Urines of two children with 17 alpha-hydroxylase deficiency contained a number of 5-pregnane- and pregnenediols, -triols and -tetrols with a hydroxy or oxo group in position 11 of the steroid ring. They are formed mainly from progesterone via 11-hydroxyprogesterone, pregnanolone and corticosterone, respectively, or from pregnenolone. Three metabolites not previously described, 16-hydroxypregnenolone, 6,21-dihydroxypregnanediol and 6-hydroxytetrahydrocorticosterone, were identified.

Adrenal Hyperplasia, Congenital↗

PubMed1986

Neopterin in AIDs, other immunodeficiencies, and bacterial and viral infections.

An increase in total urinary neopterin was observed in 12 of 13 patients with acquired immunodeficiency syndrome (AIDS), seven of 13 patients with lymphadenopathy, one of six healthy homosexual males, seven of ten adult patients with staphylococcal pneumonia, 11 of 12 children with viral infections, four of seven children with bacterial infections, and 12 of 13 children with various immune defects. Extremely high values of total urinary neopterin and monapterin were observed in severely ill patients with AIDS and those with familial hemophagocytic lymphohistiocytosis. Neopterin excretion was normal in two AIDS patients with Kaposi's sarcoma, but without opportunistic infections at that time. On reexamination of one of these patients later on, elevated neopterin values were noted. Parallel increases in neopterin and monapterin were found, whereas biopterin was usually normal. The increase in total neopterin was mainly due to 7,8-dihydroneopterin and was accompanied by an increase in 3'-hydroxysepiapterin. Increased neopterin in urine is assumed to reflect the increase in GTP pool and GTP cyclohydrolase I activity as observed in stimulated monocytes. Thus, neopterin, as a measure of the activation of the nonspecific cellular immune system, may be used diagnostically to detect allograft rejection after transplantations and to follow-up HTLV-III positive patients.

Acquired Immunodeficiency Syndrome↗

PubMed1986

The application of 8-aminoguanosine triphosphate, a new inhibitor of GTP cyclohydrolase I, to the purification of the enzyme from human liver.

GTP cyclohydrolase I from human liver and Escherichia coli is competitively inhibited by 8-aminoguanosine triphosphate with a dissociation constant (Ki) of 0.25 mumol/l. 8-Aminoguanosine triphosphate, prepared from GTP and hydroxylamine-O-sulfonic acid, was coupled to Sepharose 4B and used as an affinity adsorbent for a 309-fold purification of GTP cyclohydrolase I from human liver. GTP cyclohydrolase I from human liver is a relatively heat-stable enzyme with a half-life of 2 min at 80 degrees C, an isoelectric point (pI) of about 5.6, and a Km for GTP of 31 mumol/l. Addition of KCl (0.3 mol/l) increased the Km to 153 mumol/l. No cofactors were required for activity. L-erythro-5,6,7,8-Tetrahydrobiopterin, L-erythro-7,8-dihydrobiopterin, L-sepiapterin and 8-aminoguanosine triphosphate were strong inhibitors.

Aminohydrolases↗

PubMed1985

Increase of GTP cyclohydrolase I activity in mononuclear blood cells by stimulation: detection of heterozygotes of GTP cyclohydrolase I deficiency.

An assay is described for GTP cyclohydrolase I activity in human mononuclear cells isolated from 20 ml of heparinized blood. The activity of this enzyme was low in unstimulated cells and increased 5-10 times after stimulation by phytohemagglutinin (formation of 0.8-1.3 pmol dihydroneopterin triphosphate/min per mg protein at 37 degrees C, n = 15) or mixed lymphocyte culture. No activity was detected in phytohemagglutinin-stimulated mononuclear cells of a patient with proven GTP cyclohydrolase I deficiency in liver; the samples from the father and mother of the patient showed 30 and 46%, respectively, of the mean of 15 healthy controls. In unstimulated cells, neopterin was the main component of the total intracellular pterins (after oxidation). After stimulation, dihydroneopterin triphosphate, measured as neopterin triphosphate by high performance liquid chromatography, was increased 10-30 times; neopterin and pterin were increased only 2- to 6-fold. Since the immunoreactive cells from this patient were unable to produce pterins and all immunological tests on the patient were normal, it is concluded that neither dihydroneopterin triphosphate, nor one of its metabolites are of primary importance for an immune reaction. The assay described can be used for the detection of heterozygotes of GTP cyclohydrolase I deficiency.

Aminohydrolases↗

PubMed1985

GTP-cyclohydrolases: a review.

The occurrence, properties and functions of GTP-cyclohydrolases in mammalian and non-mammalian systems is reviewed. GTP-cyclohydrolases catalyse the removal of C-8 atom from GTP as formic acid. GTP-cyclohydrolase I (EC 3.5.4.16) converts GTP into D-erythro-7, 8-dihydroneopterin triphosphate, whereas GTP-cyclohydrolase II forms 2,5-diamino-4-oxo-6-(5'-phosphoribosyl) -amino pyrimidine, a possible intermediate in the biosynthesis of riboflavin. GTP-cyclohydrolase I is the first enzyme in the biosynthesis of tetrahydrobiopterin, a cofactor of the monooxygenases of the aromatic amino acids. It is the rate limiting enzyme in many mammals, but not in man. Recently, patients with GTP -cyclohydrolase I deficiency were described, a variant form of tetrahydrobiopterin-deficient hyperphenylalaninaemia.

Aminohydrolases↗

PubMed1985

Serum bile acids determined with an RA 1000 analyzer.

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Autoanalysis↗

PubMed1984

GTP cyclohydrolase I deficiency, a new enzyme defect causing hyperphenylalaninemia with neopterin, biopterin, dopamine, and serotonin deficiencies and muscular hypotonia.

A 4-year-old patient is described with hyperphenylalaninemia, severe retardation in development, severe muscular hypotonia of the trunk and hypertonia of the extremities, convulsions, and frequent episodes of hyperthermia without infections. Urinary excretion of neopterin, biopterin, pterin, isoxanthopterin, dopamine, and serotonin was very low, although the relative proportions of pterins were normal. In lumbar cerebrospinal fluid, homovanillic acid, 5-hydroxyindoleacetic acid, neopterin and biopterin were low. Oral administration of L-erythro tetrahydrobiopterin normalized the elevated serum phenylalanine within 4 h, serum tyrosine was increased briefly and serum alanine and glutamic acid for a longer time. Urinary dopamine and serotonin excretion were also increased. Administration of an equivalent dose of D-erythro tetrahydroneopterin was ineffective and demonstrated that this compound is not a cofactor in vivo and cannot be transformed into an active cofactor. GTP cyclohydrolase I activity was not detectable in liver biopsies from the patient. The presence of an endogenous inhibitor in the patient's liver was excluded. This is the first case of a new variant of hyperphenylalaninemia in which the formation of dihydroneopterin triphosphate and its pterin metabolites in liver is markedly diminished. Normal activities of xanthine oxidase and sulfite oxidase were apparent since uric acid levels were normal and no increase in hypoxanthine, xanthine, and S-sulfocysteine concentrations could be observed in urine. It is concluded that the molybdenum cofactor of these enzymes may not be derived from dihydroneopterin triphosphate in man. Also, since no gross abnormalities in the patient's immune system could be found, it seems unlikely that dihydroneopterin triphosphate metabolites, such as neopterin, participate actively in immunological processes, as postulated by others. See Note added in proof.

Adolescent↗

PubMed1983

Guanosine triphosphate cyclohydrolase I assay in human and rat liver using high-performance liquid chromatography of neopterin phosphates and guanine nucleotides.

D-erythro-7,8-Dihydroneopterin triphosphate (NH2TP) formed from guanosine triphosphate (GTP) by GTP cyclohydrolase I (EC 3.5.4.16) in the presence of EDTA was oxidized to neopterin triphosphate (NTP) by iodine, separated from substrate and other compounds by ion-paired reverse-phase HPLC, and quantitated by fluorometric detection at 365/446 nm. Excess GTP at the end of reaction was controlled by simultaneous detection of guanine nucleotides at 254 nm. The method required only 15 mg of liver tissue for the measurement of GTP cyclohydrolase I and is suitable for activity measurement in liver biopsies. The detection limit was 4 pmol of NTP at a signal to noise ratio of 10:1. The activity of GTP-cyclohydrolase I in homogenates of human liver (n = 10) was 45 pmol NH2TP (range 32-60) formed per milligram protein per hour at 37 degrees C. Liver homogenates from Wistar rats (n = 8) formed 47 pmol NH2TP (range 35-61) per milligram protein per hour.

Aminohydrolases↗

PubMed1980

[Neck muscular tension due to repetitive work].

In our laboratory study 19 students effected 4 repetitive tasks of 70 min each. All four conditions had a motor task at the base and in addition two had to deal with discrimination. In the 2 tasks with discrimination, the electromyography of the neck muscles was distinctly higher than in the 2 other conditions. The tasks with discrimination were accompanied by a higher subjective tension, a lower heart rate variability and a slightly increased urinary excretion. The main cause for an augmentation in the muscle tonus might be the immobilisation of the neck.

Electromyography↗

PubMed1979

Simple rapid method for the separation and quantitative analysis of carbohydrates in biological fluids.

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Chromatography, Thin Layer↗

PubMed1978

Mitral valve prolapse syndrome.

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Adult↗

PubMed1977

A new semiautomated fluorometric method for estimation of small amounts of L-dopa in human urine.

A semiautomated fluorometric method for the quantitative determination of urinary dopa, 3-(3,4-dihydroxyphenyl)-L-alanine, is described. It provides a simple, sensitive and reproducible analytical technique for routine use. Dopa is isolated from interfering substances, especially catecholamines, by adsorption onto aluminium oxide, elution with 0.1 M HCl, then passed through a cation-exchange column. By mild oxidation with potassium ferricyanide, dopa is cyclized to dopachrome. This is isomerised with strong alkali to 5,6-substituted indole, which is highly fluorescent but very unstable in the presence of oxygen. The addition of ascorbic acid and 3-mercaptopropionic acid to the alkaline solution stabilizes the fluorescence. Concentrations of chemicals, pH and reaction times are made optimal for maximal sensitivity. Recovery of dopa added to the urine samples averaged 79% (range, 75 to 83). Reproducibility of results from the same urine specimen gave a coefficient of variation of 2.4%. In healthy adults, we found daily excretion ranges from 17.3 to 54.9 (mean: 36.1) microng/24 h or from 0.015 to 0.048 (mean: 0.021) microng/mg cretinine.

Autoanalysis↗

PubMed1977

Coronary artery fistula: estimation of shunt using 99m Tc-albumin particles.

A 60-year-old man presented with complaints on angina pectoris and was found to have a coronary artery fistula between his left main truck and main pulmonary artery. Particles of 99m Tc-Albumin were injected in the ostium of the left coronary artery, and differential radioactive counts were injected in the ostium of the left coronary artery, and differential radioactive counts were obtained over both lung fields and myocardium. The degree of left to right shunt was calculated at 56% of total left coronary artery flow. The patient underwent ligation of the fistula without any complications. This case report represents a new application of myocardial radioisotopic scanning.

Albumins↗