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Biomedical subjects

W B Rizzo

Publications and source records attributed to W B Rizzo.

71 records · Page 4Linked to original sources
PubMed1987

Adrenoleukodystrophy: dietary oleic acid lowers hexacosanoate levels.

Adrenoleukodystrophy (ALD) is an X-linked disorder characterized by demyelination, adrenal insufficiency, and accumulation of saturated very-long-chain fatty acids (VLFA), particularly hexacosanoate (C26:0). We treated 5 patients with adrenoleukodystrophy (3 males and 2 symptomatic female carriers) for 6 months with a diet enriched in oleic acid (C18:1) and moderately restricted in C26:0. Elevated plasma and erythrocyte levels of C26:0 decreased in a time-dependent manner during treatment. Total plasma C26:0 concentration was lowered by 50 +/- 9% (p less than 0.01); it became normal in the female carriers. The total erythrocyte level of C26:0 decreased (44 +/- 5%; p less than 0.001) into the normal range in all patients. Significant decreases were noted in the saturated VLFA composition of plasma and erythrocyte sphingomyelin and erythrocyte phosphatidylcholine during dietary treatment. In general, decreases in saturated VLFA levels were accompanied by increases in monounsaturated VLFA levels, while total VLFA values did not change. This novel approach to the treatment of adrenoleukodystrophy, in which there is an exchange of monounsaturated VLFA for the more toxic saturated VLFA, may prove clinically beneficial in this disorder.

Adrenoleukodystrophy↗
PubMed1986

Effect of biotin deficiency and supplementation on lipid metabolism in rats: saturated fatty acids.

The effects of biotin deficiency and supplementation upon saturated fatty acids in serum, liver, cerebrum, and cerebellum of rats were investigated. Serum total fatty acids were reduced in deficient animals to 29% of normal. The percentage composition of some odd-chain fatty acids was increased in the serum and liver of deficient rats. The relative composition of most saturated fatty acids with carbon-chain lengths greater than or equal to 22 were increased in serum and liver of deficient rats. In contrast, there were no differences in the brain saturated fatty acids of deficient animals compared to those of normal and supplemented animals. These results may indicate that alterations in saturated fatty acids do not play a major role in the neurologic abnormalities in human biotin or inherited multiple-carboxylase deficiencies.

Animals↗
PubMed1986

Adrenoleukodystrophy: oleic acid lowers fibroblast saturated C22-26 fatty acids.

Monounsaturated fatty acids, especially oleic acid (C18:1), decreased the content of saturated very-long-chain fatty acids (VLFA) in cultured skin fibroblasts from patients with adrenoleukodystrophy (ALD) and controls. When confluent ALD fibroblasts were incubated with oleic acid for 5 days in lipid-free medium, which eliminates uptake of exogenous VLFA, the mean cell content of C26:0 was decreased by 33.7 +/- 10.1%. Oleic acid inhibited C26:0 synthesis in ALD fibroblasts by 58% and total fatty acid synthesis by 68 to 78%. Therefore, the elevated C26:0 levels in ALD cells may be lowered by inhibiting fatty acid biosynthesis, and inhibition of saturated VLFA synthesis by oleate may be useful in treating ALD.

Adrenoleukodystrophy↗
PubMed1985

Plasma and muscle free carnitine deficiency due to renal Fanconi syndrome.

Plasma and urine free and acyl carnitine were measured in 19 children with nephropathic cystinosis and renal Fanconi syndrome. Each patient exhibited a deficiency of plasma free carnitine (mean 11.7 +/- 4.0 [SD] nmol/ml) compared with normal control values (42.0 +/- 9.0 nmol/ml) (P less than 0.001). Mean plasma acyl carnitine in the cystinotic subjects was normal. Four subjects with Fanconi syndrome but not cystinosis displayed the same abnormal pattern of plasma carnitine levels; controls with acidosis or a lysosomal storage disorder (Fabry disease), but not Fanconi syndrome, had entirely normal plasma carnitine levels. Two postrenal transplant subjects with cystinosis but without Fanconi syndrome also had normal plasma carnitine levels. Absolute amounts of urinary free carnitine were elevated in cystinotic individuals with Fanconi syndrome. In all 21 subjects with several different etiologies for the Fanconi syndrome, the mean fractional excretion of free carnitine (33%) as well as acyl carnitine (26%) greatly exceeded normal values (3 and 5%, respectively). Total free carnitine excretion in Fanconi syndrome patients correlated with total amino acid excretion (r = 0.76). Two cystinotic patients fasted for 24 h and one idiopathic Fanconi syndrome patient fasted for 5 h showed normal increases in plasma beta-hydroxybutyrate and acetoacetate, which suggested that hepatic fatty acid oxidation was intact despite very low plasma free carnitine levels. Muscle biopsies from two cystinotic subjects with Fanconi syndrome and plasma carnitine deficiency had 8.5 and 13.1 nmol free carnitine per milligram of noncollagen protein, respectively (normal controls, 22.3 and 17.1); total carnitines were 11.8 and 13.3 nmol/mg noncollagen protein (controls 33.5, 20.0). One biopsy revealed a mild increase in lipid droplets. The other showed mild myopathic features with variation in muscle fiber size, small vacuoles, and an increase in lipid droplets. In renal Fanconi syndrome, failure to reabsorb free and acyl carnitine results in a secondary plasma and muscle free carnitine deficiency.

Carnitine↗
PubMed1984

Adrenoleukodystrophy: very long-chain fatty acid metabolism in fibroblasts.

We studied very long-chain fatty acid (VLFA) metabolism in cultured fibroblasts from patients with adrenoleukodystrophy (ALD). Total hexacosanoate (C26:0) content of ALD fibroblasts was sixfold higher than normal and did not return to normal when cells were grown in lipid-free medium. When normal or ALD fibroblasts were grown in medium containing 10% ALD serum (which is enriched in C26:0), there was no further increase in C26:0 content compared with cells grown in 10% normal human serum. Uptake and loss of 1-14C-palmitate (C16:0) and 1-14C-lignocerate (C24:0) by ALD fibroblasts were similar to normal fibroblasts. Catabolism of exogenous 3H-C26:0 to 3H2O was about 30% of normal. Oxidation of exogenous 1-14C-hexacosanoate, 1-14C-lignocerate, and 1-14C-palmitate in intact ALD fibroblasts was 42%, 27 +/- 13% (SD), and 73 +/- 47%, respectively, of normal. These results are consistent with, but do not conclusively prove, a VLFA oxidation defect in ALD fibroblasts.

Adrenoleukodystrophy↗
PubMed1983

Tetrahydropterin therapy for hyperphenylalaninemia caused by defective synthesis of tetrahydrobiopterin.

A patient with hyperphenylalaninemia caused by a defect in the synthesis of tetrahydrobiopterin was treated with 6-methyltetrahydropterin. This synthetic analog of the naturally occurring hydroxylation cofactor tetrahydrobiopterin, when given orally at a daily dose of 20 mg per kilogram of body weight increased depressed plasma and cerebrospinal fluid levels of norepinephrine. At a daily dose of 8 mg/kg, this pterin increased depressed cerebrospinal fluid levels of the biogenic amine metabolites dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid. At these doses of 6-methyltetrahydropterin, there was an improvement of the patient's neurological symptoms, including a pronounced decrease in eye rolling and drooling and a marked increase in muscle strength, coordination, and physical activity.

Biopterins↗
PubMed1983

Liposome-mediated transfer of simian virus 40 DNA and minichromosome into mammalian cells.

We have investigated the use of liposomes as carriers for the transfer of simian virus 40 (SV40) DNA into mammalian cells. The amount of DNA entrapped in liposomes was dependent on the input DNA concentration and lipid composition. DNA remained intact after liposome encapsulation and was resistant to deoxyribonuclease digestion. Combined transfer to and expression of liposome-entrapped SV40 DNA in monkey kidney cells was assayed by infectious plaque formation. Negatively-charged liposomes containing phosphatidylserine were more effective in DNA transfer and expression than neutral liposomes. The inclusion of carrier salmon sperm DNA inhibited liposome-entrapped SV40 DNA infectivity. Infectivity of liposome-entrapped DNA was directly related to both liposome DNA concentration and number of vesicles added. Liposome-entrapped SV40 minichromosome was 20-fold more infective than free minichromosome, but only 20% more infective than liposome-entrapped SV40 DNA. Thus, the presence of hyperacetylated histones on the DNA failed to enhance liposome-mediated DNA transfer appreciably. Incubation of cells with various modulators of endocytosis implicated the endocytotic pathway in the mechanism of liposome-mediated DNA transfer. These studies show that liposomes are suitable carriers for the introduction of viral DNA and chromatin into mammalian cells.

Animals↗
PubMed1983

Membrane microviscosity is increased in the erythrocytes of patients with adrenoleukodystrophy and adrenomyeloneuropathy.

Adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) are related X-linked disorders characterized by adrenal, gonadal, and nervous system dysfunction. While the pathologic finding common to these tissues appears to be the accumulation of excessive amounts of very long chain fatty acids, the mechanism leading to functional impairment in these tissues is unclear. Measurements of fluorescence polarization (P), using the lipid probe diphenylhexatriene, demonstrate a highly significant increase in the microviscosity of erythrocyte membranes in affected patients (P = 0.286 +/- 0.012) vs. normals (P = 0.239 +/- 0.020). Analyses of these membranes by gas-liquid chromatography revealed 1.9-, 1.6-, and 1.3-fold increases above normal values in the C25:0, C26:0, and C27:0 fatty acids, respectively. These observations are compatible with previously obtained data in animals that correlate membrane microviscosity with the number of hormone receptors in target tissues. The present data support the thesis that a decrease in responsiveness to trophic hormones in ALD and AMN is secondary to changes in the membrane microviscosity of the target tissues and suggest a mechanism by which adrenal and gonadal failure occur in such patients.

Adrenal Insufficiency↗
PubMed1982

Use of tetrahydropterins in the treatment of hyperphenylalaninemia due to defective synthesis of tetrahydrobiopterin: evidence that peripherally administered tetrahydropterins enter the brain.

Substantial amounts of tetrahydrobiopterin and 6-methyltetrahydropterin can be detected in CSF when these pterins are given peripherally to patients with hyperphenylalaninemia due to defective biopterin synthesis. Results of this study suggest that administration of either of these pterins in proper doses may prove to be a treatment not only for the impaired peripheral phenylalanine metabolism, but also for the neurologic disorders that are characteristic of the variant forms of hyperphenylalaninemia due to defective tetrahydrobiopterin synthesis or metabolism.

Biopterins↗
PubMed1977

Lectins as probes of chromatin structure. Binding of concanavalin A to purified rat liver chromatin.

Concanavalin A (Con A) binds specifically to rat liver chromatin. The extent of binding is directly proportional to both chromatin and concanavalin A concentration. It is reversible and inhibited by specific sugars for which concanavalin A has a binding site. Scatchard analysis reveals the presence of one type of Con A-binding site, with an apparent dissociation constant of 3 X 10(-7) M. A maximum of 10 pmol of Con A binds to 10 microgram of chromatin, indicating an average of one binding site/1400 base pairs of DNA. To identify the polypeptide chains which contain Con A-binding sites, chromosomal proteins were separated by electrophoresis on polyacrylamide gels containing sodium dodecyl sulfate. Con A receptors were localized by incubating the gel in 125I-Con A and subsequent autoradiography. Three major polypeptide bands which bind Con A were identified among the nonhistone chromosomal proteins. The apparent molecular weights of these glycoproteins are 135,000, 125,000, and 69,000. We suggest that lectins may serve as probes for the study of the organization of specific components in chromatin.

Animals↗
PubMed1977

Oogenesis in the female sterile (1)42 mutant of Drosophila melanogaster.

The sex-linked mutation fs(1)42 was induced by ethyl methane sulfonate. It has no effect on either the external morphology or longevity of adult hemizygotes or homozygotes. Heterozygotes and hemizygotes are fertile, but homozygotes are sterile. Egg chamber development proceeds through stages 8, and thereafter chambers degenerate. Dying follicle cells are seen in chambers at all positions in the ovarioles. Profollicle cells also die within germaria, and clusters of sister cystocytes take longer than normal to receive their coverings of follicle cells. Egg chambers in the vitellarium contain only about 60% the normal number of follicle cells, these generally have greater lateral dimensions, and their nuclei and nucleoli are also larger than normal. The follicular envelope of mutant chambers often contains gaps through which cystocytes send cytoplasmic projections. Abnormalities seen in development of the fs(1)42 oocyte are likely to be due to its envelope of defective follicle cells.

Animals↗
PubMedDate not supplied

Sjögren-Larsson-like syndrome with bone dysplasia and normal fatty alcohol NAD+ oxidoreductase activity.

We report a boy and girl with a "new" multiple congenital anomalies/mental retardation syndrome which resemblances Sjögren-Larsson syndrome. Both patients had a concordant pattern of anomalies consisting of congenital lamellar ichthyosis with spontaneous improvement, moderate mental retardation, mild pyramidal involvement, telecanthus, flat facies, stubby long bones, and coxa valga. Severe myopia, ventriculoseptal defect, and postaxial polydactyly were present in the girl who had more severe bone involvement with dense, enlarged metaphyses, vertebral dysplasia, and advanced skeletal maturation of the lower limbs. Long-chain fatty alcohol NAD+ oxidoreductase (FAO) and steroid sulfatase were normal.

Alcohol Oxidoreductases↗
PubMedDate not supplied

Unusual clinical presentation in two cases of multiple sulfatase deficiency.

Multiple sulfatase deficiency (MSD) is an inborn error of metabolism that combines the clinical features of late infantile metachromatic leukodystrophy and mucopolysaccharidosis. The characteristic biochemical abnormality is a reduction in the activities of several sulfatases, with consequent tissue accumulation of sulfatides, sulfated glycosaminoglycans, sphingolipids, and steroid sulfates. In this study we present two unusual cases of MSD with variable enzymatic deficiency of arylsulfatases A, B, and C. Both patients had ichthyosis, broad thumbs and index fingers, an unusually slow progression of the neurologic symptoms, and lacked the hepatosplenomegaly that is typical of MSD. Olivopontocerebellar atrophy was present and one patient had a large retrocerebellar cyst. Mucopolysaccharides were not detected in the urine from either subject. Leukocyte arylsulfatase A activity in patient 1 was 0.46 nmol/mg protein/hr and in patient 2 was 0.0 nmol/mg protein/hr (normal 0.7-5.0 nmol/mg protein/hr). Leukocyte arylsulfatase B activity in patient 1 was 24 nmol/mg protein/hr and in patient 2 was 22 nmol/mg protein/hr (normal 115-226 nmol/mg protein/hr). Leukocyte arylsulfatase C in patient 1 was 0.30 pmol/mg protein/hr and in patient 2 was 0.28 pmol/mg protein/hr (normal 0.84 pmol/mg protein/hr). In conclusion, these two patients with MSD had mild clinical presentations not previously reported and variable enzymatic deficiency of arylsulfatases A, B, and C.

Adolescent↗