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Biomedical subjects

U Keller

Publications and source records attributed to U Keller.

At least 163 records · Page 9Linked to original sources
PubMed1992

FK-506-binding proteins from streptomycetes producing immunosuppressive macrolactones of the FK-506 type.

FK-506-binding proteins (FKBPs), which in T cells are supposed to mediate the immunosuppressive effects of the compounds FK-506 and rapamycin, have been isolated from Streptomyces chrysomallus, S. hygroscopicus subsp. ascomyceticus, and S. hygroscopicus. The latter two strains are producers of ascomycin (the ethyl analog of FK-506) and rapamycin, respectively. Like the 12-kDa FKBP in eukaryotic organisms such as humans, bovines, and Saccharomyces cerevisiae, or the FKBPs from gram-positive streptomycetes are peptidyl-prolyl-cis-trans isomerases. Inhibition studies using FK-506, rapamycin, or ascomycin, revealed inhibition of the peptidyl-prolyl cis-trans isomerase activity of the proteins at the nanomolar level, which is in the same range as with eukaryotic FKBPs. The M(r)s of the various FKBPs were 13,500 to 15,000, and they had the same pI of approximately 4.5. The N-terminal sequences of the three FKBPs were nearly identical in the first 20 amino acids. The amino acid sequence deduced from the gene sequence of S. chrysomallus gave a polypeptide of 124 amino acids. The homologies to FKBPs from humans, S. cerevisiae, and Neurospora crassa were 38, 39, and 50% identity in relevant positions, respectively. Significant homology of 38% was also seen with the C-terminal halves of bacterial protein surface antigens like the Mip protein of Legionella pneumophila and the 27-kDa Mip-like protein of Chlamydia trachomatis. In addition, two more open reading frames in Pseudomonas aeruginosa and Neisseria meningitidis of unknown function show regions of homology to the S. chrysomallus FKBP. In contrast to fungi, streptomycetes are resistant to macrolactones. Ascomycin-producing S. hygroscopicus subsp. ascomyceticus excretes the compound almost quantitatively into medium, which indicates that the organism has an efficient self-protection mechanism against its own secondary metabolite.

Amino Acid Isomerases↗
PubMed1992

Release of soluble receptors for tumor necrosis factor (TNF) in relation to circulating TNF during experimental endotoxinemia.

Serial plasma samples from human volunteers obtained after intravenous administration of Escherichia coli endotoxin were analyzed for the presence of circulating soluble tumor necrosis factor receptors (sTNFR). A four- to fivefold increase of type A (p75) and type B (p55) sTNFR was observed 3 h after endotoxin challenge. Pretreatment of the volunteers with ibuprofen before the injection of endotoxin resulted in a slight increase (3.87 +/- 0.2 vs. 3.27 +/- 0.3 ng/ml) and temporal shift of sTNFR-A release concurrent to a marked augmentation of TNF levels (603 +/- 118 vs. 338 +/- 56 pg/ml) as compared to the group without ibuprofen pretreatment. There was a significant correlation between peak sTNFR-A levels and peak TNF levels in the individual probands (r = 0.52, P = 0.04). On the contrary, release kinetics and plasma concentrations of sTNFR-B were identical in both groups (7.38 +/- 0.69 vs. 7.44 +/- 0.33 ng/ml) and no correlation with individual TNF levels was observed. The amount of sTNFR liberated upon endotoxin challenge was not sufficient to block TNF-mediated cytotoxic effects. Our data indicate that the release in vivo of type A and type B sTNFR upon a short exposure to endotoxin is regulated differently.

Adult↗
PubMed1992

Effect of increasing doses of recombinant human insulin-like growth factor-I on glucose, lipid, and leucine metabolism in man.

The metabolic effects of recombinant human insulin-like growth factor-I (IGF-I) were assessed in five groups of normal male overnight-fasted volunteers receiving infusions of either 0, 5, 7.5, 15, or 30 micrograms/kg.h IGF-I during 8 h, resulting in total plasma IGF-I concentrations 127 +/- 7, 247 +/- 30, 389 +/- 39, 573 +/- 62, 620 +/- 105 ng/ml, respectively. Glucose consumption (euglycemic glucose clamp) increased dose dependently during IGF-I infusion (P < 0.001) up to 6.7 +/- 1.3 mg/kg. min in the 30 micrograms/kg.h group. Plasma triglyceride concentrations decreased with increasing doses of IGF-I (P < 0.03); the fall was 43% in the 30 micrograms/kg.h group. Plasma free fatty acid concentrations decreased during 7.5, 15, and 30 micrograms/kg.h IGF-I by 23%, 34%, and 48%, respectively. IGF-I lowered plasma beta-hydroxybutyrate concentrations in a dose-dependent manner (P < 0.025). Plasma concentrations of leucine and alpha-ketoisocaproate decreased dose dependently (P < 0.001 and P < 0.015). Whole body leucine flux (1-13C-leucine infusion technique) decreased with increasing doses of IGF-I by 41% during 30 micrograms/kg.h, indicating decreased whole body protein breakdown. Leucine oxidation into 13CO2 decreased with increasing doses of IGF-I (P < 0.045) by 57% in the 30 micrograms/kg.h group, suggesting inhibition of irreversible loss of leucine. Plasma C-peptide and insulin concentrations decreased dose dependently (P < 0.005 and P < 0.02), indicating diminished insulin secretion. Thus, acute elevation of plasma IGF-I concentrations in man results in metabolic effects which are qualitatively similar to those described previously of insulin.

Adult↗
PubMed1992

Swiss hypertension treatment programme with verapamil and/or enalapril in diabetic patients.

The purpose of the present study was to assess the efficacy and tolerability of diuretic-free antihypertensive therapy with a calcium antagonist and/or an angiotensin converting enzyme (ACE) inhibitor in patients with diabetes mellitus. 54 hypertensive [blood pressure (BP) above 140/90mm Hg] patients with diabetes mellitus type 1 (n = 7) or 2 (n = 47) and normal serum creatinine levels (mean 82 +/- 6 mumol/L) received either verapamil or enalapril after a 2-week washout and a 4-week placebo phase. If BP remained elevated, both agents were combined. Verapamil or enalapril alone normalised diastolic BP (to less than 90mm Hg) in 36 patients; verapamil decreased BP from 159/98 to 147/87mm Hg (n = 19, p < 0.001) and enalapril decreased BP from 166/99 to 146/88mm Hg (n = 17, p < 0.001). In 18 patients who remained hypertensive after 10 weeks of monotherapy, a combination of both drugs decreased BP from 169/104 to 151/90mm Hg (p < 0.001). Overall, 87% of patients achieved a target BP response at 30 weeks. Urinary albumin as related to creatinine excretion (UAE; micrograms albumin:mg creatinine) was on average not significantly changed after verapamil or enalapril treatment, alone or combined. Nevertheless, in patients with initial microalbuminuria, UAE decreased (p < 0.05) during enalapril treatment. Serum potassium, total lipids, high density lipoprotein cholesterol, low density lipoprotein cholesterol, glycosylated haemoglobin, serum C peptide and fructosamine levels were not significantly modified by treatment. Subjective tolerability of the drugs was also generally good. Thus, in hypertensive patients with diabetes, a diuretic-free therapy based on the calcium antagonist verapamil or the ACE inhibitor enalapril, alone or combined, can effectively decrease BP without adversely affecting carbohydrate and lipid metabolism.

Adolescent↗
PubMed1992

A seventeen kilodaltons peptidyl-prolyl cis-trans isomerase of the cyclosporin-producer Tolypocladium inflatum is sensitive to cyclosporin A.

A peptidyl-prolyl cis-trans isomerase (PPIase) was purified to homogeneity about 24-fold from the cyclosporin-producing fungus Tolypocladium inflatum. The molecular mass of the enzyme was in the range of 17 kdaltons. Remarkably, the enzyme could be inhibited by cyclosporin A in the nanomolar range as has been shown for numerous other cyclophilins from eukaryotic organisms. This indicates, that Tolypocladium inflatum must possess a self protection system in order to survive in the presence of cyclosporin.

Amino Acid Isomerases↗
PubMed1991

Trimethylsilyl-O-methyloxime derivatives for the measurement of [6,6-2H2]-D-glucose-enriched plasma samples by gas chromatography-mass spectrometry.

A new method for the determination of the enrichment of [6,6-2H2]-D-glucose in human plasma by gas chromatography-mass spectrometry (GC-MS) is described. (2,3,4,5,6)-Pentakis-O-trimethylsilyl-O-methyloxime-D-glucose is used as a derivative for the GC measurement. Using GC-MS with electron-impact ionization, the enrichment is measured in the single-ion monitoring mode observing the masses m/z 319 and 321. In contrast to other methods the use of this glucose derivative reduced the amount of plasma needed from 200 to 10 microliters and no chemical ionization equipment is needed for the mass spectrometer.

Blood Glucose↗
PubMed1991

[Meat consumption and serum cholesterol concentration].

In a representative cross-sectional study of the population of Basel, Switzerland (252 men, 281 women, mean age 48 [25-74] years), there was a significant association between the consumption of meat and sausages, determined from a questionnaire, and the total serum cholesterol concentration. In subjects who ate meat or sausages daily, the mean cholesterol concentration was 6.29 mmol/l (242 mg/dl) (95% confidence interval 6.06-6.52 mmol/l) for men, and 6.63 mmol/l (255 mg/dl) (95% confidence interval 6.35-6.91 mmol/l) for women. In subjects who consumed meat or sausages at most once per week, the mean cholesterol concentration was 5.66 mmol/l (218 mg/dl) (95% confidence interval 4.99-6.33 mmol/l) for men, and 5.33 mmol/l (205 mg/dl) (95% confidence interval 4.98-5.68 mmol/l) for women. The association remained significant (P less than 0.001) using multiple linear regression (taking age, sex, social grouping, body mass index and consumption of whole-grain bread, yoghurt or cottage cheese, eggs and alcohol as possible confounding factors). The HDL-cholesterol fraction was not influenced by consumption of meat and sausages. These results support the nutritional advice concerning, among other things, a reduction in the intake of animal fats.

Adult↗
PubMed1991

[Comparison of a calorie-defined diet with the conventional exchange diet in Type 2 diabetes mellitus].

Meal planning using food exchange lists is problematic for many elderly type 2 diabetic subjects because the system is too complicated and too rigid regarding the daily meals. In addition, exchange lists are calorically imprecise. 12 non-insulin-dependent diabetic subjects agreed to participate in the present study (6 male, 6 female; age 40-82 years, weight 80 +/- 6 kg; HbA1c 7.3 +/- 0.3%); they received sequentially in randomized order either a diet using exchange lists, or a diet defined by total amount of allowed daily calories ("calorie diet"), both containing approx. 25 calories/kg ideal body weight/day, each for 8 weeks. The "exchange lists" mainly contained foods which were defined according to their content in carbohydrates (including bread exchanges, fruit exchanges, milk exchanges, vegetable exchanges). With the "calorie diet" the patients were relatively free during the day, the only rule being that they were allowed to consume a certain amount of calories per day, using a "calorie ruler". The results demonstrated that body weight decreased similarly during both diet periods (2.0 +/- 0.8 kg during the exchange list diet; 2.5 +/- 0.9 kg during the "calorie diet"). Fasting blood glucose concentration decreased during the "calorie diet" by 7% (p less than 0.05; fasting blood glucose at the end of the "calorie diet" was lower than after the exchange list diet (p less than 0.016). Serum lipoproteins were similar after both diet periods. 10/12 patients preferred the "calorie diet" because of its simplicity and flexibility. It allowed consumption of instant food which was calorically defined but difficult to convert into the exchange system.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

13C NMR for the assessment of human brain glucose metabolism in vivo.

Proton-decoupled 13C NMR spectra of the human head were obtained during hyperglycemic glucose clamping using intravenous infusions of [1-13C]glucose in normal volunteers. In addition to 13C signals of mobile lipids, a variety of new metabolite resonances could be resolved for the first time in the human brain. At an enrichment level of 20% [1-13C]glucose, the signals of alpha- and beta-glucose at 92.7 and 96.6 ppm, respectively, could be detected in the human brain after only an infusion period of 15 min. The spatial localization of the different regions of interest was confirmed by 13C NMR spectroscopic imaging with a time resolution of 9 min. Increasing the enrichment level to 99% [1-13C]glucose not only improved the time resolution but allowed the detection of metabolic breakdown products of [1-13C]glucose. The time course of 13C label incorporation into the C2, C3, and C4 resonances of glutamate/glutamine and into lactate could be recorded in the human brain. These results suggest the possibility of obtaining time-resolved, spatially selective, and chemically specific information on the human body.

Adult↗
PubMed1991

[Effects and side effects of a 1-year treatment of primary hypercholesterolemia with simvastatin].

The HMG-CoA-reductase inhibitors lovastatin, pravastatin and simvastatin (statins) represent a new group of drugs for the treatment of hypercholesterolemia. The present study was performed with simvastatin, the first statin introduced in Switzerland, and involved 46 patients with primary hypercholesterolemia during one year. The dose of simvastatin was adjusted according to the serum cholesterol level; during treatment with 10, 20 and 40 mg, total cholesterol was lowered by 18, 26 and 27% respectively and LDL cholesterol by 27, 38 and 35% respectively, after one year. A combination of 40 mg simvastatin with a bile acid sequestrant or a nicotinic acid derivative resulted in a cholesterol lowering of 38% and an LDL lowering of 48% respectively. The serum triglycerides decreased only at a dose of 10 mg. The changes in LDL and HDL cholesterol were accompanied by parallel alterations in apoprotein B and A1 concentrations. Although none of the patients showed a significant increase (greater than 3 x UNL) in serum ASAT, ALAT or CK, all these values increased slightly but significantly. Tolerance of the drug was otherwise excellent; gastrointestinal side effects were only rarely reported. Therefore, simvastatin is an effective and well tolerated cholesterol-lowering drug. Whether prevention of coronary heart disease is possible, however, is not yet proven.

Anticholesteremic Agents↗
PubMed1991

[Hormone substitution in the menopause: effect on lipids and cardiovascular risk].

After the menopause the risk for cardiovascular diseases increases to a similar extent in females compared to males. An increase in low density lipoproteins (LDL) as most frequent change in blood lipoprotein composition is in part responsible. Estrogens and gestagens affect the lipoproteins profile differently. Estrogens at doses for substitution lead to a minor decrease of LDL accompanied by an increase in protective high density lipoproteins (HDL). Under estrogen therapy triglycerides rise apparently with little effect on atherogenicity. A multitude of epidemiologic studies point to a decrease of cardiovascular morbidity and mortality under estrogen substitution. This is in part explained by the more favorable lipoprotein profile (decreased LDL, increased HDL). The available data have not remained unchallenged (Framingham Study) and a prospective randomized trial of the effects of estrogen substitution on cardiovascular risk has not been undertaken. Oral administration of estrogens shows a trend for higher effects on lipid-profile improvement when compared to the transdermal route. Gestagens have an effect opposed to the action of estrogens, notably those with an androgenic component (such as norethisterone) reducing HDL and triglycerides and raising LDL. This effect is however--if present--small. Women with hypercholesterolemia or at risk for ischemic heart disease should only receive minimal doses of gestagens. In hysterectomized patients gestagens are not needed. A hypertriglyceridemia can be aggravated by estrogens. A careful dosing scheme should be used in these patients. A history of thrombotic episodes precludes estrogen prescription. Because of the high cardiovascular morbidity and mortality in postmenopausal women the improvement of the lipoprotein profile may be of great significance.

Arteriosclerosis↗
PubMed1991

Unaltered insulin sensitivity during calcium channel blockade with amlodipine.

The sensitivity of peripheral tissues to insulin is of pathophysiological, therapeutic and possibly also of prognostic relevance. Calcium channel blockers are widely used in the treatment of cardiovascular disorders that are commonly associated with decreased insulin sensitivity (SI). To evaluate the effects of calcium channel blokkade on SI, glucose homoeostasis and lipid profiles, studies were made of SI (determined by the Minimal Model Method of Bergman), basal glucose and insulin levels, serum total triglyceride (Tg) and lipoprotein cholesterol (C) fractions and certain other variables in 38 healthy young men (24 y) during placebo and after 3 weeks of calcium channel blockade with amlodipine 5 mg once daily. Measurements were made after 3 days on a standard diet (2200 kcal.day-1, 45% carbohydrates, 40% fat and 15% proteins) and after an overnight fast. Compared to placebo, amlodipine decreased supine systolic blood pressure (P less than 0.01). Heart rate, body weight and 24 h urinary sodium excretion were unaltered, and so were fasting plasma glucose (placebo vs amlodipine: 4.86 vs 4.83 mmol.l-1, respectively) and insulin levels (7.7 vs 7.9 microU.ml-1), SI (10.5 vs 9.6.10(-4) x min-1 pro microU.ml-1), serum total Tg, C and lipoprotein C fractions. The findings demonstrate unchanged insulin sensitivity and secretion, as well as lipoprotein regulation, during maintenance administration of 5 mg amlodipine daily to healthy young men.

Adult↗
PubMed1991

Physiological role of cholecystokinin on postprandial insulin secretion and gastric meal emptying in man. Studies with the cholecystokinin receptor antagonist loxiglumide.

Cholecystokinin was previously proposed to play an important role in the regulation of postprandial insulin secretion either indirectly, by inhibiting gastric meal emptying, or directly, by acting as an incretin promoting the release of insulin. The aim of this investigation was therefore to clarify the role of endogenous cholecystokinin in the regulation of insulin release and gastric emptying applying the highly potent and specific cholecystokinin receptor antagonist loxiglumide. Five healthy volunteers were examined after an overnight fast. Gastric meal emptying was measured by the double indicator technique using a multiple lumen tube in the duodenum and 99mTc-diethylenetriamine pentaacetate as a meal marker and polyethylene glycol 4000 as a duodenal perfusion marker. Postprandial insulin, C-peptide, cholecystokinin and glucose levels were measured after ingestion of two isocaloric meals of a) Ensure (containing fat, protein and glucose), and b) a pure glucose meal (1.11 mol/l). The meals were given either with an intravenous infusion of loxiglumide (22 mumol.kg-1.h-1) or placebo. The infusion of loxiglumide markedly accelerated the gastric emptying of the mixed meal (area under curve, 5576 +/- 352 min vs 3498 +/- 109 min; p less than 0.001) and the pure glucose meal (area under curve 5662 +/- 537 min vs 3551 +/- 534 min; p less than 0.05). Simultaneously, loxiglumide induced a more rapid rise in postprandial insulin levels after both meals resulting in significantly higher (p less than 0.05) insulin levels during the first postprandial hour, but similar insulin levels in the second postprandial hour. Accordingly, we found a close correlation between meal emptying and insulin release (r = 0.748, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Pseudohypoaldosteronism and mineralocorticoid receptor abnormalities.

Pseudohypoaldosteronism is a rare inherited disease characterized by renal salt loss, hyperkalemia and metabolic acidosis despite highly elevated aldosterone values. We previously reported absent or reduced numbers of mineralocorticoid receptors in mononuclear leukocytes and defective effector mechanism as shown by no response in vitro to the incubation of aldosterone in terms of intracellular electrolyte content. We have studied the inheritance of this disorder in ten families and found two different kinds of inheritance: autosomal recessive--often in interrelated families--and autosomal dominant in unrelated families. Parallel studies in the families with the autosomal dominant form of inheritance demonstrated in addition that the effector mechanism of aldosterone is impaired in vitro both in the affected patients and in the carrier relatives characterized by a low number of mineralocorticoid receptors.

Aldosterone↗
PubMed1991

Pretreatment with ibuprofen augments circulating tumor necrosis factor-alpha, interleukin-6, and elastase during acute endotoxinemia.

Plasma levels of tumor necrosis factor-alpha (TNF alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6) were monitored after intravenous administration of Escherichia coli endotoxin with or without ibuprofen pretreatment to healthy volunteers. Intravenous endotoxin (n = 7) resulted in elevated plasma TNF alpha concentrations with maximal levels at 90 min (369 +/- 44 pg/ml, P less than .001 vs. saline controls, n = 7). The rise in TNF-alpha was followed by a rise in plasma IL-6 (27 +/- 12.8 ng/ml), peaking 30-90 min thereafter. Pretreatment with ibuprofen (n = 6) caused a significant augmentation and temporal shift in cytokine elaboration with maximal TNF alpha levels (627 +/- 136 pg/ml) at 120 min and IL-6 peaks (113 +/- 66 ng/ml) at 180 min. In ibuprofen-treated volunteers, the additional increase in TNF alpha was paralleled by increased levels of circulating elastase. In vitro experiments suggest a causal relationship between these events. Thus, the cyclooxygenase inhibitor ibuprofen blunts the clinical response to endotoxin but augments circulating cytokine levels and leukocyte degranulation.

Adult↗
PubMed1991

Growth hormone and lipids.

It has been known for more than 30 years that growth hormone has a lipolytic properties and growth hormone excess (acromegaly) and growth hormone deficiency have been reported to be associated with abnormalities in serum lipoprotein concentrations. Due to the lipolytic effect of growth hormone, its administration in man has been reported to increase plasma nonesterified fatty acid (NEFA) concentrations. Ketone body production increases during acute growth hormone excess as a result of increased NEFA concentrations; similarly, the increase in serum triglycerides may be explained by an increase in substrate (NEFA) supply to the liver for VLDL production. The effect may be enhanced by a simultaneous decrease of serum lipoprotein lipase activity. The cholesterol-lowering effect of growth hormone administration has not been investigated in detail, specifically, the effect of growth hormone on LDL kinetics is unknown. Growth hormone-excess and growth hormone deficiency have been reported to be associated with increased risk for atherosclerosis; an association with serum lipoprotein changes is likely but evidence for a causal link is yet lacking.

Diabetes Mellitus↗