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OBJECTIVE: To explore the effect of birth weight on urea kinetics in young healthy children. DESIGN: Observational study. SETTING: Tertiary center for treatment of malnutrition. SUBJECTS: A total of 17 male children, 6-24 months old, who had recovered from malnutrition. INTERVENTIONS: Urea kinetics were measured using stable isotope methodology with [(15)N(15)N]-urea over 36 h. RESULTS: Birth weight was negatively related to urea hydrolysis after controlling for the intake of protein (adjusted R (2 ) = 0.91, P = 0.001) and separately for energy intake (adjusted R (2) = 0.95, P = 0.001), age (adjusted R (2) = 0.90, P = 0.001) and rate of weight gain (adjusted R (2) = 0.91, P = 0.001). There was a tendency for higher urea production in the children with lower birth weight after controlling for nitrogen intake (adjusted R (2) = 0.93, P = 0.099), and separately for age (adjusted R (2) = 0.94, P = 0.06) and rate of weight gain (adjusted (R (2) = 0.92, P = 0.096). Urea excretion was not significantly related to birth weight. CONCLUSIONS: The salvaging of urea nitrogen following urea hydrolysis contributed significantly more to the nitrogen economy in children with lower birth weight compared to those with higher birth weight. This may be as a result of reductive adaptation in the children with lower birth weight as a consequence of inappropriate prenatal nutrition and growth.

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In Trinidad and Tobago, cardiovascular disease and Type 2 diabetes mellitus are important causes of morbidity and mortality, and birth weight is significantly less than reference standards. Lower birth weight is associated with increased risk of these diseases. Variation in birth weight is due, in part, to deposition of adipose tissue in the foetus during the last trimester at the same time that maternal plasma triacylglycerol (TAG) increases. We conducted a pilot cross-sectional analysis of maternal plasma lipid status and birth weight in healthy, non-pregnant, primigravida Trinidadian women. Non-pregnant and pregnant women, in their second and third trimesters, and at term, were recruited at random from an antenatal clinic. Adult and umbilical cord plasma TAG, non-esterified fatty acids (NEFA) and phosphatidylcholine (PC) concentrations were determined from gas chromatographic analysis of fatty acids. Maternal height, weight, skinfold thickness and infant birth weight were measured. The infants born to Afro-Trinidadian and Indo-Trinidadian women were of low to normal birth weight (medians 3.07 and 3.22 kg, respectively). At term, plasma TAG concentration was approximately two fold (p < 0.05) greater than for non-pregnant women. The increment between 30-34 weeks was 1.5 to 1.9 fold lower than reported in other populations. There was a strong relationship (r = 0.8771, p = 0.019) between maternal and cord plasma TAG and NEFA, but not PC concentrations. There was no significant relationship between maternal TAG concentration at term and birth weight. The result suggests an impaired ability to increase plasma TAG concentrations during late gestation.

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In Trinidad and Tobago, cardiovascular disease and Type 2 diabetes mellitus are important causes of morbidity and mortality, and birth weight is significantly less than reference standards. Lower birth weight is associated with increased risk of these diseases. Variation in birth weight is due, in part, to deposition of adipose tissue in the foetus during the last trimester at the same time that maternal plasma triacylglycerol (TAG) increases. We conducted a pilot cross-sectional analysis of maternal plasma lipid status and birth weight in healthy, non-pregnant, primigravida Trinidadian women. Non-pregnant and pregnant women, in their second and third trimesters, and at term, were recruited at random from an antenatal clinic. Adult and umbilical cord plasma TAG, non-esterified fatty acids (NEFA) and phosphatidylcholine (PC) concentrations were determined from gas chromatographic analysis of fatty acids. Maternal height, weight, skinfold thickness and infant birth weight were measured. The infants born to Afro-Trinidadian and Indo-Trinidadian women were of low to normal birth weight (medians 3.07 and 3.22 kg, respectively). At term, plasma TAG concentration was approximately two fold (p < 0.05) greater than for non-pregnant women. The increment between 30-34 weeks was 1.5 to 1.9 fold lower than reported in other populations. There was a strong relationship (r = 0.8771, p = 0.019) between maternal and cord plasma TAG and NEFA, but not PC concentrations. There was no significant relationship between maternal TAG concentration at term and birth weight. The result suggests an impaired ability to increase plasma TAG concentrations during late gestation.

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The case mortality for severe malnutrition in childhood remains high, but established best approaches to treatment are not used in practice. The energy and protein content of the diet at different stages of treatment appears important, but remains controversial. The effect on growth, urea kinetics and the urinary excretion of 5-L-oxoproline was compared between a standard infant formula (HP group) provided in different quantities at each stage of treatment and a recommended dietary regimen, which differentiates the requirements of protein and energy during the acute phase of resuscitation (maintenance intake of energy and protein, relatively low protein to energy ratio, LP group) from those during the restoration of a weight deficit (energy and nutrient dense). The energy required to maintain weight was less in the HP than the LP group, but the HP group was not able to achieve as high an energy intake during repletion of wasting because of the high volume which would have had to be consumed. Compared to the LP group, in the HP group during catch-up growth there was significantly greater deposition of lean tissue and higher rates of urea production, hydrolysis and salvage of urea-nitrogen. These, together with higher rates of 5-L-oxoprolinuria, suggest a greater constraint of the formation of adequate amounts of nonessential amino acids, especially glycine, in the face of enhanced demands. Although more effective rehabilitation might be achieved using a standard formula, there is the need to determine the extent to which it might impose metabolic stress compared with the modified formulation.

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Birth weight is related to neonatal health and long-term risk of chronic disease. Since animal studies have shown that birth outcome is related to placental function, the present project was designed to explore the relationship between birth weight and placental growth and composition with maternal factors during pregnancy among normal term pregnancies in 51 primiparous and 40 multiparous women delivering at the University Hospital of the West Indies. Both groups were followed from 15 weeks of gestation to term. The primiparous group was generally younger than the multiparous (mean age 22 +/- 4 versus 31 +/- 5 yr). They were significantly lighter (55 +/- 8 versus 61 +/- 9 kg) with a lower body mass index (21 +/- 3 versus 23 +/- 4 kg/m2) during early pregnancy, but gained more weight during pregnancy, 11 kg compared with 8 kg, respectively. The duration of pregnancy was similar for both groups. Although the size of the placenta was not significantly different between the two groups, the mean weight of the multiparous placentae was more than that of the primiparous placentae. Also, for all mothers both placental weight and initial maternal weight related directly to birth weight. Placental non collagen protein (NCP), sodium and potassium contents were significantly higher for multiparous women and were related to birth weight. The primiparous group had babies who were significantly lighter, 3.03 kg compared with 3.36 kg, for the multiparous and this could be attributed to differences in placental function and maternal weight. When account was taken of the difference in maternal weight at the start of pregnancy and the difference in placental weight, parity no longer explained any of the differences in birth weight. It is concluded that maternal body weight at the time of becoming pregnant and the early development of the placenta determine the efficiency with which nutrients might be delivered to the foetus and hence foetal growth. The difference in birth weight between primiparous and multiparous women can be explained by the differences in maternal weight at the time of becoming pregnant.

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The demand for glycine to satisfy normal growth during early life is considerable and most has to be made endogenously. The extent to which adequate glycine is available can be assessed by measuring the urinary excretion of 5-L-oxoproline. The excretion of 5-L-oxoproline at 6 weeks of age for infants in Trinidad of African, Indian or mixed parentage (398 mumol/mmol creatinine) was significantly greater than for infants born in England of Caucasian parentage (194 mumol/mmol creatinine). There was no relationship between 5-L-oxoproline excretion and either sex or pattern of feeding. There were significant inverse relationships between 5-L-oxoproline/creatinine and birth weight, and head circumference either at birth or 6 weeks of age, suggesting that limited availability of glycine is associated with poorer growth before and after birth. For a group of infants born in England of Indian parentage, excretion of 5-L-oxoproline (155 mumol/mmol creatinine) was not different to infants of Caucasian parentage, but significantly less than infants born in Trinidad. The demonstration that 5-L-oxoproline/creatinine was similar in infants born in England, regardless of parentage, shows that the differences between England and Trinidad are related to environment and are unlikely to be accounted for by genetic differences or ethnicity.

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The fetus has a substantial demand for glycine, which is satisfied in part by placental formation. The ability to form glycine through the activity of alanine:glyoxylate aminotransferase enzyme was measured in placentae from normal term human pregnancies and placentae from rats at day 20 of gestation. There was no detectable enzyme activity in either human or rat placentae, although activity was measured in rat liver. It is concluded that in the placenta glycine is only formed from serine through the activity of serine hydroxymethyl transferase enzyme, which uses folate as a cofactor, because there are no other known metabolic pathways for endogenous glycine production.

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OBJECTIVE: To determine the pattern of excretion in urine of 5-L-oxoproline, as a measure of glycine status, during the first six weeks of life in Jamaican infants. DESIGN: Spot samples of urine were collected from term and preterm infants at birth and longitudinally to four weeks of age, or at six weeks of age. 5-L-oxoproline was isolated by column chromatography and hydrolysed to L-glutamic acid, which was measured enzymatically and the results expressed relative to creatinine excretion. SETTING: Maternity wards and postnatal clinic of the University Hospital of the West Indies. SUBJECTS: African-Caribbean infants, 19 term and 21 preterm, from birth to four weeks of age, and 79 term infants at six weeks of age. RESULTS: There were no differences between term and preterm infants. Excretion of 5-L-oxoproline increased progressively from birth, 141 mumol/mmol creatinine, to 270 mumol/mmol creatinine at four weeks of age. At six weeks of age, excretion was significantly greater than at birth or four weeks of age, 525 mumol/mmol creatinine. Compared with infants born in England, the excretion of 5-L-oxoproline was not different at birth, but was significantly greater in Jamaican infants at six weeks of age. CONCLUSIONS: Glycine status, indicated by increased excretion of 5-L-oxoproline, is marginal in Jamaican infants at six weeks of age, and this possibly reflects a limitation in the endogenous biosynthesis of glycine due to a dietary limitation of folate or vitamin B-12.

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OBJECTIVE: We have measured urea kinetics in normal adult men and women of different body composition to determine whether adiposity is associated with differences in the rate of urea production or endogenous urea hydrolysis. DESIGN: Urea kinetics were determined from the excretion of [15N15N]urea in urine over a period of 48 h following a single oral dose of [15N15N]urea, in nine lean and nine obese women and in seven light and seven heavy males while they were consuming their habitual diets. Urinary 5-L-oxoproline was measured as an index of glycine metabolic status. SETTING: The studies were carried out in the research ward of the Tropical Metabolism Research Unit, University of the West Indies. RESULTS: Successful studies were completed in eight obese and five lean women and in six heavy and five light men. When compared with lean women, in obese women the rate of urea production and hydrolysis was significantly greater and this difference could not be accounted for by the greater fat-free mass alone, and was in part associated directly with the increase in fat mass. The rate of urea production and hydrolysis was greater in heavy men than in light men, a difference which was attributed to an increase in dietary protein. In obese women and heavy men there was a significantly higher rate of excretion of 5-L-oxoproline in urine when compared with lean women and lean men respectively. CONCLUSION: This paper highlights the difficulty in identifying an appropriate reference with which to express results in people of different body composition. In obese women urea production and the hydrolysis of urea are increased, in part related to the increased fat-free mass, but also related to the increased fat mass itself. In obese women and men on high protein diets the greater rate of hydrolysis urea may be a reflection of an increased demand for the synthesis of non-essential amino acids, especially glycine.

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Urinary 5-L-oxoproline was measured during normal pregnancies in Southampton, England and Kingston, Jamaica. The CV of 5-L-oxoproline excretion in urine, determined over 7 d in a non-pregnant woman and three pregnant women, was 10-36%. Compared with non-pregnant women, urinary 5-L-oxoproline increased three to four times from early pregnancy in women in Southampton, a highly significant difference, and remained elevated at similar levels during mid and late pregnancy. For women in Kingston, the excretion of 5-L-oxoproline was similar to that of Southampton women in the non-pregnant group and during early pregnancy. However, there was a progressive increase in the excretion of 5-L-oxoproline as pregnancy advanced and by late pregnancy excretion was from three to ten times greater than the average for the non-pregnant women. There was a significant difference between the women in Southampton and the women in Kingston during mid and late pregnancy, with women in Kingston excreting twice as much 5-L-oxoproline during late pregnancy. If the excretion of 5-L-oxoproline is a measure of glycine insufficiency, the results would indicate that in some pregnancies the ability of the mother to provide glycine for herself and the developing fetus is marginal or inadequate and the constraint appears more marked in Jamaica than in England.

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Urea kinetics were measured non-invasively in 12 Chilean schoolboys aged 8-10 years who were receiving one of two diets, either predominantly animal protein or predominantly vegetable protein. Both the diets provided an equivalent level of gross protein, 1.2 g/kg/day. The study diets were given for 10 days to enable adaptation to take place. On the eighth day a single oral dose of 15N15N-urea, 100 mg, was given and the amount of label excreted as 15N15-urea in urine over the subsequent 48 hours was measured. There was little difference in any aspect of urea kinetics between the two diets with urea production (animal, 173 +/- 50 mgN/kg/day; vegetable 179 +/- 53 mgN/kg/day), urea excretion (animal, 86 +/- 19 mgN/kg/day; vegetable, 105 +/- 13 mgN/kg/day), urea nitrogen hydrolysis (animal, 87 +/- 49 mgN/kg/day; vegetable, 74 +/- 42 mgN/kg/day), and the salvaged urea-nitrogen derived from hydrolysis which returned to urea formation (animal, 12 +/- 5 mgN/kg/day; vegetable, 17 +/- 9 mgN/kg/day) all being similar. A very high proportion of the salvage nitrogen derived from urea hydrolysis was maintained within the metabolic pool, about 80%, which was equivalent to 0.4 g protein/kg/day. This is the first time urea kinetics have been measured in children of this age and shows that 57% of the ura produced is excreted in urine on average with about 43% of the urea-nitrogen being salvaged for further metabolic interaction. It is concluded that the vegetable based protein diet taken habitually by Chilean children is metabolically equivalent in terms of urea kinetics to a diet based upon animal protein at this level of intake, but that high rates of salvage of urea nitrogen are found on both diets.

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Moderate and severe malnutrition are endemic in much of the developing world and in association with pockets of deprivation in the developed world. The cost in terms of individual and social development is high. The principles of effective management are clearly documented. A low cost, community based treatment programme for moderately and severely malnourished children under 3 years of age was established at a health centre in rural Jamaica. Children were followed up monthly and defaulters were rigorously recalled. Management consisted of carefully delivered dietary advice, antibiotics, anthelminthics, and vitamin supplements. All children improved and the response of 36 children, who were treated in the first year, showed an accelerated weight gain, with catch-up growth and the maintenance of length gain. There was a significant increase in the weight for age, at 1.9% per month over six months, which exceeds the rate reported with food supplementation programmes and nutrition rehabilitation centres.

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The pattern of aggregate nitrogen demand during pregnancy and the fetal and maternal components are unclear. Excess demand enhances efficiency of nitrogen utilization. Urea salvage contributes to enhanced efficiency. Dietary protein intake, urea production, and salvage of urea nitrogen were measured in eight nonpregnant control subjects, and trimesterly in nine pregnant women. Production was measured after prime-intermittent intravenous doses of [15N 15N]-urea by dilution of label in urinary urea. Dietary protein intake was greater in trimester 1 than in nonpregnant women (167 +/- 36 vs 224 +/- 60 mg N.kg-1.d-1), and increased further in trimester 2 (266 +/- 59 mg N.kg-1.d-1). Urea production was not higher during pregnancy. Despite higher protein intake, urea salvage was higher in pregnancy (40 +/- 24 nonpregnant vs 77 +/- 23, 61 +/- 31, and 51 +/- 12 mg N.kg-1.d-1). Therefore, the demand-supply gap for nitrogen was greatest early in pregnancy when fetoplacental growth is slowest, and implies heightened maternal demand.

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The rates of weight gain and urea kinetics were measured in 12 children receiving one of two energy dense, isonitrogenous formulae (711 kJ/kg/day, 170 kcal/kg/day) during recovery from severe undernutrition. Both formulations contained added arachis oil but in one a source of complex carbohydrate was added in the form of pectin (3.4% of total energy). The children taking the pectin diet had a rate of weight gain which was highly significantly less (7 g/kg/day) than the children not receiving pectin (14 g/kg/day). Urea production was significantly less on the pectin diet (0.37 +/- 0.07 vs 0.55 +/- 0.18 gN/kg/day). On the pectin diet there was a reduction in the rate of excretion of urea in urine and in the rate at which urea nitrogen was salvaged by the lower bowel, but these differences failed to reach statistical significance.

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Urea kinetics were measured on two separate occasions in five adults with normal haemoglobin genotype (HbAA) and in four who were homozygous for sickle cell disease (HbSS). Prime/intermittent doses of [15N15N]urea were given orally on one occasion and intravenously on the other. In three of the nine individuals there appeared to be significant hydrolysis of the oral dose of urea before absorption, leading to spurious results for the urea kinetics. When only the studies in which isotope was given intravenously were considered, there was a difference in the rate at which urea-N was salvaged, with more urea-N being salvaged by HbSS subjects than HbAA. It is concluded that the oral presentation of isotope can be used to measure urea kinetics provided care is taken to exclude those subjects who are likely to display upper intestinal hydrolysis, and that there are differences in aspects of urea kinetics between HbAA and HbSS which may be of metabolic importance.

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Levels of blood glutathione (GSH) were measured in 26 type II diabetes mellitus patients compared to 36 controls. Total blood GSH did not differ significantly between the two groups (mean +/- s.d., 8.0 +/- 1.5 vs. 7.7 +/- 1.3 mmol/g Hb, respectively); however reduced GSH was lowered in diabetes mellitus (5.0 +/- 1.0 vs. 5.8 +/- 1.0 mmol/gHb; P = 0.01), whereas oxidized GSH was increased (0.4 +/- 0.2 vs. 0.2 +/- 0.1 mmol/gHb; P = 0.001). Urinary excretion of 5-oxoproline was excessive in the diabetic patients (14.5 +/- 9.9 vs. 3.8 +/- 1.4 mmol/24 h; P = 0.004), and was positively correlated with levels of glycosylated haemoglobin (r = 0.69; P less than 0.01).

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Six male children, aged 8-28 months, were studied for three consecutive periods of 1 week each. They were given diets that provided 1.7 g protein/kg per d and supplements of minerals and vitamins, with a metabolizable energy intake during the 1st, 2nd and 3rd week of 419, 293 and 335 kJ (100, 70 and 80 kcal)/kg per d, diets 1, 2 and 3 respectively. All the food offered was consumed. Each child was weighed at the same time each day on an electronic balance. On the 6th and 7th day of each study period urine and stool were collected for 24 h to assess nitrogen balance. Using linear regression analysis it was shown that all children gained weight on diet 1, 2.3 (SD 1.3) g/kg per d, and five of six children gained weight on diet 3, the mean for the whole group being 2.7 (SD 2.3) g/kg per d, not significantly different. On diet 2 all children lost weight, -5.4 (SD 1.3) g/kg per d, highly significantly different from each of the other dietary periods. Using asymptotic regression analysis it could be shown that the rate of weight loss during the first part of the week on diet 2, -11 g/kg per d, was greater than at the end of the week, -2 g/kg per d, with a tendency towards a steady weight by day 7. Apparent N retention (mg/kg per d) was positive at the end of each of the three dietary periods: diet 1, 112 (SD 25); diet 2, 54 (SD 34); diet 3, 82 (SD 20). In five of the six children there was a marked reduction in stool frequency on diet 2 compared with diet 1, that was maintained to the period on diet 3. The findings suggest that during the period on diet 2 there was a saving of energy of the order of 105 kJ (25 kcal)/kg per d, which lasted through into the period on diet 3.

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1. Whole body protein turnover and resting metabolic rate were measured in six adults with homozygous sickle cell disease (genotype HbSS) and in six normal adults (genotype HbAA) of similar age. 2. Turnover was measured with prime/intermittent oral doses of [15N]glycine over 18 h and resting energy expenditure was measured by indirect calorimetry. 3. In HbSS, nitrogen flux (0.9 +/- 0.08 g day-1), protein synthesis (6.0 +/- 0.5 g day-1 kg-1) and protein degradation (5.6 +/- 0.5 g day-1 kg-1) were significantly increased compared with HbAA nitrogen (flux 0.5 +/- 0.02 g day-1 kg-1, protein synthesis 3.2 +/- 0.2 g day-1 kg-1 and protein degradation 2.8 +/- 0.2 g day-1 kg-1). 4. Resting energy expenditure was significantly higher in HbSS compared with HbAA when expressed per unit of body weight (115 +/- 3 and 94 +/- 4 kJ day-1 kg-1, respectively) or weight 0.75(317 +/- 6 and 269 +/- 8 kJ day-1 kg-0.75, respectively). 5. The increase in protein turnover and energy expenditure suggest that patients with HbSS exist in a hypermetabolic state that requires greater dietary energy compared with HbAA.

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The urinary excretion of 5-oxoproline, which may be used as an index of glycine status, was investigated in 30 normal pregnant women during different stages of pregnancy and in 18 non-pregnant female volunteers. During an 18-h study there was little variation in the 5-oxoproline/creatinine index, and a single sample gave a representative value. The excretion of 5-oxoproline/creatinine (mumol/mmol) rose progressively as pregnancy advanced (non-pregnant mean 10, SD 5, first trimester mean 46, SD 12, second trimester mean 150, SD 180, and third trimester mean 280, SD 320) and by the third trimester was over 20 times greater than in non-pregnant women. The data suggest that as pregnancy advances the endogenous production of glycine may be insufficient to satisfy the increasing demands.

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