per millimole of bile acid, was increased about twofold (p less than 0.05) and biliary ferritin concentration about fivefold (p less than 0.001) in hemochromatosis. Four of the patients with hemochromatosis were reexamined after completed treatment with venesection; this resulted in normalized biliary concentrations of iron and ferritin. We conclude that biliary secretion of ferritin occurs in humans and that both iron and ferritin excretion are enhanced in hepatic iron overload. The apparently limited capacity of biliary iron excretion may be of importance for the hepatic iron accumulation in hemochromatosis.

Adult↗
PubMed1989

Serum concentrations of unconjugated and conjugated cholic acid in portal venous and systemic venous blood of fasting man.

The fasting concentrations of unconjugated and conjugated cholic acid were determined in the peripheral venous serum of 15 healthy subjects, eight patients with ileal resection and six patients with known bacterial overgrowth of the upper small intestine. In addition, the estimated hepatic uptake of unconjugated and conjugated cholic acid was determined in 15 gallstone patients undergoing cholecystectomy. A highly accurate and specific mass-fragmentographic technique with high sensitivity was used. The proportion of unconjugated cholic acid averaged 34% in the healthy subjects. The estimated fractional hepatic uptake of unconjugated cholic acid was lower than that of conjugated cholic acid, 71% and 87%, respectively (means). Patients with ileal resection had an increased proportion of unconjugated cholic acid in their peripheral venous serum, 49% (mean). The patients with bacterial overgrowth of the upper small intestine also displayed a high proportion of unconjugated cholic acid, 63% (mean). It is suggested that determination of the proportion of unconjugated cholic acid in peripheral venous blood may possibly be used for detection of bacterial contamination of the upper small intestine.

Adult↗
PubMed1989

Studies on acyl-coenzyme A: cholesterol acyltransferase activity in human liver microsomes.

The aim of the present study was to characterize the acyl-coenzyme A: cholesterol acyltransferase (ACAT) activity in human liver microsomes. Liver biopsies were obtained from patients undergoing elective cholecystectomy under highly standardized conditions. In 34 patients the enzyme activity of the microsomal fraction averaged 6.6 +/- 0.7 (mean +/- SEM) pmol.min-1.mg protein-1 in the absence of exogenous cholesterol. Freezing of the liver biopsy in liquid nitrogen increased the enzyme activity five- to sixfold. Similarly, freezing of the microsomal fraction prepared from unfrozen liver tissue increased the enzyme activity about twofold. These results may help to explain previous disparate results reported in the literature. The enhanced ACAT activity obtained by freezing was at least partly explained by a transfer of unesterified cholesterol to the microsomal fraction and possibly also by making the substrate(s) more available to the enzyme. Preincubation of the microsomal fraction, prepared from unfrozen liver tissue, with unlabeled cholesterol increased the enzyme activity about fivefold. This finding indicates that hepatic ACAT in humans can also utilize exogenous cholesterol as substrate. Addition of cholesterol to frozen microsomes prepared from unfrozen liver tissue increased the ACAT activity two- to threefold, whereas addition of cholesterol to microsomes prepared from frozen liver tissue did not further increase the enzyme activity. No evidence supporting the concept that ACAT is activated-inactivated by phosphorylation-dephosphorylation could be obtained by assaying the enzyme under conditions similar to those during which the human HMG-CoA reductase is inactivated-activated.

Acyl Coenzyme A↗
PubMed1988

Occurrence of cholesterol monohydrate crystals in gallbladder and hepatic bile in man: influence of bile acid treatment.

The occurrence of cholesterol monohydrate crystals was examined and related to the degree of cholesterol saturation in gallbladder bile and hepatic bile of gallstone (GS) patients (n = 34), gallstone-free (GSF) subjects (n = 33) and GS patients treated with chenodeoxycholic acid (CDCA (n = 7) or ursodeoxycholic acid (UDCA) (n = 11) for 3 weeks prior to cholecystectomy. Twenty-five untreated GS patients (74%) and four UDCA-treated patients (40%) displayed cholesterol crystals in the gallbladder bile. Only two GSF subjects (6%) and none of the CDCA-treated patients had crystals. Half of the patients with crystals in the gallbladder bile had crystals also in the hepatic bile. Cholesterol saturation of the gallbladder bile was higher in GS (142 +/- 15%, mean +/- SEM) than in GSF patients (74 +/- 5%). Saturation was also higher in GS patients with crystals (157 +/- 20%) than in those without crystals (99 +/- 12%). Gallbladder bile was unsaturated in all CDCA- and UDCA-treated patients. The results underline the importance of the degree of cholesterol saturation for the formation of cholesterol crystals. The data also give further support to the concept that the mechanism for inducing gallstone dissolution is different for CDCA and UDCA.

Adult↗
PubMed1987

Altered action of glucagon on human liver in type 2 (non-insulin-dependent) diabetes mellitus.

Glucagon may play a role in the metabolic derangements of overt Type 2 (non-insulin-dependent) diabetes mellitus. We therefore have evaluated the early steps in glucagon action by investigating the hormone-sensitive adenylyl cyclase system in liver membranes from seven Type 2 diabetic patients with fasting hyperglycaemia and two-fold elevations in plasma glucagon. The comparison was made with seven control subjects matched for age, sex and body weight. Glucagon receptor binding was almost identical in the two groups. There were, however, marked alterations in the adenylyl cyclase activity in membranes from the diabetic patients. This activity was reduced by 35-50% when compared to control activity. Basal cyclase activity, as well as the activity after stimulation with glucagon or with agents (i.e., sodium fluoride and forskolin) that act beyond the glucagon receptor, was significantly decreased (p less than 0.05, p less than 0.001 respectively). In conclusion, uncontrolled Type 2 diabetes in associated with an over-all loss of responsiveness of the hormone-sensitive adenylyl cyclase in human liver, which apparently results from post-receptor alterations. This change may provide a mechanism for reducing the effect of hyperglycagonaemia in Type 2 diabetes mellitus.

Adenylyl Cyclases↗
PubMed1987

In vitro studies of lipid metabolism in human liver.

To study the regulation of lipid metabolism in human liver, we have developed assay systems for three rate-determining microsomal enzymes of hepatic cholesterol metabolism: 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (regulating cholesterol biosynthesis), cholesterol 7 alpha-hydroxylase (governing bile acid formation), and acyl-CoA:cholesterol acyltransferase (ACAT; rate limiting for cholesterol esterification). In addition, we have obtained an assay for low-density lipoprotein binding to its specific receptor in human liver, and we have studied a possible rate-determining enzymatic step in triglyceride biosynthesis, cytosolic phosphatidic acid phosphatase. These assays allow us to study the effects of metabolic perturbations on hepatic lipid metabolism in humans and thus to evaluate the important role of the liver in lipoprotein synthesis and degradation.

Cholesterol↗
PubMed1987

On the possible use of the serum level of 7 alpha-hydroxycholesterol as a marker for increased activity of the cholesterol 7 alpha-hydroxylase in humans.

The possibility was investigated that the serum level of 7 alpha-hydroxycholesterol can be used as a marker for cholesterol 7 alpha-hydroxylase activity. Six patients with gallstone disease were found to have a mean level of 7 alpha-hydroxycholesterol in serum of 30 +/- 4 ng/ml (mean +/- SEM) as measured by isotope dilution-mass spectrometry, using deuterated 7 alpha-hydroxycholesterol as internal standard. After treatment with cholestyramine in a dose of 8 g twice daily for 2-3 weeks preoperatively, the serum level increased to 128 +/- 20 ng/ml (P less than 0.001). Eight other patients with gallstone disease had a mean level of 7 alpha-hydroxycholesterol in serum of 29 +/- 7 ng/ml. Treatment with chenodeoxycholic acid, 15 mg per kg body weight per day for 3-4 weeks before surgery, decreased the mean level to 20 +/- 7 ng/ml (P greater than 0.05). The activity of the cholesterol 7 alpha-hydroxylase in liver biopsies taken during operation was found to be 38 +/- 5 pmol/min per mg of protein in the group of patients treated with cholestyramine and 1.3 +/- 0.5 pmol/min per mg in the group of patients treated with chenodeoxycholic acid. Liver biopsies from a group of untreated patients (n = 13) had a mean cholesterol 7 alpha-hydroxylase activity of 7.6 +/- 1.5 pmol/min per mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗