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J Dancis

Publications and source records attributed to J Dancis.

At least 37 records · Page 2Linked to original sources
PubMed1988

Placental transfer of thiamine in the human subject: in vitro perfusion studies and maternal-cord plasma concentrations.

The transfer of thiamine across human placenta has been studied in an in vitro perfusion system. With the maternal and fetal perfusates not recirculated, the transfer index (ratio of clearance of thiamine to that of L-glucose) toward the fetus was 2.09 +/- 0.36, suggesting a mediated transport system. In the reverse direction, the transfer rate approximates that expected from simple diffusion (transfer index 0.78 +/- 0.25). Stepwise increases in thiamine concentration in the maternal perfusate were associated with parallel increases in transfer rates up to 500 nmol/L. Above that concentration, the rate of increase declined and the transfer index fell. When the maternal perfusate was recirculated and the fetal circulation was kept open, the thiamine concentration rapidly decreased, reaching a plateau in 30 to 40 minutes at a level about 0.1 to 0.2 of the fetal perfusate. In contrast, the concentration within the placenta greatly exceeded those in the perfusates. The observations indicate an effective transport system directed toward the fetus, saturable at low concentrations and capable of establishing a transplacental gradient. Measurement of thiamine concentrations in 20 paired samples of plasma obtained at term demonstrated a mean (+/- SD) cord:maternal ratio of 2.5 +/- 1.4. Differential protein binding was excluded as a cause of the gradient. The in vivo gradient is probably attributable to placental transport.

Blood Proteins↗
PubMed1988

Placental transport of riboflavin: differential rates of uptake at the maternal and fetal surfaces of the perfused human placenta.

The kinetics of riboflavin transfer across the perfused human placenta has been studied. With both circulations open, the transfer index (clearance of riboflavin: clearance of antipyrine) toward the fetus was 3.3 +/- 0.08 (+/- SD) versus 0.87 +/- 0.02 in the reverse direction (p less than 0.01). Galactoflavin reduced the materno-fetal transfer rate. The uptake of riboflavin and L-glucose after bolus injection into the maternal perfusate was 35% +/- 9.6% versus 3% +/- 16%, p = 0.005, which indicates an uptake rate in excess of diffusion. There was no significant difference in uptake at the fetal surface. With recirculation of either the maternal or fetal perfusate, the transplacental gradient that was established was lower at high concentrations of riboflavin, which indicates the saturability of this function. Riboflavin was concentrated in the intracellular space and partly metabolized to flavin mononucleotide and flavin adenine dinucleotide. An equilibrium was approximated when both perfusates were recirculated, with the concentration lowest in the maternal perfusate, highest in the placenta, and intermediate in the fetal perfusate. It is concluded that the major factor directing riboflavin toward the fetus is the difference in rates of uptake at the two surfaces of the placenta.

Biological Transport↗
PubMed1988

Zellweger syndrome amniocytes: morphological appearance and a simple sedimentation method for prenatal diagnosis.

Zellweger syndrome is the prototype of a growing group of genetic diseases caused by an absence or deficiency of peroxisomes. The defect causes the enzyme catalase to remain in the cytosol instead of being packaged into peroxisomes. This mislocalization can be easily detected by sedimentation analysis. Amniocytes were homogenized and then centrifuged to pellet organelles. Catalase was found to sediment with the peroxisomes in the homogenates of normal cells, but to remain in the supernatant with Zellweger syndrome amniocyte homogenates. This striking difference is unambiguous and reproducible, and provides a simple method for prenatal diagnosis. Moreover, it allows one to differentiate diseases in which peroxisomes are deficient from other peroxisomal diseases in which the organelle is intact, but one enzyme is defective. Electron microscopic observations support the biochemical determinations. Normal amniocytes contain small peroxisomes in which a weak cytochemical reaction for catalase may be demonstrated. Zellweger amniocytes appear to lack these organelles, although some cells have rare structures that might be residual or abnormal peroxisomes.

3,3'-Diaminobenzidine↗
PubMed1987

Riboflavin concentration in maternal and cord blood in human pregnancy.

Riboflavin concentration was measured in sera of a control population and in a series of paired maternal and cord sera. The assay technique was carefully validated and appears to be specific and reproducible. The mean riboflavin concentration in 12 apparently healthy adults was 116 +/- 46 nmol/L (SD). In 20 uneventful pregnancies the cord serum concentration was generally higher than the maternal concentration (158 +/- 47 nmol/L versus 113 +/- 35 nmol/L; p = 0.001). The cord-to-maternal ratio in paired sera averaged 1.45 +/- 0.44. There was no detectable difference in binding of riboflavin to cord and maternal serum proteins as measured by equilibrium dialysis (59.0% +/- 17% versus 60.8% +/- 16%). Comparison of protein binding by paired cord and maternal sera yielded a ratio of 0.99 +/- 0.13. The transplacental gradient of riboflavin concentration is unrelated to protein binding and is consistent with active transport by the placenta, as previously demonstrated in vitro.

Blood Proteins↗
PubMed1986

L-pipecolaturia in Zellweger syndrome.

Purified rat peroxisomes have been reported to oxidize D-pipecolic acid and the pipecolaturia of Zellweger syndrome has been attributed to the absence of peroxisomes. The logical consequences would be excesses of D-pipecolic acid in the urine of patients with Zellweger syndrome. The urine of two patients with Zellweger syndrome has been analyzed by complexing the pipecolic acid to copper-aspartame to separate the L- and D-isomers. L-Pipecolic acid constituted 100% and 78% of the total pipecolic acid in the two urines. The possibility of preferential retention of D-pipecolic acid was excluded by measuring renal excretion in two control subjects following administration of each isomer. The clearance of L-pipecolic acid was 1.1 and 0.2 ml/min and of D-pipecolic acid was 36.4 and 43.6 ml/min. These results do not support the contention that the pipecolaturia of Zellweger syndrome is the direct result of peroxisomal deficiencies.

Brain Diseases↗
PubMed1986

Dopamine agonist induced self-mutilative biting behavior in monkeys with unilateral ventromedial tegmental lesions of the brainstem: possible pharmacological model for Lesch-Nyhan syndrome.

We have investigated the effects of various dopamine (DA) agonists on induction of abnormal involuntary movements (AIM) in a group of monkeys which had denervated nigro-striatal DA neurons for 10-14 years rendered by a unilateral surgical ventromedial tegmental (VMT) lesion of the brainstem. The surgical lesions were placed when the monkeys were 2-4 years old. The administration of mixed DA agonists, such as L-DOPA, apomorphine (Apo) and abeorphine 201-678, elicit a self-mutilative biting behavior (SMB) of the forelimb digits contralateral to the lesion, and spasticity of the contralateral hindlimb. These dysfunctions resemble, in some aspects, the neurological disturbances associated with Lesch-Nyhan syndrome. The SMB behavior was elicited by mixed DA agonists which predominantly stimulate D1, but not D2 DA receptors, and was prevented or abolished by the D1 DA antagonist SCH 23390 or by the D1 and D2 DA antagonist fluphenazine (Flu), but not by the D2 antagonist (+/-)sulpiride. These results suggest that DA agonist-induced SMB behavior is mediated by D1 and/or by both D1 and D2 DA receptor pathways. To study the relationships between HPRT, the defective enzyme in Lesch-Nyhan syndrome, and the DA neuronal systems, we have measured the effects of nigro-striatal DA degeneration and intrastriatal neuronal degeneration on HPRT activity. The unilateral 6-OHDA-induced nigro-striatal DA degeneration does not significantly alter the HPRT activity on the lesioned side of the striatum, while the quinolinic acid-induced intrastriatal neuronal degeneration significantly reduces the enzyme activity. These results suggest that HPRT is localized on intrastriatal neurons which are also known to contain DA receptors. It is postulated that HPRT deficiency in Lesch-Nyhan syndrome results in abnormal guanine nucleotide metabolism which may affect the regulation of DA receptors.

Animals↗
PubMed1986

The significance of hyperpipecolatemia in Zellweger syndrome.

The plasma pipecolic acid concentration in two newborn infants with Zellweger syndrome at ages 4 and 10 days were 7.8 and 7.7 microM. Reported concentrations from this laboratory for normal newborn infants averaged 12 microM +/- 5.6 (SD). Both patients had the facies and severe hypotonia characteristic of the disease. Autopsy examination at age 6 days in one of these patients revealed the developmental microscopic abnormalities in brain, liver, and kidney that are associated with Zellweger syndrome. In three additional patients ages 3 1/2 weeks, 2 months, and 2 months, the pipecolic acid concentrations were 15, 17, and 25 microM. The concentrations increased to distinctly pathological levels on subsequent assays at a later age. It is concluded that the hyperpipecolatemia in Zellweger syndrome occurs postpartum and that the plasma concentrations may not be diagnostic early in life. The major manifestations of the disease, already evident at birth, cannot be attributed to pipecolatemia. Currently available data do not exclude the possibility of pipecolic acid accumulation in the brain where it has been reported to be a major metabolite of lysine. Hyperpipecolatemia of considerable degree is also consistently found in familial hyperlysinemia where it appears to be benign.

Abnormalities, Multiple↗
PubMed1986

Establishment of gradients of riboflavin, L-lysine and alpha-aminoisobutyric acid across the perfused human placenta.

The mechanism for establishing transplacental gradients was studied in the dually perfused human placental lobule by recirculating either the maternal or fetal perfusate and leaving the other circuit open. Antipyrine, used as a reference molecule, rapidly reached equivalent concentrations in both perfusates regardless of which was recirculated. In contrast, riboflavin, L-lysine and alpha-aminoisobutyric acid showed distinctive kinetics at each surface of the placenta. Recirculation of the maternal perfusate quickly depressed the concentrations of these compounds and maintained them at levels of 50-70% of the fetal concentration. Recirculation of the fetal perfusate was followed by a gradual increase in concentrations, establishing gradients 1.2-1.7 times the maternal. It appears that uptake at the maternal surface greatly exceeds release, whereas the two rates are more nearly balanced at the fetal surface. The net effect is extraction of substrate from the maternal circulation and transfer to the fetal, where it accumulates to form a gradient.

Aminoisobutyric Acids↗
PubMed1985

Transfer of riboflavin by the perfused human placenta.

The transfer of radioactive riboflavin across the human term placenta has been studied in an in vitro perfusion system. The clearance index (clearance riboflavin:clearance antipyrine) toward the fetus averaged 0.69 and the transfer index (clearance riboflavin:clearance L-glucose) averaged 3.40. The respective indices in the reverse direction were 0.25 and 0.87. Stepwise increases in the concentration of riboflavin in the maternal perfusate were associated with parallel increases in transfer rates, expressed as ng/min, up to concentrations approximating 100 ng/ml. Above that concentration, the transfer rates continued to increase at a slower rate. Concurrently, there was a reduction of the transfer index from 2.7 to 1.1 at 1000 ng/ml. With the fetal circulation closed, the placenta established a gradient toward the fetus over a period of 150 min of 1.7. The transferred radioactivity was identified as riboflavin by high-performance liquid chromatography, whereas that retained within the placenta was metabolized to flavin mononucleotide (33-75%). The observations indicate a very effective active transport system directed toward the fetus which is limited in capacity to low concentrations of riboflavin.

Antipyrine↗
PubMed1985

Zellweger syndrome: biochemical and morphological studies on two patients treated with clofibrate.

Two infants with Zellweger syndrome (cerebro-hepato-renal syndrome) have been studied biochemically and morphologically. Peroxisomal enzymes involved in respiration, fatty acid beta-oxidation, and plasmalogen biosynthesis were assessed. In liver, catalase was present in normal amounts but was located in the cell cytosol. Dihydroxyacetone phosphate acyltransferase activity was less than one-tenth of normal. The amount of the bifunctional protein catalyzing two beta-oxidation reactions was found by immunoblotting to be greatly reduced. Catalase activity was normal in intestine. D-Amino acid oxidase was subnormal in kidney. The observed enzyme deficiencies may plausibly explain many of the metabolite imbalances observed clinically. Morphologically, peroxisomes were absent from liver. In intestine, normal peroxisomes were also missing, but some rare, smaller (0.04-0.13 micrometer) bodies were seen with a slight positive cytochemical reaction for catalase. These results, together with current concepts of peroxisome biogenesis, suggest but do not prove, that the primary defect in Zellweger syndrome may be in peroxisome assembly. The infants were treated with clofibrate, but it was ineffectual as assessed biochemically, morphologically, and clinically.

Abnormalities, Multiple↗
PubMed1984

Transfer of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 across the perfused human placenta.

The rates of placental transfer of 25-hydroxyvitamin D3 [25-(OH)D3] and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] were determined in an in vitro perfusion system. Antipyrine was included in each perfusion, and the data are expressed as clearance index, the ratio of hydroxyvitamin D3 to antipyrine clearance. In most experiments, serum, 0.2%, was added to the perfusates as a source of vitamin D3-binding protein. Binding as measured by dextran-coated charcoal assay for 25-(OH)D3 was over 90%, for 1,25-(OH)2D3, only 25% to 50%. The clearance index from the maternal to fetal circulation averaged 0.02 and 0.26 for 25-(OH)D3 and 1,25-(OH)2D3, respectively. When vitamin D3-binding protein was omitted from the perfusate, the clearance indices of 25-(OH)D3 were 0.12 and 0.46 in two experiments. Binding to vitamin D3-binding protein is a major determining factor for the transfer rates of 25-(OH)D3 and 1,25-(OH)2D3.

Antipyrine↗
PubMed1983

The determination of pipecolic acid: method and results of hospital survey.

A method is described for the quantitative assay of pipecolic acid in biological fluids using column chromatography, with acid ninhydrin for color development. The technique permits measurement of plasma pipecolic acid in normal individuals with blood samples of 1 ml. The mean value in 29 pediatric patients, aged 4 months to 17 years, hospitalized with a variety of diagnoses was 2.1 mumol/1 +/- 1.6. Newborn infants had slightly elevated plasma levels with a mean of 12 mumol/1 +/- 5.6. Among the diagnostic categories, patients with liver disease were distinctive in commonly having levels at the upper limits of normal. In some cases, the levels were exceedingly high, reaching 78 mumol/1 in one fatal case.

Amino Acids↗
PubMed1983

Hair root analysis in X-linked ichthyosis.

Hair roots have been analysed in a large kindred with X-linked ichthyosis associated with steroid sulphatase deficiency. Enzyme activity in individual hair roots was assayed for the steroid sulphatase:neutral alpha-glucosidase ratio, the latter serving as an indicator of the general metabolic activity of the hair root. The distribution of the enzyme ratios in the individual hair roots in the heterozygotes described a normal curve suggesting origin from a single population of cells. The results differed strikingly from the irregular distribution of enzyme activities in hair roots of Lesch-Nyhan disease, where mosaicism occurs. It is suggested that the maternal and paternal genes for steroid sulphatase remain active in vivo in each cell in the hair root in apparent contradiction to the Lyon hypothesis. The observation is consistent with that previously reported for skin fibroblasts in vitro. Sulphatase activity in female controls was minimally greater than in males but the difference was not statistically significant.

Female↗