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Human Nutrition and Metabolism

Supplementation with Aromatic Amino Acids Improves Leucine Kinetics but Not Aromatic Amino Acid Kinetics in Infants with Infection, Severe Malnutrition, and Edema^1,2

Marvin Reid^*,, Terrence Forrester^*, Asha Badaloo^*, William C. Heird and Farook Jahoor^,3

^* Tropical Metabolism Research Unit, University of the West Indies, Mona, Kingston 7, Jamaica and U.S. Department of Agriculture/Agricultural Research Service, Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030

³To whom correspondence should be addressed. E-mail: fjahoor{at}bcm.tmc.edu.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
We investigated whether supplementation with an aromatic amino acid (AAA) cocktail consisting of 0.5 mmol each of phenylalanine, tryptophan, and tyrosine compared with isonitrogenous amounts of alanine (Ala) would improve measures of protein kinetics in 14 (8 with AAA, 6 Ala) children with edematous malnutrition (aged 6–24 mo) during the infected acute malnourished state. Supplementation started immediately after the baseline experiment, 2 d postadmission and continued to the end of the acute phase of treatment. The second (postsupplementation) experiment was done 12 d postadmission. We measured leucine kinetics, phenylalanine and tyrosine fluxes, using an i.g. 8-h prime continuous infusion of ²H₃-leucine, and an i.v. 6-h prime continuous infusion of ¹³C-leucine, ²H₂-tyrosine, and ²H₅-phenylalanine in the fed state. Leucine flux tended to be faster (P = 0.06) in the AAA group compared with Ala group after supplementation (mean difference ± SEM): 22.6 ± 10.9 µmol/(kg · h). The rate of leucine appearance from protein breakdown [28.1 ± 9.4 µmol/(kg · h)] and the nonoxidative disposal of leucine [i.e., leucine to protein synthesis; 35.4 ± 12.9 µmol/(kg · h)] were faster (P < 0.02) in the AAA group than in the Ala group. There was no significant effect of supplementation on leucine splanchnic metabolism, phenylalanine, and tyrosine fluxes. These findings are consistent with the hypothesis that the blunting of the protein catabolic response to infection in children with edematous malnutrition syndrome is due to limited availability of aromatic amino acids.

KEY WORDS: • leucine kinetics • aromatic amino acids • protein metabolism • edematous protein-energy malnutrition • stable isotope

We reported previously that children with protein energy malnutrition (PEM)⁴ are able to mount a partial positive acute phase protein response to the stress of infection although the magnitude of the response is lower in those children with edema (1). Additionally, although the concentrations of negative acute phase proteins were lower in infected children with PEM, the rates of synthesis were maintained (2–4). For example, although the albumin concentration of infected malnourished children was 10% lower than that of malnourished uninfected children, there was no difference in the fractional synthesis rates of albumin (2). Together, these findings suggest that the stress of infection imposes a metabolic demand for increased synthesis of acute phase proteins in severely malnourished children.

The essential amino acid requirements for the synthesis of positive and negative acute phase proteins are met from dietary protein intake and protein breakdown. The acute phase proteins as a group have a much higher content of the aromatic amino acids (AAA), tryptophan, phenylalanine, and tyrosine, than either muscle protein or most dietary protein sources (5). We proposed that the ratio of endogenous protein that must be mobilized to supply the necessary amounts of AAA for synthesis of acute phase proteins is 2:1 (5). In children with PEM and edema, whole-body protein breakdown rates are slower even in the face of infection (6), thus restricting the endogenous supply of AAA to satisfy the increased synthesis of acute phase proteins. This can result in a relative shortage of these amino acids to support the synthesis of other important peptides and proteins necessary for recovery, especially during the acute resuscitative phase of rehabilitation when energy and protein intakes are kept near maintenance levels to avoid overloading the metabolic capacity of the child (7). We propose that this resuscitative diet may not be providing sufficient AAA to facilitate the synthesis of acute phase proteins in addition to the synthesis of other body proteins necessary to replenish metabolic systems. Hence, we hypothesized that supplementing the resuscitative diet of severely malnourished children with AAA would lead to an overall improvement of whole-body protein synthesis. To test this hypothesis, we used stable isotope tracer methods to quantify protein metabolism. Simultaneous i.g. (²H₃-leucine) and i.v. infusions of labeled leucine (¹³C-leucine), ²H₅-phenylanaline, and ²H₂-tyrosine were used to measure leucine, phenylalanine, and tyrosine kinetics in infected malnourished children with edema pre- and post-AAA supplementation. The studies were performed in the fed state because we were also interested in the effect of supplementation on splanchnic uptake and the efficiency of utilization of dietary leucine for protein synthesis.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Subjects. All children were admitted to the Tropical Metabolism Research Unit, University of the West Indies, for treatment of severe PEM. The diagnosis of infection was based on the presence of one of the following clinical criteria: 1) leukocyte count > 11 x 10⁹ cells/L; 2) temperature on admission > 37°C or < 35.5°C; 3) an abnormal chest X-ray or positive culture of blood, urine, skin, or stool. The diagnosis of edematous PEM, that is, kwashiorkor or marasmic kwashiorkor, was based on the Wellcome Classification (8). This study was approved by the Medical Ethics Committee of the University Hospital of the West Indies and the Baylor Affiliates Review Board for Human Subject Research of Baylor College of Medicine. Written informed consent was obtained from at least one parent of each child enrolled.

    Treatment. Clinical treatment included the correction of fluid and electrolyte imbalances and the treatment of infections with broad-spectrum antibiotics, usually parenteral penicillin and gentamycin, plus oral metronidazole. The children were fed a milk-based diet providing maintenance energy and slightly more generous protein. This diet was made using a commercial milk powder (Nan, Nestlé SA Switzerland), corn oil and water; the amount offered was 417 kJ/(kg · d) and 1.2 g/(kg · d) protein. This provided 105 mg/(kg · d) of AAA [L-phenylalanine, 48 mg/(kg · d); L-tyrosine, 57 mg/(kg · d); and 20 mg/(kg · d) L-tryptophan]. The diets, which were administered every 3 h, also were supplemented with vitamins (Federated Pharmaceuticals) and minerals: 2 mL/d of Tropivite (vitamin A, 1.6 µmol all-trans retinol equivalent; vitamin D, 10 µg; thiamin, 2 mg; riboflavin, 3.2 mg; vitamin C, 120 mg; vitamin B-6, 4 mg; and nicotinamide 28 mg); 5 mg/d folic acid; 2 mL/kg/d mineral mix of potassium chloride, magnesium chloride hexahydrate, and zinc acetate dihydrate salts [37.28 g KCl + 50.84 g MgCl₂ · 6H₂O + 3.36 g (CH₃COO)₂Zn · 2H₂O/L H₂O, BDH chemicals].

Weight and length were monitored throughout hospitalization, the former daily with an electronic balance (Sartorius model F150S) and the latter weekly with a horizontally mounted stadiometer (Holtain).

    Study design. Whole-body and splanchnic leucine kinetics were determined by the simultaneous infusion of 2 different isotopes of leucine at 2 times during hospitalization, i.e., 3 d after admission when the subjects were both infected and malnourished but clinically stable as indicated by blood pressure, pulse, and respiration rates (baseline experiment) and 12 d after admission when the subjects were still severely malnourished but no longer infected, (i.e., all clinical features of the infective episode had resolved), edema had disappeared, and affect and appetite had improved (postsupplementation experiment). Total body water was also measured at each time by dilution of deuterium oxide.

Enrolled patients were randomly assigned to be administered either an aromatic amino acid cocktail (AAA group), providing 70 mg/(kg · d) phenylalanine, 60 mg/(kg · d) tyrosine [given as 80 mg/(kg · d) acetyl-tyrosine] and 30 mg/(kg · d) tryptophan or an isonitrogenous amount [114 mg/(kg · d)] of alanine (Ala group). The amounts of AAA are based on our hypothesis (5) that during acute infections or physiologic stress, 2 g of body protein must be degraded to provide enough AAA to synthesize 1 g of mixed acute phase proteins and on the observed increase in rates of synthesis and amino acid composition of 5 major acute phase proteins in infected malnourished children (1). The total daily supplement was given in divided doses every 3 h before each feeding. The amino acid supplementation started immediately after the baseline experiment and continued through to the morning of the postsupplementation experiment. No supplementation was given during the kinetic measurements. Because the experiments were done in the fed state, the diet [417 kJ/(kg · d) and 1.2 g/(kg · d) of protein] was fed during the experiments. The subjects had consumed this diet for 3 d at the time of the baseline experiment and for 12 d at postsupplementation.

    Infusion protocol. A diagrammatic illustration of the infusion protocol is shown in Figure 1. At 0700 h, a nasogastric tube was inserted into the child’s stomach and a Flexiflo Magna-Port Y-Port connector (Ross Products Division, Abbott Laboratories) was attached to the proximal end. About 42% of the child’s daily intake was then given over the next 10 h by continuous intragastric infusion into one limb of the Y-port using an enteral infusion pump (Flexiflo companion enteral nutrition pump, Ross Laboratories). Two i.v. access sites were established in opposite arms by the insertion of 22 or 24G catheters after preparation of the access sites with a topical anesthetic (EMLA cream, Astra Pharmaceuticals). One i.v. catheter was used for infusion of the labeled substrates and the other for blood sampling.

View larger version (13K): [in this window] [in a new window]   FIGURE 1 Diagram of the isotope infusion protocol.

During the infusions, additional 1-mL blood samples were drawn at 1200, 1300, and 1400 h for the measurement of deuterium content and at 1600, 1615, 1630, 1645, and 1700 h for the measurement of -keto-isocaproic acid (-KICA), leucine, phenylalanine, and tyrosine tracer/tracee ratios. Before each blood sample, the arm was warmed for 10 min by the application of a latex glove containing water preheated to 40°C. For each aliquot of blood removed, an equal volume of 9 g/L of sterile NaCl was infused. Breath samples were taken at 15-min intervals from 1000 to 1100 h and from 1600 to 1700 h as previously described (6).

    Sample analyses. The blood samples were drawn into prechilled tubes containing Na₂EDTA and a cocktail of sodium azide, merthiolate, and soybean trypsin inhibitor. They were centrifuged immediately at 4°C and the plasma was removed immediately and stored at –70°C for later analyses.

The ²H₂ content of plasma water was determined by gas-isotope-ratio MS (Delta-E, Finnigan MAT) (9). Plasma amino acids were isolated by ion exchange (Dowex 200x) chromatography and converted to the n-propyl ester, heptafluorobutyramide derivative. The tracer/tracee ratio of leucine, phenylalanine, and tyrosine were measured by negative chemical ionization GC/MS (NCI-GC/MS), using a Hewlett-Packard 5890 quadrupole mass spectrometer and selectively monitoring ions at m/z ratios 349–352 (leucine), 383–388 (phenylalanine), and 595–600 (tyrosine). The plasma -KICA tracer/tracee ratio was measured by NCI-GC/MS of its pentafluorobenzyl derivative monitoring ions at m/z 129–132. The breath samples were analyzed in duplicate for ¹³C abundance in carbon dioxide by gas-isotope-ratio MS (Europa Scientific), monitoring ions at m/z ratios 44 and 45. Hemoglobin and white blood cell counts were measured by a hematology analyzer (Beckman Coulter Gen System 2), serum albumin by Abbott Alcycon 300i, and serum urea, creatinine, total bilirubin, and serum glutamic oxaloacetate transaminase by an Abbott Spectrum Clinical Chemistry Analyzer.

    Calculations. Plateau enrichment for all isotopes used in the infusions was established by inspection of the slope of the regression line of the respective plasma or breath enrichments of the samples taken during the last hour of each infusion period against time. In each case, the slope of the line was not different from zero, hence values were calculated from the mean of the 4 points. Details of the calculation of the kinetic data were reported previously (6). Kinetic data were normalized by body weight and fat free mass. To discount the contribution of edema fluid to total body weight in the baseline experiment, body weights obtained after disappearance of edema (i.e., the lowest weight observed between the baseline experiment and the postsupplementation experiment) were used for weight-normalized variables.

    Statistics. Data are expressed as means ± SEM. The effects of supplementation on post-treatment means were tested using analysis of covariance (ANCOVA) models in which the pretreatment measurements were the covariates (10). This technique has the advantage of statistically adjusting the dependent variable (post-treatment means) to remove the effects of the portion of uncontrolled variation represented by the covariate (baseline means), thereby yielding a more precise and less biased estimate of the group effects. Data analysis was performed with the Stata statistical software, version 7 for Windows. Differences were considered significant at P < 0.05.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Anthropometry and total body water. A total of 16 children were enrolled, 8 in the AAA group and 8 in the Ala group. One child in the Ala group died after the baseline experiment but before the postsupplementation experiment and another was HIV positive. Because data from both children were excluded from the analysis, this report includes data for 14 children, 8 from the AAA group and 6 from the Ala group. All subjects were anemic, hypoalbuminemic, and infected at admission (Table 1). At admission, the children were 11.3 ± 1.5 mo old (Table 2). All were severely malnourished with a body weight of 5.7 ± 0.4 kg; weight-for-age and height-for-age were 61 ± 2.9% and 87 ± 1.3% of expected, respectively (Table 2). Based on the Wellcome Classification (8), 10 children had kwashiorkor and 4 had marasmic kwashiorkor.

Total body water did not differ between the 2 groups at baseline or postsupplementation. However, on average, total body water was 0.12 L greater at baseline vs. postsupplementation, reflecting the presence of edema (Table 2). Total body water also did not differ as a proportion of body weight between the groups or between experiments. Fat free mass did not differ between supplement groups.

    Leucine, phenylalanine and tyrosine kinetics. The rate of leucine appearance from protein breakdown [mean difference 28.1 ± 9.4 µmol/(kg · h)] and the nonoxidative disposal (NOD) of leucine [i.e., leucine to protein synthesis; mean difference 35.4 ± 12.9 µmol/(kg · h)] were higher (P < 0.02) in the AAA group than in the Ala group (Table 3). However, the difference in values of leucine flux normalized for body weight observed after supplementation with aromatic amino acids [mean difference 22.6 ± 10.9 µmol/(kg · h)] tended to be significant, P = 0.06. A similar pattern was observed for leucine flux normalized for fat free mass (Fig 2).

View larger version (16K): [in this window] [in a new window]   FIGURE 2 The difference in leucine kinetics normalized by fat free mass in 14 severely malnourished children after supplementation with an aromatic amino acid cocktail (AAA group) that provided 70 mg/(kg · d) phenylalanine, 60 mg/(kg · d) tyrosine, and 30 mg/(kg · d) tryptophan or an isonitrogenous amount of alanine (Ala group) 114 mg/(kg · d) adjusted for differences in baseline means. Values are means ± SEM. Asterisks indicate difference from the Ala group: *P = 0.07, **P < 0.03.

Supplementation did not affect phenylalanine, endogenous phenylalanine, tyrosine, and endogenous tyrosine fluxes whether normalized by weight (Table 4) or fat free mass (Fig 3).

View larger version (12K): [in this window] [in a new window]   FIGURE 3 The difference in phenylalanine and tyrosine kinetics normalized by fat free mass in 14 severely malnourished children after supplementation with an aromatic amino acid cocktail (AAA group) that provided 70 mg/(kg · d) phenylalanine, 60 mg/(kg · d) tyrosine, and 30 mg/(kg · d) tryptophan or an isonitrogenous amount of alanine (Ala group) 114 mg/(kg · d) adjusted for differences in baseline means. Values are means ± SEM. Abbreviation: Endo, endogenous.

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

The dietary management of children with edematous malnutrition in the resuscitative phase when the children are infected and malnourished is based on the premise that malnourished children, despite a large deficit in body tissues, are unable to utilize nutrients at a normal rate during the early stages of treatment and that administration of nutrients at rates in excess of utilization will precipitate metabolic collapse and further deterioration of immune capacity with worsening of infections, cardiac failure, and death (7,11). Thus, during this phase of management, affected children are fed a diet that provides energy at 417 kJ/(kg · d) and protein at 1.2 g/(kg · d).

We proposed that at this level of protein intake, there is relative dietary deficiency of AAA in malnourished, infected children because of the need to synthesize acute phase proteins, which are enriched with AAA. The resuscitative diet provides 125 mg/(kg · d) of AAA which is 3 times the WHO recommended AAA intake of 45 mg/(kg · d) for maintenance, defined as the nitrogen intake required to achieve nitrogen balance assuming no growth (12). This estimate according to Dewey et al. (12) likely overestimates the "true" requirements of uninfected, well-nourished children. In general, in children, the demand for amino acids is driven by maintenance needs as well as the need for tissue deposition. In the infected state, there is the additional requirement to synthesize immunoproteins to counteract the pathogen. Further, if the quality or pattern of available amino acids is a poor match for the composition of the proteins being synthesized during the host response, then excess amino acids will be oxidized with an increase in urea formation and excretion (13). Indeed the results of studies performed by Manary et al. (14) give credence to this view. Those authors supplemented the resuscitative diet of severely malnourished children with 10 mg/(kg · d) tryptophan, which resulted in the supplemented children receiving 142 mg/(kg · d) of AAA compared with a control group that received 134 mg/(kg · d). They reported that the tryptophan-supplemented group had lower rates of urea production after 24 h of supplementation, indicating decreased oxidation of amino acids. There was, however, no improvement in protein synthesis as measured by nonoxidative leucine flux.

In contrast to the findings of Manary et al. (14), in the present study, leucine oxidation and the proportion of leucine flux that was oxidized were not affected, although the direction of the change suggested a reduction as a result of supplementation. In addition there was an increase in protein synthesis associated with a better leucine balance. The reasons for the differences between the leucine kinetic results of Manary et al. (14) and those of the present study may be due to the duration and/or the amount of supplementation as well as methodological differences. First, in our experiments, the children were administered the supplement for 12 d compared with 1 d in the study of Manary et al. (14). Second, although the ratio of tryptophan:phenylalanine:tyrosine was similar in the 2 studies (1:3:2 vs. 1:2.5:2.5), the total amount of AAA administered in the present study was 285 mg/(kg · d) compared with 142 mg/(kg · d) in their study. Finally, in the study by Manary et al. (14), the leucine tracer was administered orally and leucine oxidation was estimated from urea production.

Whether the positive effect of supplementation on leucine kinetics and balance will translate into significant clinical outcomes such as a reduction in infective morbidity and mortality and accelerated lean tissue deposition is unclear because this study is underpowered to answer such questions. However, we reported previously that when children with severe PEM and edema were exposed to the stress of infection, they could not mount a protein catabolic response to the infection (6). This dysadaptation likely contributes to the continued high case fatality of children with the edematous malnutrition syndrome (15,16). Thus, the present observations provide a basis for the performance of clinical trials of AAA supplementation in children with edematous malnutrition syndrome.

The positive effect on leucine turnover and balance was not associated with changes in phenylalanine and tyrosine fluxes. Tyrosine is synthesized de novo from the indispensable amino acid phenylalanine. In addition to being an important component of positive acute phase proteins, tyrosine is the precursor for the neurotransmitters dopamine, norepinephrine, and epinephrine and of melanin. Therefore a shortage of tyrosine or its precursor, phenylalanine, may lead to a blunting of the acute phase protein response and to the neurological and dermatological abnormalities of severe malnutrition with edema syndromes (kwashiorkor and marasmic kwashiorkor). To our knowledge, this study represents the first report of phenylalanine/tyrosine kinetics in infants with severe malnutrition. However, in adults, the adaptation to a marginal protein intake [0.75 mg/(kg · d)] involves a substantial reduction in phenylalanine flux, NOD (phenylalanine to protein synthesis), and net protein catabolism with maintenance of tyrosine flux (17). In this study, we were not able to assess the contribution of phenylalanine to protein synthesis or oxidation, nor could we measure the rate of conversion of phenylalanine to tyrosine because we did not prime the ²H₄-tyrosine pool. Nevertheless, the values we obtained for phenylalanine flux were similar to values reported for children in the literature. For example, van Toledo-Eppinga (18) measured the rate of phenylalanine appearance in low-birth-weight infants in the fed state and obtained values of 94 ± 18 to 115 ± 6 µmol/(kg · h). Similarly Denne et al. (19) measured phenylalanine rate of appearance in newborns administered TPN and obtained a value of 83 ± 3 µmol/(kg · h). In general, estimates of whole-body protein turnover in newborn and preterm infants in the fed state are 200–300% higher than similar estimates in infants with severe malnutrition using the leucine tracer (18,19). Therefore, the higher values reported here for phenylalanine flux as a proportion of whole-body protein turnover suggest a specific demand for AAA.

In summary, compared with Ala-supplemented children, children with PEM and edema had significantly faster NOD of leucine and protein-derived leucine appearance after 12 d of supplementation with 160 mg/(kg · d) AAA. This was associated with a higher leucine balance. These findings are consistent with the hypothesis that the blunting of the protein catabolic response to infection in children with edematous malnutrition syndrome is due to the limited availability of AAA. These observations have to be extended by clinical trials to determine whether such intervention reduces mortality and improves the rate and quality of lean tissue deposited during recovery.

	ACKNOWLEDGMENTS

 
We are grateful to the physicians and nursing staff of the TMRU for their care of the children and to Hyacinth Gallimore, Bentley Chambers, Sharon Howell, Margaret Frazer, and Melanie Del Rosario for their excellent work and support in the conduct of the studies and analysis of the samples.

	FOOTNOTES

 
¹ Portions of this data were presented in abstract form at Experimental Biology 03, April 2003, San Diego, CA [Reid, M., Forrester, T., Badaloo, A., Heird, W. C. & Jahoor, F. (2003) The effect of aromatic amino acid supplementation on protein metabolism in edematous malnutrition syndrome. FASEB J. 17: Abstract # 8376].

² This research was supported by National Institutes of Health Grant RO1 HD34224–01A1, grants from the International Atomic Energy Agency and The Wellcome Trust, and with federal funds from the U.S. Department of Agriculture, Agricultural Research Service under Cooperative Agreement No. 58–6250-6001.

⁴ Abbreviations used: AAA, aromatic amino acids; -KICA, -keto-isocaproic acid; NCI-GC/MS, negative chemical ionization GC-MS; NOD, nonoxidative disposal; PEM, protein energy malnutrition.

Manuscript received 12 May 2004. Initial review completed 3 June 2004. Revision accepted 24 August 2004.

	LITERATURE CITED

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

1. Reid, M., Badaloo, A., Forrester, T., Morlese, J. F., Heird, W. C. & Jahoor, F. (2002) The acute-phase protein response to infection in edematous and nonedematous protein-energy malnutrition. Am. J. Clin. Nutr. 76:1409-1415.[Abstract/Free Full Text]

2. Morlese, J. F., Forrester, T., Badaloo, A., Del, R. M., Frazer, M. & Jahoor, F. (1996) Albumin kinetics in edematous and nonedematous protein-energy malnourished children. Am. J. Clin. Nutr. 64:952-959.[Abstract/Free Full Text]

3. Morlese, J. F., Forrester, T., Del, R. M., Frazer, M. & Jahoor, F. (1997) Transferrin kinetics are altered in children with severe protein-energy malnutrition. J. Nutr. 127:1469-1474.[Abstract/Free Full Text]

4. Morlese, J. F., Forrester, T., Del, R. M., Frazer, M. & Jahoor, F. (1998) Repletion of the plasma pool of nutrient transport proteins occurs at different rates during the nutritional rehabilitation of severely malnourished children. J. Nutr. 128:214-219.[Abstract/Free Full Text]

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6. Reid, M., Badaloo, A., Forrester, T., Heird, W. C. & Jahoor, F. (2002) Response of splanchnic and whole-body leucine kinetics to treatment of children with edematous protein-energy malnutrition accompanied by infection. Am. J. Clin. Nutr. 76:633-640.[Abstract/Free Full Text]

7. World Health Organization (1999) Management of Severe Malnutrition: A Manual for Physicians and Other Senior Health Workers 1999 WHO Geneva, Switzerland.

8. Wellcome Working Party (1970) Classification of infantile malnutrition. Lancet 2:302-303.

9. Wong, W. W., Cochran, W. J., Klish, W. J., Smith, E. O., Lee, L. S. & Klein, P. D. (1988) In vivo isotope-fractionation factors and the measurement of deuterium- and oxygen-18-dilution spaces from plasma, urine, saliva, respiratory water vapor, and carbon dioxide. Am. J. Clin. Nutr. 47:1-6.[Abstract/Free Full Text]

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12. Dewey, K. G., Beaton, G., Fjeld, C., Lonnerdal, B. & Reeds, P. (1996) Protein requirements of infants and children. Eur. J. Clin. Nutr. 50((suppl. 1)):S119-S147 discussion S147–S150.

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14. Manary, M. J., Yarasheski, K. E., Hart, C. A. & Broadhead, R. L. (2000) Plasma urea appearance rate is lower when children with kwashiorkor and infection are fed egg white-tryptophan rather than milk protein. J. Nutr. 130:183-188.[Abstract/Free Full Text]

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18. van Toledo-Eppinga, L., Kalhan, S. C., Kulik, W., Jakobs, C. & Lafeber, H. N. (1996) Relative kinetics of phenylalanine and leucine in low birth weight infants during nutrient administration. Pediatr. Res. 40:41-46.[Medline]

19. Denne, S. C., Karn, C. A., Ahlrichs, J. A., Dorotheo, A. R., Wang, J. & Liechty, E. A. (1996) Proteolysis and phenylalanine hydroxylation in response to parenteral nutrition in extremely premature and normal newborns. J. Clin. Investig. 97:746-754.[Abstract/Free Full Text]

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