A defect in pyruvate decarboxylase in a child with an intermittent movement disorder

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Abstract

A patient with an intermittent movement disorder has been found to have an inherited defect in pyruvate decarboxylase ((2-oxo-acid carboxy-lyase, E.C. 4.1.1.1.). The patient is a 9 yr old boy who since infancy has had repeated episodes of a combined cerebellar and choreoathetoid movement disorder. He has an elevated level of pyruvic acid in his blood, an elevated urinary alanine content, and less marked elevations in blood alanine and lactate.

Authors

John P. Blass, Joel Avigan, B. William Uhlendorf

Studies on the pathogenesis of acute inflammation: IX. The influence of hyperosmolality secondary to hyperglycemia upon the acute inflammatory response induced by thermal injury to ear chambers of rabbits

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The inflammatory reaction induced in ear chambers of rabbits by heat injury was studied in nondiabetic animals made hyperglycemic with continuous infusions of glucose. Hypertonic solutions of glucose administered intravenously to rabbits induced the following triad: hyperglycemia, hyperosmolality, and metabolic lactic acidosis. It was found that relatively short periods of this metabolic abnormality were associated with a significant reduction in the intensity of the inflammatory reaction.

Authors

Sterling K. Ainsworth, Fred Allison Jr.

A study of vertebral bone powder from patients with chronic renal failure

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Bone powder from patients dying with chronic renal failure of more than 1 yr duration was shown to release less calcium and more phosphate when equilibrated with a buffer solution. pH 7.4 at 4°C. This change persisted after removal of the organic component and was associated with a reduction in the bone carbonate content. Crystal size and surface area showed no consistent changes from the controls and it was concluded that an alteration in the apatite crystal composition had occurred in long-standing uremia with carbonate-phosphate interchange. Support for this was provided by synthesis of apatites which were carbonate deficient and behaved in a similar manner to the uremic bones.

Authors

Michael Kaye, A. J. Frueh, M. Silverman

Hypercatabolism of normal IgG; an unexplained immunoglobulin abnormality in the connective tissue diseases

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The metabolism of radioiodinated IgG was studied in a series of 42 patients with connective tissue diseases (16 systemic lupus erythematosus, nine rheumatoid arthritis, five polymyositis, five vasculitis, and seven miscellaneous diagnoses). Fractional catabolic rates were increased and survival half-lives were shortened in all diagnostic categories indicating hypercatabolism of IgG. This hypercatabolism was masked by increased IgG synthesis, resulting in elevated serum concentrations of IgG in patients with systemic lupus erythematosus and rheumatoid arthritis and in generally normal concentrations in the others.

Authors

R. Dean Wochner

Formation of cholesteryl ester-rich particulate lipid during metabolism of chylomicrons

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The metabolism of chylomicrons doubly labeled with cholesterol-3H and triglyceride-14C was studied in unanesthetized rats which were absorbing a fatty test meal. 10 min after intravenous injection, 80% of chylomicron cholesteryl ester, but only 20% of chylomicron triglyceride, was found in the liver. Treatment of recipient rats with puromycin to block hepatic triglyceride release did not increase the proportion of chylomicron triglyceride found in the liver.

Authors

T. G. Redgrave

Pressure-flow studies in man: effect of atrial systole on left ventricular function

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In order to evaluate the effects of atrial contraction on left ventricular function, the pressure gradient technique was used to measure instantaneous aortic blood flow and pressure in nine patients, six having complete heart block and three having normal sinus rhythm. From these data both left ventricular stroke volume and stroke work were calculated. Ventricular rate was controlled by transvenous right ventricular pacing over a range of 50-158 beats/min. At each heart rate, beats which were not preceded by a P wave served as controls. The other beats were divided into six groups according to the duration of the preceding PR interval. The results indicated that stroke volume and stroke work were always affected similarly. In one patient the presence of a P wave did not alter the subsequent stroke volume significantly. In the other patients, beats preceded by P waves had stroke volumes greater than the controls. In general, there was no difference in stroke volume for beats preceded by a P wave having a PR interval within the range of 0.05-0.20 sec. As the PR interval lengthened beyond 0.20 sec stroke volume tended to decrease, especially at more rapid heart rates. The absolute increase in stroke volume after a beat preceded by a P wave (PR interval 0.05-0.20 sec) was quite variable among the patients. For a given patient the absolute increase in stroke volume was essentially independent of heart rate. The percentage change in stroke volume, however, was always greater as the heart rate increased.

Authors

Jerome Ruskin, Philip A. McHale, Alexander Harley, Joseph C. Greenfield Jr.

Silent cholinesterase gene: variations in the properties of serum enzyme in apparent homozygotes

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The cholinesterase activity of the sera of 25 subjects diagnosed as homozygotes for the silent cholinesterase gene was studied by a sensitive enzymatic method employing several thiocholine esters and various inhibitors, and by disc electrophoretic, immunochemical, and chromatographic methods.

Authors

H. M. Rubinstein, A. A. Dietz, L. K. Hodges, T. Lubrano, V. Czebotar

Studies on the biological activity of porcine proinsulin

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The biological activity of purified porcine proinsulin was investigated in rats. In vivo studies revealed that proinsulin produced a hypoglycemic response similar to insulin but of lesser magnitude. Hypophysectomized and adrenalectomized animals proved to be more sensitive to proinsulin than normal. In vitro studies with rat hemidiaphragm were consistent with the in vivo findings. No competition with insulin action could be demonstrated.

Authors

Norman R. Lazarus, Juan C. Penhos, Tomio Tanese, Leslie Michaels, Raul Gutman, Lillian Recant

Human serum proinsulin

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Abstract

Gel filtration of human serum extracts on Bio-Gel P-30 columns produced two peaks of material reactive with insulin antisera. The earlier eluting fraction appeared at the elution position of proinsulin (serum proinsulin-like component, PLC) while the second fraction corresponded in elution volume to insulin. In assays using porcine insulin-131I and an antiserum against porcine insulin, human pancreatic proinsulin was less reactive than human insulin. Serial dilutions of the serum PLC in the immunoassay showed immunological identity with the human proinsulin standard. Partial tryptic digestion of the serum PLC yielded products with increased immunological reactivity as estimated with insulin as the standard. With larger amounts of trypsin, all the serum PLC was converted to insulin-like components (desthreonine and desoctapeptide insulin). On the basis of these results we conclude that the earlier eluting fraction of human serum extracts is proinsulin.

Authors

F. Melani, A. H. Rubenstein, D. F. Steiner

Induction of rat liver alkaline phosphatase: the mechanism of the serum elevation in bile duct obstruction

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Bile duct ligation in the rat leads to a rapid increase in hepatic and serum alkaline phosphatase activity. Within 12 hr after bile duct ligation, hepatic alkaline phosphatase has increased 7-fold and serum alkaline phosphatase activity 2½-fold. The elevation in the serum activity is completely due to an increase in an isozyme that appears to originate in the liver. This serum isozyme and liver phosphatase, both partially purified by DEAE-cellulose column chromatography, have identical Michaelis constants, pH optima, and rates of heat denaturation. These isozymes migrate identically when subjected to electrophoresis on polyacrylamide gel, and their migration rates are equally slowed after neuraminidase digestion. The data suggest that the rise in hepatic alkaline phosphatase activity is dependent on de novo protein synthesis. Cycloheximide, in a dose that inhibited incorporation of leucine-14C into protein by 68%, inhibited the rise in liver phosphatase by 98% and that in serum by 80%. The rise in liver phosphatase activity could not be accounted for by simple retention of alkaline phosphatase that would normally appear in bile. The rise in liver activity after bile duct ligation was 240 times greater than the amount of phosphatase that normally appears in bile over a similar period of time. Cycloheximide had no effect on the bile duct ligation-induced changes in the serum and liver glutamic pyruvic transaminase.

Authors

Marshall M. Kaplan, Adriana Righetti

Ferritin metabolism in reticulated-siderocytes

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Reticulated-siderocytes (reticulocytes which contain siderotic granules), obtained from the circulation of pigs after vigorous phlebotomy, were incubated in vitro. A rapid disappearance of granules from the reticulocytes was observed over 24 hr. Simultaneously with the decrease in granules, soluble ferritin accumulated in the media and siderotic granules developed in monocytes. The disappearance of the granules from the reticulated-siderocytes was oxygen-dependent and the loss of granules and the accumulation of ferritin in the media were both prevented by the addition of cyanide or dinitrophenol.

Authors

Andrew Deiss, G. E. Cartwright

The gastrointestinal stimulus to insulin release: II. A dual action of secretin

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The insulin release after an oral glucose load is both earlier and greater than would be expected from the glycemic stimulus. This augmentation of insulin release has been attributed to humoral factors from the gut.

Authors

E. W. Kraegen, D. J. Chisholm, J. D. Young, L. Lazarus

Effect of colchicine on intestinal disaccharidases: correlation with biochemical aspects of cellular renewal

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There was a significant depression of the activities of intestinal lactase, invertase, and alkaline phosphatase in rats given drinking water containing 2.5 mg of colchicine per 100 ml. Activities of intestinal maltase, aspartate transcarbamylase, and dihydroorotase were not affected by the drug. Injection of colchicine (1 mg/kg) caused depression of intestinal invertase activity within 8 hr. Investigation of the effect of colchicine on the disaccharides in vitro demonstrated that invertase and maltase were not affected by concentrations up to 125 mg/100 ml. Intestinal lactase was inhibited by concentrations exceeding 5 mg/100 ml. Calculation of the concentration of colchicine present in the intestine, after a single injection, indicated that the in vivo effect of colchicine was not due to simple enzyme inhibition.

Authors

John J. Herbst, Ruth Hurwitz, Philip Sunshine, Norman Kretchmer

Hepatic metabolism of free fatty acids in normal and diabetic dogs

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Fasted dogs prepared with catheters in the femoral artery, portal vein, and hepatic vein and infused intravenously with palmitate-1-14C were used to estimate uptake of free fatty acids in liver and their conversion to major metabolic products secreted into hepatic venous blood. Animals were studied under ordinary conditions and when fat mobilization was increased abruptly by infusing norepinephrine or for a prolonged period by withdrawing insulin from depancreatized dogs. 80% of hepatic blood flow was assumed to be derived from the portal vein.

Authors

Laurence V. Basso, Richard J. Havel

Mechanism of bicarbonate absorption and its relationship to sodium transport in the human jejunum

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Using a constant perfusion technique, sodium and bicarbonate absorption was studied in human subjects.

Authors

Leslie A. Turnberg, John S. Fordtran, N. W. Carter, Floyd C. Rector Jr.

Interrelationships of chloride, bicarbonate, sodium, and hydrogen transport in the human ileum

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Using a triple-lumen constant perfusion system, the following observations were made in normal subjects. First, chloride, bicarbonate, and sodium were found to exhibit net movement across ileal mucosa against electrochemical gradients. Second, during perfusion with a balanced electrolyte solution simulating plasma, the ileum generally absorbed, but sometimes secreted fluid. A reciprocal net movement of chloride and bicarbonate was noted when sodium movement was zero. Increasing rates of sodium absorption were associated with decreasing bicarbonate secretion rates and finally bicarbonate absorption. Even when bicarbonate was absorbed ileal contents were alkalinized (by contraction of luminal volume). Third, net chloride movement was found to be sensitive to bicarbonate concentration in ileal fluid. For instance, chloride was absorbed from solutions containing 14 or 44 mEq/liter of bicarbonate, but was secreted when ileal fluid contained 87 mEq/liter of bicarbonate. Fourth, when chloridefree (sulfate) solutions were infused, the ileum absorbed sodium bicarbonate and the ileal contents were acidified. Fifth, when plasma-like solutions were infused, the potential difference (PD) between skin and ileal lumen was near zero and did not change when chloride was replaced by sulfate in the perfusion solution.

Authors

Leslie A. Turnberg, Frederick A. Bieberdorf, Stephen G. Morawski, John S. Fordtran

C[unk] inactivator inhibition by plasmin

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Plasmin incubated with partially purified C[unk] inactivator produced a decrease in inhibitory activity which was related to the time of incubation and to the concentration of plasmin. This effect of plasmin was not influenced by the purity of the inhibitor preparations. Soybean trypsin inhibitor and tosyl arginine methyl ester (TAMe), substances which block the active enzymic center of plasmin, prevented the plasmin-induced inactivation. Double diffusion analysis of the functionally deficient, plasmin-treated C[unk] inactivator using a specific antibody, showed a reaction of identity with the untreated inhibitor. Agarose and acrylamide gel immunoelectrophoresis of a plasmin, inhibitor mixture showed the appearance of an additional precipitin band with immunologic reactivity similar to that of the untreated inhibitor. These results demonstrate that plasmin alters both the functional and immunoelectrophoretic properties of C[unk] inactivator, and that the active proteolytic site of plasmin is necessary for this interaction. Since C[unk] inactivator has been shown to inhibit several different proteolytic enzymes including C[unk], kallikrein, PF/Dil, and plasmin, this investigation provides a theoretical relationship between the fibrinolytic, kallikrein, and complement systems which may have pathophysiologic relevance to various human disease states.

Authors

Peter C. Harpel

Renal and intestinal hexose transport in familial glucose-galactose malabsorption

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Glucose transport by jejunal mucosa in vitro and kidney in vivo was investigated in a 3 yr old patient with congenital glucose-galactose malabsorption, her family, and 16 normal volunteers. Glucose transport by normal human jejunal mucosa was concentrative, saturable, sodium and energy dependent, and exhibited competitive inhibition. Biopsy specimens from six normal controls and an asymptomatic 5 yr old brother of the proband accumulated glucose to concentrations 16 times that in the incubation medium. The proband's mucosa was unable to concentrate glucose throughout a 60 min incubation period. Both of her parents and a half sister demonstrated impaired glucose transport. Their values fell between normal and those of the proband. Influx of glucose was impaired but efflux of glucose from the mucosa of these three heterozygotes was identical with that in three normal controls. A kinetic analysis indicated a reduced capacity (Vmax), but a normal affinity (Km) for glucose transport by their intestinal mucosa. All subjects accumulated fructose similarly.

Authors

Louis J. Elsas, Richard E. Hillman, Joseph H. Patterson, Leon E. Rosenberg

Regulation of renal bicarbonate reabsorption by extracellular volume

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The ability of the kidney to reabsorb bicarbonate is held to be a function of plasma CO2 tension, carbonic anhydrase activity, and potassium stores. The effects of alterations of extracellular volume on bicarbonate reabsorption were studied in dogs whose arterial Pco2 was kept constant at 40 mm Hg (range 35-45 mm Hg).

Authors

Neil A. Kurtzman

Defect in urinary acidification induced in vitro by amphotericin B

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An experimental defect in urinary acidification was induced in the isolated turtle bladder by amphotericin B and the nature of the defect was examined. Net hydrogen ion secretion was little affected by amphotericin when passive electrochemical forces across the epithelium were held at a minimum in the short-circuited state under isohydric conditions. Hydrogen ion secretion against a gradient, however, was markedly reduced by amphotericin and abolished at gradients of more than 2 pH units.

Authors

Philip R. Steinmetz, Lois R. Lawson

Effects of allopurinol and oxipurinol on purine synthesis in cultured human cells

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In the present study we have examined the effects of allopurinol and oxipurinol on the de novo synthesis of purines in cultured human fibroblasts. Allopurinol inhibits de novo purine synthesis in the absence of xanthine oxidase. Inhibition at lower concentrations of the drug requires the presence of hypoxanthine-guanine phosphoribosyltransferase as it does in vivo. Although this suggests that the inhibitory effect of allopurinol at least at the lower concentrations tested is a consequence of its conversion to the ribonucleotide form in human cells, the nucleotide derivative could not be demonstrated. Several possible indirect consequences of such a conversion were also sought. There was no evidence that allopurinol was further utilized in the synthesis of nucleic acids in these cultured human cells and no effect of either allopurinol or oxipurinol on the long-term survival of human cells in vitro could be demonstrated.

Authors

William N. Kelley, James B. Wyngaarden

Aggregation of γG3 proteins: relevance to the hyperviscosity syndrome

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Studies on the sera and isolated proteins from 14 patients with γG3 multiple myeloma revealed a concentration- and temperature-dependent aggregation which was not encountered in 26 sera from patients with multiple myeloma involving other γG subgroups. When the γG3 myeloma sera were diluted and characterized by analytical ultracentrifugation, complex formation was minimal. However, when these sera were examined undiluted, marked complex formation was observed. Studies on the isolated proteins, their enzymatic fragments, as well as their heavy and light polypeptide chains localized the aggregating sites to the Fd fragment of the heavy chains. The findings were also documented by acrylamide-gel electrophoresis and capillary tube viscometry.

Authors

J. D. Capra, H. G. Kunkel

Effects of controlled interruption of the enterohepatic circulation of bile salts by biliary diversion and by ileal resection on bile salt secretion, synthesis, and pool size in the rhesus monkey

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Abstract

Authors