Biomedical subjects
J C Waterlow
Publications and source records attributed to J C Waterlow.
Notes on the new international estimates of energy requirements.
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Metabolic adaptation to low intakes of energy and protein.
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Observations on the variability of creatinine excretion.
This paper reports the intra-individual variability of creatinine excretion under conditions of variable food intake and stress. Urine collections over 24 h were made by six subjects for 24 d in the course of an expedition to the Colombian Andes. The average coefficient of variation (CV) of day-to-day creatinine excretion was 11.4 per cent and of N excretion 28 per cent. When the outputs were averaged by 3-d period the mean CV of creatinine excretion was reduced to 5.7 per cent. It is concluded that in metabolic studies the 3-d creatinine excretion is a useful index even when food intakes and other conditions are not controlled.
Requirements for specialist training.
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The contribution of endogenous urea to faecal ammonia in man, determined by 15N labelling of plasma urea.
To establish the role of endogenous urea as a source of faecal ammonia, the plasma urea of two healthy men was labelled with 15N at a constant level for several days and its 15N enrichment was compared with that of faecal ammonia and total nitrogen. Faeces collected after one complete gastrointestinal transit from the onset of plasma labelling had ammonia 15N enrichments which were only 8.5 +/- 1.2% and total nitrogen enrichments which were 6.8 +/- 0.7% of the plasma urea 15N enrichment. These results show that endogenous urea is not the main precursor of faecal ammonia, which is probably derived by bacterial deamination from the protein of dietary residues, intestinal secretions and shed epithelial cells. The minor contribution of endogenous urea to faecal ammonia suggests that the lumen of the large bowel is not the main site of endogenous urea hydrolysis. The similar labelling of faecal total nitrogen and ammonia nitrogen supports other evidence that these faecal nitrogen fractions are in a constant state of exchange.
Apparent compartmentation of body nitrogen in one human subject: its consequences in measuring the rate of whole-body protein synthesis with 15N.
The rate of protein synthesis in the whole body was measured in one fed subject with seven 15N-labelled amino acids (intravenous and oral doses) and two 15N protein mixtures (oral doses only). The rates were determined individually from the urinary excretion of ammonia and total urea over a 12 h experimental period. Except with oral glycine and alanine, the synthesis rates given by ammonia and urea were appreciably different within each study when calculated on the assumption of a single pool of metabolic nitrogen in the body. In general, intravenous administration of the tracers gave higher rates with urea and the oral route gave higher rates with ammonia. The differences between intravenous and oral doses of 15N could be reduced significantly by calculating synthesis rates from either the arithmetic or harmonic average of flux rates given by ammonia and urea. The averages correspond to estimates of the total flux in a two-pool model of metabolic nitrogen when it is assumed either that both pools receive an equal amount of tracer (arithmetic) or that both have the same rate of nitrogen turnover (harmonic). By so reducing the effect of physical separation of nitrogen in the body, the metabolic aspects of compartmentation of the tracer could be examined. The results show that the absolute value obtained for protein synthesis depends on the source of labelled nitrogen. The data are discussed in this empirical context.
The effect of tri-iodothyronine (T3) on protein turnover and metabolic rate.
Obese patients who had an unusually slow weight loss on a restricted energy intake (2 MJ/d) were treated for approximately two weeks with small doses of T3 (20 micrograms three times daily). At the beginning and end of treatment whole body protein turnover was measured with a single dose of 15N-glycine and both ammonia and urea as end-products. T3 increased the rate of weight loss, with a significant increase in urinary nitrogen excretion. There were small increases in basal metabolic rate and protein turnover, which were not significant. It is concluded that the extra weight loss produced by T3 was at the expense of lean body mass and not of fat.
The concept of the single body pool of metabolic nitrogen in determining the rate of whole-body nitrogen turnover.
The concept of the single pool of metabolic nitrogen in measuring the rate of whole-body protein turnover has been examined both with the practical evidence which is available in the literature and from a theoretical point of view. It is concluded that for the most part the concept is not valid. The main problem is one of introducing the isotope uniformly throughout the body. It is suggested that better results may be obtained if the 15N tracer is given simultaneously by both the oral and intravenous route.
Kwashiorkor revisited: the pathogenesis of oedema in kwashiorkor and its significance.
Cicely Williams, in her original description of kwashiorkor, implied that deficiency of protein in the baby's food could be a main cause of the syndrome. The hallmark of kwashiorkor is oedema. According to the 'classical' theory, an inadequate intake of protein leads to a low plasma albumin concentration, which in turn causes oedema. This theory has been contested from several points of view: that hypoalbuminaemia is not the major factor determining the presence of oedema, and that there is no real evidence of dietary protein deficiency. The resolution of this question is of some importance from the point of view of public health diagnosis and prevention. A crucial point in the argument is the pathogenesis of oedema, which is discussed in some detail. Although it is clearly multifactorial, with electrolyte disturbances--potassium deficiency and sodium retention--playing an important role, it is contended that the classical theory is essentially correct. On the dietary side, recent experimental work supports the earlier view that the development of oedema depends on a relative deficiency of protein with a relative excess of energy. Comparisons of intakes with requirements are unconvincing in view of uncertainty about the validity of the estimates of children's needs for protein.
Our society in the 1980s.
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Protein turnover with special reference to man.
This review is concerned with rates of N flux in the living animal rather than with mechanisms of protein synthesis and breakdown at the cellular level. Methods of measuring protein turnover in the whole body are discussed, with special emphasis on studies in man, and results obtained by different methods have been compared. Aspects of whole body protein turnover which are of physiological interest include its relation to body size, growth and development, energy metabolism and food intake. There are substantial increases in protein turnover in injury, and changes that occur in exercise are beginning to be explored. From the physiological point of view these results point the need for future research along two main lines. The first is that of regulation: a wide variety of hormones stimulate or repress protein synthesis and breakdown, with varying actions in different tissues. These effects, however, do not in themselves explain the mechanism by which a balance between synthesis and breakdown is maintained. Secondly, the fact that all cellular proteins are in a dynamic state poses questions about the relation between structure and function in tissues such as muscle and brain, which physiologists have hardly begun to tackle.
Rates of whole body protein synthesis and breakdown increase with the severity of inflammatory bowel disease.
Rates of whole body protein synthesis and breakdown were estimated in 19 undernourished patients with inflammatory bowel disease from the cumulative nine hour excretion of urinary 15NH3 after intravenous injection of 15N glycine. Thirty six studies were made during constant nutrient input either parenterally by 3 litre bag technique (29 studies), or enterally by nasogastric infusion of protein containing liquid feeds (four studies), or by diet kitchen prepared food eaten at two hourly intervals (three studies). Mean daily intakes were 50.7 kcal and 0.29 g nitrogen/kg body weight. Synthesis and break down rates correlated significantly with disease activity as judged by erythrocyte sedimentation rate and by ranking by an observer unaware of the turnover results. Rates for synthesis and breakdown by this method were about 2.1 and 1.7 g protein/kg/24 h respectively for ESR 10 increasing to 4.0 and 3.3 for ESR 100.
The effect of surgical trauma and insulin on whole-body protein turnover in parenterally-fed undernourished patients.
Ten undernourished patients receiving total parenteral nutrition and undergoing major intestinal surgery were restarted on intravenous feeds identical to their pre-operative regimens within 24 h of their operation. Five, chosen at random, received post-operatively 1-2 units insulin/kg body weight/24 h with their feed, while the other five received the feed only. Pre-operatively, and 2 h after commencing their post-operative feeds, rates of whole-body protein synthesis and breakdown were measured over a 9-h period following intravenous injection of a single tracer dose of 15N-glycine by the ammonia and urea end-product methods. During these 9-h study periods measurements were also made of blood glucose, plasma insulin and glucagon, urinary ammonia, nitrogen, creatinine and 3-methylhistidine. Blood glucose and plasma insulin and glucagon concentrations rose post-operatively whether or not insulin was given, but the increment in insulin concentration was significantly greater when insulin was given. Apparent nitrogen balance was positive pre-operatively and became less so post-operatively whether insulin was given or not. Similarly, post-operative increments in urinary excretion of ammonia, creatinine and 3-methylhistidine were not altered by addition of insulin. Protein turnover, as estimated by the ammonia end-product method, tended to rise post-operatively, but there was no significant difference between the increases observed with or without insulin. The urea end-product method suggested that there was no change in whole-body protein turnover after surgery, whether or not insulin was given. This study does not support the clinical use of insulin as a means of modifying protein metabolic losses after major surgery.
The extent of protein synthesis in muscle in man.
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Protein turnover, nitrogen balance and rehabilitation.
Not many studies have been done on protein turnover during recovery from malnutrition. Some relevant information can, however, be obtained from measurements on normal growing animals, since rehabilitation and normal growth have in common a rapid rate of net protein synthesis. The key question is the extent to which net gain in protein results from an increase in synthesis or a decrease in breakdown or both. Different studies have used different methods, and all methods for measuring protein turnover have some disadvantages and sources of error. It is important to bear this in mind in evaluating the results. Consequently, part of this paper will be devoted to questions of methodology. Whole body protein turnover has been measured in children recovering from severe malnutrition. During the phase of rapid catch-up growth the rate of protein synthesis is increased. As might be expected, it increases linearly with the rate of weight gain. At the same time there is a smaller increase in the rate of protein breakdown. The resultant of these two processes is that, over and above the basal rate of protein synthesis, 1.4 grams of protein have to be synthesized for 1 gram to be laid down. Very similar results have been obtained in rapidly growing young pigs. Experimental studies on muscle growth in general confirm the conclusion that, at least in muscle, rapid growth is associated with rapid rates of protein breakdown as well as of synthesis. This has been shown in muscles of young growing rats, as well as in muscles in which hypertrophy has been induced by stretch or other stimuli. In contrast, the evidence suggests that rapid growth involves a fall in the rate of protein degradation. The magnitude of the nitrogen balance under any conditions is determined by the difference between synthesis and breakdown. In the absence of any storage of amino acids, this must be the same as the difference between intake and excretion (S - B = I - E). A question of great interest is whether, at a given intake, the extent of N balance is determined primarily by regulation of synthesis and breakdown or by regulation of amino acid oxidation. Clearly, a reduction in amino acid degradation is equivalent to an increase in amino acid intake. An interesting subject for future research is the extent to which the amino acid degrading enzymes adapt to the requirements imposed by growth and rehabilitation.
The combined effects of infection and malnutrition on protein metabolism in children.
Twenty-two children were studied as inpatients at a Nigerian Hospital. They were divided into four groups on the basis of weight for age: I, adequately nourished, acutely infected; II, moderately under weight, acutely infected; III, malnourished, chronically infected; IV, malnourished, uninfected. Urinary nitrogen excretion was highest in group I and lowest in groups III and IV. Urinary creatinine was highest in group I, but did not differ significantly in groups II, III and IV. The excretion of 3-methylhistidine closely paralleled that of creatinine. It is suggested that the high rates of creatinine and methylhistidine excretion in group I resulted in part from destruction of muscle. Rates of whole body protein turnover were measured by administration of a single dose of [15N]glycine with measurement of the excretion of 15N in urinary NH3 for the next 9 h. Rates of protein synthesis and breakdown were very high in infected children of groups I and II. Although rates were lower in the malnourished groups, in infected children of group III they were nearly twice as high as in the uninfected group IV. The net balance of protein (synthesis minus breakdown) was negative in group I, less negative in group II, zero in group III and positive in group IV. Repeat measurements in group I during recovery from infection showed a decline in rates of excretion of nitrogen, creatinine and 3-methylhistidine. Rates of protein synthesis and breakdown declined and the protein balance became less negative, but these changes were not statistically significant. Multiple regression analysis of the results of all groups taken together showed independent contributions to rates of protein metabolism from infection and nutritional state, especially plasma albumin. It was concluded that infection caused a rise in protein breakdown which was larger than the concomitant rise in synthesis, leading to net loss of protein, and that these responses were reduced by malnutrition.
Rate of endogenous methionine oxidation in rats at different levels of methionine intake.
The fractional rates of loss of 14C and body-weight were measured in growing female rats after a single dose of [l-14C]methionine. After the dose, the rats were maintained for 30 d on diets containing graded amounts of methionine and killed at 30 d. By 20 d after the dose the level of labelling of body proteins was fairly uniform. From 20 to 30 d, 14CO2 was collected at intervals. The rats were killed at 30 d and the total radioactivity remaining in the body was measured. The fractional loss of 14CO2 between days 20 and 30 was constant regardless of methionine intake except at the highest intake level. After correcting the fractional loss of 14CO2 for urinary 14C loss, a value of 35 mg/kg body-weight (20 mg/kg body-weight 0.75) was obtained for the rate of endogenous methionine oxidation.