Biomedical subjects
Publications and source records attributed to R A Roesel.
A child with the Dyggve-Melchior-Clausen syndrome associated with elevated pipecolic acid levels in plasma and urine is described. Other studies of peroxisomal function, including phytanic acid, very long-chain fatty acids, and plasmalogen synthesis, were normal. This disorder may represent an incompletely characterized defect in peroxisomal metabolism.
In this investigation, we have demonstrated that the renal brush-border membrane of Fischer 344 rats from the Japanese Charles River Inc. specifically lacks dipeptidyl peptidase IV (DPP IV) activity, whereas the renal brush-border membrane of Fischer 344 rats from three different sources within the United States possesses normal levels of DPP IV activity. Comparison of the brush-border proteins between Charles River (U.S.A.) Fischer 344 rats (DPP IV positive) and Japanese Charles River Fischer 344 rats (DPP IV negative) revealed that a protein band (Mr = 100,000), apparently identical with DPP IV, was absent in the membranes from Japanese Charles River Fischer 344 rats. We examined the handling of radiolabeled beta-casomorphin fragment 1-5 (Tyr-Pro-[3H]Phe-Pro-Gly), a specific substrate for DPP IV, in renal brush-border membrane vesicles isolated from DPP IV-positive and DPP IV-negative rats. Although the membrane vesicles from DPP IV-positive rats were able to hydrolyze the pentapeptide to di- and tripeptides with the subsequent active transport of these products via the H+ gradient-dependent peptide transport system, the membrane vesicles from DPP IV-negative rats failed to hydrolyze the pentapeptide and hence lacked the ability to transport the radiolabel actively from the parent peptide. The H+ gradient-dependent glycyl-sarcosine uptake and the Na+ gradient-dependent proline uptake, however, were normal in DPP IV-negative rats. Urine analysis revealed that the DPP IV-negative rats excreted proline- and hydroxyproline-containing peptides in significantly increased amounts in their urine compared with control rats. Furthermore, following intravenous administration of Tyr-Pro-Phe-Pro-NH2, a peptide that is exclusively hydrolyzed by DPP IV, urinary excretion of the peptide in the intact form was many-fold greater in DPP IV-negative rats than in control rats. These data provide conclusive evidence for the obligatory role of DPP IV in the renal handling of proline (and hydroxyproline)-containing peptides.
Propionic acidemia usually presents in the newborn period with severe metabolic acidosis and lethargy. A 31-year-old man with adult onset chorea and dementia had propionic acidemia due to propionyl CoA carboxylase deficiency. Metabolic investigations may prove useful in patients with movement disorder of unknown etiology.
A 25-year-old woman with Kearns-Sayre syndrome (KSS) had complete external ophthalmoplegia, short stature, ataxia, cardiac conduction defects, and pigmentary retinopathy. Muscle biopsy revealed ragged-red fibers. Electron microscopy showed increased numbers of mitochondria with disordered structure and paracrystalline inclusions. Enzymatic analysis revealed a deficiency of complex II of the mitochondrial respiratory chain, and, more specifically, a deficiency of succinic dehydrogenase, although both subunits of this enzyme proved to be present by immunologic analysis. Therapy with vitamin cofactors did not result in short-term improvement. This appears to be the first report of complex II deficiency in a patient with KSS.
Blood spots on filter paper are used to screen for phenylketonuria. We have developed a high pressure liquid chromatographic assay of phenylalanine and tyrosine after elution of these amino acids from filter paper. The analysis time is 20 min. The amino acids are separated using an ion-exchange resin with post-column ortho-phthalaldehyde derivatization and subsequent fluorescence detection. Other common amino acids do not interfere. The assay is linear from 20 pmol to at least 2,000 pmol with a coefficient of variation of 3%. The assay is as accurate as the determination of phenylalanine by ion-exchange ninhydrin-reactive methods currently in use, but is 100 times more sensitive. The method has the advantages of avoiding venipuncture, is cost effective, has a high sensitivity, and a rapid turnaround.
Increased urinary excretion of xanthine, hypoxanthine, sulphite, thiosulphate and decreased serum uric acid were observed in an infant with profound failure to thrive. Other clinical findings included refractory seizures, spastic quadriplegia and profound psychomotor retardation. The patient died at 20 months of age. There were no detectable activities for xanthine oxidase and sulphite oxidase in the postmortem liver. Urothione, which is the metabolic excretory product of the molybdenum cofactor for molybdoenzymes was not present in the urine. A deficiency of the molybdenum cofactor which is common to both xanthine and sulphite oxidase is presumed to be the metabolic defect responsible for the absent activities of both enzymes.
A patient with the hyperornithinemia, hyperammonemia, homocitrullinuria syndrome is described. This patient represents the 12th documented case of this rare, presumably autosomal recessive condition. Increased levels of ammonia, ornithine and homocitrulline were demonstrated in blood and cerebrospinal fluid. The blood ammonia concentration could be lowered by supplementation of the diet with low doses of arginine. High doses of arginine precipitated seizures, although plasma levels of arginine and ornithine were not altered. The uptake of ornithine by the particulate fraction of the patient's fibroblasts was lower than that of controls, but still measurable. It is suggested that HHH patients have a partial impairment of the uptake of ornithine by mitochondria.
Histidyl-L-proline diketopiperazine is excreted in increased amounts by infants receiving Nutramigen or Pregestimil. When these formulas are discontinued, its excretion becomes undetectable. The compound was isolated from Nutramigen and Pregestimil, as well as from the urine of the infants receiving these formulas, and was identified by comparison with authentic histidyl-L-proline diketopiperazine standard in various chromatographic and electrophoretic systems. A neuropeptide widely distributed in the brain and gut and having a variety of biological functions, histidyl-L-proline diketopiperazine may have as-yet-undetermined effects on infants who are receiving these formulas.
We examined the effects of captopril on prolidase activity of crude homogenates of various tissues in the rat and in the human. It was found that captopril caused significant inhibition of prolidases from liver, kidney, and intestine in both species, whereas it showed minimal inhibitory effect on erythrocyte prolidase. In the rat, Ki for the inhibition of kidney and liver prolidases was in the range of 25-35 microM while, in the human, the value was considerably higher. The nature of inhibition was found to be competitive both in the rat and in the human. Oral administration of captopril (daily dose, 40 mg/kg) for 7 days in the rat resulted in increased urinary excretion of peptide-bound 4-hydroxy-L-proline compared to controls, indicating in vivo inhibition of tissue prolidases by captopril.
A case of hepatic fructose-1,6-diphosphatase deficiency is described. She presented with congenital bilateral cataracts, failure to thrive, hypoglycaemia and hyperlactacidaemia. A liver biopsy revealed normal levels of gluconeogenic enzymes except fructose-1,6-diphosphatase which was present at 30% of the level of the lower control values. The residual activity had a normal affinity for fructose-1,6-diphosphate, a decreased sensitivity for inhibition by fructose-2,6-diphosphate and an increased resistance toward conversion to the AMP-insensitive form of the enzyme. As a result of this mutation, the residual FDPase will always be maintained in the AMP-inhibited form.
Explore the source record for details and available documents.
Serum carnosinase deficiency (McKusick 21220) is a rare condition, described in 13 cases. Ten additional individuals with serum carnosinase deficiency have been identified. All continued to excrete increased amounts of carnosine in their urine despite a meat-free diet for 3 days. Serum carnosinase activity ranged from 0-30% of normal. In four individuals a normal Km for carnosine of 0.12 mM was observed, while in five individuals an increased Km was found. Homocarnosine levels in CSF in three individuals ranged from 3.4 to 15 mM. Clinical symptoms in these individuals were as follows: attention deficit disorder: 4; non progressive developmental delay: 1; neurofibromatosis: 1; absences seizures: 1; severe, but non-progressive mental retardation, seizures and neurosensory hearing loss: 1; progressive childhood dementia; 1; clinically normal: 1. There was no correlation between severity and type of the neurological symptoms and residual serum carnosinase activity. Although a definite conclusion can only be made after a considerably higher number of individuals has been analyzed, the suspicion that serum carnosinase deficiency is unrelated to the neurological symptoms is strengthened by these observations. There may, however, be an association with a predisposition for mental deficiency.
The gonadal steroids--estrogens and androgens--appear to have a mood-elevating, psychotonic effect. The improved sense of well-being and increased vigor probably is engendered by restoration of somatic efficiency and psychic equilibrium. 1. The male climacteric, as observed in a limited number of men, is associated with a low level of serum testosterone. The levels of follicle-stimulating hormone and luteinizing hormone are not elevated because estrogen concentration continues unaltered well into old age. Androgen replacement therapy often lessens fatigue, depression and headaches, and headaches, and improves libidinous drives. 2. In the aging female, many climatric symptoms other than those due to vasomotor instability were heretofore considered merely coincidental. Recent studies suggest that the metabolism of cerebral hormones is markedly influenced by endogenous and exogenous gonadal steroids. Thus, postmenopausal depression, headaches, and nervousness may be hormone-dependent symptoms. 3. The incidence of endometrial cancer is no greater and is probably less in estrogen-treated women than in women not treated with estrogen, if regular cyclic courses of an oral progestogen are added to the regimen.
Hydroxyproline metabolism was evaluated in two sisters with hydroxyprolinemia and their mother. 33 and 21% of an oral hydroxyproline load (200 mg/kg) was excreted by the sisters, 5.4% by the mother, and 1.3% by normal subjects. Plasma and erythrocyte values in the sisters and their mother were elevated, indicating that extra- and intracellular hydroxyproline pools were increased. Analysis for urinary glycolate and oxalate (metabolic products of hydroxyproline) showed no increased excretion by the two sisters, although the mother's excretion was normal. A deficiency of hydroxyproline oxidase in the two sisters was indicated by the lack of delta 1-pyrroline-3-hydroxy-5-carboxylic acid excretion.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Rapid loss of erythrocyte galactose-1-phosphate uridyl transferase in hemolysates from an infant 26 days after transfusion led to investigation of the possiblity of an unstable enzyme or other variant of galactosemia. However, the child was found to have the classic type of galactosemia. The seeming transferase instability was attributable to loss of enzyme activity in hemolysates from blood containg aged, transfused cells, the source of the enzyme. Thus when transfusion is necessary, transferase assay for diagnosis of the enzyme deficiency before transfusion avoids confusion attributable to the enzyme supplied in the transfused cells.
Explore the source record for details and available documents.