1 United States Department of Agriculture/Agricultural Research Service, Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; and 2 Tropical Metabolism Research Unit, University of the West Indies, Mona, Kingston 7, Jamaica
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ABSTRACT |
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Although the compromised GSH status of children with edematous protein-energy malnutrition (PEM) has been documented, the in vivo kinetic mechanism(s) responsible for this is not known. To determine if decreased synthesis contributes to the alteration of GSH homeostasis, the fractional and absolute rates of synthesis of erythrocyte GSH were determined shortly after admission (study 1), ~9 days postadmission (study 2), and at recovery (study 3) in seven children with edematous PEM and seven children with nonedematous PEM. Children with edematous PEM had significantly lower erythrocyte GSH and slower absolute rates of GSH synthesis than children with nonedematous PEM both shortly after admission, when they were both malnourished and infected, and ~9 days later, when the infection had resolved but they were still malnourished. At these times, the edematous group also had significantly lower erythrocyte GSH concentrations and absolute rates of synthesis than at recovery. Plasma and erythrocyte-free cysteine concentrations of the edematous group were significantly lower at studies 1 and 2 than at recovery. In contrast, erythrocyte GSH concentrations, rates of GSH synthesis, and plasma and erythrocyte free cysteine concentrations of the nonedematous group were similar at all three time points and greater at studies 1 and 2 than in the edematous group. These results confirm that GSH deficiency is characteristic of edematous PEM and suggest that this is due to a reduced rate of synthesis secondary to a shortage in cysteine.
kwashiorkor; marasmus; cysteine; stable isotope; lipid hydroperoxides
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INTRODUCTION |
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THE THREE MAJOR CLINICAL syndromes of severe protein-energy malnutrition (PEM) are marasmus, kwashiorkor, and marasmic-kwashiorkor. The former is easy to treat and has a low mortality rate, but the latter two have a more complex etiology, are difficult to treat, and have high morbidity and mortality rates (3, 12, 22, 25). In addition to marked body weight deficits, kwashiorkor and marasmic-kwashiorkor are characterized by gross edema, low plasma protein concentrations, dermatosis, hypopigmented hair, impaired immune function, neurological abnormalities, and hepatomegaly caused by intense fatty infiltration (3, 12, 22, 25). Despite extensive research, the underlying cause(s) of these complex pathophysiological changes remains unknown.
In the acutely malnourished state, plasma and whole blood GSH
(-glutamylcysteinylglycine) concentrations have consistently been
found to be lower in children with edematous PEM than in children with
marasmus (2, 6, 12). Because the GSH redox cycle is a major component
of the body's overall antioxidant defense system, this suggests that
antioxidant defenses are impaired and that free radical damage of
cellular membranes is responsible for the phenotypic expression of the
edematous syndromes of PEM (2, 6). Indeed, Lenhartz et al. (15)
recently reported that the plasma concentrations of malondialdehyde and
hexanal, biomarkers of oxidant-induced tissue damage (8, 19), are elevated in kwashiorkor and that the values normalize as soon as
clinical signs and symptoms resolve. Whether this increased oxidative
stress is consequent to increased production of oxidant species because
of concomitant infections, or is due to an underlying defect in
antioxidant defenses, including GSH synthesis, is not known.
GSH is a tripeptide that is present in high concentrations in all
mammalian cells. It is synthesized de novo from glycine, cysteine, and glutamate in reactions catalyzed by -glutamylcysteine synthetase and GSH synthase and can be regenerated from GSSG by GSH
reductase. It is irreversibly consumed in the detoxification of
electrophilic metabolites and xenobiotics in reactions catalyzed by GSH
S-transferases (17). Despite several reports of the compromised GSH status of children with edematous PEM (2, 6, 12), the in vivo
kinetic mechanism(s) responsible for GSH deficiency has not been
determined. One obvious mechanism in the severely malnourished state is
suppressed synthesis secondary to a shortage of amino acids. Such a
mechanism is supported by the studies of Grimble et al. (7) and Hunter
and Grimble (11), which show that the slower hepatic and pulmonary GSH
synthesis and lower GSH concentrations of rats fed protein-deficient
diets or with low food intakes return to control values when the
deficient diets are adequately supplemented with either methionine or
cysteine plus glycine.
In theory, a shortage of GSH precursor amino acid supply secondary to protein deficiency should impart a similar and possibly more profound effect on GSH synthesis of children with nonedematous PEM who, in general, are more protein wasted than children with edematous PEM. Yet blood GSH concentrations are normal in children with nonedematous PEM. Furthermore, Persaud et al. (21) have reported that the rate of 5-oxoproline excretion, an index of glycine insufficiency, does not differ as a function of GSH concentration. Inability to sustain a normal rate of GSH synthesis also can result from a defect in its biosynthetic pathway. However, based on the observation that intracellular GSH concentration increases during in vitro incubation of whole blood from children with kwashiorkor, Golden and Ramdath (6) concluded that the capacity of patients with kwashiorkor to synthesize GSH was not impaired.
Alternatively, because edematous forms of PEM are almost always associated with concurrent infection(s) and GSH levels fall under conditions of increased oxidative stress, such as infection, it can be proposed that a persistent oxidative load leads to an accelerated rate of consumption of GSH that is not matched by an equal increase in the rate of synthesis of the tripeptide.
A major drawback of the experimental evidence available to date has been the reliance on in vitro measurements to make inferences about in vivo kinetics. To determine the mechanisms responsible for the altered GSH homeostasis of edematous PEM, it is necessary to measure GSH kinetics in vivo. This is now possible using a recently developed stable isotope tracer method (14). Thus we have used this method to determine if a lower rate of GSH synthesis is responsible for the lower intracellular GSH concentration of children with edematous vs. nonedematous PEM and also to determine the possible mediating role of infection on GSH homeostasis in these children. Erythrocyte GSH concentrations as well as fractional and absolute synthesis rates of GSH and plasma lipid hydroperoxides, an index of oxidative damage, were measured on three occasions in edematous and nonedematous PEM patients with concurrent infection(s). The first measurements were made shortly after admission, when they were both malnourished and infected. The measurements were repeated ~1 wk later, after infections had cleared, but they were still severely malnourished. The final measurements were made after they had achieved at least 90% of expected weight for height (~postadmission day 59).
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METHODS |
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Overview. Erythrocyte GSH concentration, plasma and erythrocyte free amino acid concentrations, and rates of erythrocyte GSH synthesis were determined at three times in seven children with edematous PEM and seven children with nonedematous PEM. All were admitted to the Tropical Metabolism Research Unit, University of the West Indies, for treatment of severe PEM. All had a deficit in body weight for age of >20% and clinical evidence of infection (i.e., a leukocyte count >11 × 109 cells/l, temperature on admission of >37°C or <35.5°C, an abnormal chest X ray, and/or a positive blood, urine, skin, or stool culture). The first study was performed shortly after admission, when they were both infected and malnourished. The second study was performed 7-10 days later when they were no longer infected but still severely malnourished, and the third study was determined after full recovery. The diagnosis of edematous (kwashiorkor or marasmic-kwashiorkor) vs. nonedematous PEM (marasmus) was based on the Wellcome (26) criteria.
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.
During hospitalization, the children were managed according to a
standard treatment protocol (12). This involved correction of fluid and
electrolyte imbalances and administration of broad-spectrum antibiotics, usually parenteral penicillin and gentamicin, plus oral
metronidazole. After correction of fluid and electrolyte imbalances,
the subjects were started on a maintenance milk-based diet that
provided 417 kJ · kg1 · day
1
and 1.2 g · kg
1 · day
1
of protein with supplements of vitamins and trace elements. This diet
was continued until appetite returned (~9 days postadmission), when
they were switched to an energy-dense, milk-based formula that provided
625-750
kJ · kg
1 · day
1
and ~3 g
protein · kg
1 · day
1.
This diet was continued until the growth rate plateaued and weight for
length was at least 90% of expected.
Study design. The first study was performed shortly after admission, when patients were both infected and malnourished but clinically stable as indicated by blood pressure, pulse, and respiration rates. The second was performed 7-10 days later, when they were still severely malnourished but no longer infected; they also had lost edema, their affect and appetite had recovered, and all clinical features of the infective episode (e.g., diarrhea, chest crepitations) had resolved. The third study was performed just before discharge after they were fully recovered, the rate of catch-up growth had started to plateau, and weight for length was at least 90% of expected.
The same maintenance diet (417 kJ · kgInfusion protocol.
About 33% of the subject's daily food intake was given by constant
intragastric infusion starting 2 h before the isotope infusion commenced and continuing throughout the 6-h infusion. A sterile solution of [2H2]glycine (Cambridge
Isotope Laboratories, Woburn, MA) was prepared in 9 g/l saline. After a
2-ml venous blood sample was drawn, a priming dose of
[2H2]glycine (40 µmol/kg) was
administered by nasogastric tube and followed immediately by a
continuous 6-h nasogastric infusion of the tracer at a rate of 40 µmol · kg1 · h
1.
Additional 2-ml blood samples were drawn at 3, 4, 5, and 6 h during the
infusion. The infusion and blood sampling protocols for all three
studies were identical.
Sample analyses.
A 1-ml aliquot of each blood sample was placed immediately in an equal
volume of isotonic ice-cold monobromobimane (MBB) buffer (ph 7.4)
solution (in mM: 5 MBB, 17.5 Na2EDTA, 50 potassium
phosphate, 50 serine, and 50 boric acid) for GSH derivatization and
isolation. The whole blood-MBB buffer mixture was centrifuged at 1,000 g for 10 min at 4°C. The plasma-MBB supernatant was then
removed and placed in the dark at room temperature for 20 min for
development of the plasma free cysteine- and GSH-MBB derivatives. The
packed erythrocytes were immediately lysed with acetonitrile, 1 ml of MBB buffer and 0.045 ml of 20 mM penicillamine (internal standard) were
added, and the mixture was left in the dark at room temperature for 20 min for development of the erythrocyte GSH-MBB derivative. Proteins
were precipitated from both mixtures with ice-cold 1 mol/l perchloric
acid, and the supernatants were stored at 70°C for later
analysis. Hematocrit was determined on each blood sample using a Micro
Hematocrit Centrifuge (Damon/IEC Division, Needham Heights, MA).
Calculations.
The fractional synthesis rate (FSR) of erythrocyte-GSH was calculated
according to the precursor-product equation (14)
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Statistical analysis.
Data are expressed as means ± SE for each group. The data were
analyzed by repeated-measures ANOVA, with the between-group factor
being the clinical diagnosis at admission and the measurements done
over time (study 1 through study 3) as the
repeated-measures factor. As there was a significant interaction
between the between-group factor and the repeated-measures factor, we
compared differences between the clinical categories at each study and
differences between the means of measured variables within each
clinical category at each study by the least significant difference
(LSD) method (18). Thus the between-group differences were significant
if the absolute value of this difference was greater than
LSDg where
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RESULTS |
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Seven children with edematous PEM (6 kwashiorkor; 1 marasmic-kwashiorkor) and seven with nonedematous PEM (marasmus) were studied. At admission, all had evidence of infection, and most were
anemic (Table 1). The mean ages of the two
groups were not significantly different (Table
2). As expected, the mean weight and length
of the marasmic children were lower than those of the edematous
children at each study (Table 2). These differences were statistically
significant at study 1 and study 2 (P < 0.04) but not at study 3. The weight and length of both groups
increased significantly from study 1 to study 3 (P < 0.001).
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The tracer-to-tracee ratio of erythrocyte free glycine reached a steady state after 4 h of the isotope infusion in all three studies, and there was a linear increase in the amount of labeled glycine incorporated in the erythrocyte GSH during this time; hence, the FSR of GSH was calculated from the rate of incorporation of labeled glycine into GSH during the last 2 h of the isotope infusion.
Compared with values of children with nonedematous PEM, children with
edematous PEM had significantly lower erythrocyte GSH concentrations
and absolute rates of GSH synthesis at admission when they were both
infected and malnourished and at study 2 when signs and
symptoms of infection had disappeared (Fig.
1). The children with edematous PEM also
had significantly lower erythrocyte GSH concentrations and fractional
as well as absolute rates of synthesis at admission, when they were
both infected and malnourished, than after recovery. At study
2, when signs and symptoms of infections had disappeared, the
children with edematous PEM had a higher absolute rate of GSH synthesis
than at study 1 (P < 0.05), but GSH concentration
remained low. However, both the absolute rate of synthesis and
concentration of GSH were significantly lower at study 2 than
after recovery (study 3). In contrast, there were no
differences in either GSH concentration or rates of synthesis of GSH
among the three studies performed in the children with nonedematous
PEM.
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The slower rates of synthesis of GSH in the children with edematous PEM
at studies 1 and 2 were accompanied by lower plasma free cysteine and plasma free glutamate plus glutamine concentrations than at recovery (Table 3). Glycine and
serine concentrations, however, were not lower in studies 1 and
2. In contrast there were no differences in the plasma
concentration of the GSH precursor amino acids at any of the three
studies in children with nonedematous PEM. At study 1, the
children with edematous PEM also had markedly lower erythrocyte free
cysteine concentrations and lower erythrocyte free glutamine
concentrations than at recovery. Erythrocyte free glycine
concentration, on the other hand, was significantly higher in children
with edematous PEM at studies 1 and 2. There were no
differences in the erythrocyte concentration of the GSH precursor amino
acids among the three studies in the nonedematous PEM children.
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At admission, the lower concentration and rate of synthesis of GSH of
the edematous PEM children was associated with a significantly higher
plasma concentration of lipid hydroperoxide compared with that of
children with nonedematous PEM (Fig. 2). At
study 2, the plasma hydroperoxide concentration of the children
with edematous PEM was comparable to that of children with nonedematous
PEM. Interestingly, after complete recovery (study 3), both
groups had higher plasma concentrations of lipid hydroperoxide than at study 2.
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DISCUSSION |
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Although GSH deficiency has been implicated in the pathogenesis of edematous PEM (6, 15), the mechanism(s) responsible for the altered GSH homeostasis has remained elusive largely because of the inability to measure in vivo rates of GSH synthesis. In this study, a recently developed technique was used to determine the rates of synthesis of GSH in the erythrocytes of children with edematous and nonedematous PEM. The data reported demonstrate that erythrocyte GSH concentration and rate of synthesis were considerably lower in children with edematous PEM than in children with nonedematous PEM both shortly after admission when they were infected and malnourished and 7-10 days later when they were still malnourished but were free of infection. At both times, the slower GSH synthesis rates were associated with lower erythrocyte and plasma free cysteine concentrations. These findings strongly suggest that the GSH deficiency of patients with edematous PEM is due to impaired synthesis secondary to a shortage in the supply of cysteine.
The concentration of any metabolite represents the balance between its rate of synthesis and the rate at which it is consumed. Golden and Ramdath (6) proposed that depletion of erythrocyte GSH in children with edematous PEM was due primarily to increased consumption rather than decreased synthesis. This proposal was based on their observation that intracellular erythrocyte GSH concentrations increased when whole blood from children with edematous PEM was incubated for 6 h at 25°C without exogenous cysteine, glycine, and glutamine. They argued that the observed increase in GSH concentration indicated that substrates were not limiting for its in vivo synthesis. In a later study, they reported elevated erythrocyte GSH S-transferase activity in children with edematous PEM, further supporting their notion of an increased consumption of GSH (23). In other words, because kwashiorkor and marasmic-kwashiorkor are almost always associated with concurrent infection(s) and GSH levels fall under conditions of increased oxidative stress, such as infections (27), an increased oxidative load leads to an accelerated rate of consumption of GSH and, hence, depletion of GSH. The data reported here do not necessarily refute this possibility. They demonstrate, however, that, despite severe malnutrition in both the nonedematous and edematous groups of children, erythrocyte GSH concentrations and synthesis rates were markedly lower only in the edematous group, suggesting that impaired GSH synthesis was the primary cause of GSH depletion in the children with edematous PEM.
The inability of children with edematous PEM to sustain an adequate
rate of synthesis of GSH can result from either a shortage in the
supply of one of the precursor amino acids or from a defect in the GSH
biosynthetic pathway. Golden and Ramdath's (6) findings that
erythrocytes from children with edematous PEM synthesized GSH in vitro
without the addition of exogenous precursors and that this synthetic
capacity was abolished by the addition of L-methionine-S-sulfoximine (an inhibitor of
-glutamylcysteine synthase, the rate-limiting enzyme of GSH
synthesis) strongly suggest that severe malnutrition does not interfere
with the erythrocyte GSH biosynthetic pathway of these children.
Similarly, Hunter and Grimble (11) found no significant differences in
the activity of hepatic
-glutamylcysteine synthase between control
rats and rats fed a low-protein diet; this also was true with and
without the added stress of an inflammatory stimulus. On the other
hand, based on the observations that GSH concentration decreases in response to short-term food deprivation (9) and with a decline in
protein intake from an adequate to a deficient level (1, 10), it is
reasonable to assume that the reduction in erythrocyte GSH synthesis in
children with edematous PEM represents a response to a restricted
intracellular supply of the component amino acids.
GSH is synthesized from glycine, cysteine, and glutamate. The rate of synthesis, therefore, can be impaired by a shortage in the supply of one or all of these precursor amino acids. Previous studies have shown that children with edematous PEM have an overall reduction in total plasma free amino acid concentration of ~45%, including reduced glutamine and cysteine but not glycine concentrations (e.g., see Refs. 4, 5). The lower concentrations of cysteine and glutamine suggest an overall shortage in the supply of these two precursors for GSH synthesis in edematous PEM. In addition, the plasma concentration of methionine, the precursor for de novo cysteine synthesis, is 60% lower in children with edematous PEM than in healthy children (24).
Our data corroborate these earlier findings. Plasma free cysteine plus cystine, glutamine plus glutamate (but not glycine), and erythrocyte free glutamine and cysteine (but not glutamate and glycine) concentrations were lower in the edematous PEM children at study 1 compared with the values at recovery, suggesting a shortage of cysteine and glutamine but not of glycine. At study 2, plasma concentrations of glycine, glutamine, and glutamate had increased to levels that were similar to those at recovery, and erythrocyte glutamate and glycine concentrations were even higher than those observed at recovery. However, cysteine concentration remained significantly lower at study 2 than at recovery, and the rate of GSH synthesis also remained lower than at recovery. The consistently lower extra- and intracellular concentrations of cysteine at both times when GSH concentration and rates of GSH synthesis were low strongly suggest that a shortage in cysteine supply is primarily responsible for the impaired GSH synthesis of children with edematous PEM.
It is interesting that the children with nonedematous PEM, despite having similar infections and degree of severity of PEM, were still able to maintain normal concentrations and rates of synthesis of GSH, a finding which suggests that GSH precursor supply was also adequate. This raises the question of why the children with nonedematous PEM can maintain adequate supplies of GSH precursors, but the children with edematous PEM cannot. The supply of a nonessential amino acid derives from the diet, from de novo synthesis, and from the endogenous breakdown of body proteins. Because diets associated with severe malnutrition are believed to be low in sulfur amino acid content (24), it could be argued that the shortage in cysteine supply in the children with edematous PEM is the result of chronically restricted dietary intake of protein and of sulfur amino acids in particular. If this was the case, then both the dietary supply of cysteine and the de novo synthesis of cysteine will be affected because of the concomitant reduction in dietary methionine intake. Because glycine is the precursor for serine synthesis, and both glycine and serine are used in the conversion of methionine to cysteine, the lower plasma methionine concentration but higher plasma serine and glycine concentrations in studies 1 and 2 strongly suggest that de novo cysteine synthesis is compromised because of a shortage in the supply of methionine. However, unless it is possible for nonedematous PEM children but not edematous PEM children to compensate for such a shortage with the sulfur amino acids released from the breakdown of body proteins, this shortage of methionine should have a similar effect on the cysteine supply of the children with nonedematous PEM. Based on the recent work of Manary et al. (16), such a scenario is plausible. These investigators reported that the rate of whole body protein breakdown is markedly suppressed in kwashiorkor and marasmic-kwashiorkor vs. marasmic patients. Thus, in the child with kwashiorkor or marasmic-kwashiorkor, the suppression of endogenous protein breakdown rate, plus the possible lack of an adequate dietary intake of sulfur amino acids, will eventually cause a shortage in cysteine supply necessary to sustain adequate GSH synthesis.
Our argument that a shortage in cysteine supply is primarily responsible for the impaired GSH synthesis of children with edematous PEM does not support the proposal of Golden and Ramdath (6) that there is no shortage of precursor amino acids for synthesis of GSH. Based on their observation that intracellular erythrocyte GSH concentrations increased when whole blood from children with edematous PEM was incubated in the absence of exogenous substrates, they argued that the observed increase in GSH concentration indicated that substrates were not limiting for the de novo synthesis of GSH. It is possible, however, that this interpretation of their results is not correct. For example, an increase in GSH concentration of 0.258 mmol/l after in vitro incubation of erythrocytes for 6 h does not mean that the precursor supply was sufficient to support a normal rate of GSH synthesis (6). Based on the absolute rate of GSH synthesis of the children with edematous PEM at study 3, after they had completely recovered, it can be calculated that these children would have synthesized two times as much GSH in 6 h. This would translate to an increase in erythrocyte GSH concentration of 0.5 mmol/l in vitro. Therefore, the increase in erythrocyte GSH concentration reported by Golden and Ramdath (6) is really indicative of an impairment in the absolute rate of GSH synthesis in the erythrocytes of children with edematous PEM.
In study 1, the lower concentration and rate of synthesis of GSH in the children with edematous PEM was associated with a significantly higher plasma lipid hydroperoxide concentration than that observed in children with nonedematous PEM, suggesting a greater degree of oxidant-mediated lipid damage. Increased lipid hydroperoxidation changes the physiochemistry of membranes (19) that could underlie the edema and skin changes observed in edematous PEM (6, 15). Treatment of infections, however, resulted in a fall in plasma hydroperoxide concentration of the children with edematous PEM to the same levels observed in children with nonedematous PEM. Interestingly, both groups of children had significantly lower plasma lipid hydroperoxide levels at study 2 than at recovery. In the children with nonedematous PEM, the observation that there was no difference in GSH synthesis and concentration among the three studies, despite lower lipid hydroperoxides at studies 1 and 2, suggests that there is less oxidative damage to lipids in the severely malnourished state because of a decrease in the rate of production of oxidants. This is reasonable in light of the lower metabolic rates of severely malnourished individuals (12, 25). If this is also true for the child with edematous PEM, then the inappropriately higher plasma lipid hydroperoxide concentration at admission (relative to the nonedematous PEM child) may not be due to an increased production of oxidants but rather to the markedly reduced antioxidant capacity secondary to the reduced availability of GSH.
In conclusion, our finding that the lower erythrocyte GSH concentration of edematous PEM children is associated with lower rates of synthesis of the tripeptide demonstrates conclusively that impaired GSH synthesis contributes to the GSH deficiency associated with the kwashiorkor and marasmic-kwashiorkor syndromes. The finding that plasma and erythrocyte cysteine concentrations also were markedly lower strongly suggests that inadequate cysteine supply was mainly responsible for the slower rate of synthesis of GSH. The results suggest that early nutritional resuscitation of edematous PEM children should include cysteine to accelerate restoration and maintenance of GSH homeostasis. Further studies of GSH metabolism are therefore necessary in this condition.
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ACKNOWLEDGEMENTS |
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We are grateful to the physicians and nursing staff of the TMRU for their care of the children and to Melanie Del Rosario for technical support.
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FOOTNOTES |
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This is a publication of the U.S. Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX. The contents of this publication do not necessarily reflect the views or policies of the U.S. Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.
This research was supported by National Institute of Child Health and Human Development Grant RO1 HD34224-01A1, grants from the International Atomic Energy Agency and The Wellcome Trust, and with federal funds from the United States Department of Agriculture, Agricultural Research Service under Cooperative Agreement Number 58-6250-6001.
This work was presented in part at the Experimental Biology '99 Meeting in Washington, DC on April 17-21, 1999, and was published in abstract form (M. Reid, J. F. Morlese, A. Badaloo, T. Forrester, and F. Jahoor. In vivo evidence of impaired antioxidant capacity in edematous compared with nonedematous malnutrition. FASEB J. 13: A562, 1999).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: F. Jahoor, Children's Nutrition Research Center, Dept. of Pediatrics, Baylor College of Medicine, 1100 Bates St., Houston, TX 77030-2600 (E-mail: fjahoor{at}bcm.tmc.edu).
Received 4 June 1999; accepted in final form 12 October 1999.
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