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K S Roth

Publications and source records attributed to K S Roth.

At least 55 records · Page 3Linked to original sources
PubMed1985

Defect in alpha-ketobutyrate metabolism: a new inborn error.

A pair of siblings with clinical symptoms of cyclic vomiting and ketoacidosis were found to have a biochemical triad of normoglycemia, ketoacidosis and elevated levels of alpha-hydroxy- and alpha-aminobutyrate in plasma and urine. Methionine loading studies in both sibs produced prompt rises in plasma methionine and alpha-aminobutyrate levels, with a subsequent increase in urinary alpha-hydroxybutyrate, as well. Leukocytes from both siblings showed normal oxidation of [3-14C]propionate. Increased inorganic sulfate excretion after methionine loading implied an intact transsulfuration pathway in both siblings. On the basis of the studies detailed in this report, we conclude that these siblings suffer from a defect in alpha-ketobutyrate oxidation, a newly described defect of organic acid metabolism.

Acidosis↗
PubMed1983

Renal brush-border-membrane vesicles prepared from newborn rats by free-flow electrophoresis and their proline uptake.

A method for the isolation of brush-border membranes from newborn-rat kidney, employing centrifugation and free-flow electrophoresis, is described. The composition and purity of the preparation was assessed by determination of enzyme activities specific for various cellular membranes. Free-flow electrophoresis resolves the newborn-rat renal membrane suspension into two populations of alkaline phosphatase-enriched brush-border membranes, designated 'A' and 'B', with the A peak also showing activity of (Na+ + K+)-stimulated ATPase, the basolateral membrane marker enzyme, whereas those of the B peak were enriched 11-fold in alkaline phosphatase and substantially decreased in (Na+ + K+)-stimulated ATPase activity. Membranes in the A peak showed a 7-fold enrichment of alkaline phosphatase, and (Na+ + K+)-stimulated ATPase activity similar to that of the original homogenate. Proline uptake employed to assess osmotic dependency revealed 7% binding of proline to the B vesicles and 31% to the A vesicles. This contrasts with 60% proline binding to vesicles prepared by centrifugation alone. Unlike vesicles from adult animals, proline uptake by B vesicles did not show an Na+-stimulated overshoot, but did exhibit an Na+-gradient enhanced rate of early proline entry. proline entry.

Animals↗
PubMed1983

L-Proline transport by isolated renal tubules from newborn and adult rats.

Proline uptake and metabolism has been examined in newborn Sprague-Dawley rat kidney and compared to that in adult animals. [14C]-Proline uptake by renal tubule fragments from newborn rats occurs at the same initial rate as in adult tubules, but at physiologic concentrations achieves significantly higher intracellular levels after 15 min of incubation. Considerable metabolism of the proline taken up was observed in tissue of both ages. Analysis of acid soluble and insoluble tubule fractions from newborn and adults indicates similar degrees of proline incorporation into protein and oxidation to CO2 relative to the amount of radioactivity taken up. A major difference exists, however, with respect to the labeled components of the acid extract: adult tubules convert [14C]-proline to metabolites at a rate twice that of newborn. Analysis of concentration-dependent uptake data reveals two distinct entry systems for proline in both isolated newborn and adult tubules. No difference in the Km or Vmax was found between the young and mature tubules.

Age Factors↗
PubMed1982

A comparison of the uptake of 3-hydroxy-3-methyl-glutaric acid in newborn and adult rat kidney.

The developmental aspects of the renal uptake of 3-OH-3-CH3-glutaric acid (HMG) was examined using isolated renal tubules prepared from both newborn and adult rats and isolated renal brush border membranes vesicles from adult rats. The accumulation of 70 microM HMG by both newborn and adult tubules reached a steady state and achieved a distribution ratio (DR) of 4.9 and 6.5, respectively; decreased DR's at higher substrate concentrations suggest concentration-dependent uptake. Lineweaver-Burk analysis of the 5 min calculated velocities of HMG uptake by newborn and adult tubules indicate a single transport system with the same apparent Km of 0.2 mM in both age groups. The Vmax in adult rats was twofold greater than in newborn (0.95 versus 0.44 mM/1/5 min). The carrier system for HMG is assumed to be distinct from those of amino acids and sugars because tubule uptake of HMG is not affected by the presence of alpha-NH2-isobutyric acid and alpha-methyl-D-glucoside. Sodium maleate and acetoacetate significantly decreased HMG uptake in tubules of both age groups. HMG uptake by isolated renal brush border membrane vesicles from adult rats suggests that uptake is both carrier-mediated and Na+-dependent. These observations are consistent with renal tubular HMG uptake by an energy-dependent, carrier-mediated system.

Acetoacetates↗
PubMed1982

Prenatal administration of biotin in biotin responsive multiple carboxylase deficiency.

Biotin responsive multiple carboxylase deficiency was suspected in a third trimester conceptus on the basis of enzymatic confirmation in fibroblasts cultured from an earlier sibling who suffered a demise in the immediate neonatal period. Maternal urinary organic acid profile was normal throughout the final 4 wk of pregnancy. Oral administration of biotin, 10 mg/day to the mother resulted in a 100-fold increase in urinary biotin excretion within 7 days. Urinary biotin excretion over the subsequent 2 wk decreased steadily, suggesting either decreased maternal absorption or increased fetal sequestration. After the birth of nonidentical twins, cord blood and urinary organic acid profiles of the infants were normal. However, cord blood biotin concentration was 4 to 7-fold that of normal newborns. Subsequent enzymatic and genetic complementation studies utilizing cultured skin fibroblasts from the infants demonstrated one of them to be affected by the multiple carboxylase defect, although he was clinically and biochemically normal throughout the neonatal period. Thus, prenatal therapy of this inborn enzymatic defect can be safely and effectively accomplished by administration of pharmacologic biotin doses in the last month of pregnancy.

Biotin↗
PubMed1982

Transport of beta-hydroxy-beta-methyl-glutarate and beta-hydroxbutyrate by renal brushborder membrane vesicles.

The uptake of beta-hydroxy-beta-methyl-glutarate (HMG) and beta-hydroxy-butyrate (beta-HB) by renal brushborder membrane vesicles prepared from normal and starved rats was examined. HMG and beta-HB uptake show a Na+ gradient-induced overshoot, suggesting luminal cotransport of these organic acids. Kinetic analysis of HMG and beta-HB uptake revealed a single component carrier system and a diffusional component for each compound. Vesicles from starved rats exhibit the same transport characteristics as those from normal rats. The transport interactions of other organic acids with HMG were examined and revealed that citrate is a competitive inhibitor, which implies that the compounds share a common organic acid carrier.

3-Hydroxybutyric Acid↗
PubMed1981

Serum and urinary biotin levels during treatment of holocarboxylase synthetase deficiency.

Measurements of blood and urine biotin levels have been performed during treatment of a patient with holocarboxylase synthetase deficiency. During the first 24 hours of therapy, the infant progressed from a moribund, shock-like state to a clinically normal baby. Urinary biotin concentration increased more that 100-fold after 12 hours of treatment. Within 48 hours of treatment, blood biotin levels were greater than 10 times control levels. On the basis of the data presented, it is suggested that therapeutic blood levels of biotin can be achieved by enteral administration of 10 mg of biotin per day.

Apoproteins↗
PubMed1981

Biotin in clinical medicine--a review.

The recent developments in cofactor therapy of inherited biochemical disease has awakened interest in biotin as a therapeutic agent. This review briefly details the physiological and biochemical aspects of human biotin metabolism. The role of biotin in therapy of human disease is critically examined and the relevant literature extensively reviewed. It is our hope that this review will stimulate further clinical interest in the treatment of biotin-responsive human disorders.

Acetyl-CoA Carboxylase↗
PubMed1980

Holocarboxylase synthetase deficiency: a biotin-responsive organic acidemia.

The clinical and biochemical features of an infant affected by holocarboxylase synthetase deficiency are presented. The patient was the sibling of the deceased child in whose cultured skin fibroblasts the precise enzymatic disorder was first determined. This fact permitted administration of specific therapy in the form of oral biotin, resulting in immediate improvement from impending respiratory failure and shock. The clinical response to biotin was accompanied by recovery of the biochemical mechanisms known to be biotin-dependent, as manifested by disappearance of intermediates in urine and blood. The variability of biotin responsiveness and the diversity of clinical presentation in the patients originally thought to have a deficiency of beta methylcrotonylCoA carboxylase, a biotin-dependent enzyme, raises the question of a separate, specific apocarboxylase defect.

Amino Acid Metabolism, Inborn Errors↗
PubMed1980

The effects of diazene dicarboxylic acid bis-(N, N-dimethylamide) on glycine uptake by newborn renal cortex.

Glycine uptake by newborn rat renal cortical slices in the presence of 2 mM diamide remained unchanged from control value during incubation times up to 30 minutes. Longer exposure to diamide resulted in decreased net uptake. Kinetic analysis of this phenomenon indicated a noncompetitive inhibitory effect of diamide upon the low-affinity glycine uptake system, whereas glycine uptake on the high-affinity system was obliterated. A similar analysis of the diamide effects on adult tissue indicated a noncompetitive inhibition of both the low- and high-affinity glycine transport systems. Diamide did not cause any demonstrable change in glycine efflux from newborn cortical slices. Thus the decreased net uptake we observed in newborn slices in the presence of diamide could be explained solely on the basis of an effect on glycine entry. Simultaneous measurements of intracellular glutathione (GSH) levels in the newborn tissue showed a lack of any direct relationship between the transport effects of diamide and its oxidative effect on reduced glutathione.

Animals↗
PubMed1979

L-proline transport by newborn rat kidney brush-border membrane vesicles.

The transport of L-proline was studied in brush-border membrane vesicles isolated from the kidneys of newborn rats. In contrast with the rapid initial uptake with an 'overshoot' observed in adult vesicles, uptake by the newborn vesicle was slow, showed no 'overshoot', and proline continued to accumulate at a time when the adult vesicle had already equilibrated. L-Proline transport in the newborn rat occurs by Na+-dependent and independent mechanisms. There appeared to be essentially no uptake by anti-luminal vesicles isolated from newborn rat kidney. These observations may help to explain the prolinuria that occurs in the newborn animal.

Animals↗
PubMed1979

Uptake of glycine by human kidney cortex.

The transport of glycine was investigated in histologically normal adult human kidney cortical slices. Uptake occurs against a gradient and shows concentration dependence. Kinetic analysis reveals two systems for transport of glycine with apparent transport Km values of 0.511 and 34.2 mM. Glycine transport on the high-Km system is competitively inhibited by 50 mML-proline. Transport inhibition on the low-Km system could not be directly evaluated, but on theoretic grounds appears not to be inhibited by L-proline or hydroxyproline. Alpha-aminoisobutyric acid, valine, and thioproline are also shown to inhibit glycine uptake. Low medium sodium or anaerobic incubation depress the uptake of glycine. These observations are consistent with previous reports of glycine transport in rat kidney and support the proposals for the mechanism of familial iminoglycinuria based on in vivo investigations.

Adult↗
PubMed1978

On the development of glycine transport systems by rat renal cortex.

The initial uptake of glycine by renal cortical slices from newborn Sprague-Dawley and Long-Evans rats is the same as that observed in adult tissues. Both newborn and adult tissue possess similar high and low affinity glycine transport systems which require an examination of velocity measurements over a wide range of concentration (0.02--50.0 mM) for their discernment. Initial rates of glycine uptake by isolated renal tubule fragments from newborn and adults are similar at a physiological substrate concentration but at high glycine levels there appears to be a decrease in velocity of uptake (V) associated with the high Km system in the young. Whatever preparation of renal cortex is studied, there is a consistent finding that immature tissue is able to accumulate much higher intracellular levels of glycine than the adult, a finding consistent with slower efflux from the cell. An interpretation of the etiology of physiologic aminoaciduria in young animals should take this into account.

Aging↗
PubMed1978

Urinary citrate excretion in the diagnosis of distal renal tubular acidosis.

Since hypocitraturia in distal renal tubular acidosis, we screened the asymptomatic children in three families with familial dRTA, by comparing their 24-hour urine citrate excretion to values obtained in 45 normal children. Subsequent acid loading uncovered four new cases of dRTA suspected because of the finding of hypocitraturia. Because hypocitraturia probably contributes to nephrolithiasis/nephrocalcinosis and subsequent renal damage in dRTA, affected family members were treated with alkali (4 mEq/kg/day), which normalized urine citrate in three children; in a fourth child citrate excretion rose but was not normal. Measurement of urine citrate excretion was superior to other currently proposed screening tests for dRTA (first morning urine pH and sediment, urine concentration).

Acidosis, Renal Tubular↗