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Biomedical subjects

R Mandell

Publications and source records attributed to R Mandell.

At least 19 recordsLinked to original sources
PubMed1989

Molybdenum cofactor biosynthesis in humans. Identification of two complementation groups of cofactor-deficient patients and preliminary characterization of a diffusible molybdopterin precursor.

Molybdenum cofactor deficiency is a devastating disease with affected patients displaying the symptoms of a combined deficiency of sulfite oxidase and xanthine dehydrogenase. Because of the extreme lability of the isolated, functional molybdenum cofactor, direct cofactor replacement therapy is not feasible, and a search for stable biosynthetic intermediates was undertaken. From studies of cocultured fibroblasts from affected individuals, two complementation groups were identified. Coculture of group A and group B cells, without heterokaryon formation, led to the appearance of active sulfite oxidase. Use of conditioned media indicated that a relatively stable, diffusible precursor produced by group B cells could be used to repair sulfite oxidase in group A recipient cells. Although the extremely low levels of precursor produced by group B cells preclude its direct characterization, studies with a heterologous, in vitro reconstitution system suggest that the precursor that accumulates in group B cells is the same as a molybdopterin precursor identified in the Neurospora crassa molybdopterin mutant nit-1, and that a converting enzyme is present in group A cells which catalyzes an activation reaction analogous to that of a converting enzyme identified in the Escherichia coli molybdopterin mutant ChlA1.

Cells, Cultured↗
PubMed1989

Age differences in corneal hydration control.

Dynamic changes in corneal thickness were measured in eight young and eight older normal subjects (mean ages 24.4 +/- 4.3 years and 71.9 +/- 7.3 years, respectively) to provide data for quantitative assessment of corneal hydration control and thereby provide information for studying age differences in this important aspect of corneal function. For each subject, pachometry data were obtained by (A) monitoring corneal recovery following hypoxic stress, and by either (B1) measuring recovery after sleep or (B2) by measuring corneal thickness in the late afternoon. The combined data from A and B1 or A and B2 were analyzed through an exponential model to provide information on the: (1) percent recovery per hour (PRPH) following induced corneal hydration; (2) open-eye steady-state (OESS) corneal thickness; (3) residual corneal swelling just before the hypoxic stress test; (4) amount of corneal edema induced by hypoxic stress; and (5) time to reach 95% recovery back to the OESS thickness level (T95%). The results show that between the two age groups, there are substantial differences in some characteristics of corneal hydration while other aspects are similar. For example, the mean PRPH values (58.9 +/- 7.8% and 34.2 +/- 6.4%/hr) were significantly higher in the younger subjects (P = 0.0002) and the mean time for 95% recovery to OESS thickness (207 +/- 42 min and 452 +/- 117 min) was significantly lower in the younger vs. the older group (P = 0.0002).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Molybdenum cofactor deficiency in a patient previously characterized as deficient in sulfite oxidase.

The metabolic status of a patient previously characterized as deficient in sulfite oxidase was reexamined applying new methodology which has been developed to distinguish between a defect specific to the sulfite oxidase protein and sulfite oxidase deficiency which arises as a result of molybdenum cofactor deficiency. Urothione, the metabolic degradation product of the molybdenum cofactor, was undetectable in urine samples from the patient. Analysis of molybdenum cofactor levels in fibroblasts by monitoring reconstitution of apo nitrate reductase in extracts of the Neurospora crassa mutant nit-1 revealed that cells from the patient were severely depleted. Quantitation of urinary oxypurines showed that hypoxanthine and xanthine were highly elevated while uric acid remained in the normal range. These results were interpreted to indicate a severe but incomplete deficiency of the molybdenum cofactor. The presence of very low levels of active cofactor, supporting the synthesis of low levels of active sulfite oxidase and xanthine dehydrogenase, could explain the metabolic patterns of sulfur and purine products and the relatively mild clinical symptoms in this individual.

Cells, Cultured↗
PubMed1988

Clinical results of pericardial xenograft valves: the Ionescu-Shiley and Hancock valves.

Between 1979 and 1985, 552 Ionescu-Shiley valves were implanted in 511 patients. The Hancock valve was implanted in 122 patients (129 valves) between 1982 and 1983. Sixty percent of procedures were isolated aortic valve replacements. In the Ionescu series, 59% of these were 19 or 21 mm valves while only 15% of the Hancock valves were of this size. For isolated mitral valve replacement, 76% of Ionescu-Shiley valves were 25 to 27 mm, compared to 36% of the Hancock valves. Patient age, sex, prior operations, concomitant surgery (usually coronary bypass), operative mortality and late deaths were similar for both valves. A mean follow-up of 38 months was obtained for each valve population (99% complete) representing a cumulative 1497 patient-years for the Ionescu-Shiley valve and 375.4 patient-years for the Hancock valve. Actuarial survival for the former was 73 +/- 4% at 72 months, and 65 +/- 14% for Hancock valves at 60 months. The frequency of major events during follow-up (thromboembolism, anticoagulant related hemorrhage, bland perivalvular leak and prosthetic valve endocarditis) were similar, but the frequency of primary tissue valve failure was markedly different for the two valves (1.1% per patient-year for Ionescu-Shiley valves and 5.9% for the Hancock valve). The mean interval to replacement of an Ionescu mitral prosthesis was significantly shorter (23.4 months) than for replacement of an aortic prosthesis (42 months) while the mean interval to replacement of an Ionescu aortic and/or a Hancock aortic or mitral were all similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Actuarial Analysis↗
PubMed1988

Pyridoxine effects on ornithine ketoacid transaminase activity in fibroblasts from carriers of two forms of gyrate atrophy of the choroid and retina.

Gyrate atrophy of the choroid and retina that is due to ornithine ketoacid transaminase (OKT) deficiency is an autosomal recessive disorder. Fibroblasts from heterozygotes for the pyridoxine-responsive variant as well as those for the pyridoxine-nonresponsive variant contain intermediate levels of OKT activity. These two variants can be distinguished by the in vitro responsiveness of OKT activity to pyridoxal phosphate (PLP) stimulation. The ratios of OKT activity at 0.04 mM PLP compared with activity at 0 mM PLP were, respectively, lowest for controls (1.18 +/- 0.18; N = 12), intermediate for pyridoxine-nonresponsive heterozygotes (1.43 +/- 0.26; N = 5), and highest for pyridoxine-responsive heterozygotes (2.20 +/- 0.14; N = 3).

Atrophy↗
PubMed1979

Medium for selective isolation of Fusobacterium nucleatum from human periodontal pockets.

A selective medium, CVE agar, was developed for the isolation of Fusobacterium nucleatum from subgingival plaque of periodontally diseased patients. The medium contained 1.0% Trypticase (BBL Microbiology Systems), 0.5% yeast extract, 0.5% NaCl, 0.2% glucose, 0.02% L-tryptophan, 1.5% agar, and 5% defibrinated whole sheep blood. Erythromycin and crystal violet were added as the selective inhibitory agents at concentrations of 4 and 5 micrograms/ml, respectively. The medium permitted almost total recovery of F. nucleatum when compared with a nonselective medium and suppressed the recovery of most remaining species by nonselective medium and suppressed the recovery of most remaining species by 6 to 8 orders of magnitude. Microorganisms suppressed to a lesser degree included Selenomonas sputigena, Actinobacillus actinomycetemcomitans, Eikenella corrodens, and some strains of Peptostreptococcus. The distinct colonial morphology of F. nucleatum on CVE agar made differentiation relatively easy when contaminants were present. With this medium, F. nucleatum was enumerated from 278 subgingival plaque samples and accounted for less than 1.0 to greater than 25% of the cultivatable microbiota.

Adolescent↗
PubMed1979

Oxygen-transmitting hard contact lenses.

Nine PMMA contact lens wearers with persistent corneal edema were refitted with CAB contact lenses. All of the patients showed less corneal swelling with CAB lenses than with PMMA lenses.

Acetates↗
PubMed1978

Ornithine ketoacid transaminase deficiency in gyrate atrophy of the choroid and retina.

Gyrate atrophy of the choroid and retina is a chorioretinal degeneration associated with hyperornithinemia with an autosomal recessive mode of inheritance. Cultured skin fibroblasts from five affected patients showed a virtual absence of ornithine ketoacid transaminase (OKT) (L-ornithine:2-oxoacid aminotransferase E.C.2.6.1.13) activity. Fibroblasts from four carrier parents showed a 42%-65% reduction in OKT activity. Increasing the concentration of pyridoxal phosphate (vitamin B6 in the assay media resulted in partial restoration of OKT activity in fibroblasts from one out of five patients studied. We conclude that OKT deficiency is closely associated with the genetic defect in gyrate atrophy of the choroid and retina and that genetic heterogeneity exists in this disease.

Adolescent↗
PubMed1977

Sulfite oxidase deficiency. Biochemical and clinical investigations of a hereditary metabolic disorder in sulfur metabolism.

Study of a 4 1/2-year-old boy with the unusual combination of acute infantile hemiplegia, ectopia lentis and the absence of homocystinuria showed large amounts of abnormal sulfur-containing metabolites (sulfite, thiosulfate and S-sulfocysteine) in the urine. Sulfite and S-sulfocysteine were also present in the plasma. His inorganic sulfate excretion was only 50 per cent of total sulfur, as compared with 75 to 95 per cent by controls. Loading with L-cysteine hydrochloride and L-methionine further increased the excretion of sulfite and thiosulfate, but not inorganic sulfate excretion. Sulfite oxidase activity in skin fibroblasts average 1.07 nmol of cytochrome d reduced per milligram of protein per minute in control lines; it was not detectable (less than 5 per cent) in the patient. Activity was reduced in both parents (0.50 in the father and 0.32 in the mother)--compatible with autosomal recessive inheritance. Good biochemical responses to a low sulfur amino acid diet suggest that early treatment may benefit the patient.

Amino Acids, Sulfur↗
PubMed1976

Metabolism of [1-(14)C] and [2-(14)C] leucine in cultured skin fibroblasts from patients with isovaleric acidemia. Characterization of metabolic defects.

Leucine metabolism in cultured skin fibroblasts from patients with isovaleric acidemia was compared with that in normal fibroblasts and in cells from patients with maple syrup urine disease using [1-(14)C] and [2-(14)C] leucine as substrates. Inhibitory effects of methylenecyclopropylacetic acid on leucine metabolism in normal cells were also investigated. Production of 14CO2 from [2-(14)C] leucine was very reduced (96-99%) in both types of mutant cells. Radioactive isovaleric acid accumulated in assay media with isovaleric acidemia cells but not in those with maple syrup urine disease cells. Unexpectedly, 14CO2 production from [1-(14)C] leucine was partially depressed (80%) in isovaleric acidemia cells whereas in maple syrup urine disease cells it was strongly depressed (99%) as expected. These two mutant cells were clearly distinguished by detection of 14C-isovaleric acid accumulation after incubation with [2-(14)C] leucine. A pattern of inhibition of leucine oxidation similar to that seen in isovaleric acidemia cells was induced in normal cells by the addition of 0.7 mM methylenecyclopropylacetic acid to the assay medium. The partial inhibition of [1-(14)C] leucine oxidation seen in isovaleric acidemia cells and also in normal cells in the presence of the inhibitor appears to be, at least in part, due to an accumulation of isovalerate in the cells. Isovaleric acid (5-10) mM) inhibited [1-(14)C] leucine oxidation 32-68% when added to the assay medium with normal cells. Addition of flavin adenine dinucleoside to culture medium or assay medium or both did not restore oxidation of either leucine substrate in isovaleric acidemia cells.

2-Methyl-4-chlorophenoxyacetic Acid↗
PubMed1975

Comparison of galactose-1-phosphate uridyl transferase in fetal and adult tissues.

Galactose-1-phosphate uridyl transferase, the enzyme deficient in galactosemia, is demonstrated to be present in erythrocytes from fetuses of 12--30 weeks gestation. The specific activity and starch gel electrophoretic pattern of this enzyme in fetal erythrocytes is virtually identical to that found in erythrocytes postnatally. This enzyme was also studied in cultured fibroblasts from skin and amniotic cells and found to have similar specific activity and identical electrophoretic mobility in tissues from both sources. There does not appear to be a fetal isozyme for galactose-1-phosphate uridyl transferase in either erythrocytes or cultured fibroblasts. Thus, with fetal erythrocytes obtained by fetoscopy, it is likely that prenatal diagnosis of galactosemia can be rapidly and reliably accomplished.

Adult↗
PubMed1975

Galactose-1-phosphate uridyl transferase in fibroblasts: isozymes in normal and variant states.

Electorphoretic properties of galactose-1-phosphate uridyl transferase in cultured skin fibroblasts of normal humans and individuals with different enzyme variants have been studied. Normal fibroblast lysates showed four activity bands, each slower moving than the erythrocyte enzyme. The transferase variants revealed different mobilities analogous to those found in erythrocytes. These findings suggest that subunits of human transferase associate variously with one another in a manner specific for each tissue and that in transferase variant states, an altered subunit results in a characteristic alteration in electrophoretic mobility which is analogous for each tissue.

Electrophoresis, Starch Gel↗