Biomedical subjects
Publications and source records attributed to J C Crawhall.
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Several organic acids, among them the acidic catabolites of the branched chain amino acids and tyrosine, have been found to be elevated in the sera of non-diabetic patients presenting acute ketoacidosis associated with alcohol abuse. These findings are interpreted in terms of insufficiency of dietary co-factors required for their further catabolism. Butane-2,3-diol is also found frequently elevated in the urine of these patients and suggests interception of hydroxyethyl thiamine pyrophosphate by circulating high levels of acetaldehyde.
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1. CK-MB isoenzyme fractionation has been compared between DEAE-sephadex chromatography and the CK-M-subunit inhibiting antibody procedure. 2. It was found that the inhibiting antibody method generally gave lower values than the chromatography procedure. 3. The above difference can be partially attributed to inhibitory factors in the antibody system. 4. It was concluded that although there was general agreement between the two procedures, the CK-M-subunit inhibiting antibody procedure should be viewed with caution at low creatine kinase activities, and should never be done without the appropriate reagent blanks.
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The cystine content of cystinotic fibroblasts increases with the length of time in cultivation. Four of five cystinotic cell strains showed an increase in cystine content with increased passage number. Cystinotic fibroblasts did not increase in cell number after 3 days in dialyzed fetal bovine serum. However, their cystine content increased almost 2-fold on a per cell number basis. Cystinotic cells incubated in cystine-free medium lost approximately 50% of their free cystine over a period of 12 hr and subsequently remained at about this level for 12 additional hr. Treatment of cystinotic cells with 1.0 mM dithiothreitol in complete medium reduced their free cystine content to about 25% of the initial level in 5 hr. The free cystine remained at this level after incubation overnight incystine-free medium without dithiothreitol. When dithiothreitol is added in the presence of a cystine-free medium, even more free cystine is removed from cystinotic cells (90%), and the free cystine content remains at this low level for as long as 48 hr if the cells are kept in a cystine-free medium. Cystinotic cells depleted of more than 50% of their intracellular free cystine by incubation in cystine-free medium reaccumulate cystine rapidly after replacement of cystine-containing medium. When cystinotic cells were depleted of their free cystine by treatment with dithiothreitol in a cystine-free medium and were then replaced in complete medium the intracellular free cystine reaccumulated rapidly, regaining its initial value in about 4 hr. The intracellular free cystine content found after 10 hr in complete medium reflected the cystine content of the medium. Cells in medium containing 0.266 mM cystine reaccumulated almost 60% more cystine than cells in medium with 0.066 mM cystine. When cystinotic and normal control fibroblasts were incubated for 2, 4, and 24 hr in either [35S]methionine or [35S]cystathionine, no radioactivity was recovered as cystine, cysteine, or glutathionine.
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The association between hypokalemia and increased serum creatine kinase has been investigated. Two patients were found who had severe hypokalemic hyperaldosteronism who had elevation of serum creatine kinase activity. The CPK activity returned to normal values after fluid and potassium replacement. In a prospective study of 129 patients with hypokalemia which did not include any patients with hyperaldosteronism, 12 were found to have increased CPK activity but each of these had some other severe disease process which could account for the increased CPK. Three other patients with K+ (2.2 MEq/1 did not have increased CPK. It is concluded that patients with severe hypokalemia such as that occurring in hyperaldosteronism with muscle weakness may have elevated CPK directly related to their hypokalemia. In other patients with hypokalemia, 10% may have increased CPK but this is related to other disease processes.
The enzyme p-hydroxyphenylpyruvate hydroxylase (EC 1.13.11.27) from rat liver was studied with the assay method which measures the release of 14CO2 from p-hydroxyphenyl [carboxy-14C]pyruvate. Extensive dialysis of the crude enzyme extract against Tris buffer or purification involving ammonium sulfate, gel filtration, and ion exchange results in loss of enzyme activity that can be reactivated by Fe2+, dichlorophenolindophenol, and various other agents. The effect of these activators depends critically on their final concentration in the assay media. A 70-fold purification of the enzyme fraction yielded a preparation which behaved as a single protein band in Sephadex G-150. It had an isoelectric point at 5.85 and molecular weight of 63 000. The enzyme obtained appears to be different in some respects from those described by other workers from the liver of dog, human, chicken, and frog.
Certain aminothiols rapidly deplete cultured cystinotic skin fibroblasts of their abnormally high free (nonprotein) cystine pool. The free cystine content of these cells if reduced by over 90% in 1 h with 0.1 mM cysteamine. This is more rapid than previously known methods of removing free cystine from cystinotic fibroblasts. The disulfide, cystamine, is also able to deplete cystinotic cells of free cystine. A patient with nephropathic cystinosis and end-stage renal disease was treated with cysteamine, both intravenously and orally. Both methods of administration rapidly lowered the free cystine content of the patient's peripheral leukocytes. Study of the patient's urinary sulfur excretion did not conclusively determine the effect of this therapy on the total body cystine pool. Her renal status remained at end stage after 1 mo of oral cysteamine, when an episode of grand mal seizures prompted cessation of the study. Determination of the proper place of aminothiol therapy in this disease will depend upon further clinical trial with patients whose kidney function has not deteriorated to the point of irreversible change, accompanied by careful monitoring of plasma aminothiol levels.
The etiology of hyperuricemia following myocardial infarction was investigated by uric acid kinetic studies carried out on seven male patients following myocardial infarction and on two control subjects. The patients selected had uncomplicated myocardial infarction and were maintained on a low-purine diet. Measurements of uric acid pool size and turnover rates using 2-C14 uric acid were made, commencing on days 2-5 following myocardial infarction. Initial concentration of serum uric acid ranged from 2.9 to 9.8 mg/100 ml. Uric acid pool size was elevated in six of seven patients. Five had a pool size of from 36.9 to 79.6 mg/kg, while the single gouty subject demonstrated 104 mg/kg compared with 12.6 and 16.8 mg/kg for the control subjects. Turnover rates were also increased, ranging from 1036 to 2772 mg/day (controls, 612 and 872 mg/day). Twenty-four-hour urine uric acid excretions ranged from 358 to 623 mg/24 hr. Serum lactic acid concentration was normal (1.03 plus or minus 0.17 muM/ml), and endogenous creatinine clearance in all cases was 77.9 ml/min or greater. These data suggest that following myocardial infarction there is an expansion of the uric acid pool with an increased uric acid turnover rate. Only the patient with a previous history of gout had uric acid excretion outside the normal range.
1. Uric acid estimations by the uricase-UV and the autoanalyzer colorimetric procedures were compared. 2. At all levels of serum uric acid concentration measured, results with the uricase-UV method were significantly lower than those with the phosphotungstate method. 3. The data indicate that the critical uric acid level (measured by the autoanalyzer) at which allopurinol, uricosuric, and other agents are instituted should be decreased approximately 10 per cent when determinations are done by the uricase method.