Valproate inhibition of urea synthesis.
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Biomedical subjects
Publications and source records attributed to J D Kay.
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The biochemical response to an intravenous alanine load of 0.25 g/kg was studied in nine adult female relatives of children with ornithine carbamoyltransferase deficiency. Six were classified as affected by partial deficiency and three as unaffected. The plasma ammonium concentration showed no change after the alanine load in the unaffected group, but marked increases occurred in all but one of the affected groups. The maximum rate of urea synthesis after the alanine load was decreased by 37% (P = 0.02) and delayed by 43% (P = 0.02) in the affected group. In the affected group a low rate of urea synthesis was associated with high urinary orotate excretion, high maximum plasma ammonium concentration and delay in the time taken to reach the maximum rate of urea synthesis (Kendall concordance W = 0.55, P less than 0.05). The effects of a higher dose of alanine and of oral protein were compared. The alanine load of 0.25 g of alanine/kg body weight was shown to provide an adequate stimulus to urea synthesis with a more rapid return of ammonium concentration to the pre-load level than with the protein load. The implication of these results in determining the distribution of flux control of urea synthesis, the discrepancy between them and predicted results and the necessary modifications to quantitative simulations are discussed.
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The response of the plasma concentration of urea to the oral and intravenous administration of alanine was studied in healthy adult humans. The instantaneous rate of urea synthesis was calculated by using a model-dependent procedure. The errors in this procedure were calculated and it was shown that analytical precision and sampling frequency, and the estimates of the distribution volume and elimination fluxes, were adequate to determine the synthesis parameters. A direct test of the compartmental model was made by the intravenous injection of exogenous urea. The one-compartment model with first-order elimination gave a good fit to the experimental results at times greater than 8 min after the injection. Both oral and intravenous loads of alanine had dose-dependent effects on the rate of urea synthesis. There was no evidence of a limit to the maximum possible rate of urea synthesis in these experiments and the values obtained were similar to published results for different stimuli and methods of measurement. The rate of synthesis increased more rapidly after intravenous loads and subjective side-effects were less severe. The intravenous administration of alanine appears to be a suitable stimulus for urea synthesis.
A method is described by which the rate of synthesis of urea can be calculated from the change of plasma concentration of urea after an alanine load. The results can be expressed in terms of f, the maximum increase in the rate of urea synthesis, and t, the time at which urea synthesis reaches its maximum. These parameters are calculated by an algebraic curve-fitting technique which is suitable for a desk computer. The method removes the need for isotopic analysis and urine collections. The effect of various errors and experimental conditions on the calculated synthesis parameters is investigated.
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In the past year, ten infants have been admitted to hospital with a new or previously unrecognised disorder, characterised by an acute onset of encephalopathy, fever, shock, watery diarrhoea, severe disseminated intravascular coagulation, and renal and hepatic dysfunction. Seven of the infants died. No specific causative agent has been identified, but preliminary studies suggest that the pathophysiology of the disease may involve release of proteolytic enzymes (such as trypsin) into the circulation, with destruction of the microcirculation.
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1. The breathing pattern, that is the changes in tidal volume (VT), and in inspiratory (TI) and expiratory (TE) durations, has been studied as ventilation increases in exercise. 2. Five healthy subjects were studied in steady-state exercise on a bicycle ergometer, breathing air, at two speeds of pedalling and at six different loads. The pattern was recorded for single breaths. Two of the subjects were also studied while walking on a treadmill with four combinations of speed and gradient. 3. In bicycle exercise, as the CO2 output increased mean VT increased, and mean TI and TE decreased, the absolute decrease in TI being small. The pedalling speed did not affect these relationships. 4. Individual breath durations showed no tendency to group around multiples of the period of rotation of the pedals. 5. In treadmill exercise, no clear influence of stride rate on respiratory rate could be found. The pattern was similar to that found in bicycle exercise. Again no grouping could be found. 6. No evidence of an effect of frequency of limb movement on breathing pattern in submaximal exercise has been found. The selection of breathing pattern seems to be unrelated to the nature of the stimulus but closely geared to the metabolic needs of the body.
1. The breathing pattern, that is the relation between tidal volume (VT) and the inspiratory (TI) and expiratory (TE) durations, has been studied for individual breaths (forty in each steady state). 2. Five healthy subjects were studied in steady-state exercise on a bicycle ergometer breathing air; three of them were also studied in hypercapnia, at rest and during exercise, and two of them also during exercise on a treadmill. 3. Tidal volume and respiratory frequency both increased with work load. The increase in frequency was largely due to a progressive decrease in TE; TI also decreased. 4. At any constant level of respiratory drive (constant work load or chemical load) VT was positively correlated with both TI and TE in more than 95% of cases. 5. A simple model of the respiratory cycle which fits both the observed mean and breath-by-breath patterns and which involves no new assumptions is presented.
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1. A ribonuclease isolated from porcine thyroid cytosol using phenol: sodium dodecylsulfate treatment was associated with RNA and identical to latent alkaline ribonuclease. 2. Distribution of activity between aqueous and phenolic phases depended on pH, RNA, and ribonuclease inhibitor. 3. The ribonuclease was totally resistant to urea, guanidinium: HCl, chloroform:isoamyl alcohol, ethanol, heating at 100 degrees C for 10 min or at 80 degrees C plus 100 mM NaCl. It was highly resistant to hydrolysis by proteinase K except in the presence of detergent. 4. The extreme stability and other properties of latent alkaline ribonuclease could be the result of its association with RNA.