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The cerebral blood flow (CBF) and cerebral metabolic rate (CMR) of oxygen, glucose, lactate, pyruvate, ketone bodies, and 24 amino acids were examined in 10 healthy subjects, five 21-24 and five 55-65 years old. The subjects were free from drugs. The results of psychometric and neurological examinations were negative. CBF was determined with the nitrous oxide method on the subjects who were awake and normocapnic and had fasted overnight. No differences were found between the young and the old groups except in arterial levels of four amino acids, viz. aspartic acid, methionine, lysine, and tryptophan. In the whole group of 10 subjects, a significant cerebral net uptake (expressed as median values in mumol X kg-1 X min-1) was found not only for oxygen (1719) and glucose (248), but also for acetoacetate (4.3), D-beta-hydroxybutyrate (6.2), arginine (2.0), leucine (5.2), and isoleucine (1.2). There was a significant net release of lactate (-28). CBF was positively correlated to the CMR of oxygen and D-beta-hydroxybutyrate. Arterial concentrations and CMR were positively correlated for ketone bodies, glutamic acid, proline and taurine. It is of particular interest that the whole group of healthy subjects showed a significant cerebral uptake of branched-chain and dibasic amino acids.

Summary During the first hours of extrauterine life the venous plasma of the fasting normal newborn shows a fast decline of valine, leucine, isoleucine, lysine and alanine levels, while the glycine level and the ornithine/arginine quotient seem to increase. These changes are not caused by urinary excretion and are the same as those found in calorie undernutrition. The fasting newborn of mothers with hypertension of pregnancy, who are underweight and short for gestational age, have increased levels of valine, leucine and isoleucine during the first hours after birth and a tendency towards a more rapid decline of the levels thereafter. The alanine and proline levels seem to “resist” the general decline during the initial fast. These changes in the homeostasis of plasma free amino acids are not due to short gestational period. They are the same as those found in protein deficiency.

Twenty preterm infants undergoing neonatal intensive care were randomly allocated to one of two feeding regimens: human milk enriched with either human milk protein (HMP) or adapted cow's milk protein (CMP). The birthweights (1076 +/- 301 g; 1031 +/- 309 g) and the gestational ages (28.4 +/- 1.6 weeks; 27.7 +/- 2.1 weeks) were comparable. The amount of protein added to the milk was set at 0.7 g/100 ml in order to provide a total supply of 3.0-3.5 g/kg/24 h. All infants received additional amounts of carbohydrate, calcium, phosphorous, and sodium chloride. Capillary whole blood amino acids were measured with high pressure liquid chromatography (HPLC). The amino acid levels did not differ significantly when the feeding groups were compared week by week, but the glycine/valine ratio was higher (p less than 0.05) in the HMP group after three weeks of fortification. Longitudinal changes after protein enrichment could be demonstrated in both groups. Alanine and threonine increased after one week (p less than 0.01) in both groups. Glycine in the HMP group peaked after two weeks (p less than 0.02), and valine in the CMP group increased (p less than 0.02) after one week on the feeding regimen. However, the amino acids never reached levels above those seen after a meal in normal term newborns. Other variables related to protein intake, such as protein and urea in serum, did not vary between the groups. Growth, expressed as gains in weight, length, and head circumference was poor but comparable. The quality of the protein, whether a human milk protein isolate or a cow's milk whey protein product, used for the fortification of human milk up to a protein load of 3.0-3.5 g/kg/24 h, did not cause any alterations of significance in the amino acid profiles of peripheral blood.

Objective. To investigate whether intrauterine growth retardation (IUGR) and preterm delivery in a poor population of South Asia was associated with altered maternal and fetal levels of folate, vitamin B12, and homocysteine.Subjects and methods. Hundred and twenty-eight pregnant women from a low socioeconomic strata in the city of Lahore, Pakistan were followed with ultrasound of fetal growth from the 12th week of pregnancy. Blood samples were drawn from the woman and the cord at delivery. Serum was analyzed by a chemiluminescent immunoassay for folate and vitamin B12 and by fluorescence polarization immunoassay for total homocysteine (tHcy).Results. Fourty-six infants showed IUGR. In term, but not preterm, deliveries with IUGR, maternal and cord blood folate levels were half of those in deliveries of normal birth weight infants (P ¼0.004 and P ¼0.005). The risk of IUGR was reduced among women with folate levels in the highest quartile (OR 0.31, 95% CI 0.10–0.84). There was no association between vitamin ...

The objective of this study was to evaluate risk factors for death due to diarrhoea among hospitalized children at the Aga Khan University Hospital (AKUH), Karachi. We conducted a retrospective case-control study of all diarrhoea deaths at AKUH over the period 1988-93. For each death, the next two consecutive admissions matched for gender and type of diarrhoea were identified as controls. Data were analysed by univariate methods and logistic regression analysis. A total of 42 deaths and 84 matched controls were identified. Blood cultures at admission were obtained in all deaths and 94% of controls. The rates of isolation of organisms from blood cultures were significantly higher among deaths [38 versus 9%, odds ratio (OR) 6.5, 95% confidence interval (CI) 2.2-19.9], the majority of which were Gram-negative Enterobacteriaceae (94 versus 57%, Fisher's exact test p0.02). Conditional logistic regression revealed that several clinical and laboratory features of systemic infection were associated with a significantly increased risk of mortality, such as anorexia (OR 3.9, 95% CI 1.4-10.9), drowsiness (OR 4.4, 95% CI 1.3-15.3), respiratory distress (OR 7.0, 95% CI 1.4 36.6), anaemia (OR 5.8, 95% CI 2.0-16.6) and a positive blood culture (OR 8.7, 95% CI 2.5-30.7). Our data suggest that bacteraemia with Enterobacteriaceae is common among hospitalized malnourished children with diarrhoea and systemic infection may be an important risk factor for mortality.

The effects of medically-orientated labour ward routines were studied during the the first hour after birth, in 48 vaginal, single deliveries. All infants were immediately separated from their mothers and left on a resuscitation table. There was no significant difference in onset of crying if the infant received cutaneous stimulation or not. It was found that 17 infants, not showing hand-to-mouth activity, were bathed at an average time of 17 min (12-23 min) after birth, while those who did were bathed at 28.5 (24.5-41.5) min (P = 0.002). One infant was breastfed during the first hour. Being separated from its mother, bathed early, and swaddled after birth seemed to interfere with the infant's inborn ability to signal hunger. Forty-one infants were hypothermic at 1 hour. According to a multiple regression analysis infant body temperature at 60 min of age corresponded positively with birth weight (P = 0.0001) and time of oxygen administration (P = 0.0002). A plausible explanation for the effect of oxygen exposure is that there is brown fat inactivation in normal newborn infants and administration of oxygen activates the brown fat. It might be advantageous to let the mother keep the baby warm, rather than manipulate the baby's metabolism with oxygen.

Ingestion of Escherichia coli O83 bacteria by adults resulted in a transient irregular colonization leading to a serum antibody response in only four out of 14 cases examined. In all of three pregnant women, however, IgA antibodies against E. coli O83 antigen were released from colostral cells after similar bacterial ingestion although no serum antibody response was noted. The findings indicate a link between the antigenic exposure to the gut and secretory antibodies of the IgA class, presumably locally formed in the mammary gland. Antibodies of the secretory IgA class registered in colostrum may, at least partly, reflect the antigenic exposure of the gut. These antibodies are probably important in protecting against E. coli infections in the neonate, as suggested by the findings of antibodies in human milk against O and K antigens of non-enteropathogenic as well as enteropathogenic serotypes of E. coli. Furthermore, in milk of women from low socio-economic groups in Pakistan, neutralizing antibodies were present against enterotoxins of E. coli bacteria and occasionally against Vibrio cholerae enterotoxins. In addition, secretory IgA antibodies against food proteins were detected in human milk. This suggests that intestinal exposure to such antigens could stimulate a local immune response in the gut resulting in triggered lymphoid cells homing to the mammary gland. These human milk secretory IgA antibodies against bovine milk proteins may help to prevent cow's milk allergy in infants on mixed feeding, since these infants tend to have a lower serum antibody response to cow's milk proteins than infants fed mostly artificially. Furthermore, children suffering from cow's milk protein intolerance and gluten enteropathy may have higher serum levels of antibody to cow's milk protein antigens than normal children, possibly reflecting increased permeability of the intestinal mucosa for various antigens.

This investigation aims at monitoring the formation of diamines in the gastrointestinal tract of human infants, and thereby also the bacterial colonization of the intestine, by studying the urinary excretion of the heterocyclic amine piperidine during development and in different malabsorptive states. A gas chromatographic assay of the dinitrophenyl derivative of piperidine and a mass spectrometric method of identification were worked out and applied. The piperidine excretion was expressed in units of urinary creatinine concentration. Adult women show a greater variation than men, both inter- and intra-individually. The piperidine excretion is very low and mostly undetectable in the first week of life. There is an increase in weaning, with a significant difference between breast-fed and formula-fed infants at 4--6 months. There is a significant difference between infants suffering from untreated coeliac disease and infants without malabsorption. The findings indicate that piperidine excretion is a sensitive biochemical index of changes in the gastrointestinal flora. The high excretion in coeliac disease suggests that piperidine, which is known to have nicotine-like synaptic activity in the CNS, is one of the hitherto unidentified 'auto-intoxicating' substances arising from the bacterial decomposition of protein suggested by Metchnikoff in 1903.

This paper describes a method of quantifying the amount of smaller peptides in physiological fluids and reports the preliminary results of studying the mesenteric blood of adult guinea-pigs during absorption of a partial hydrolysate of casein. Because of the different roles suggested for plasma and erythrocytes in the inter-organ transport of amino acids, both plasma and whole blood have been studied. Whole blood and plasma samples were deproteinized with sulphosalicylic acid, and amino acids and small peptides separated from residual small amounts of protein on a Sephadex G-25 column. Ion exchange chromatography was then performed before and after acid hydrolysis. The concentration of small peptides in blood seems to be much lower than was previously believed. The adult guinea-pig did not absorb small peptides across the intestine into mesenteric whole blood or plasma in our experiments. However, casein hydrolysates are not necessarily representative of all protein hydrolysates, and further studies are required using different proteins and varying degrees of hydrolysis. The possibility of peptide transfer during development, and in conditions involving mucosal damage, should also be investigated. The present investigation confirms the assumption that predominantly plasma, and not red blood corpuscles, carries amino acids from the gut to the liver. It is worth noting, however, that taurine, aspartic acid, glutamic acid, citrulline and arginine were found in higher concentrations in whole mesenteric blood than in plasma.

OBJECTIVE. Low maternal folate levels during pregnancy correlate with low birth weight, a perinatal risk factor for later cardiovascular disease. We studied relationships between red blood cell folate levels, birth weight, and vascular endothelial function (a key factor in the early pathophysiologic processes of heart disease) in newborn infants. METHODS. We included 82 infants (30 low birth weight) and their mothers. A laser Doppler technique was used to measure skin perfusion during transdermal iontophoresis of acetylcholine (an endothelium-dependent vasodilator). Red blood cell folate, vitamin B12, and homocysteine levels were determined. RESULTS. The perfusion response to acetylcholine was lower in low birth weight infants than in normal birth weight control subjects (mean: 35 vs 76 perfusion units). The neonatal acetylcholine response correlated with red blood cell folate levels in both infants and their mothers. The folate levels of low birth weight and control infants did not differ significantly (mean: 1603 vs 1795 nmol/L), but mothers of low birth weight infants had lower folate levels than did mothers of control infants (mean: 805 vs 1109 nmol/L). In multivariate analysis, low birth weight and red blood cell folate levels contributed independently to endothelial function in newborn infants. The levels of vitamin B12 and homocysteine were similar in the 2 groups and did not correlate with endothelial function. CONCLUSION. The data presented here provide the first evidence for a relationship between folate levels and vascular endothelial function in newborn infants.

Cut-off levels for serum retinol levels of 20 micrograms/dl for marginal and 10 micrograms/dl for definite deficiency have been advocated and extensively used in population studies. However, the blood serum levels of retinol of the newborn are known to be very low and although the age dependency of the retinol binding protein has been described, the normal levels of serum retinol at different ages have not been reported from larger series. While studying poor populations of young infants in Lahore, Pakistan, we thought it necessary to try to achieve appropriate reference values by analysing the levels of serum retinol of expatriates from the Indian subcontinent who live in the affluent United Arab Emirates, where retinol deficiency is not seen either at the hospital or the community levels. We have studied material, cord blood, infantile and adult levels of retinol and found a highly significant age relationship of serum retinol levels. During very early infancy the 'normal' mean is below what has been considered deficiency. This is new information and important in the evaluation of retinol status of individuals as well as populations. In addition, we found lower levels in women, pregnant or non-pregnant, than those in adult men. This sex difference in adults was not seen in infants. We recommend a cut off level for deficiency of 10 micrograms/dl, but only for those above 1 month of postnatal age.

During 1992 and 1993, 309 children aged 1-22 months (mo) and their mothers visiting an immunization facility in Al Ain city, Abu Dhabi Emirate, United Arab Emirates, were studied to (1) define blood haemoglobin (Hb) levels; (2) estimate the prevalence of anaemia; (3) examine the role of iron deficiency in causing anaemia; (4) identify the correlates of anaemia prevalence; and (5) assess the acceptability to parents of an anaemia screening test for their young children. The levels of Hb in all subjects and the levels of serum ferritin in anaemic (Hb11 g/dl) children agedor = 6 mo and in non-pregnant women with Hb11 g/dl were determined by a HemoCue Photometer and an enzyme immunoassay, respectively. Each woman was interviewed to obtain pertinent data. In children, anaemia was detected in 3% of those aged 1-2 mo (Hb9 g/dl), in 8% of those aged 3-5 mo (Hb10 g/dl), and in 25-39% of those agedor = 6 mo (Hb11 g/dl). Of 19 children tested, ten (53%) were iron-depleted (serum ferritin12 micrograms/l). After multivariate adjustment, the only significant positive correlate of anaemia in children was older age (1-5 mo vs 6-22 mo; odds ratio [OR]: 9.51; 95% confidence interval [CI]: 3.92-23.08). Anaemia was detected in 14% of pregnant women (Hb11 g/dl) and 16% of non-pregnant women (Hb12 g/dl).(ABSTRACT TRUNCATED AT 250 WORDS)

The trend of declining infant mortality has stopped or has increased in at least 21 developing countries. In the last 30 years in Pakistan infant mortality has been over 100/1000 live births. Population size has increased from 35 to 120 million between 1950 and 1993. Pakistan is experiencing a simultaneous rise in urbanization. Breast feeding and postpartum abstinence are often responsible for long birth intervals in certain populations. Breast feeding patterns have changed greatly from exclusive breast feeding to at most partial breast feeding. Partial breast feeding can have a contraceptive effect if sucking is frequent enough. For example mothers who breast fed for less than 4 months had many more new pregnancies than those who breast fed longer than 4 months (p < 0.05). Lymphoid cells that have migrated to mammary glands produce secretory IgA antibodies which are passed to the infant via the milk. These antibodies protect breast fed infants from infection and death. For example in Lahore Pakistan neonatal septicemia occurred 18 times more often among non-breastfed infants than partially breast fed infants. The risk of diarrhea-related death was 23.5 times greater among non-breastfed infants compared to exclusively breast fed infants. Frequent infections brings about undernutrition which only serves to increase the risk of poor growth and development or death. The practice of giving prelacteal feeds and supplementary feeds increases the risk of infection. In conclusion promotion of breast feeding improves the life and prevents the death of many children. Breast feeding campaigns should begin immediately especially in poor societies.

This study was carried out to obtain reliable prospective data on the incidence, home management and duration of infantile diarrhoeal disease in a developing and rapidly urbanizing community. Fourteen hundred and seventy six infants from 4 different communities of Lahore, representing different stages of urbanization, were followed prospectively from birth to 2 years of age. Each child had an average of 3.6 episodes of diarrhoea during one year; 4.3 episodes per child per year in the village, 4.4 in the periurban slum, 3.4 in the urban slum and 1.4 in the upper middle (Um) class control group. The maximum incidence of diarrhoeal episodes occurred in children between 9-10 months of age. No sex difference was found. The seasonal variation showed a peak incidence during April-June. Bloody diarrhoea, in 3-5% of the episodes, was predominantly seen in winter months and in older infants. The maximum use of ORS was seen in the Um class (53%). Antibiotics were used in 75% of all diarrhoeal episodes maximally in the Um class, and morphine derivatives in 1% of all cases. The overall incidence of persistent diarrhoea was 14% of all acute cases, being highest in the village (18%), followed by the periurban slum (14%), Um class (10%) and urban slum (8%) with peak incidence occurring in June and July. Our results confirm the magnitude of the problem of diarrhoea.(ABSTRACT TRUNCATED AT 250 WORDS)

Publisher Summary This chapter discusses the role of breast milk in neonatal host defense. Human milk is rich in host defense factors, although so far only SIgA antibodies have been shown to be protective per se. Defense via human milk may largely be anti-inflammatory. Thus, milk lactoferrin seems to be able to prevent IL-6 release after exposure of human macrophages and gut epithelial cells to lipopolysaccharides (LPS). The start of breast-feeding is traditionally delayed during the first days of life in some, possible many, societies in the developing world, for example, in Pakistan. Thereafter partial breast-feeding is most common with the addition of animal milk and extra water using a bottle, especially during the hot season when there is increased incidence of diarrhea. Such partial breast-feeding protects strongly against neonatal sepsis and early diarrheal diseases. Breast-feeding also protects against necrotizing enterocolitis. Mortality in lower respiratory tract infections is decreased as well by breast-feeding.

Protection against neonatal sepsis by breast feeding was investigated in a developing community. A case-control study was carried out with 42 cases from a hospital and 270 controls, matched for age and socioeconomic conditions from the community. Exclusive breast feeding was extremely rare, most babies being partially breast fed and a few being given formula feed or animal milk. A highly significant odds ratio of 18 was obtained, showing that even partial breast feeding protects against neonatal sepsis in such a population.

The response of C-peptide in serum and urine and of glucose and branched chain amino acids in blood to formula and breast feeding was assessed in six breast-fed and six formula-fed infants 3-6 months of age. We analysed serum C-peptide, branched chain amino acids (BCAA) in blood, and blood glucose in the fasting state at 90' and 180' after a regular meal. The excretion of urinary C-peptide and creatinine was also determined. The formula-fed infants received a formula in current use, containing 15-16 g protein/l and with a casein/whey ratio of 40/60. In the fasting state, no significant inter-group difference was found in the level of serum C-peptide or the valine/glycine ratio. Postprandially, the formula-fed infants had significantly higher serum C-peptide values and valine/glycine ratio than the breast-fed infants, p less than 0.05. No significant inter-group difference was found for blood glucose. The urinary C-peptide/creatinine ratio was significantly lower in the breast-fed group, p = 0.02, and significantly correlated both to the valine/glycine ratio at 90', rs = 0.75, p = 0.02 and to the serum C-peptide value at 90', rs = 0.66, p = 0.03. These results confirm that in formula-fed infants the insulin response to a meal is enhanced compared to that in breast-fed infants. The finding of similar blood glucose values in the two groups may also indicate an insulin resistance in the formula-fed infants following a meal.

This paper describes a rapid analysis of free amino acid levels in capillary blood samples using a modified HPLC system. Capillary whole blood (25 microliters) is dried on a filter paper, extracted and the equivalent of 0.25 microliter of the initial blood sample is used for each amino acid analysis. Nineteen free amino acid levels are determined with a reproducibility of better than +/- 10% for the entire procedure of sampling, preparation and analysis, with the exception of ornithine (+/- 19%) and lysine (+/- 12%). Cystine and proline cannot easily be determined by this method. Alanine, tyrosine, methionine, valine, phenylalanine, isoleucine and leucine concentrations on the filter paper are unaltered after 1, 2 and 21 wk. Storage at room temperature should not be for longer than 2 wk, but storage at +4 degrees C, -18 degrees C and -70 degrees C is acceptable for 21 wk. This new micromethod seems to be a practical and reliable tool. Because of its simplicity and, above all, the need for a minimal amount of capillary blood, it is a valid means for the routine monitoring of amino acid profiles in sick preterm infants on different protein regimens. The sampling and storage methods are also examples of 'appropriate technology' for field studies of nutritional adequacy in population samples derived from infants. This is because centrifugation is not necessary and the fact that the relevant amino acids on the dried filter paper samples display high stability.

The antibody content of milk from healthy Swedish mothers was compared with that of milk from mothers of a very low socio-economic group in a developing country. Antibodies of various immunoglobulin classes against E. coli O antigens were determined with the enzyme-linked immunosorbent assay (ELISA). The milk antibodies which mainly belonged to the secretory IgA class appeared in similar concentrations in milk from the two groups using E. coli antigens of Swedish as well as Pakistani origin. The secretory IgA antibodies could be demonstrated in the stool of the breast-fed infants of the undernourished mothers. Also the concentration of serum IgG and IgA antibodies to E. coli O antigens were similar in the Pakistani and Swedish mothers. The serum IgM antibody levels of the Pakistani mothers were higher, however, presumably due to a higher frequency of infections. It was noted that the milk production decreased considerably upon the hospitalization of the healthy and well-to-do Swedish mothers. The small milk volumes of the undernourished Pakistani mothers suggest that the lactation failure observed was mainly due to inadequate milk flow and not to decreased milk quality. The results indicate the necessity of studying the nutritional, psychological and social factors responsible for low milk yield and add yet another reason to stimulate prolonged breastfeeding.

The capacity of subcutaneous cholera vaccination to induce an antibody response in milk and saliva was studied in lactating Swedish and Pakistani women, since secretory immunoglobulin A (SIgA) antibody responses in these secretions may reflect intestinal immunity. Before immunization, most of the Pakistani women had significant titers of specific SIgA antibodies against Vibrio cholerae lipopolysaccharide in milk, whereas only a few of the Swedish women had measurable, low titers. In the Pakistani women a single subcutaneous injection of cholera vaccine gave rise to a significant SIgA titer rise in 70% of the milk and 45% of the saliva samples. The Swedish women, on the other hand, did not respond with a significant antibody response of any immunoglobulin class in milk or saliva, either after a single or after a booster dose 14 days later. In serum, however, the vaccination induced significant titer rises, mainly of IgG antibodies, also in the Swedish women, but these rises were of lower magnitude than those in the Pakistani group. The results suggest a significant difference in the capacity of parenterally administered cholera vaccine to stimulate SIgA antibody formation in naturally primed and nonprimed individuals.

Tetanic convulsions are not uncommon among severely dehydrated children in the developing countries. This raises the question whether these children have disturbances in the homeostasis of divalent ions. Serum values are reported of calcium, magnesium, phosphorus, sodium and potassium, as well as blood pH in children below 3 years of age with acute watery diarrhoea and with an estimated weight loss of about 10%. The study was performed on dehydrated children with (DC) or without (D) convulsions. Values were obtained on admission and following rehydration therapy (RT). On admission serum calcium was low in both D and DC children. Serum phosphorus was likewise elevated in both D and DC children. Serum magnesium was slightly elevated in the DC but not in the D group. No patient had Hypernatremia. During RT, serum calcium increased significantly and serum phosphorus decreased significantly in D and DC children. Serum calcium showed a significant inverse correlation with serum phosphorus and a significant direct correlation with blood pH. Treatment of DC children with i.v. calcium and i.m. magnesium had no immediate effect on the convulsions. Our conclusion is that severely dehydrated children will develop hypocalcemia. The cause may be a redistribution of calcium into the cells, parallelled by a redistribution of phosphorus from the intra- to the extracellular space.

1. Re-examination of data for the chemical analysis of peptide-bound amino acids in the mesenteric venous blood of anaesthetized guinea-pigs suggests that there are small, but significant, amounts of small peptides in the blood of fasted animals. 2. Furthermore, there is a significant increase in the peptide content of the mesenteric venous blood during intraduodenal infusion of a partial digest of casein. 3. The data are consistent with the view that some 10% of the amino nitrogen entering the mesenteric blood during absorption of a casein digest in vivo may be in the form of small peptides, although it is not possible to define confidence limits for this estimate.

Two regimens (A and B) for TPN were designed to meet the requirements of newborn infants for calories, amino acids, fatty acids, electrolytes, trace elements and vitamins. Both “A” and “B” included fat emulsion (Intralipid®). “A” contained fructose and glucose, “B” glucose only. “A” provided amino acids (Vamin®) in proportions similar to those of whole egg, “B” similar to those of human milk. All nutrients were given simultaneously into peripheral veins by constant infusion. Nineteen patients (11 newborns, 8 infants) were studied for 1–28 days. Twelve infants recovered, 7 died. In none could TPN be regarded as the cause of death. Treatment was complicated by sepsis in 5 infants. During the course of treatment, blood levels of substrates and insulin were measured before, during and 30 min after discontinuation of TPN. Highly raised concentrations of circulating substrates seen in 3 infants seemed to be related to a poor clinical condition rather than to the regimen used. Infants in good condition tolerated TPN well. Low levels of branch-chained amino acids and tendency to ketonemia, when infusion was stopped, suggested that minimal rather than optimal supply of energy and of amino acids in relation to energy was provided with both regimens. Low insulin levels associated with elevated blood levels of substrates suggested that insulin administration to selected cases might be indicated. Fructose (0.30 g/kg × hour-1) given with regimen A increased blood lactate concentrations. Homocystinaemia appeared in 2 cases; disappearance after excess vitamin B6 administration indicated increased B6 requirement.

The effect of poliovirus vaccination on mucosal immunity was studied in lactating women because secretory IgA antibodies to poliovirus in milk may reflect intestinal immunity. Swedish mothers lacked significant titers of secretory IgA antibodies in their milk before vaccination. Subcutaneous vaccination with killed poliovirus vaccine resulted in low but transient increases in titers of secretory IgA antibodies in the milk of most of these women. Pakistani mothers had significant titers of secretory IgA antibodies in their milk before immunization; these titers increased after subcutaneous poliovirus vaccination in 45% of the women. Peroral vaccination of Pakistani women with liver poliovirus vaccine diminished already existing titers of secretory IgA antibodies in their milk. The decrease in titer was especially pronounced when the liver poliovirus vaccine was given together with a subcutaneous vaccine consisting of killed Vibrio cholerae organisms; the mean titer of secretory IgA antibodies in milk 14 days after vaccination was about 40-fold lower than it was before vaccination.

Akbani, Y., Bolme, P., Lindblad, B. S. and Rahimtoola, R. J. (The Paediatric Clinics ofJinnah Postgraduate Medical Centre, Karachi, Pakistan and St. Goran's Children's Hospital, Stockholm, Sweden). Drug control of streptomycin and isoniazid in malnourished children treated for tuberculosis. Acta Paediatr Scand, 66:237, 1977.—In 12 malnourished children, who were treated for tuberculosis, plasma levels of streptomycin and isoniazid were followed. Streptomycin was administered i.m. in a dose of 25–50 mg/kg/24 hours. High initial plasma levels were reached (mean: 44.3 μg/ml at 30 min). Streptomycin levels were followed for 5 hours and the mean plasma level at that time was 17.0 μg/ml. From the present data a plasma half life of streptomycin of 3.5 hours has been estimated. It is advised that streptomycin should not be given in doses above 25 mg/kg/24 hours to avoid potential toxic plasma levels especially if plasma levels cannot be measured. It is also concluded from our study that renal function is not affected in malnourished children to an extent where streptomycin clearance is greatly affected. Isoniazid was given orally, 10 mg/kg/24 hours. From 30 min to 6 hours after administration, mean plasma levels of isoniazid above 0.5 μg/ml were observed. In all children measurable plasma levels were obtained. It is concluded that also children with malnutrition can absorb isoniazid after oral administration. From our data it is suggested that the majority of the children in our study were rapid inactivators of isoniazid.

This report presents a new approach to the study of the colonization of the digestive tract after birth. We have examined the development of four microflora associated characteristics, MACs, defined as the recording of any anatomical structure, biochemical or physiological function in the macroorganism, which has been influenced by the microflora. These MACs may create a basis for later investigations into the impact of diarrheal diseases and antibiotic therapy. The following biochemical characteristics were studied in feces from children of 0-61 months of age: conversion of cholesterol to coprostanol and bilirubin to urobilins, inactivation of trypsin and degradation of mucin. These results indicate establishment of microbes capable of converting bilirubin to urobilins within the second year of life. The mucin degrading and cholesterol converting microbes are established in most of the children during the same period. Tryptic activity was found to be absent in meconium, present in feces from all children up to 21 months of age, and absent in 6 out of 15 children in the age group 46-61 months. The study indicates that the establishment of the MACs in the digestive tract is a remarkably long drawn out process

Photometric determination of alpha-amino nitrogen in peripheral venous plasma and urine from 20 healthy, full-term infants, 1--5 months of age, showing normal growth and development during an uncomplicated lactation, revealed lower plasma levels than what has been found in adults, or 3.7 +/- 1.1 mg/100 ml, and a urinary excretion of 41 +/- 14 mg/24 hours. Ion-exchange chromatography of deproteinized peripheral venous plasma showed low valine concentrations, an increased glycine/valine ratio and high cystine and very high taurine levels when compared to the levels of healthy American infants of comparable ages fed 3--3.5 g/kg of cow-milk protein. The findings indicate that a formula based on cow-milk protein should optimally contain only 1.0--1.2 g protein/100 ml provided that it is "humanized" not only with regard to the lactalbumin/casein ratio, but also to the cystine and taurine content. The pattern of the plasma concentrations of free amino acids reported in the present investigation may be used as a normal reference for breast-fed infants.

60 male infants with acute watery diarrhea and moderate dehydration--but without the complications of fever or vomiting--were treated with either the standard WHO oral rehydration salt solution or with a modified solution in which the glucose was removed and powdered rice and dried edible seeds (Dal moong) were added. The rice-Dal moong combination is a traditional weaning food in India and has been noted to decrease the stool output in children with diarrheal disease. Infants who received rice and Dal moong had a significantly lower stool output already evident at 0-6 hours than infants who received the traditional oral rehydration solution. The weight gain was also significantly greater in the group of infants who received the rice-Dal moong mixture. As a result of the lower purging rate infants who received rice and Dal moong required significantly less fluid replacement than infants who received only the oral rehydration solution. Although the mechanisms by which rice and Dal moong decrease the purging rate in diarrhea are not understood it is clear that their addition to the WHO oral rehydration solution results in a more rapid and efficient rehydration and should become a standard practice. Both ingredients are inexpensive and readily available throughout India.

During the first 6 months of life the plasma levels of branch-chained amino acids are related to the amount of protein ingested. Thus, the concentrations are lower in breast-fed infants than in artificially fed infants who are on a formula with a protein content which is about 50 per cent higher than in breast milk. At 3, 4 1/2, and 6 months of age the concentrations of valine in plasma and C-peptide in urine and the ratio between C-peptide and creatinine in urine are 2-3 times higher in artificially fed than in breast-fed infants. Plasma valine values correlate significantly with the urinary C-peptide/creatinine ratio. The enhanced insulin response induced by a cow's milk formula is related to the protein content.

Supine length has been registered longitudinally in 302 infants surviving to at least two years of age in an urban area of Lahore, Pakistan. According to the "ICP-growth model", normal linear growth can be represented during this age period by a combination of a sharply decelerating Infancy component with the addition of a slowly decelerating Childhood component, the latter acting from the second half of the first postnatal year. Between birth and 24 months of age the Pakistani children grew about 7.5 cm less than expected according to the Swedish standard. The difference in the gain was mainly related to the late onset of the Childhood component found in 56% of the infants. The onset of the Childhood component in the Pakistani children occurred on an average some 5 months later than in the Swedish controls, which explains the age-dependent reduction in the gain at about 1 year of age. Children with late onset showed no "catch-up growth" during the observation period after the onset. This might very well indicate the functional implications of stunted height in populations of developing countries.

Intestinal permeability was assessed with different-sized polyethylene glycols (PEG 400 and PEG 1,000) in small children with acute diarrhea. All children with acute diarrhea absorbed and excreted less PEG of all molecular sizes into the urine when compared with healthy control children (p less than 0.001). Children with acute rotavirus infection excreted significantly less PEG of all sizes than children with Shigella, Salmonella, and enteropathogenic Escherichia coli (EPEC) infection (p less than 0.001-0.01), suggesting a more severe mucosal lesion caused by rotavirus. In patients with severe malnutrition there was also a significant decrease in absorption of PEGs observed. In addition, malnourished patients with rotavirus diarrhea showed a pronounced decrease of PEGs in comparison with well-nourished patients. The ratio between the recovery of a large PEG molecule, 1,074 Da, and a small molecule, 370 Da, was utilized to assess the absorption of large molecules in relation to that of smaller ones. On applying this ratio, it was noted that the intestine in children with Shigella and EPEC infection was relatively more permeable to larger molecules than in healthy controls, while in rotavirus and Salmonella infection it was less permeable to larger molecules. In this study significant differences in the permeability characteristics were observed, suggesting etiology-specific effects on the mucosal barrier.

Summary The plasma aminograms of mother's and cord vein plasma during delivery were studied in selected cases from a lower socio-economi-cal group in West Pakistan with a high incidence of intrauterine growth retardation of the foetus. There was a highly significant increase in the levels of the non-essential amino acids glycine and ornithine in the mother's plasma and of glycine and proline in cord plasma. The plasma glycine/valine quotient was significantly increased in maternal as well as in cord plasma. It is suggested that the plasma glycine/valine quotient may serve as an index of subclinical protein undernutrition (low intake of dietary nitrogen) of mother and foetus and thus become a tool in the investigation of the immediate and late effects of this condition during pregnancy in human populations. The maternal quotient is not changed by short gestation or hypertensive disorder during pregnancy.

In two subjects with hereditary tyrosinemia attacks of severe pains in the abdomen and legs and pareses of peripheral type have been observed. The similarity of these attacks with the crises seen in acute intermittent porphyria prompted us to measure the excretion of δ-aminolevulinic acid, porphobilinogen and porphyrins in these patients and in 4 other patients with hereditary tyrosinemia. The urinary excretion of δ-aminolevulinic acid was from 10 to 250 mg per g of creatinine, i.e., up to a 100-fold increase above the normal range. The excretion of porphobilinogen and porphyrins fell within the normal ranges or was only slightly elevated.

Summary The clinical and biochemical features of a case of methylmalonic acidemia, a newly described inborn error of metabolism, are reported. The cardinal feature was chronic metabolic acidosis which was controlled by restriction of the protein intake. Periodically, exacerbations with vomiting, dehydration, lethargy, coma, and even peripheral circulatory failure have appeared. The crisis have been induced by trivial acute infections and by overloading with protein. Mild symptoms appeared in the neonatal period, crises after an age of 4 months. When the protein intake was high, there was marked muscular hypotonia, developmental retardation, and neutropenia. When acidosis was controlled by protein restriction and treatment with bicarbonate the baby made marked progress. At 23/12 years of age the development was normal. The patient excreted large amounts of methylmalonic acid in the urine and the blood level was elevated. Other biochemical abnormalities were hyperglycinemia, hyperglycinuria, and hyperlactatemia. The hypothesis that the basic metabolic defect in methylmalonic acidemia and the ketotic type of hyperglycinemia is the same is discussed, as are the similarities between methylmalonic acidemia and infantile lactic acidosis.

An increased glycine/valine ratio in the maternal and cord vein plasma was observed in under-privileged women and their newborn babies in Ethiopia. There was a delay in the decrease of branch-chained amino acids during the immediate neonatal period. These findings indicate malnutrition in utero and are identical with those of a previous study in an under-privileged group in Pakistan. A reduced cord/maternal ratio of tyrosine and methionine was found in the Ethiopian material, indicating placental dysfunction of unknown origin.

We have examined the effect of high protein intake on kidney growth and function in growing rats. The rats were kept on an isocaloric diet containing 12%, 21% and 50% protein, from weaning (16 days) until the time of investigation (18, 20, 24,40 or 80 days). There was no significant difference between the 12% and 21% protein groups in any of the parameters studied. 50% protein increased body weight (BW) and kidney weight (KW). The increase in kidney weight was already evident after 2 days and exeeded the increase in body weight in all age groups. At 24 days renal cortical DNA and the protein/DNA ratio were significantly increased in the 50% protein group. At 40 days the cortical DNA content, but not the protein/DNA ratio, was significantly increased in the 50% group. The glomerular filtration rate (GFR) was studied at 40 days. Total GFR as well as GFR/BW was significantly higher in the 50% group than in the 21% group. In one protocol the diet was discontinued at age 40 days and the rats were studied at age 80 days. In these rats all parameters of renal size and function were the same as in the rats that had had a normal (21%) protein intake from weaning. We conclude that in young rats high protein intake reversibly increases GFR out of proportion to BW and selectively and reversibly stimulates kidney growth by stimulating cell proliferation.

Cerebral blood flow (CBF) and cerebral av-differences of oxygen and circulating substrates were measured in normocapnic infants during general anaesthesia before elective surgery in order to study possible age-dependent variations. CBF was determined by a minor modification of the Kety-Schmidt technique from desaturation curves of nitrous oxide (N2O) in arterial and cerebral venous blood (N2O analysed by gas chromatography on 15 mul blood samples) after reduction of inhaled N2O from 75 to 50%. The reproducibility was +/-4.6%. Lactate, pyruvate and oxygen were determined in whole blood and amino acids in plasma by ion-exchange chromatography. Reliable av-differences of glucose, acetoacetate and D-beta-hydroxybutyrate could be calculated from plasma values and hematocrits. Mean values from 12 infants (age 11 days-12 months) were: CBF 69 ml/100 g0min-1; cerebral uptake (in mumoles/100 g-min-1): oxygen 104, glucose 27, acetoacetate 0.9, D-beta-hydroxybutyrate 2.3; cerebral release: lactate 2.4 and pyruvate 0.8. Significant uptake of amino acids was found only for histidine 0.95 and arginine 0.7. Significant correlations between arterial concentration and cerebral exchange were found for: ornithine, arginine, phenylalanine, aspartic acid, serine, glutamine and acetoacetate. CBF and substrate exchange were unrelated to age within the group. Infants had higher mean CBF and greater uptake of ketone bodies than has been reported in adults.

Pooled breast milk was ultra-filtrated and freeze-dried to give a product with a protein content of 60 g/100 g powder. More than half of the secretory IgA activity against E. coli O antigen was preserved. This concentrated protein was added to the mother's fresh milk providing a protein supply of 3.0-3.5 g/kg/24 hours in four VLBW infants, at a calorie supply of 110 kcal/kg/24 hours. Growth followed the intrauterine rate. Free amino acid levels, acid-base balance and urea concentrations of peripheral whole blood indicated tolerance of the increased supply of human milk protein.

Insulin (0.1 IW/kg) later followed by glucose was injected intravenously in nine diabetic women in the supine position both during pregnancy and one year post partum. C-peptide was present in five subjects, indicating some residual beta-cell function. Their mean basal C-peptide level, before insulin, was twice as high in the pregnant as inthe non-pregnant state. C-peptide decreased progressively after insulin. The mean basal plasma glucose level was lower during pregnancy (4.8 mmol/l) than after it (9.6 mmol/l), but decreased to the same level (2.2 mmol/l) after insulin. The rate of fall in glucose was thus lower during pregnancy (kt = 2.54) than after (kt = 4.08), but was unrelated to the basal glucose levels. Basal levels of free fatty acids (FFA), 3-hydroxybutyrate (3-HB), cyclic AMP, and lactate were similar, while glycerol was lower during pregnancy. Insulin-induced changes in FFA, glycerol, 3-HB, cyclic AMP, and lactate were similar during and after pregnancy. Plasma amino acid concentrations were generally lower in pregnancy, significantly so only for arginine and glycine. Amino acid levels were unaffected by insulin in pregnancy, whereas leucine, isoleucine and tyrosine decreased significantly in the non-pregnancy, whereas leucine, isoleucine and tyrosine decreased significantly in the non-pregnancy, whereas leucine, isoleucine and tyrosine decreased significantly in the non-pregnancy state. We conclude that there are differences in metabolic responses to insulin in diabetic women during and after pregnancy, indicating a decreased sensitivity to insulin during pregnancy in some tissues.

The occurrence of specific antibodies to Vibrio cholerae lipopolysaccharide in serum, milk, and saliva of Pakistani women from a very low socioeconomic group was studied before and after a single subcutaneous cholera vaccination. Before immunization all women had low levels of specific antibodies in serum, primarily of IgM class, and in many cases cholera IgA angibodies were found in milk and saliva as well, indicating earlier natural exposure. The vaccination consistently induced a marked rise in serum antibody titer, and notably also produced significant titer increases in 70% of the milk and in 45% of the saliva samples. Whereas the serum antibodies induced were predominantly of the IgG class, secretory IgA was responsible for most of the titer increase in the secretions. The results indicate that parenteral cholera vaccination can boost local secretory IgA antibody responses in intestinally primed individuals.

One of the anti-infection principles of maternal milk is the predominant milk immunoglobulin, secretory IgA. This immunoglobulin contains antibodies against many pathogens and potential pathogens, viruses as well as bacteria, including several members of Enterobacteriacae. The antigenic stimuli for these milk antibodies seem to take place in the Peyer's patches of the intestine. Lymphoid cells leaving the patches after antigenic exposure seem to home to the mammary glands via the lymph and blood circulation. As a result, the milk contains secretory IgA antibodies against, among other things, the intestinal bacteria of the mother. These milk antibodies might reflect the spectrum of bacteria and viruses in the community and may be important for the protection of the breast-fed baby. Via the same homing mechanism the maternal milk obtains antibodies against dietary antigens, including cow's milk proteins. Studies of infants on mixed feeding suggest that the secretory IgA antibodies against the bovine proteins diminish the antigenic exposure, indicating the possibility of an anti-allergic mechanism.It has been discovered through various studies that human milk protects infants against infections. 1 of the antiinfection elements of maternal milk is the main milk immunoglobin, secretory IgA, which contains antibodies against many pathogens and potential pathogens, viral as well as bacterial. The antigenic stimuli for these milk antibodies seem to occur in the Peyer's patches of the intestine. Lymphoid cells which leave the patches after antigenic exposure seem to home to the mammary glands through the lymph and blood circulatory systems. It, thus, results that the milk contains secretory IgA antibodies against the intestinal bacteria of the mother, as well as other substances. The mechanism for production and the mode of function of the secretory IgA is explained in detail and diagrammed. Subcutaneous vaccination with a cholera vaccine has been shown to induce an increase in SIgA antibodies in milk and saliva. Breast-feeding, it is believed, largely eliminates possible allergens and provides antibodies to protect against the allergens of mixed feeding.

We have examined the control of serum sodium concentration (S-Na) in 60 male infants with acute diarrheal disease, moderate dehydration, but without the presence of fever, vomiting or other conditions. The infants were studied on admission and during oral rehydration therapy (ORT). We examined the effect of rapid reduction of the purging rate on the control of S-Na by adding pulverized rice and pulses (dal moong) to the rehydration solution. On admission S-Na was significantly inversely related to age. This correlation could not only be attributed to difference in stool sodium losses. Changes in S-Na and urinary K/Na ratio during oral rehydration therapy (ORT), were analyzed seperately in infants below and above 4 month of age. During the first six hours of ORT, there was an increase in S-Na in all groups. During the following 18 hours, S-Na tended to normalize around 138 mmol/1. Normalization occrred faster if purging rate was reduced. In all groups urinary K/Na ratio (index of aldosterone production and, inversely, of sodium balance), was high at admission and fell during ORT. In the youngest infants (below 4 month of age) the fall was significantly more pronounced if the purging was reduced. We conclude that it is important to consider age when prescribing ORT. The capacity to correct distrubances in S-Na becomes more efficient during maintenance stage of ORT. Correction of S-Na and sodium balance is enhanced by rapid reduction of abnormal intestinal losses.

Human milk is rich in secretory IgA (SIgA) antibodies, many of which are directed against food vroteins and antigens of microorganisms found in the intestine(1,2,3). The appearance of these milk antibodies against antigens from the intestinal content is explained by the enteromammaric link: antigenic exposure of the Peyer’s patches leads to homing of cells committed to IgA sunthesis to various exocrine glands, including the mammary gland (4,5). In addition there may be a selective transfer via serum or IgA dimer-J chain complexes that are taken up by secretory component (SC). The SC which is produced in epithelial cells in exocrine glands functions as a receptor on the cell membrane of these epithelial cells. SIgA is formed by the binding of IgA-J to the SC and is transferred into the exocrine secretion. At least in mice this serum transfer may provide a substantial portion of the milk SIgA(6 Halsey personal communication). Presumably the serum IgA dimers originate from the extensive production of IgA in the intestinal lamina propria.