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Biomedical subjects

O Stokke

Publications and source records attributed to O Stokke.

At least 55 records · Page 3Linked to original sources
PubMed1989

Difference in cytotoxicity of (22R)-cholest-5-ene-3 beta,7 alpha,22-triol and (22R)-cholest-5-ene-3 beta,7 beta,22-triol is not explained by different patterns of metabolites.

Ehrlich ascites tumor cells in suspension culture were incubated with the plant-derived sterol isomers (22R)-cholest-5-ene-3 beta,7 alpha,22-triol and (22R)-cholest-5-ene-3 beta,7 beta,22-triol. Both sterols were 7-dehydroxylated by the neoplastic cells, and the product was identified as (22R)-22-hydroxycholesta-4,6-dien-3-one. At sub-toxic sterol concentrations the conversion of the 7 alpha-hydroxy compound was about 5 times higher than that of the 7 beta-isomer. At higher sterol concentrations the 7 beta-hydroxy compound caused growth inhibition of the Ehrlich ascites cells, whereas the 7 alpha-hydroxylated sterol was ineffective. The rate of 7 alpha-dehydroxylation was, however, too low to be considered a likely pathway for detoxification. No other lipid-extractable products were detected, and no water-soluble products with influence on cell proliferation were present. Thus, the cytotoxicity is probably attributed to a property of the 7 beta-hydroxyl group of the (22R)-cholest-5-ene-3 beta,7 beta,22-triol.

Animals↗
PubMed1988

Mass spectrometry in diagnosis of metabolic disorders.

Mass spectrometry is an important part of multicomponent analytical systems designed for diagnosis of metabolic disorders. In our laboratory capillary gas chromatography/mass spectrometry (GC/MS) with computerized library search is used primarily to separate and identify urinary organic acids. About 50 different diseases with increased excretion of organic acids are recognized today. Other techniques, including thin-layer chromatography, high-performance liquid chromatography with diode array detector, automatic amino acid analysis and two-dimensional electrophoresis are used to detect other compounds of diagnostic significance. The diagnostic use of GC/MS is exemplified by studies on two siblings. One died of his disease at approximately 1 year old. Both excreted 3-hydroxydicarboxylic acids (C8-C12) as identified by mass spectrometry. These metabolites are secondary to systemic carnitine deficiency. Low-fat diet normalized the clinical condition of the surviving sibling. GC/MS is now used to monitor the efficacy of dietary treatment by analysing the dicarboxylic acid excretion in this patient. Modern DNA technology is rapidly becoming increasingly important for diagnosis, particularly prenatal diagnosis, of metabolic diseases. It is suggested, however, that mass spectrometry will continue to be an important diagnostic tool for many years ahead.

Female↗
PubMed1988

Infantile Refsum's disease: a generalized peroxisomal disorder. Case report with postmortem examination.

Infantile Refsum's disease (IRD) is a peroxisomal deficiency disease which is closely related to neonatal adrenoleukodystrophy (NALD) and the Zellweger syndrome (ZS). Recent observations suggest that NALD and ZS are separate genetic disorders but the delimitation towards IRD remains uncertain. We present here the first autopsy report of a patient who was clinically and biochemically diagnosed as having IRD, and we compare the findings with those from NALD and ZS. The main gross and microscopic findings comprised micronodular liver cirrhosis, small hypoplastic adrenals without degenerative changes, and large groups of lipid macrophages in liver, lymph nodes and certain areas of the cerebral white matter. The brain showed no malformations except for a severe hypoplasia of the cerebellar granule layer and ectopic location of the Purkinje cells in the molecular layer. A mild and diffuse reduction of axons and myelin was found in the corpus callosum and periventricular white matter, the corticospinal tracts, and the optic nerves. Large numbers of perivascular macrophages were present in the same areas but there was no active demyelination. The retina and cochlea showed severe degenerative changes. Peripheral nerves, skeletal system and kidneys were normal. Electron microscopy showed characteristic cytoplasmic inclusions with bilamellar profiles in macrophages in the liver, lymph nodes and brain but not in the adrenals. Similar inclusions were found in liver cells and astrocytes. The findings differ from ZS which shows cortical renal cysts, skeletal changes, liver changes, cerebral micropolygyria, neuronal heterotopias, and demyelination of the white matter. Cases with NALD show mild cerebral malformations, active demyelination, degenerative changes of the adrenals, liver changes, and bilamellar electromicroscopic inclusions in macrophages. Our cases thus resembled NALD but lacked active demyelination, cerebral cortical malformations and adrenal degenerative changes. Further autopsy studies will be necessary to determine whether these changes are consistent findings in IRD.

Adrenoleukodystrophy↗
PubMed1988

Neurological disorders and phytanic acid metabolism.

Fifty patients with neurological symptoms and signs resembling those of Refsum's disease were analyzed for phytanic acid in serum. In addition, the phytanic acid oxidase capacity in skin fibroblasts was determined. The patients suffered from retinitis pigmentosa, cerebellar ataxia and/or chronic polyneuropathy of unknown cause. The serum level of phytanic acid was not increased, and the alpha-oxidation of (1-14C) phytanic acid was found to be normal in all patients. The present investigation lends no support to the theory that so-called atypical or mild cases of Refsum's disease exist. This disorder appears to be a disease entity with a specific genetic phenotype.

Adolescent↗
PubMed1988

Evidence against alpha-hydroxyphytanic acid as an intermediate in the metabolism of phytanic acid.

It was established 20 years ago that phytanic acid is degraded by an initial alpha-oxidation, and that alpha-hydroxyphytanic acid is an intermediate in the reaction. Patients with Refsum's disease, as well as those with the so-called peroxisomal disorders, have an enzymatic defect in this alpha-oxidation. The present work shows that when cultured skin fibroblasts from both groups of patients as well as from healthy controls are incubated with (1-14C)phytanic acid, the only radioactive compounds which can be detected are 14CO2 and unmetabolised phytanic acid. The degradation of (1-14C)alpha-hydroxyphytanic acid to 14CO2 takes place in the mitochondrial fraction of rat liver. Unlabelled alpha-hydroxyphytanic acid added to rat liver homogenate or mitochondria and (1-14C)phytanic acid reduced considerably the production of 14CO2. However, 14C-labelling of the alpha-hydroxyphytanic acid pool did not occur. Thus, we have been unable to confirm the previous demonstration of alpha-hydroxyphytanic acid as an intermediate in the degradation of phytanic acid.

Animals↗
PubMed1987

The subcellular localization of phytanic acid oxidase in rat liver.

Peroxisomal disorders (Zellweger's syndrome, neonatal adrenoleukodystrophy, infantile Refsum's syndrome, rhizomelic chondrodysplasia) show a series of enzymatic defects related to peroxisomal dysfunctions. Accumulation of phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) has been found in several of these patients, caused by a defect in the alpha-oxidation mechanism of this acid. The fact that the alpha-oxidation of phytanic acid is defective in the peroxisomal disorders as well as in classical Refsum's disease makes it likely that this oxidation normally takes place in the peroxisomes. A series of experiments preformed to localize the phytanic acid oxidase in subcellular fractions of rat liver show, however, that the alpha-oxidation of phytanic acid is a mitochondrial process. Free phytanic acid is the substrate, and the only cofactors necessary are ATP and Mg2+.

Animals↗
PubMed1987

Clinical and biochemical heterogeneity in conditions with phytanic acid accumulation.

Phytanic acid accumulation has for more than 20 years been used as a diagnostic criterion of Refsum's disease. Recently, however, phytanic acid has also been found in peroxisomal disorders (Zellweger's syndrome, neonatal adrenoleukodystrophy, infantile Refsum's syndrome, rhizomelic chondrodysplasia punctata). The 17 patients with Refsum's disease in the present study had serum phytanic acid values differing from 73 to less than 0.5 mg/dl (normal). alpha-Oxidation of phytanic acid in skin fibroblast cultures showed a defective capacity in all, with only small differences in residual activity. Phytanic acid determinations in serum from 3 of the 7 patients with peroxisomal disorders showed slightly elevated levels in 2. The alpha-oxidation capacity in the fibroblasts was defective in all, with a residual activity similar to that of Refsum's disease. An assay of the alpha-oxidation capacity may be useful in the diagnosis of both Refsum's disease and the peroxisomal disorders. The distinction between Refsum's disease and the peroxisomal disorders can easily be done on a clinical basis.

Adrenoleukodystrophy↗
PubMed1987

Pharmacologic effects of iopentol after intravenous injection in healthy volunteers. Preliminary report.

The effects of the first injections in humans of iopentol, a new non-ionic contrast medium, are briefly reported. Detailed descriptions will be published elsewhere. Iopentol was well tolerated when injected intravenously into 24 healthy male volunteers in doses of 300 to 1,200 mg I/kg body weight and was excreted almost entirely in the urine in unchanged form. The results indicate that iopentol may be used in clinical trials in patients.

Adult↗
PubMed1986

N-acetylaspartic aciduria in a child with a progressive cerebral atrophy.

Excessive excretion of N-acetylaspartic acid in urine is reported in a 6-yr-old child with extensive and progressive cerebral atrophy. The concentration in urine was 947-1,433 mumol/mmol creatinine (controls, n = 10, 5-21 mumol/mmol creatinine) and the daily excretion approximately 3-4 mmol. In cerebrospinal fluid from the patient the concentration was 611 mumol/l (controls, n = 10, not detectable, detection limit 2.3 mumol/l). The concentration of N-acetylaspartic acid in serum was 7 mumol/l. The low level in serum compared to the high urinary excretion of NAA suggests the possibility that NAA is synthesized in the kidneys in addition to the brain. This patient may cast new light on the functional role of N-acetylaspartic acid in humans.

Amino Acid Metabolism, Inborn Errors↗
PubMed1986

Liver transplantation in a 23-year-old tyrosinaemia patient: effects on the renal tubular dysfunction.

Orthotopic liver transplantation was performed on a 23-year-old female with hereditary tyrosinaemia. The disorder was diagnosed at 7 years of age due to severe rickets, and the patient was treated with a diet restricted in phenylalanine and tyrosine. Nineteen months before the transplantation she had an acute episode of diffuse gastrointestinal bleeding due to portal hypertension. Three subsequent bleeding episodes with accompanying ascites and signs of encephalopathy were considered life-threatening. Nine months after the liver transplantation the patient is well, but serum transaminases are slightly elevated. Without dietary restrictions serum tyrosine and inorganic phosphate are normalized, no succinylacetone can be detected in serum, and urinary excretion of p-hydroxyphenyllactate and p-hydroxyphenylpyruvate is normal. Excretion of amino acids, glucose and beta 2-microglobulin decreased significantly after the transplantation but is still elevated. The succinylacetone concentration in urine is about 20% of the preoperative level. After an oral tyrosine load, succinylacetone excretion increased sevenfold but no deterioration of the renal tubular function was observed and no tyrosine metabolites were detectable in serum. The findings indicate that the defective tyrosine metabolism occurs in the kidneys, but does not produce tubular dysfunction. The residual tubular dysfunction of the patient is probably due to irreversible damage of the tubular epithelium.

Adult↗
PubMed1986

Phytanic acid oxidase activity in cultured skin fibroblasts. Diagnostic usefulness and limitations.

Patients with Refsum's disease lack the ability to degrade phytanic acid to pristanic acid and CO2. This defect is expressed in fibroblasts from the patients. An assay system for the degradation of phytanic acid in cultured skin fibroblasts is described. The assay makes it possible to single out patients with Refsum's disease from the cob-web of clinically related conditions. The sensitivity is, however, not good enough to diagnose the heterozygous state. A defect of the same pronounced degree as in Refsum's disease is also found in fibroblasts from patients with Zellweger's syndrome, neonatal adrenoleukodystrophy, and infantile Refsum's disease. The radioactive material remaining in the cells after incubation was identified as unmetabolized phytanic acid. No traces of radioactive intermediates could be found in the cells from any of the patient groups. This might indicate that the defects both in Refsum's disease and in the peroxisomal disorders are located either at the same metabolic step or at steps which are closely linked to each other.

Carbon Dioxide↗
PubMed1986

Disorders related to the metabolism of phytanic acid.

The phytanic acid found in man stems from exogenous sources, mainly as minor parts of fish and animal fats. Free phytol, which is easily converted to phytanic acid in mammals, is present in fats of vegetable origin. Healthy individuals are able to degrade the small amounts of phytanic acid and phytol which are ingested. Accumulation of phytanic acid has been considered diagnostic for Refsum's disease, and a prerequisite for this diagnosis. However, a few patients with proven Refsum's disease have eliminated their phytanic acid stores by dietary means. Two healthy mothers of patients with Refsum's disease have been reported, in whom serum phytanic acid was considerably increased. Furthermore, phytanic acid has recently been found in patients with several socalled peroxisomal disorders (Zellweger's syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease, hyperpipecolic acidemia, rhizomelic chondrodysplasia punctata, Leber disease). Skin fibroblasts both from patients with classical Refsum's disease and from those with the peroxisomal disorders have a defect in the alpha-oxidation of phytanic acid, with a residual enzyme activity less than 10% of normal. The presence of this defect in the patients with peroxisomal disease makes it tempting to suggest that alpha-oxidation of phytanic acid normally takes place in the peroxisomes. Subcellular studies in rat liver show, however, unequivocally that the alpha-oxidation of phytanic acid is located to the mitochondria. Thus, patients with the peroxisomal syndromes must probably have a defect also in the mitochondria, in addition to the many peroxisomal deficiencies.

Animals↗
PubMed1986

Systematic laboratory diagnosis of human metabolic disorders.

A multicomponent analytical system for diagnosis of human metabolic disorders is overviewed. After preliminary analysis of the urine with simple chemical tests and standard clinical chemistry methods, the samples undergo a variety of chromatographic separations. Paper chromatography and thin-layer chromatography determine carbohydrates and mucopolysaccharides. Amino acids are analysed by automatic ionexchange chromatography. Gas chromatography - mass spectrometry with computerized library search is used to separate and identify organic acids, and high performance liquid chromatography with computerized diodearray detector is used to analyse metabolites of nucleic acids and other non-volatile or labile constituents. The system, gradually developed during the past two decades, is routinely used to diagnose, via its detection of pathological metabolites, around 100 different metabolic disorders. The methods may also be used to monitor the efficacy of therapeutic treatment in some of the cases where this is possible.

Chromatography, High Pressure Liquid↗
PubMed1986

Ionized calcium in plasma during cardiopulmonary bypass.

The composition of the priming fluid in the heart-lung machine is of importance for the homeostasis of the patient during and after cardiopulmonary bypass. We have studied the effect of 5 different priming solutions on the degree of ionization of calcium. The primingsolutions all contained 1700 ml of a basic solution and 800 ml of one of the following solutions: CPD-plasma CPD-plasma added heparine and CaCl2 heparinized plasma 5% albumin in saline 6% dextran 70 in saline. With CPD-plasma in the priming solution, the concentration of ionized calcium dropped to very low values, followed by a normalization during the next 30 minutes, as the citrate disappeared. The addition of CaCl2 to CPD-plasma prevented the abrupt initial drop, but resulted later on in values above the normal range. Heparinized plasma, albumin, and dextran in the priming solution lead to small changes only. Bolus injections of CaCl2 during weaning from bypass resulted in substantial increases in ionized calcium, while the use of CPD-blood products lead to decreases. Citrate has great affinity to calcium ions, making strong complexes. When significant amounts of citrate are used, the level of ionized calcium cannot be predicted, but has to be measured directly. These measurements must be performed frequently.

Adult↗
PubMed1986

Urinary excretion of N-acetyl amino acids in patients with some inborn errors of amino acid metabolism.

Urinary organic acid profiles of patients with Maple Syrup Urine Disease (MSUD), hereditary tyrosinemia and phenylketonuria (PKU) have been studied by means of capillary GC-MS-computer technique. In addition to the characteristic metabolites of these disorders, increased amounts of N-acetylleucine, N-acetylisoleucine and N-acetylvaline were found in MSUD-urine. Increased excretion of N-acetylphenylalanine occurred in PKU, and in tyrosinemia both the latter compound and increased N-acetyltyrosine excretion were observed. These results together with literature reports of similar studies on patients with other aminoacidopathies may indicate that most disorders which result in accumulation of one or more specific amino acids, will convert a small fraction of them into their corresponding N-acetyl derivative.

Acetylation↗
PubMed1985

Timolol maleate and HDL cholesterol after myocardial infarction.

The influence of long-term timolol treatment on plasma lipids was analysed in cohorts of the Norwegian timolol multicentre study. The prognostic importance of high-density lipoprotein (HDL) cholesterol concentration after myocardial infarction was also examined. One year timolol treatment was related to a significant reduction in HDL cholesterol levels, from 1.32 mmol l-1 to 1.26 mmol l-1 (P less than 0.05). After one year the HDL cholesterol levels were significantly lower in the timolol treated patients (1.26 mmol l-1) than in the placebo treated patients (1.32 mmol l-1, P less than 0.01). However, the HDL cholesterol values after myocardial infarction had no prognostic importance, and in the placebo group total mortality was the same in patients with low HDL cholesterol (less than 1.25 mmol l-1) and high HDL cholesterol (greater than or equal to 1.25 mmol l-1), respectively 15.0% and 14.8%. Timolol treatment was related to a reduction in mortality both in patients with low (24%, NS) and with high (43%, P less than 0.05) HDL cholesterol levels. Thus, any deleterious effects of timolol on serum lipids did not attenuate its protective effect on the damaged myocardium.

Cholesterol↗