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Biomedical subjects

O Sperling

Publications and source records attributed to O Sperling.

At least 127 records · Page 7Linked to original sources
PubMed1977

Superactivity of phosphoribosylpyrophosphate synthetase, due to feedback resistance, causing purine overproduction and gout.

A mutant feedback-resistant, physiologically superactive, phosphoribosylpyrophosphate (PP-ribose-P) synthetase was found in a family with purine overproduction, gout and uric acid lithiasis. In haemolysates and cultured fibroblasts from the propositus, the mutant enzyme exhibited resistance to feedback inhibition by normal cell constituents, such as ADP and GDP; normal affinity to substrates and to activator Pi was demonstrated in the haemolysate. In both erythrocytes and cultured fibroblasts, the superactivity of the mutant enzyme was manifest in increased PP-ribose-P content and availability for nucleotide synthesis, leading to an acceleration of the rate of purine synthesis de novo in the fibroblasts. The enzyme abnormality and the resulting increase in PP-ribose-P content and generation were demonstrated in the erythrocytes of one of the propositus' two siblings who was similarly affected but not in the propositus' father, his second brother and four sons, who were all clinically and biochemically normal, nor in the erythrocytes of the clinically normal hyperuricosuric mother. However, cultured fibroblasts from her skin exhibited variability in PP-ribose-P content and availability and in the rate of purine synthesis de novo, these parameters being increased in most cultures. The mother's fibroblast cultures were found to contain two cell populations, one with normal and the other with mutant PP-ribose-P synthetase, indicating an X-linked pattern of inheritance of the synthetase superactivity in this gouty family.

Adolescent↗
PubMed1977

Implications of disorders of purine metabolism for the kidney and the urinary tract.

The spectrum of kidney and urinary tract disorders related to purines comprises acute hyperuricosuric nephropathy, chronic urate nephropathy and urolithiasis. Two factors in the development of acute hyperuricosuric nephropathy are increased uric acid concentration and low pH in the tubular fluid. Chronic urate nephropathy still possess several problems: incidence (although this seems to be decreasing, presumably owing to effective prevention), the source of interstitial urate, the cause of the interstitial deposition of urate, and the role of urate deposits in the pathogenesis of the interstitial nephropathy. The relation of the experimental nephropathy to the pathogenesis of chronic urate nephropathy in the human is not yet clear but a model is proposed according to which interstitial urate derives from two sources: hyperuricaemic plasma and hyperuricosuric tubular fluid. Urolithiasis related to purines leads to uric acid-urate stones, xanthine stones, 2,8-dihydroxyadenine stones, iatrogenic xanthine and oxipurinol stones, and possibly calcium stones. Pathogenetic factors in uric acid lithiasis are hyperuricosuria (whether due to an inborn enzyme abnormality or of unknown aetiology) and low urinary pH; oliguria is a contributory factor. There remain several open questions about uric acid lithiasis: incidence, the shift of its location from lower to upper urinary tract, the interplay of pathogenetic factors, and the role of compounds which inhibit crystallization.

Adenine Phosphoribosyltransferase↗
PubMed1977

Urolithiasis associated with hypercalciuria.

Fifty male patients with urolithiasis (UL), associated with idiopathic hypercalciuria (IH), were studied in comparison to a group of 18 male normocalcemic patients with inactive calcium stone disease of unknown etiology. In the group of IH-UL, in addition to hypercaliuria, statistically significant hyperphosphaturia with decreased tubular reabsorption of phosphate and hyperuricemia were observed; there was a tendency to hypophosphatemia although non-significant. In 36% of the IH-UL patients the first episode of renal colic appeared at age 40 to 50. Thirty-eight per cent of the IH-UL patients had recurrent stone formation. Twenty per cent of the IH-UL patients had a family history of urolithiasis. Forty-six per cent of all stones contained oxalate in addition to calcium, and 25% of the stones contained oxalate and phosphate.

Adult↗
PubMed1977

Evidence for X-linkage of phosphoribosylpyrophosphate synthetase in man. Studies with cultured fibroblasts from a gouty family with mutant feedback-resistant enzyme.

Skin fibroblast cultures were utilized to study the mode of inheritance of a mutant feedback-resistant phosphoribosylpyrophosphate synthetase in a gouty family with purine overproduction. Selective conditions were applied to allow the survival in culture of mutant cells only. Whereas in the male gouty propositus the cell culture was homogenous for the mutant enzyme, in the cell culture from his nongouty mother two cell populations were demonstrated, one normal and the other mutant. The mosaicism in the mother is compatible with X-linkage of the enzyme. From this finding, together with the clinical and biochemical data available, it is concluded that in this family the enzyme mutation is transmitted in a X-linked recessive pattern.

Adolescent↗
PubMed1977

Familial hypouricemia due to isolated renal tubular defect. Attenuated response of uric acid clearance to probenecid and pyrazinamide.

A 37-year-old female was found to have hypouricemia (1.1-1.9 mg%) with markedly increased uric acid clearance (24.7039.5 ml/min). Uric acid excretion was only slightly affected by pyrazinamide, a drug which suppresses renal tubular uric acid secretion, and by probenecid, a drug which inhibits tubular uric acid reabsorption. The attenuated response in this subject to both drugs suggest a renal tubular defect in the proximal high capacity-high affinity uric acid reabsorption mechanism. No other renal tubular or metabolic abnormalities were detected. A survey of the family-three sisters and two brothers, revealed two similarly affected sisters. The abnormality described in this family is defined as familial renal hypouricemia due to an isolated renal tubular defect with attenuated response of uric acid clearance to probenecid and pyrazinamide.

Adult↗
PubMed1976

Elevation of serum xanthine oxidase following halothane anesthesia in the rat.

Halothan anesthesia was found to be hapatotoxic in the rat, as demonstrated by a significant elevation of serum xanthine oxidase (SXO) level. SXO appeared to be more sensitive marker of liver damage than serum glutamic oxalacetic transaminase. SXO was found to be elevated also following exposure to relative hypoxia.

Anesthesia, General↗
PubMed1976

The effect of ribose 5-phosphate and 5-phosphoribosyl-1-pyrophosphate availability on de novo synthesis of purine nucleotides in rat liver slices.

The effect of increasing cellular ribose 5-phosphate (ribose-5-P) availability by methylene blue-induced acceleration of the oxidative pentose phosphate pathway on the rate of 5-phosphoribosyl-1-pyrophosphate (P-ribose-PP) generation, was studied in slices of rat liver at varying Pi concentration. It was found that at Pi concentration prevailing in the tissue of extracellular physiological Pi concentration, ribose-5-P availability is saturating for P-ribose-PP generation, as gauged by the rate of adenine incorporation into tissue nucleotides. The effect of altering P-ribose-PP availability on the rate of de novo purine production gauged by the rate of formate incorporation into purines, was also studied. It was found that the physiological P-ribose-PP concentration in rat liver tissue is limiting for purine synthesis de novo. Depletion of cellular P-ribose-PP, achieved by increase of P-ribose-PP consumption, decelerated purine synthesis, while increase of P-ribose-PP availability, achieved by activation of P-ribose-PP synthetase occurring at elevated Pi concentration, resulted in acceleration of purine synthesis.

Animals↗
PubMed1976

De novo synthesis of purine nucleotides in human peripheral blood leukocytes. Excessive activity of the pathway in hypoxanthine-guanine phosphoribosyltransferase deficiency.

Human peripheral blood leukocytes were studied for the presence and the regulatory properties of the pathway of de novo synthesis of purine nucleotides. The cells were found to incorporate the labeled precursors formate and glycine into purines. The rate of [14C]-formate incorporation was decreased by several compounds known to inhibit purine synthesis by affecting the activity by glutamine phosphoribosylpyrophosphate (PRPP) amidotransferase, the first committed enzyme in the pathway, either through decreasing the availability of PRPP, a substrate for this enzyme, or through exerting inhibition on this enzyme. PRPP availability in the leukocyte was found to be limiting for purine synthesis. Increased PRPP availability resulting from activation of PRPP synthetase by increasing inorganic phosphate (Pi) concentration caused acceleration of purine synthesis. On the other hand, no clear-cut evidence was obtained for the availability of ribose-5-phosphate in the leukocyte being rate limiting at physiological extracellular Pi concentration for PRPP generation, and thus for purine synthesis. However, the addition of methylene blue, which accelerates the oxidative pentose shunt that produces ribose-5-phosphate, resulted in acceleration of PRPP generation and of purine synthesis only when PRPP synthetase was largely activated at high Pi concentration. These results may be taken to suggest that ribose-5-phosphate availability is indeed not limiting for PRPP generation under physiological conditions. Purine synthesis de novo was accelerated more than 13-fold in the leukocytes of two gouty patients affected with partial deficiency of hypoxanthine-guanine phosphoribosyltransferase, but was normal in the leukocytes of an obligate heterozygote for this enzyme abnormality. The results domonstrate in peripheral human leukocytes the presence of the complete pathway of de novo synthesis of purine nucleotides and the manifestation in these cells of the biochemical consequences of hypoxanthine-guanine phosphoribosyltransferase deficiency, i.e., increased availability of PRPP and acceleration of purine synthesis de novo. The results indicate the usefulness of leukocytes as a model tissue for the study of purine metabolism in man.

Amidophosphoribosyltransferase↗
PubMed1976

Elevated serum xanthine oxidase activity following biliary tract and gastric surgery.

The activity of serum xanthine oxidase, an enzyme mainly found in the liver, was determined in a random series of patients who underwent abdominal surgery of varying severity. Enzyme activity rose markedly on completion of operation in almost all patients undergoing biliary tract and gastric surgery, but not in those undergoing surgery of other abdominal organs, Serum glutamic oxaloacetic transaminase level rose to a smaller degree and in a smaller proportion of the patients. Elevation of the serum level of both enzymes following biliary and gastric surgery reflects hepatocellular damage caused by surgical trauma to the liver.

Aspartate Aminotransferases↗
PubMed1975

Serum xanthine oxidase in jaundice.

Serum xanthine oxidase activity was measured by a radiochemical method in 137 consecutive patients with jaundice of varying etiology and in 40 non-jaundiced patients with liver or other disease. Serum xanthine oxidase was markedly increased, up to 50 times the upper normal limit (mean + 2 S.D.), in 32 out of 34 patients with infectious hepatitis. A slight elevation of serum xanthine oxidase, up to twice the upper normal limit, was found in 2 out of 49 patients with extrahepatic obstructive jaundice and in 4 out of 20 patients with chronic renal failure. In comparison to serum glutamic-oxaloacetic transaminase and lactate dehydrogenase serum xanthine oxidase appeared to be the more sensitive and specific indicator of acute hepatocellular damage.

Aspartate Aminotransferases↗