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Biomedical subjects

L Berglund

Publications and source records attributed to L Berglund.

At least 181 records · Page 10Linked to original sources
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

Effect of n-3 fatty acids on the key enzymes involved in cholesterol and triglyceride turnover in rat liver.

The effect of long-chain n-3 fatty acids on hepatic key enzymes of cholesterol metabolism and triglyceride biosynthesis was investigated in two rat models. In the first model, rats were intravenously infused for two weeks with a fat emulsion containing 20% of triglycerides in which either n-6 or n-3 fatty acids predominated. The treatment with n-3 fatty acids led to a reduction primarily of serum cholesterol (45%), but also of serum triglycerides (18%). HMG-CoA reductase activity and cholesterol 7 alpha-hydroxylase activity were reduced by 45% and 36%, respectively. There were no significant effects on diacylglycerol acyltransferase (DGAT) or phosphatidate phosphohydrolase (PAP) activities. In the second model, rats were fed a diet enriched with sucrose, coconut oil and either sunflower oil (n-6 fatty acids) or fish oil (long-chain n-3 fatty acid ethyl esters). The treatment with n-3 fatty acids decreased serum triglycerides (41%) and, to a lesser extent, serum cholesterol (17%). Neither glycerol 3-phosphate acyltransferase (GPAT) or DGAT were affected by n-3 fatty acids. In contrast, PAP activity was reduced by 26%. HMG-CoA reductase was not significantly affected, whereas cholesterol 7 alpha-hydroxylase activity was reduced by 36%. The results indicate that part of the TG-lowering effect of long-chain n-3 fatty acids may be mediated by inhibition of the soluble phosphatidate phosphohydrolase. The effect on serum cholesterol may be partly due to inhibition of HMG-CoA reductase.

Acyltransferases↗
PubMed1991

The distal radioulnar ligaments: a biomechanical study.

The mechanical roles of the triangular fibrocartilage have been examined in three experiments. Kinematic analysis by a stereophotogrammetric method revealed that the palmar radioulnar ligament was taut in supination and that the dorsal radioulnar ligament was taut in pronation. In full pronation, the palmar radioulnar ligament decreased to an average of 71% of its length in tension. In full supination, the dorsal radioulnar ligament decreased to an average of 90% of its length. Mechanical testing of the triangular fibrocartilage under axial load disclosed a significant laxity (mean: 10.4 mm), which was decreased in pronation. Transverse loading tests demonstrated that the triangular fibrocartilage is less stiff in neutral forearm rotation. Study of the material properties of the palmar and dorsal parts of the triangular fibrocartilage showed these structures to be strong ligaments with material properties similar to those of the radiocarpal ligaments.

Biomechanical Phenomena↗
PubMed1991

Extensor mechanism of the fingers. I. A quantitative geometric study.

A close-range stereophotogrammetric measurement system was used to determine the three-dimensional geometric characteristics of the extensor assembly in seven human finger specimens and five finger configurations. The numerical data obtained showed that, although changes in length of the different bundles are small, their spatial orientation varies considerably from one to another position. This information should help to improve the accuracy of models derived to understand the extensor assembly behavior in normal and pathological conditions.

Fingers↗
PubMed1991

Gemfibrozil in familial combined hyperlipidaemia: effect of added low-dose cholestyramine on plasma and biliary lipids.

Gemfibrozil is frequently used for lipid-lowering in familial combined hyperlipidaemia (FCHL) and in other forms of combined hyperlipidaemia. This therapy increases biliary cholesterol saturation, enhancing the risk for gallstone formation. Furthermore, in hypertriglyceridaemia, LDL cholesterol levels often tend to rise. We have explored the possibility that addition of a low dose of cholestyramine to gemfibrozil therapy obliterates these phenomena. Eighteen gallstone-free patients with definite (n = 5) or probable (n = 10) FCHL, or combined hyperlipoproteinaemia (n = 3) were randomized to a 6 week treatment with gemfibrozil, 600 mg b.i.d., or gemfibrozil 600 mg b.i.d. plus 4 g cholestyramine o.d. After 6 weeks the patients were crossed over to the alternative treatment. Plasma lipoproteins and biliary lipids were determined at baseline and at the end of each period. Institution of gemfibrozil treatment resulted in a decrease in plasma cholesterol by 15% (P less than 0.05) and in plasma triglycerides by 47% (P less than 0.05); HDL cholesterol increased by 18% (P less than 0.05). Addition of cholestyramine further decreased plasma and LDL total cholesterol by 9% (P less than 0.05). Total triglycerides and HDL cholesterol did not change. Gemfibrozil treatment was associated with a rise in the relative biliary concentration of cholesterol from 5.6 +/- 0.4 to 6.9 +/- 0.5 molar percent (P less than 0.01), and a parallel decrease in the relative concentration of bile acids, resulting in an increased cholesterol saturation of the bile, from 77 +/- 5 to 90 +/- 6% (P less than 0.05). This change was not observed during the combined therapy (mean cholesterol saturation, 82 +/- 4%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Maternal blood volume in placenta of the rhesus monkey measured in vivo by positron emission tomography.

The relative volume of the intervillous space of the placenta of the rhesus monkey was measured in vivo using positron emission tomography (PET), a noninvasive tracer technique. 11CO-Hb and 68GaCl3 were both used in three experiments and 68Ga-EDTA in two. The tracers were administered intravenously as bolus doses to 6 pregnant monkeys during 7 different pregnancies. Measurements with 11CO-Hb gave a volume of 48.0% of the total placental volume. Transplacental transfer of 11CO to the fetal circulation is probably a minor problem due to the small fetal blood volume and the prolonged time before the same concentration is reached in the maternal and fetal blood. Measurements with 68GaCl3, which binds to transferrin, gave an intervillous space volume of 55.6% of the placental volume. The concentration of radioactivity in the placenta did not attain a steady state, indicating a clearance of the tracer from the blood only to a small extent. Measurements with 68Ga-EDTA displayed a volume of 60.4% of the placental volume. Transplacental transfer and the additional distribution of radioactivity to fetal and maternal extracellular spaces, including the placenta, when 68Ga-EDTA was used will make this tracer unsuitable in measurements of the blood volume of the placenta with PET.

Animals↗
PubMed1991

Influence of age on the metabolism of plasma low density lipoproteins in healthy males.

The plasma concentration of the atherogenic low density lipoproteins (LDL) increases with age. To clarify the mechanism of this change, we studied the kinetics of autologous 125I-LDL apolipoprotein B (apo B) in 41 normolipidemic, nonobese healthy males. For comparison, they were divided into three age groups: young, 21-39 yr (n = 18), middle-aged, 40-59 yr (n = 11), and old, 60-80 yr (n = 12). The levels of plasma LDL cholesterol and LDL apo B increased from respectively 3.4 +/- 0.1 (SEM) mmol/liter and 86 +/- 2 mg/dl in the young to 4.1 +/- 0.1 mmol/liter and 95 +/- 3 mg/dl in the old (P less than 0.01), and this increase was linked to a progressively decreased (r = -0.38, P less than 0.02) fractional catabolic rate of LDL apo B (0.348 +/- 0.010 pools per day in the young vs. 0.296 +/- 0.009 pools per day in the old, P less than 0.01). The production rate of LDL apo B did not differ significantly between the groups. The reduced fractional catabolic rate of LDL apo B in the old was not associated with a decrease in binding affinity of the LDL particle to its receptor, as judged from its ability to compete for 125I-LDL fibroblast binding. When hepatic LDL receptor expression was stimulated by cholestyramine treatment in six old males, their LDL apo B fractional catabolic rate increased to the levels observed in the young subjects. We conclude that the increase in LDL which normally occurs with age is explained by a reduced capacity for its removal, and hypothesize that this is mediated via a reduced hepatic LDL receptor expression.

Adult↗
PubMed1991

Stimulation and inhibition of the activity of rat liver cytosolic phosphatidate phosphohydrolase by various phospholipids.

The influence of phospholipids on the activity of the soluble phosphatidate phosphohydrolase from rat liver was studied. Phosphatidylethanolamine stimulated the enzyme activity whereas phosphatidylglycerol, phosphatidylserine, and phosphatidylinositol were inhibitory. At a phospholipid concentration of 0.7 mg/ml, phosphatidylglycerol inhibited phosphatidate phosphohydrolase activity by 75%, while the enzyme activity was stimulated twofold in the presence of phosphatidylethanolamine. Both lysophosphatidylglycerol and lysophosphatidylethanolamine inhibited phosphatidate phosphohydrolase activity as did octylglucoside, sodium cholate, and Tween 20. The finding that phospholipids influence hepatic phosphatidate phosphohydrolase activity indicates that changes in the lipid environment may modulate the enzyme activity.

Animals↗
PubMed1991

Plasma-free amino acid concentrations during ketamine anesthesia in the rhesus monkey: a short methodological study.

The effect of ketamine anesthesia on the pattern of free amino acids in plasma was investigated in four healthy non-pregnant rhesus monkeys. Blood samples were collected at intervals during a period of 150 min both with and without anesthesia. Repeated measures analysis of variance, with time and ketamine/control as trial factors, was used. In only four amino acids were any changes with time or with ketamine treatment observed, the rest remaining unchanged. Ketamine anesthesia seemed to reduce the concentrations of several amino acids, but the findings were not conclusive.

Amino Acids↗
PubMed1991

Effects of pravastatin and cholestyramine on products of the mevalonate pathway in familial hypercholesterolemia.

Patients with heterozygous familial hypercholesterolemia (n = 12) were treated either with pravastatin, a specific inhibitor of HMG-CoA reductase, or cholestyramine, followed by a period of combined treatment with both drugs. Initially, these patients had increased serum levels of low density lipoprotein (LDL) cholesterol (8.77 +/- 0.48 mmol/l; SEM), lathosterol (5.32 +/- 0.60 mg/l), and ubiquinone (0.76 +/- 0.09 mg/l), while the serum dolichol concentration was in the normal range. Cholestyramine treatment (n = 6) decreased the levels of LDL cholesterol (-32%) and increased lathosterol (+125%), but did not change dolichol or ubiquinone levels in a significant manner. Pravastatin treatment (n = 6) decreased LDL cholesterol (-27%), lathosterol (-46%), and ubiquinone (-29%). In this case, the amount of dolichol in serum also showed a small but statistically insignificant decrease (-16%) after 12 weeks of treatment. Combined treatment with cholestyramine and pravastatin (n = 6) resulted in changes that were similar to, but less pronounced than, those observed during pravastatin treatment alone. In no case was the ratio between ubiquinone and LDL cholesterol reduced. Possible effects on hepatic cholesterol, ubiquinone, and dolichol concentrations were studied in untreated (n = 2), cholestyramine-treated (n = 2), and pravastatin-treated (n = 4) gallstone patients and no consistent changes could be observed. The results indicate that treatment with pravastatin in familial hypercholesterolemia decreases serum ubiquinone levels in proportion to the reduction in LDL cholesterol.

Adult↗
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

Apolipoprotein(a) and ischaemic heart disease in familial hypercholesterolaemia.

Serum concentrations of apolipoprotein(a) were measured in patients with heterozygous familial hypercholesterolaemia. The levels in 47 patients were a median of 2.5 times higher than those in controls matched for age and sex (240 [range 25-1245] vs 97 [7-1040] mg/l). Among patients with familial hypercholesterolaemia apo(a) levels were higher in those with (n = 48) than in those without (n = 72) ischaemic heart disease (283 [18-1245] vs 144 [7-741] mg/l); both in univariate and multivariate analysis serum apo(a) was the most significant variable distinguishing between the groups. Despite reducing LDL cholesterol by 30%, treatment with cholestyramine or pravastatin did not reduce apo(a) levels in these patients. These findings support the concept that apo(a) concentration is a genetic trait predisposing to ischaemic heart disease and imply that it may be useful in the identification of familial hypercholesterolaemia patients at high risk of coronary disease.

Adult↗
PubMed1990

The effect of Acipimox on triacylglycerol metabolism in rat.

The mechanism behind the hypolipidaemic effect of the drug Acipimox was studied in rat. The triacylglycerol (TG) lowering effect of the drug was accompanied by a marked reduction in free fatty acid (FFA) levels in the plasma. Also, the flux of TG from the liver to the plasma was substantially reduced. The liver TG content was not significantly changed. No significant effect of Acipimox treatment on the activities of glycerol 3-phosphate acyltransferase, phosphatidate phosphohydrolase or diacylglycerol acyltransferase in rat liver was observed. These findings strongly support the contention that Acipimox exerts its TG-lowering effect mainly by reducing FFA influx to the liver and thereby reducing the de novo biosynthesis of TG in the liver.

Acyltransferases↗
PubMed1990

Treatment of familial hypercholesterolaemia: a controlled trial of the effects of pravastatin or cholestyramine therapy on lipoprotein and apolipoprotein levels.

The efficacy and safety of a new, selective inhibitor of cholesterol synthesis, pravastatin, and the bile acid-binding resin, cholestyramine, were compared in a randomized, double-blind study of 120 patients with familial hypercholesterolaemia. After a run-in period of 8-10 weeks with assessment of dietary habits, the patients were treated with pravastatin + placebo, placebo + cholestyramine, or placebo alone. Active pravastatin therapy was initiated with 10 mg b.i.d. for 6 weeks, and was increased to 20 mg b.i.d. for the following 6 weeks. Cholestyramine was given at 24 g d-1, or the highest tolerable dose. After 6 weeks of therapy, serum total and LDL cholesterol levels were reduced by 17% and 21%, respectively, on pravastatin treatment, whereas the corresponding reductions with cholestyramine treatment were 24% and 30%, respectively. With an increased dose of pravastatin, serum and LDL cholesterol concentrations were reduced by 23% and 28%, respectively, after 12 weeks; the effect of cholestyramine was unchanged. HDL cholesterol levels increased in response to pravastatin, by 7% and 9% after 6 and 12 weeks, respectively. Concomitant changes in the concentrations of apolipoproteins B and AI were observed. Three patients discontinued the study because of side-effects: two subjects were treated with pravastatin and one was given placebo. The prevalence of side-effects (including laboratory abnormalities) was 35% for pravastatin, 30% for placebo, and 53% (significantly higher) for cholestyramine. We conclude that pravastatin, in a 40 mg daily dose, is as effective as cholestyramine in lowering LDL cholesterol in familial hypercholesterolaemia. Since the frequency of side-effects is higher with cholestyramine, pravastatin offers a promising alternative for the therapy of this genetic disease.

Adult↗
PubMed1990

Studies with the haeme oxygenase inhibitor Sn-protoporphyrin in patients with primary biliary cirrhosis and idiopathic haemochromatosis.

Sn(tin4+)-protoporphyrin, a potent competitive inhibitor of haeme oxygenase, the rate limiting enzyme in the degradation of haeme to bile pigments, was given intravenously to six patients with primary biliary cirrhosis and to four patients with idiopathic haemochromatosis. Serum bilirubin concentrations decreased in all patients after administration of 1-2 mumol/kg body weight of the metalloporphyrin, given in two doses eight to 24 hours apart. This reduction lasted approximately four to five days after injection of the compound. Excretion of endogenous haeme in bile increased (mean increase approximately two to threefold) in parallel with the decrease in serum bilirubin concentrations in both patient groups, and the highest biliary haeme concentrations were found during the first 48 hours after treatment. Sn-protoporphyrin was cleared rapidly from plasma with a half-life of 3.4 hours. Biliary bilirubin concentrations decreased (mean decrease, 49%) in the haemochromatosis patients after Sn-protoporphyrin administration. No decrease in biliary bilirubin concentrations could be detected in the primary biliary cirrhosis patients under the same conditions. Thus, Sn-protoporphyrin treatment resulted in a decrease in serum bilirubin concentrations and an increase in biliary haeme excretion in patients with haemochromatosis and primary biliary cirrhosis, as has previously been shown in normal subjects. The results indicate that the synthetic haeme analogue inhibits haeme oxidation activity in the two patient groups studied, as it does in normal people and in experimental animals. The lack of effect of Sn-protoporphyrin on biliary bilirubin excretion in primary biliary cirrhosis may be related to a differently affected hepatic clearance system or to a different distribution of tissue bilirubin pools in this condition.

Adult↗
PubMed1990

Amino acid transport across the placenta measured by positron emission tomography and analyzed by compartment modelling.

The materno-fetal transfer of methionine in the Rhesus monkey was investigated using positron emission tomography, a non-invasive in vivo tracer technique based on short-lived radionuclides. A bolus dose of [11CH3]-l-methionine was administered intravenously and the radioactivity concentrations in the placenta, the fetus and the maternal arterial blood were measured as functions of time and fitted to an equation derived from a four compartment model of the feto-placental complex. Rate constants were calculated describing maternal placental blood flow, the transfer of [11CH3]-l-methionine to the placental tissue and the fetus. The transfer rate of methionine to the fetus was estimated as 0.8-1.5 nmol/min/g placenta and was similar to the transfer to the placental tissue. An approximate blood flow through the intervillous space of 128 ml/min was found. The correlation between placental transfer to the fetus and the maternal blood flow in the intervillous space was low.

Animals↗