Hibbard E. Williams

L-glyceric aciduria. A new genetic variant of primary hyperoxaluria.

Abstract Four patients (three of them sibs) with recurrent calcium oxalate kidney stones excreted urinary oxalic acid and also an organic acid absent from normal urine and shown to be L-glyceric ac...

Disorders of oxalate metabolism.

Abstract Oxalate is a useless metabolic endproduct, formed as an unfortunate byproduct of the metabolism of glyoxylate and ascorbate. When formed it is excreted in the urine where it constitutes a hazard because of the insolubility of its calcium salt. In the majority of patients with calcium oxalate stones the urinary excretion of oxalate is normal. Reviewed herein are the acquired and genetic disorders associated with excessive oxalate excretion, in particular primary hyperoxaluria types I (glycolic aciduria) and II (glyceric aciduria). The demonstration of specific enzyme defects associated with these diseases has clarified the pathogenesis of oxalate production. Although rare, these diseases are important since they most frequently lead to early death from renal failure. Newer approaches to treatment are therefore being pursued; if successful, they might also find application in the treatment of patients with idiopathic calcium oxalate nephrolithiasis.

Contribution of Kinins to Endotoxin Shock in Unanesthetized Rhesus Monkeys

The effects of endotoxin (Escherichia coli and Pseudomonas pseudomallei) were studied in 18 unanesthetized rhesus monkeys restrained in primate chairs. Indwelling arterial and venous catheters were used for hemodynamic measurements and blood sampling. Whole blood kinin, plasma kininogen, lysosomal enzymes, complete blood counts, and blood gas tensions were measured. Within an hour of beginning the infusion of the endotoxin, the mean arterial pressure and systemic peripheral resistance decreased significantly in the 18 experimental monkeys compared to 13 control monkeys. These early changes were associated with significant elevation in whole blood kinin concentration and a decrease in plasma kininogen. All of these early changes were most marked in the animals that died. Granulocytopenia occurred within 15 minutes, and the concentration of free lysosomal enzyme in the plasma rose 2 hours after endotoxin infusion. The preterminal phase of shock was characterized by a low peripheral vascular resistance and decreasing cardiac output without elevation of kinin levels. These findings support the hypothesis that kinins play a pathogenetic role in the early phase of endotoxin-induced shock and that the severity of the early phase may influence the animals survival. The relation of kinins to other vasoactive substances released after endotoxin-induced shock is unknown.

Adenosine metabolism in human erythrocytes

Abstract 1. 1. The metabolism of [8-14C]adenosine was examined in human erythrocytes and erythrocyte lysates. 2. 2. The metabolism of [8-14C]adenosine in erythrocytes is largely dependent upon its concentration. 3. 3. Adenosine deaminase and adenosine kinase activities were assayed in crude erythrocyte lysates. No adenosine phosphorylase activity was detected. 4. 4. Adenosine deaminase exhibited a Km for adenosine of 4 · 10−5 M. Substrate inhibition of the enzyme was exhibited at concentrations of adenosine greater than 2 · 10−4 M. No inhibition of deaminase activity by equimolar or greater concentration of AMP, ADP, ATP, GDP, GTP, Pi, guanylic acid or 2,3-diphosphoglycerate was noted, but 20 % inhibition by high concentrations of adenine and inosine was observed. 5. 5. Adenosine kinase required ATP (Km = 4 · 10−4 M), adenosine (Km = 1.9 · 10−6 M), and Mg2+ for activity. No substrate inhibition by adenosine occurred at concentrations 20 times its Km. Adenosine 5′-triphosphate and Mg2+ were inhibitory at concentrations greater than 1.25 mM and 0.50 mM, respectively. The reaction of ATP with adenosine kinase was competitively inhibited by AMP, ADP, guanylic acid, GDP, IMP, and adenine. Adenosine 5′-triphosphate was variably replaceable as the phosphate donor by a wide range of triphosphates.

Hyperoxaluria in L-glyceric aciduria: possible pathogenic mechanism.

The effect of hydroxypyruvate on synthesis of oxalate and glycolate from glyoxylate was studied in in vitro preparations from normal human erythrocytes and leukocytes, rat liver, and with purified lactate dehydrogenase from beef heart. In the presence of reduced nicotinamide adenine dinucleotide, hydroxypyruvate stimulated the oxidation of glyoxylate to oxalate and decreased the reduction of glyoxylate to glycolate. These findings may explain the hyperoxaluria seen in L-glyceric aciduria (type II primary hyperoxaluria).

Nephropathy, xanthinuria, and orotic aciduria complicating Burkitt's lymphoma treated with chemotherapy and allopurinol☆

Abstract Xanthine crystalluria and xanthine nephropathy are reported in an American boy treated with cyclophosphamide for Burkitts lymphoma and with allopurinol for hyperuricemia. Orotic acid and orotidine were also excreted in large amounts at the same time. The presence of this so-called African lymphoma in the United States is reemphasized.

α-glucosidase activity in human leucocytes

Abstract α-Glucosidase (α- D -glucoside glucohydrolase, EC 3.2.1.20) activity was measured in leucocytes from normal subjects and relatives of a patient with Type II glycogenosis. Enzyme activity was greatest in the granular fraction of leucocytes at pH 4.0, was inhibited by turanose, was similar in men and women, was reproducible in the sam subject, and did not change with freezing. Leucocyte α-glucosidase activity was low in relatives of the patient with Type II glycogenosis, suggesting that the heterozygote state may be demonstrable by this technique.

The muscular variant of Pompe's disease

A patient with the muscular variant of Pompes disease is presented. Premortem studies showed normal leukocyte α-1, 4 glucosidase activity. Muscle and liver α-1, 4 glucosidase activity was absent. A review of the literature on this variant is presented, and a therapeutic approach is discussed.

Inhibition of oxalate synthesis: In vitro studies using analogues of oxalate and glycolate

Abstract Fourteen analogues of oxalate or glycolate were studied as potential inhibitors of oxalate synthesis. Their inhibitory properties were determined in human erythrocytic preparations, in which the enzymatic activity seems to be predominantly, if not exclusively, lactic dehydrogenase (LDH), and in a partially purified glycolic acid oxidase preparation from rat liver. Evidence is presented that, in rat liver, nicotinamide-adenine dinucleotide (NAD)-dependent oxidation, probably catalyzed by LDH, is the major pathway for oxalate synthesis rather than flavin mononucleotide (FMN)-dependent oxidation catalyzed by glycolic acid oxidation. Of the oxalate analogues, oxalatehydrazide was found to be the most potent inhibitor of LDH-catalyzed oxalate synthesis. None of the oxalate analogues were very active as an inhibitor of glycolic acid oxidase. Hydroxymethanesulfonate was demonstrated to be a potent inhibitor of erythrocytic LDH, and the most effective compound studied for glycolic acid oxidase inhibition. Five of its structural analogues-acetoxymethanesulfonate, aminomethanesulfonate, iodomethanesulfonate, chloromethanesulfonate, and fluoromethanesulfonate—were less active in the two in vitro systems used. Other approaches to the control of oxalate synthesis are discussed. These studies furnish a background for the testing of inhibitors of oxalate synthesis in vivo .