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Biomedical subjects

J Dancis

Publications and source records attributed to J Dancis.

At least 73 records · Page 4Linked to original sources
PubMed1978

Transient and long-term differential modulations of branched-chain alpha-keto acid decarboxylase activity in hypophysectomized rats.

Hypophysectomy caused a marked but transient increase in branched-chain alpha-keto acid decarboxylase activities in rat liver mitochondria, peaking at about nine days post-surgery. The magnitude of increase is different for each of the three branched-chain alpha-keto acids. The activities then fall to a new steady state in three weeks with alpha-ketoisovalerate decarboxylase activity within the normal range, alpha-keto-beta-methylvalerate decarboxylase activity at twice normal, and alpha-ketoisocaproate decarboxylase activity decreased to a level too low for accurate measurements.

Animals↗
PubMed1978

Quantitative studies of dorsal root ganglia and neuropathologic observations on spinal cords in familial dysautonomia.

Intrauterine development and postnatal maintenance of dorsal root ganglion neurons are abnormal in familial dysautonomia, an autosomal recessive disorder associated with autonomic, motor and sensory deficits. Normally, dorsal root ganglion weight increases with age. This does not occur in the cervical plexus ganglia of dysautonomic patients. Neurons in dorsal root ganglia are found to be markedly diminished in the youngest patients and slow degeneration causes further depletion with age. Quantitative studies on C8 dorsal root ganglia show the normal neuron content to be between 42,500 and 53,600. In 3 patients with familial dysautonomia the range was 4,090-8,590 with the smallest number being in the oldest patient. Lateral root entry zones and Lissauer's tracts are severely depleted of axons. In older patients loss of dorsal column myelinated axons becomes evident and is first seen in lumbar fasciculus gracilis, cervical fasciculus cuneatus and interfascicular fasciculus. Temperature sensation is markedly impaired from infancy in familial dysautonomia. Loss of pain sensation is prominent and worsens with age. Vibration sense diminishes in adolescence and coordination of limb movements becomes poor in older patients. Neuron depletion in dorsal root ganglia and the progressive pattern of cord changes correlate well with these clinical observations.

Adolescent↗
PubMed1978

Effect of protein binding on transfer and metabolism of cortisol in perfused human placenta.

The transfer and metabolism of cortisol and cortisone and the effect of protein binding on these processes have been investigated in vitro in the perfused human placenta. The clearance of cortisol in buffer, expressed as a fraction of the antipyrine transfer rate (clearance index), was 0.50 +/- 0.05 SEM in either direction. Extensive conversion to cortisone (85%) occurred during transfer. Addition of corticosteroid-binding globulin (CBG) in amounts sufficient to bind 50% of the cortisol reduced the clearance (0.40 +/- .026) insignificantly, whereas human serum albumin (HSA) in amounts sufficient to bind 50% of the cortisol reduced the clearance to 0.28 +/- 0.012 (P less than 0.001) even though the association constant for albumin is approximately 1000-fold less. The percent of conversion to cortisone did not change significantly with protein binding. The clearance index of cortisone from a protein-free perfusate was 0.74. With CBG and albumin in the same concentrations as used in the cortisol experiments, the binding of cortisone to CBG was 23% and its clearance was 0.70; with albumin, the binding was 45% and the clearance index was 0.45. The addition of albumin and CBG to the same perfusate resulted in a cortisol clearance equal to that obtained with perfusate containing only albumin. Binding to albumin may be more significant than binding to CBG in controlling the transfer rate of cortisol to the fetus.

Carrier Proteins↗
PubMed1977

Maple syrup urine disease: branched-chain keto acid decarboxylation in fibroblasts as measured with amino acids and keto acids.

Branched-chain keto acid decarboxylase activity in skin fibroblasts from control subjects and from patients with classical and variant forms of maple syrup urine disease (MSUD) was measured with leucine and alpha-ketoisocaproic acid. When the keto acid was used as substrate in high concentrations (more than 5 mM), the three groups overlapped extensively, even classical cases of MSUD exhibiting decarboxylase activity. With leucine as substrate, decarboxylase activity plateaued at about 1.5 mM, and the three groups could be clearly differentiated. Classical cases of MSUD had minimal or no decarboxylase activity.

Caproates↗
PubMed1977

Treatment of hypoplastic anemia in mice with placental transplants.

A genetic mutation in mice (W/Wv) causes an autosomal recessive disease characterized by hypoplastic anemia which lasts throughout life. Double-dominant W/Wv anemic mice were sublethally irradiated to facilitate repopulation of marrow with transplanted cells and were injected intravenously with suspensions of 5-10 million placental cells of 15 days gestation derived from normal, isogeneic donors. Red cell counts fell promptly after irradiation and then rose progressively over a period of weeks, reaching normal levels of the nonmutant. Mean corpuscular volume and hemoglobin electrophoresis patterns of red cells in recipient W/Wv mice resembled those of normal donor animals. The therapeutic effect lasted for the duration of the observation period, in some instances over 9 mo. W/Wv mice that were administered Hanks' solution or fetal blood, instead of placental transplants, remained anemic. Late gestation placentas (18 days) were also ineffective.

Aging↗
PubMed1976

In vitro perfusion of human placenta. V. Oxygen consumption.

02 consumption by human term placenta has been measured during perfusion in vitro, with a technique that permits perfusion of the intervillous space as well as the umbilical circulation. The rate at which 02 was consumed was directly related to the rate at which it was supplied, within the limits studied. Previous estimates of 02 consumption yielded figures approximating 3 ml. per minute per kilogram of placenta, but these estimates were attained under conditions of limited oxygen supply. When oxygen was delivered to the placenta at rates believed to be those achieved in vivo, oxygen consumption approximated 10 ml. per minute per kilogram. This rate of 02 consumption is similar to those obtained from studies of animal placentas in vivo and is more consistent with that of an active metabolic organ. If one were to accept estimates of 02 consumption by the human fetus in utero, the present studies indicate that approximately one fifth of maternal oxygen supplied to the conceptus is diverted to support placental metabolism.

Female↗
PubMed1976

The effect of L-5-hydroxytryptophan on self-mutilatin in Lesch-Nyhan disease: a negative report.

Four patients with Lesch-Nyhan disease were treated with L-5-hydroxytryptophan, alone, or in combination with carbidopa, and their effect on self-mutilatory behavior was compared to that observed during periods in which placebo was administered. Observation periods were carefully standardized because of the ease with which patient-observer interactions can influence the behavior of the Lesch-Nyhan patient. The dosage level was sufficient to produce undesirable side-effects (diarrhea and vomiting). No effect on self-mutilation was observed under test conditions in the hospital or in the natural environment of the home. These results contrast with previous beneficial effects reported by others.

5-Hydroxytryptophan↗
PubMed1976

Studies on cell communication with enucleated human fibroblasts.

Metabolic cooperation, the correction of the mutant phenotype in cells deficient in hypoxanthine phosphoribosyltransferase (HPRT-) by intimate contact with normal cells (HPRT+), represents a form of cell communication that is easily studied with radioautography. In the present study it was found that the formation of cell junctions needed for communication does not require protein synthesis nor is it under the immediate control of the cell nucleus. Enucleated normal cells efficiently communicate with HPRT- mutant cells. The effectiveness of enucleated cells as donors in metabolic cooperation provides evidence that it is the transfer of small molecules, nucleotide, or nucleotide derivatives that is responsible for correction of the mutant phenotype. Karyoplasts (nuclei with small amounts of cytoplasm surrounded by a plasma membrane) are unable to efficiently communicate with intact cells. The utilization of [3H]hypoxanthine by communicating mixtures of HPRT+ and HPRT- human cells is not significantly different than in the normal cells alone. Metabolic cooperation, as studied involves a redistribution of purine-containing compounds among communicating cells.

Adenine↗
PubMed1976

Hypoxanthine phosphoribosyltransferase activity in intact fibroblasts from patients with X-linked hyperuricemia.

Discordance between clinical phenotype and the level of a mutant enzyme activity may reflect differences between enzyme function in vivo and that measured by the customary enzyme assays on cell extracts. In the present study, the conversion of hypoxanthine to phosphorylated products was measured in intact skin fibroblasts and in cell extracts from seven patients with mutant hypoxanthine-guanine phosphoribosyltransferase (HPRT) and six control subjects. The patient's phenotypes ranged from asymptomatic hyperuricemia to the Lesch-Nyhan syndrome. Although there was a general correlation between the HPRT activity in cell extracts assayed by the usual methods and the function of the purine salvage pathway in patients, as reflected by urinary oxypurine excretion, there were notable exceptions. A more accurate appraisal of the functioning of the pathway at the cellular level is achieved by measuring the conversion of substrate to product in the intact cell at physiological concentrations of substrates, activators, and product and metabolite inhibitors, and in a physiological ionic environment. In one of the seven patients, the standard enzyme assay indicated normal function, whereas measurements in the intact cell exposed severe dysfunction of the salvage system. In another, the standard assay suggested a severe deficiency not evident in the intact cell or in the patient.

Adolescent↗
PubMed1976

Transfer across perfused human placenta. IV. Effect of protein binding on free fatty acids.

The effect of protein binding on the rate of placental transfer of hexanoic (C 6) and decanoic (C 10) acids was investigated in an in vitro perfusion system of human placenta. As much as 30% of transferred C 6 was converted to more polar compounds, so that the observations related to the combined effects on transfer and metabolism. Less than 10% of C 10 was similarly metabolized. Both fatty acids are soluble in buffered salt solutions at the concentrations used (40 muM) and both are bound to serum albumin, C-10 having higher association constants (K' for C 6, 1.48 X 10(4); for C 10, 1.03 X 10(5). When the placenta is perfused with buffered salt solution, the transfer of C 6 is 22% more rapid than that of C 10. It is suggested that binding within the placenta retards C 10 more than C 6. The addition of 1 g/100 ml bovine serum albumin to the maternal perfusate reduces the transfer rate of C 10 by 80%, whereas 2 g/100 ml serum albumin has a more moderate effect on C 6 (a reduction of 50%). The addition of 1 g/100 ml serum albumin to the fetal perfusate increases transfer rate of both free fatty acids (FFA), C 6 by 25% and C 10 by about 250%. With equivalent concentrations of serum albumin in maternal and fetal perfusates, the transfer rate of C 10 was reduced by 65%, whereas there was no detectable effect on transfer of C 6 in two of three experiments. The transfer rate of FFA increase logarithmically with progressive shortening of the carbon chain from C 16 to C 8 when maternal and fetal perfusates contain serum albumin. Protein binding is apparently the determining factor. The rate of transfer falls off at C 6 and C 4, 4ven though protein-binding continues to decrease. The determining factor may be the hydrophilic nature of these molecules.

Fatty Acids, Nonesterified↗
PubMed1976

Multiple enzyme defects in familial hyperlysinemia.

Lysine-ketoglutarate reductase (EC. 1.5.1.8) deficiency in skin fibroblasts has been previously reported in patients with familial hyperlysinemia, providing an adequate explanation for the biochemical derangements noted clinically. In the present study, analysis of liver obtained at autopsy from a patient with familial hyperlysinemia confirmed the lysine-ketoglutarate reductase deficiency but, unexpectedly, also revealed an absence of saccharopine dehydrogenase (EC. 1.5.1.9) and saccharopine oxidoreductase activity. Skin fibroblasts from two siblings with the disease and a third patient from an unrelated family were also deficient in all three enzymes (lysine-ketoglutarate reductase, average 9%; saccharopine dehydrogenase, average 4%; saccharopine oxidoreductase, less than 10% of normal). The possibility that saccharopine dehydrogenase is a substrate-inducible enzyme was investigated by maintaining normal skin fibroblasts in a medium with minimal lysine concentration, and exposing hyperlysinemic fibroblasts to elevated saccharopine concentrations. There was no significant modification in saccharopine dehydrogenase activity.

Adolescent↗
PubMed1976

The occurrence of new mutants in the X-linked recessive Lesch-Nyhan disease.

In a population at equilibrium for a sex-linked lethal, one-third of the genes for that lethal must arise anew each generation. Therefore, one-third of all cases of Lesch-Nyhan disease, a severe X-linked recessive lethal disorder, should be new mutants. To test this hypothesis, we have collected 47 families, 20 with a single proband and 27 with multiple affected males in which the patients' mothers and other female relatives had been studied for heterozygosity. Available carrier detection tests identify heterozygous for HPRT deficiency in hair roots and skin fibroblasts. Only four mothers were found not to be carriers. This result deviates significantly from expected (P less than .001). Statistical tests for ascertainment effects indicated absence of bias for multiple proband families but strong bias in favor of families with many heterozygous females. When the analysis was limited to single proband families, the deviation from expected was still significant (P less than .01). The incidence of new mutants among the heterozygous mothers, as determined by the ratio of +/+ to +/- maternal grandmothers, should be one-half (see Appendix). Of all 20 maternal grandmothers studied, five were +/+ and 15 were +/- (P less than .05). Considering only the single proband families, the ratio of 5 +/+ to 8 +/- was not significantly different from expected. In four of the five cases in which the heterozygous mother of an affected individual was a new mutation, the age of her parents was considerably higher than the mean parental age in the population. This raises the possibility of a paternal age effect on X-linked mutations. There appears to be a true deficiency of new mutatnts among males but not among females. Data on additional Lesch-Nyhan families are needed before conclusions regarding a possible higher mutation rate in males can be drawn.

Female↗
PubMed1976

Purine excretion by cultured skin fibroblasts from patients with abnormal purine metabolism.

Cultured fibroblasts from patients with partial or complete deficiencies of enzymes involved in purine metabolism provide a model for investigating the biosynthesis, interconversion, and excretion of purine metabolites at the cellular level. Skin fibroblast cultures were derived from five patients with hypoxanthineguanine phosphoribosyltransferase deficiency, from five subjects with idiopathic overproduction gout, from one patient with adenosine deaminase deficiency, and from four control subjects. Purine excretion was measured by recovering labeled purines from the incubation medium of cells grown in the presence of 14C-formate. In general the patterns of purine excretion by these cultured cells resembled the urinary excretion patterns of the patients from whom they were derived.

Adenosine Deaminase↗