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Biomedical subjects

U Keller

Publications and source records attributed to U Keller.

At least 19 recordsLinked to original sources
PubMed1992

[Hypoglycemia and multiple myeloma].

We report the case of a 78-year-old patient with recurrent attacks of severe fasting and late postprandial hypoglycemia, whose plasma showed highly elevated concentrations of immunoreactive insulin evidenced by high titers of spontaneous insulin and proinsulin-binding antibodies. Insulin autoimmune syndrome was diagnosed. Further investigations revealed a multiple myeloma of the kappa-light chain type. The monoclonal insulin-binding antibodies were characterized as IgG2-subclass and were identical with the paraprotein, thereby confirming that the insulin-binding antibodies were in fact produced by the myeloma. Together with initial symptomatic treatment, plasmapheresis was performed repeatedly to reduce the antibody pool. Subsequently octreotide therapy proved successful. The underlying myeloma was treated by chemotherapy.

Aged↗
PubMed1992

Purification and characterization of actinomycin synthetase I, a 4-methyl-3-hydroxyanthranilic acid-AMP ligase from Streptomyces chrysomallus.

Actinomycin synthetase I was purified to homogeneiety from actinomycin-producing Streptomyces chrysomallus. The purified enzyme is a single polypeptide chain of M(r) 45,000. It catalyzes the formation of the adenylate of 4-methyl-3-hydroxyanthranilic acid (4-MHA) from the free acid and ATP in an equilibrium reaction. 4-MHA is the precursor of the chromophoric part of actinomycin. By using the 4-MHA analogue, 4-methyl-3-hydroxybenzoic acid, as a model substrate it could be established that the equilibrium constant Keq is independent on enzyme concentration, which suggests that no stoichiometric acyladenylate-enzyme complex is formed in contrast to observations made with aminoacyl adenylates formed by aminoacyl-tRNA synthetases or multifunctional peptide synthetases. Actinomycin synthetase I does not charge itself with substrate carboxylic acid via a covalent thioester bond as is usual for amino acid activation in non-ribosomal peptide synthesis. In addition, the enzyme does not act as an acyl-coenzyme A ligase as revealed by its inability to release AMP in the presence of 4-MHA or other structurally related aromatic carboxylic acids, coenzyme A and ATP. Additional analysis of the activation reaction showed that it is exothermic, whereas the free enthalpy change delta G0 is positive due to a negative entropy change indicating a strong influence of restriction of random motion on the course of the reaction. Determinations of Km and kcat of various substrate carboxylic acids revealed the highest kcat/Km ratio for the natural substrate 4-MHA. From these properties, actinomycin synthetase I represents the prototype of novel chromophore activating enzymes involved in non-ribosomal synthesis of chromopeptide lactones in streptomycetes.

Adenosine Triphosphate↗
PubMed1992

Relationship between the degree of unsaturation of dietary fatty acids and adipose tissue fatty acids assessed by natural-abundance 13C magnetic resonance spectroscopy in man.

Natural-abundance 13C magnetic resonance spectroscopy was used for determining noninvasively the relative concentration of mono- and polyunsaturated fatty acids of adipose tissue in two groups of volunteers. The first consisted of subjects who had followed a fat-reduced diet for at least half a year before the 13C measurements. The second were control subjects who were on a usual high-fat diet. The ratio of unsaturated to total fatty acids in adipose tissue determined by 13C MRS correlated significantly with the same ratio in fat of the diet composition estimated by a dietician according to food records. The results indicate that 13C MRS is capable of assessing the degree of unsaturation of dietary fatty acids consumed during the preceding months.

Adipose Tissue↗
PubMed1992

Treatment of diabetic ketoacidosis and non-ketotic hyperosmolar diabetic coma.

Although mortality of diabetic ketoacidosis (KA) has decreased during the past 20 yr to 1-2%, hyperosmolar non-ketotic coma (HNC) is still lethal in 20-30% of cases due to severe underlying conditions or to complications. The most frequent causes of death are infections and thromboembolic disorders. The strategies of initial treatment of KA and HNC are similar; in KA, insulin, fluid and electrolyte replacement have first priority. In HNC, rehydration and electrolyte administration are of primary importance. It is now generally recognized that insulin therapy is best performed using low doses (4-8 units/h); after institution of insulin treatment and rehydration there are rapid changes of fluid and electrolytes from the extra- into the intravascular space. In this situation it is a major therapeutic challenge to avoid complications due to hypokalaemia, hypophosphataemia, hypomagnesaemia and hypovolaemia. These complications should be avoided by adequate replacement, and particularly by regular clinical and laboratory monitoring. When blood glucose concentrations decrease below 14 mmols/l, blood glucose concentrations should initially be maintained at this level because rapid lowering below this level may increase the risk of brain oedema. Too-vigorous fluid replacement with crystalline solutions also increases the risk that brain oedema or complications like the adult respiratory distress syndrome will develop. If hypovolaemia persists in spite of adequate crystalloid solutions, colloid-containing fluids such as albumin should be administered. It is not established whether replacements of phosphate and magnesium have clinical benefits. Nevertheless, it is probably justified to administer phosphate and magnesium when their serum concentrations are below the normal range, particularly if the clinical situation is critical. Mortality from diabetic coma in industrialized countries may only be decreased by prophylaxis, i.e. by education of all diabetic patients and physicians to detect metabolic decompensation early.

Diabetic Coma↗
PubMed1992

Streptomycetes possess peptidyl-prolyl cis-trans isomerases that strongly resemble cyclophilins from eukaryotic organisms.

A functionally active 17.5 kDa peptidyl-prolyl cis-trans isomerase was purified to homogeneity from Streptomyces chrysomallus, a Gram-positive filamentous bacterium. Characterization of the enzyme revealed inhibition and binding characteristics, against the immunsuppressive drug cyclosporin A, which were similar to cyclophilins from eukaryotes such as mammals, plants, fungi and yeasts, but different from those of cyclophilins from enterobacteria such as Escherichia coli. The amino acid sequence of the S. chrysomallus cyclophilin, as deduced from the gene sequence, revealed a striking degree of amino acid sequence identity with the corresponding 17 kDa proteins of humans (66%), Neurospora (70%) and yeast (69%). Comparison with cyclophilin sequences from the Gram-negative enterobacteria revealed much less homology (25% identity with E. coli b, 23% identity with E. coli a). Cyclophilin was detected in each of the four other Streptomyces species tested. The cyclophilins from the various streptomycetes differed in size, varying between 17 and 20.5 kDa. The cyclophilins were abundant in the Streptomyces cells, and present throughout growth.

Amino Acid Isomerases↗
PubMed1992

Effect of acute acidosis and alkalosis on leucine kinetics in man.

The effects of acute pH changes on whole body leucine kinetics (1-13C-leucine infusion technique) were determined in normal subjects. Plasma insulin, glucagon, and growth hormone concentrations were kept constant by somatostatin and replacement infusions of the three hormones. When acidosis was produced by ingestion of NH4Cl (4 mmol kg-1 p.os; n = 8) arterialized pH decreased within 3 h from 7.39 +/- 0.01 to 7.31 +/- 0.01 (P less than 0.001) and leucine plasma appearance increased by 0.13 +/- 0.04 mumol kg-1 min-1 (P less than 0.02); in contrast, when alkalosis was produced by intravenous infusion of 4 mmol kg-1 NaHCO3 (n = 7, pH 7.47 +/- 0.01), leucine plasma appearance decreased by -0.09 +/- 0.04 mumol kg-1 min-1 (P less than 0.01 vs. acidosis). Whole body leucine flux also increased during acidosis compared to alkalosis (P less than 0.05), suggesting an increase in whole body protein breakdown during acidosis. Apparent leucine oxidation increased during acidosis compared to alkalosis (P = 0.05). Net forearm leucine exchange remained unaffected by acute pH changes. Plasma FFA concentrations decreased during acidosis by -107 +/- 67 mumol l-1 (P less than 0.05) and plasma glucose increased by 1.90 +/- 0.25 mmol l-1 (P less than 0.02); in contrast, alkalosis resulted in an increase in plasma FFA by 83 +/- 40 mumol l-1 (P less than 0.02; P less than 0.01 vs. acidosis), suggesting an increase in lipolysis; plasma glucose decreased compared to acidosis (P less than 0.01). The data demonstrate that acute metabolic acidosis and alkalosis, as they occur in clinical conditions, influence protein breakdown, and in the opposite direction, lipolysis.

Acidosis↗
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↗