Q J Med 1999; 92: 495-503
© 1999 Association of Physicians
Hyperphenylalaninaemia in children with falciparum malaria
1 From the Departments of OCBS, School of Dentistry, and 2 Biochemistry, School of Medicine, University of Maryland, Baltimore, Maryland, USA, 3 Nigerian Institute of Medical Research, Lagos, 4 Specialist Hospital, Sokoto, and 5 Massey Street Children Hospital, Lagos, Nigeria
Received 5 February 1999 and in revised form 5 July 1999
Professor C.O. Enwonwu, Departments of Biochemistry and OCBS, Schools of Medicine and Dentistry, 666 West Baltimore Street, Room 4G31, Baltimore, MD 21201-1586, USA
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Brain monoamine levels may underlie aspects of the cerebral component of falciparum malaria. Since circulating amino acids are the precursors for brain monoamine synthesis, we measured them in malaria patients and controls. Malaria elicited significantly elevated plasma levels of phenylalanine, particularly in comatose patients, with the Tyr/Phe (%) ratio reduced from 83.3 in controls to 39.5 in infected children, suggesting an impaired phenylalanine hydroxylase enzyme system in malaria infection. Malaria significantly increased the apparent Km for Trp, Tyr and His, with no effect on Km(app) for Phe. Using the kinetic parameters of NAA transport at the human blood–brain barrier, malaria significantly altered brain uptake of Phe (+96%), Trp (-28%) and His (+31%), with no effect on Tyr (-8%), compared with control findings. Our data suggest impaired cerebral synthesis of serotonin, dopamine and norepinephrine, and enhanced production of histamine, in children with severe falciparum malaria.
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Introduction |
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Malaria is a major cause of morbidity and mortality in sub-Saharan Africa, and kills more than one million children annually.1,2 The factors that determine whether a child develops mild or severe malaria are numerous and complex.1 Severe Plasmodium falciparum malaria is a multisystem disease involving several metabolic disturbances and endocrine dysfunctions,1,2 with recurrent paroxysms of high fever, persistent vomiting, confusion, seizures, and loss of consciousness (cerebral malaria) among the danger signs.2–5 Resting energy expenditure may be increased by as much as 30%.3 The fever elicits several host responses, such as altered fat and carbohydrate metabolism, increased catabolism of skeletal muscle, complex alterations in the metabolism of individual amino acids, and enhanced nitrogen excretion, with changes in the priority for protein synthesis, and increased gluconeogenesis, among others.2,6,7 The host's responses, especially those mediated through cytokine cascade, may determine disease severity.8,9 The cytokines stimulate release of glucocorticoids which in turn inhibit cytokine gene expression, in addition to promoting catabolism of muscle proteins and increased mobilization of amino acids to the liver.9–11 Abnormalities of hepatic2,12 and renal13 functions are seen in a significant proportion of children with severe malaria.
Plasmodium falciparum infection is considered one of the commonest causes of acute encephalopathies in children residing in falciparum-malaria-infected countries.2,14 There is good evidence that some common disorders of central monoamine metabolism may underlie the pathogenesis of metabolic encephalopathies.15,16 Studies in mice and rats with Plasmodium berghei infection indicate significantly reduced whole brain contents of 5-hydroxytryptamine (serotonin) and norepinephrine, while levels of dopamine and histamine remain unaltered.17 Large neutral amino acids circulating in blood plasma are precursors for the synthesis in brain of the monoamines, as well as other putative neurotransmitters such as carnosine, and important cofactors such as S-adenosyl-methionine,18 and alterations in their concentrations or turnover in the brain could affect monoaminergic functions.19 This latter idea derives from reports that the rate-limiting steps in cerebral biosyntheses of these neurotransmitters are not saturated by normal concentrations of the relevant precursor amino acids in brain cells, and that, therefore, amino acid transport at the blood–brain barrier (BBB) plays a critical role in the overall regulation.18
Studies of changes in the free amino acid (AA) plasma pool in malaria are limited, contradictory, and based mainly on the avian malaria Plasmodium lophurae in ducklings,20,21 with the animals demonstrating selective increases in plasma concentrations of specific amino acids.21 Since the brain is uniquely vulnerable to plasma hyperaminoacidaemia,18 our study was designed to examine the changes in plasma free amino acids in African children with P. falciparum malaria. We also evaluated plasma levels of free cortisol and ascorbate, as additional indices of the metabolic consequences of the disease.
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Approval for this study was by the Ethical Committees of the Nigerian Institute of Medical Research, Yaba, Lagos, the Lagos State Health Management Board, and the Ministry of Health, Sokoto State. Informed consent was obtained from the accompanying parents or guardians of the patients, who were assured of the confidentiality of individual results.
Study areas and patients
The studies were carried out at the Massey Street Children's Hospital, Lagos, and the Sokoto Specialist Hospital, Sokoto City, Sokoto State. Both hospitals are located in very high-density areas with deplorable environmental sanitation, and grossly inadequate basic amenities such as potable water as well as an unreliable electricity supply. The former hospital draws its patients from a population of about 2 million people residing in the Lagos metropolis, while Sokoto Specialist Hospital draws its patients not only from Sokoto State, but also from the two neighbouring states of Kebbi and Zamfara. As in most states in Nigeria, malaria is endemic in the study areas, especially during the rainy season, with Plasmodium falciparum predominating.
We recruited 28 randomly-selected children (13 females and 15 males, ages 14–156 months, mean±SD age 65.14±49.05) from the low-socioeconomic urban communities in Sokoto and Lagos. These children, 13 from Sokoto and the rest from Lagos, were selected from a much larger group of patients who presented at the hospitals during a 3-week period in 1997, with fever of varying degrees ranging from 38.0 to 40.8 °C. The children recruited from the two hospitals showed no significant difference in mean weights for age Z-scores and were, therefore, treated as one single group for the purposes of the study. Most of the children complained of persistent fever of a few days duration, with loss of appetite, nausea, vomiting and headache. Exclusion criteria were presence of a chronic illness, congenital abnormalities, other overt infectious diseases, severe malnutrition as exemplified clinically by kwashiorkor or marasmus, and food consumption within 6 h prior to presentation at the hospital. Each patient was given a full clinical examination. In particular, presence of jaundice, pallor, hepatomegaly and spleen enlargement were carefully documented. Four of the patients presented at the hospital with severely-impaired consciousness, absent corneal reflexes, repeated convulsions of the whole body, poor motor response to noxious stimuli, evidence of respiratory distress, and other features associated with cerebral malaria.22 The depth of coma was not measured. For comparative purposes, 28 children (mean age 72.1±18.8 months), distributed equally between genders and without malaria and overt signs of other infections, were recruited as the control group. These control children (14 each from Lagos and Sokoto) resided in the same low-socioeconomic-status urban communities as the children with malaria. They were enrolled in the study when they visited the hospitals (out-patient clinics) and the primary health-care centres for routine immunizations and a countrywide oral health screening program. The control children were recruited into the study during the same time interval as the malaria-infected children, and like the latter, they were predominantly of Hausa, Fulani, and Yoruba ethnic origins.
Clinical methods
Axillary temperature was measured with a mercury thermometer, using 1 min stabilization time. Pyrexia was defined as any temperature of 37.5 °C and above. Finger prick blood was obtained from each malaria patient for examination for malaria parasites and determination of packed cell volume (PCV). Thick and thin blood films were prepared on the same slide for each child. The slide was stained using buffered Giemsa23, and examined under oil immersion at x700 magnification. Laboratory diagnosis of malaria was based on observation of any stage of development of malaria parasites within the red blood cells. Species of the parasite was determined from the thin film. Parasite density was determined as previously described,23 using the thick film preparation. Four hundred fields were examined and certified to contain no parasites before a slide was declared negative.
Anthropometry
Body weight of each child was measured to the nearest 0.1 kg using a scale whose precision was frequently checked. Height was measured to the nearest mm. Assessment of nutritional status was predicated on weight-for-height as an index of current nutritional state, and on height-for-age (stunting) as an index of past nutrition. Using computer programs developed by the WHO, Geneva, and the CDC, Atlanta, for nutritional anthropometry (Epi Info version 5.0 lb, 1993), weight-for-age, height-for-age, and weight-for-height Z-scores were calculated, and interpreted relative to the standard values of the National Center for Health Statistics (NCHS) published by the US Department of Health, Education and Welfare.24 The Z-score cutoff point chosen was -2 standard deviations from the reference median.
Biochemical studies
Sample collection
Venous blood was collected at 09:00–11:00 h into heparinized tubes following fasting periods that lasted 6–12 h for the various subjects. At this stage, one male patient with malaria was excluded from the group because of inadequate blood collection. The blood-filled vacutainer tubes were retained in an ice-cooled chest until centrifuged (2000 g for 10 min) usually within 30 min after collection. The separated plasma was divided into aliquots for storage at -70 °C until analyzed. The aliquot for cortisol assay was stored in a siliconized tube. The aliquot for ascorbate assay was stabilized with an equal volume of freshly prepared 10% metaphosphoric acid before storage.
Assays
Levels of free amino acids in plasma were measured by reverse-phase HPLC following pre-column derivatization with phenylisothiocyanate.25 Phenylalanine shares the same transporter at the blood brain barrier (BBB) with valine, methionine, isoleucine, leucine, tyrosine, tryptophane and histidine, and all these amino acids possess different affinities for the transport site.26 To calculate brain uptake of these amino acids, the following equations26,27 were used:
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Determination of cortisol concentration in plasma was carried out with the `Gamma Coat' 125I-Radioimmunoassay Kit (Incstar), as previously described.28 The kit contained test tubes coated with rabbit anti-cortisol serum, 125I-labelled cortisol in phosphate-buffered saline, ANS (8-anilino-1-naphthalene sulphonic acid) with 0.02 M sodium azide preservative, cortisol serum blank (cortisol-free processed human serum), phosphate-buffered saline, and cortisol standards in processed human serum in concentrations of 0, 1, 3, 10, 25 and 60 µg/dl (0, 28, 83, 276, 690 and 1655 nmol/l). Using unextracted plasma (10 µl), cortisol concentrations were determined as indicated in the instruction manual that came with the kit. Precision was checked using recovery from spiked, pooled serum samples, and was in the range of 93–102%. The reference ranges for plasma cortisol levels were 193–690 nmol/l (mornings) and 55–248 nmol/l (evenings).
Plasma concentration of total ascorbic acid (dihydro-plus-dehydro-forms) was determined following derivatization with 2,4-dinitrophenylhydrazine as previously described.29 For interpretation of the data, we considered values <11 µmol/l to signify frank deficiency, values between 11 and 23 µmol/l as marginal or moderate risk of developing clinical deficiency signs, and values >23 µmol/l as normal.30
Statistical analysis
Results were expressed as means±SD. Statistical differences between means were evaluated by using Student's t-test when comparing groups, or by an analysis of variance of repeated measurements when comparing more than two situations. Differences between proportions were analyzed using 
2 test. The level of significance was chosen as p<0.05.
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With the exception of four children who were comatose, the rest were alert on admission. The main presenting symptoms in the 27 patients included loss of appetite (96%), vomiting (70%), convulsions (30%), headache (22%), diarrhoea (26%), fever (100%), splenomegaly (10%) and hepatomegaly (24%). Pre-medication with analgesics (62%), chloroquine (41%), antihistaminics (11%), or multivitamins including folate (33%) was noted in some of the patients. The packed cell volume (PCV) in the sick children varied from 15% to 51%, with 23% of them having a PCV of less than 30%. Similarly, marked variability was noted in malaria parasite density among the patients (range 22–386 076/µl, with geometric mean parasite density of 2669/µl). The percentages of the patients who were underweight, stunted or wasted, as indicated by their weight-for-age (WAZ), height-for-age (HAZ), and weight-for-height (WHZ) Z-scores were 30.8, 17.4, and 20.0, respectively, an observation suggestive of protein-energy malnutrition (PEM) in a good number of the children.31
The most prominent changes in the plasma free amino acid profiles in the children with malaria in comparison to the non-infected children were significant (p<0.05) increases in phenylalanine and histidine, and a decrease in arginine levels (Table 1
). Non-significant alterations between the two groups were observed in the levels of most of the dietary essential and non-essential amino acids. The ratio (%) of Tyr/Phe decreased markedly from 83.3 in the non-infected children to 39.5 in the malaria group. The sum (
NAA) of the large neutral amino acids, including histidine (Val, Met, Ile, Leu, Phe, Trp, Tyr, His) which share the same transporter at the BBB, increased by 32% in the malaria group compared with the level in the non-infected group. Phenylalanine accounted for a good proportion of the increase in the children with malaria. For initial semi-quantitative evaluation of the potential effects of changing plasma amino acid concentrations on brain availability of each individual large neutral amino acid, we calculated the amino acid ratio,32 an approach that incorrectly assumed that all the large neutral amino acids have the same affinity for the BBB transporter.18,26,27 Nonetheless, the crude assessment indicated significantly increased Phe ratio (Phe/NAA)% from 12.2 in the non-infected group to 24.7 in the malaria group (Table 1). The His and Trp ratios were significantly altered in the malaria group, but the Tyr ratio was unaffected. Using the Km (apparent) for each amino acid,26,27 and published kinetic parameters of transport (Km, Vmax and Kd) for the NAA at the human BBB,27 we derived more accurate data on the brain uptake of the various amino acids. As shown in Table 2, the apparent Km for Phe was not altered in the malaria group. In contrast, the infection produced a 25% significant increase in apparent Km in each of Trp, Tyr, and His compared with values for the control children. Malaria infection elicited significant increases in brain uptake of Phe (+96%) and His (+31%), a reduction in uptake of Trp (-28%), and no change in Tyr uptake, compared with findings in the control group (Table 2). The patients with malaria were further classified into three sub-groups of those who were comatose, those with parasite density in excess of 13 000/µl, and patients pre-medicated with folate before presentation at the study site. Excluded from the second sub-group were children in coma or those pre-medicated with folate. As shown in Table 3, the four patients in coma showed the highest degree of hyperphenylalaninaemia, which was not markedly different from the level in patients with high parasite density, but significantly higher (+86%) than the level observed in nine children with a history of pre-medication with folate.
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As summarized in Table 4
, the malaria patients demonstrated prominently increased plasma free cortisol concentrations, with marked reductions in mean plasma total ascorbate levels compared to findings in the non-infected control children. Only 4 of the 27 patients (15%) had plasma ascorbate level within the normal range, while the rest had levels <23 µmol/l.
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Discussion |
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Plasmodium falciparum is considered one of the commonest causes of acute encephalopathies in children in most endemic countries.1,4,14 Since disorders of central monoamine metabolism may underlie the pathogenesis of metabolic encephalopathies,16,18 the present studies focused primarily on circulating plasma levels of the large neutral amino acids, many of which serve as precursors for synthesis in brain of the monoamines (serotonin, dopamine, noradrenaline, and histamine).18,19,26,33 As shown in Table 1
, increased plasma Phe was the most conspicuous change in the children with malaria, with Phe levels 2–3-fold those seen in uninfected children, and within the range of values reportedly characteristic of some individuals heterozygous for phenylketonuria.34 Our findings were consistent with reports showing plasma Phe concentrations 45–86% above normal, in ducklings infected with Plasmodium lophurae.20,21
Factors predisposing to hyperphenylalaninemia include glucocorticoid-mediated catabolism of skeletal muscles in infections with increased release of Phe, PKU heterozygosity, hepatic disease and renal pathology with release of putative uraemic toxins that may affect phenylalanine hydroxylase, among others.7,18,35 Some of these factors, particularly impaired liver function2,36 and hypercortisolaemia,10 as indicated in Table 4, are frequent features of severe falciparum malaria in children. The pathological consequences of hyperphenylalaninemia are mainly in the brain,37,38 and may include such features as mental retardation, spasticity, and seizures.18 Indeed, a tripling of plasma Phe level to about 200 µM, as observed in the present study (Tables 1 and 3), may cause seizures, mood changes, insomnia, nausea, abdominal pain and diarrhoea,18,26 which are among the features commonly encountered in severe malaria.2,4,14 In the very limited number of comatose patients evaluated in the present study, mean plasma Phe level was as high as 242 µmol/l, a value four-fold the normal Phe concentration in plasma (Table 3).
Plasma amino acid abnormalities characterize several health conditions including protein energy malnutrition (PEM),39,40 infections,7,28,41,42 severe trauma,43 and stress, as well as sepsis.44,45 In PEM, with the possible exceptions of His and Phe, whose plasma concentrations are marginally well maintained, all indispensable amino acids are reduced in concentration so that EAA/NEA ratio declines, but His/NEA ratio is slightly elevated.39,40,46 The activities of key Phe39,47 and His46,47 catabolic enzymes are reduced in PEM. In a study of stressed and/or septic patients, Vente and colleagues44 noted a 70% increase in plasma Phe over control level, with virtually all the other essential amino acids in plasma reduced by 10–30%, an observation prompting the suggestion that a correlation exists between plasma Phe levels and mortality during sepsis.44,45 There are also reports that in experimentally-induced sand-fly-fever virus infection in healthy human adults, plasma amino acid levels compared with pre-inoculation control levels were Phe (+4%), Val (-33%), Thr (-26%), Leu (-33%), Ile (-31%), Tyr (-24%), Trp (-15%), Met (-16%) and His (-17%).42 In multiple-trauma patients compared with controls, plasma Phe is elevated (+33%) whilst its urinary excretion is increased by 13.3 times, mainly due to a faster clearance rate.48 What emerges from the numerous published studies on the alterations of plasma amino acid levels in infections, sepsis, and malnutrition is that: (i) not all individual essential amino acids change in exactly the same manner; (ii) the magnitude of the changes often correlates with the degree of the host's febrile response; and (iii) the reported increases in plasma Phe in the various conditions do not approach the magnitude encountered in patients with severe malaria (Tables 1 and 3). It must also be emphasized that the critical factors underlying brain uptake of any individual amino acid under various conditions are not only the plasma level of the specific amino acid, but also the alterations in plasma concentrations of the amino acids that share the same transporter with the former at the BBB.18,26 The complex alterations in metabolism of individual amino acids in an infection are influenced by fever.7 The African child suffering from an acute episode of malaria may experience a resting energy expenditure increase of about 30%.3
The phenylalanine hydroxylating system complex consists of phenylalanine hydroxylase (PAH; EC 1.14.16.1), a regulatory cofactor tetrahydrobiopterin (THB), and dihydropteridine reductase (DHPR; EC 1.6.99.7) which keeps the cofactor in its active tetrahydro-form.49 DHPR deficiency and/or defective synthesis of THB, will elicit inadequate THB-dependent hydroxylase activities (Phe hydroxylase, Tyr hydroxylase, Trp hydroxylase), and consequently, impaired synthesis of dopamine, norepinephrine and serotonin, in addition to hyperphenylalaninaemia.49 In our study, patients pre-medicated with folic acid showed less prominent hyperphenylalaninaemia (Table 3), an observation suggestive of an increased dietary requirement for this vitamin in falciparum malaria and consistent with other reports of folate deficiency in severe malaria.50 Plasmodium falciparum possesses an endogenous folate synthesis pathway, but also utilises exogenous folate.51 Studies of intraerythrocytic P. falciparum grown in continuous culture51 have shown that the parasite utilises pterin from exogenous folate degradation as a precursor for synthesis of 5-CH3-H4 Pte Glu5 (5-methyl-tetrahydrofolate), and that the extremely low rate of de novo synthesis from GTP or guanosine (30.7±9.2 pmol/0.1 ml packed cells/24 h) as compared with the rate of synthesis from exogenous folate, intact or degraded forms (1732± 207 pmol/0.1 ml packed cells/24 h) suggests a predominance of the latter pathway in the acquisition of folate cofactors for the parasites. We have no explanation for the observation that pre-treatment with folic acid reduced the changes in plasma phenylalanine and tyrosine levels in patients with malaria (Table 3). It is possible that severe malaria elicits deficient activity of DHPR through mechanisms that are still unclear. There are, however, suggestions that DHPR may be involved in other enzyme systems,52 and this enzyme may keep folate in the active, tetrahydro form.53 The latter role could explain the low serum folate levels observed in some PKU patients with DHPR deficiency,54 and the inclusion of tetrahydrofolate in the therapy for these patients.52,55
Phenylalanine is transported solely by the L-system,18,27 and its Km at the BBB is 4- to 29-fold lower than those for other large neutral amino acids which share the same transporter.27 As indicated in Table 2, malaria infection had no effect on the apparent Km for Phe but elicited a significant increase (+25%) in the apparent Km for Trp, Tyr and His. Consequently, the uptake of Phe into the brain was calculated to be double in malaria patients compared with the controls, while the uptake of Trp was significantly reduced (Table 2). Both tyrosine hydroxylase and tryptophane hydroxylase, rate-limiting enzymes in the syntheses of dopamine/norepinephrine and serotonin, respectively, are competitively inhibited by increased phenylalanine.57 Loo58 has demonstrated serotonin deficiency in experimental hyperphenylalaninaemia. Similarly, in autopsied brains of PKU patients, Phe levels increase five-fold, Tyr and Trp levels are reduced, and brain contents of serotonin, dopamine and norepinephrine substantially reduced.59 Some workers17 have argued that the significantly reduced brain serotonin and norepinephrine levels in rodents infected with P. berghei may play a role in the occurrence of cerebral vasodilation in malaria. The occurrence of seizures in severe malaria2,4,5 may be related to decreased brain levels of serotonin and catecholamines (putative inhibitory neurotransmitters)60 resulting from hyperphenylalaninaemia-induced reduction in brain levels of tryptophan and tyrosine. In an animal model system of spontaneous seizures, brain levels of the inhibitory monoamine neurotransmitters are significantly decreased.61
The markedly increased brain uptake of histidine in children with malaria (Table 2) would favour an elevated brain level of histamine.62 The Km for L-histidine carboxylase (EC 4.1.1.22) in the brain is much higher than the level that can be saturated by normal brain contents of free histidine.62 Thus, elevated brain levels of histidine would promote enhanced synthesis of histamine (imidazolethylamine).62,63 It is purely speculative at this stage whether or not the brain burden of histamine is increased in malaria, but this merits some careful studies, since elevated brain levels of this monoamine may promote increased cerebral capillary permeability, resulting in cerebral oedema and elevated intracranial pressure, among other effects.63 These are pathophysiological alterations associated with cerebral malaria.2,4
Nitric oxide (NO) is implicated in some aspects of the pathogenesis of severe malaria,64,65 and the significantly reduced plasma arginine observed in the malaria patients (Table 1) could be due to increased utilization of this amino acid by the nitric oxide synthase (NOS) pathway. Our studies also demonstrated a two-fold elevation in plasma level of free cortisol in the children with malaria compared with the non-infected group (Table 4), an observation consistent with reports by others10 and attributable to stimulation of the hypothalamus-pituitary-adrenal axis by pro-inflammatory cytokines.8–10 The increased circulating levels of glucocorticoids would play a role not only in mobilizing free amino acids from the periphery to the liver, but also in suppressing excessive/inappropriate cytokine production.7,9 The marked reduction of plasma ascorbate in malaria (Table 4) confirmed earlier reports by others,66 and could be due to reduced dietary intake, and enhanced utilization in cell mediated immunity as well as in free radical quenching.
There are suggestions that there is a cerebral component in virtually all cases of falciparum malaria.14 Despite the very limited number of children with falciparum malaria examined in the present studies, the findings suggest an urgent need to evaluate some of the symptoms encountered in this disease within the context of major alterations in the metabolism of monoamines in the brain. It is perhaps relevant that the consumer-initiated complaints associated with excessive intake of aspartame (L-aspartyl-L-phenylalanine methyl ester)-containing food products include mood changes, insomnia, seizures, nausea, diarrhoea, abdominal pain, and irregular menses.67 Some of these are features of severe malaria.1,2,4,5 Unlike blood levels of aspartic acid, blood concentrations of phenylalanine rise markedly after ingestion of aspartame, and the rise is linearly related to the dose of aspartame.68 The absence of any substantial increase in plasma aspartic acid level precludes this amino acid from participating in the observed changes.60
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This study was supported in part by the Nestle Foundation, Lausanne, Switzerland. The excellent administrative assistance of Ms. Judy Pennington is also acknowledged.
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