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Summary Two infants with leucine-sensitive hypoglycemia have been studied to elucidate the specificity and mechanism of action of l -leucine. Sixteen other naturally occurring l -amino acids have been administered intravenously and tyrosine and tryptophan by gavage. Of these amino acids, only l -leucine consistently induced hypoglycemia. d -leucine also produced hypoglycemia when given intravenously. Alpha-ketoisocaproic and isovaleric acids were administered intravenously; the former induced hypoglycemia whereas the latter did not. Monocarboxylic keto-acids in the urine were measured following l -leucine or alphaketoisocaproic acid loading. The recovery of keto-acids in the urine was of a low order, similar to that of a control subject indicating no metabolic defect in the conversion of alpha-ketoisocaproic acid to isovaleric acid. Preliminary evidence is presented that leucine administration to affected patients results in increased circulating insulin levels.

Methylmalonic acidemia and ketotic glycinemia are clinically indistinguishable. Both disorders if untreated are characterized by vomiting, lethargy, failure to thrive, hepatomegaly, ketoacidosis, osteoporosis, neutropenia, and thrombocytopenia. Biochemically, however, they are distinct entities. Glycinemia patients do not excrete methylmalonate, whereas in methylmalonic acidemia massive urinary methylamalonate is an essential finding. Some patients with methylmalonic acidemia are responsive to massive doses of vitamin B 12 .

The administration of l -leucine to leucine-sensitive children produces profound hypoglycemia. The effect of l -leucine on the blood glucose concentration of normal individuals has been studied. A small but definite effect has been found which suggests that a homeostatic relationship between the amino acid and insulin exists. This relationship is abnormal in the children with leucine-sensitive hypoglycemia.

Two algorithms are provided which define two new ways of averaging waveforms. The representative average maintains shape, has average d.c. offset, average amplitude and average position of noise-free input signals whose onset varies in time after a trigger pulse. The synchronous average removes random bipolar noise, the amplitude of which is below a critical threshhold, from a randomly occuring waveform. The latter does not require a trigger pulse, maintains its shape, has an average d.c. offset and average amplitude. Its position in the output field is such that the centroid of the waveform is placed in the center of the field. Both methods involve the definition of average phase angle and a quantity called the angular standard deviation.

Summary A case of histidinemia is described in which the biochemical abnormality can be attributed to a deficiency of the enzyme histidase. As a result of this deficiency, plasma and urinary levels of histidine are markedly elevated. Imidazolepyruvic, imidazolelactic, and imidazoleacetic acids are excreted in the urine in excessive amounts. The presence of imidazolepyruvic acid in the urine is responsible for a positive test with ferric chloride similar to that due to phenylpyruvic acid found in the urine of patients with phenylketonuria. The possibility of a deficiency of urocanase was ruled out by the demonstration of considerable amounts of formiminoglutamic acid in the urine of the patient following administration of urocanic acid.

Extract: Thirty 133Xe determinations of renal blood flow were made in 20 children ranging in age from 16/12 to 10 9/12 years. In six normal kidneys average blood flows to the outer and inner cortex were 374 and 44 ml/min/100 g, respectively. Mean fractional flows to these areas were 84 and 15 ml/min/100 g, respectively. In nine children with congenital heart disease (CHD) who were not in congestive heart failure and who were evaluated before angiography, a defect in outer cortical flow was demonstrated. Average blood flows to the outer and inner cortex were 250 ml/min/100 g (P 0.0005) and 27 ml/min/100 g (P 0.22). Mean fractional flows were 76% (P 0.03) and 24% (P 0.015), respectively. After cardiac angiography, a decrease in outer conical flow occurred. The second flow study was performed 8–30 min after injection of contrast media (Hypaque-M, 75%) in amounts which ranged from 1.2 to 3.5 ml/kg body wt. After angiography, blood flows to the outer and inner cortex were 186 ml/min/100 g (P 0.001) and 24.5 ml/min/100 g (P 0.68). Average fractional flow to the outer, 74% and inner, 26% cortex, did not change (P 0.71). Speculation: Kidneys of children with CHD have decreased outer cortical flow, which may result in increased renal renin production. Therefore, a child with CHD may suffer the long term consequences of hyperreninemia. Furthermore, the balance of any metabolic system whose metabolic pathways involve the outer cortex may be altered and hemodynamic response to stressful clinical situations may be greater in the kidneys of children.

Techniques for the study of the EEG have been developed, techniques that are capable either of averaging noise or of improving the signal to noise ratio in the absence of any triggering or synchronizing pulse. These techniques show that electroencephalograms of the type ordinarily encountered in clinical work (except for EEGs during clinical seizures which have not yet been analyzed) are apparently composed of only pseudo-random noise. The results are further support of the claim that no signal wave form with features distinct from those of random noise is present in the EEG.

The clinical course, biochemical abnormalities, and the effects of vitamin therapy in subacute necrotizing encephalomyelopathy are described in a patient who was serially evaluated from birth. Important features include increased cerebrospinal protein, elevated blood lactic acid values, and abnormal macular morphology detected when the patient was asymptomatic. Renal tubular acidosis and alaninemia were noted shortly after the onset of symptoms. No clinical improvement was noted with pharmacologic doses of biotin, thiamine (hydrochloride or propyldisulfide), or lipoic acid. Hepatic pyruvate carboxylase was within the range of control values early in the disease but was negligible in postmortem material. The clinical and biochemical course suggests that low levels of hepatic pyruvate carboxylase in postmortem material were secondary effects of an otherwise as yet unknown biochemical process. Decreased cerebral pyruvate carboxylase activity at autopsy was documented for the first time.

Metabolic balance studies were performed on 5 infants with cystic fibrosis of thepancreas. One of the subjects had hypoproteinemia and intermittent edema. Large quantities of nitrogen were excreted in the stools when the infants received a soybean formula. This was most marked in the hypoproteinemic patient and was considered to be the pathogenetic explanation of his hypoproteinemia. Nitrogen retention was significantly higher when the infants received an evaporated cow's milk formula. A paracreatic enzyme preparation led to significant increase in nitrogen retention when added to soybean feedings but not when added to evaporated cow's milk feedings. It is recommended that infants with cystic fibrosis of the pancreas should not be fed soybean milk preparations.

IN the course of other investigations1 in which tyrosine was injected intraperitoneally it was noted that the level of phenylalanine hydroxylase in the liver of rats was diminished to about one-third the normal value. Since tyrosine added in vitro does not inhibit this enzyme activity2, the results were taken as evidence of product inhibition of enzyme synthesis. It was reasoned that added dietary tyrosine would decrease the enzyme formation and therefore lower the amount of phenylalanine being oxidized to tyrosine; the excess phenylalanine would then be transaminated to phenylpyruvate. Other workers3 had already shown that phenylalanine added to liver slices would also inhibit the oxidation of tyrosine to acetoacetate and fumarate. It seemed worth while therefore to feed various combinations of tyrosine and phenylalanine in order to evaluate metabolic alterations in the rat. Initial experiments with Commercial rat food plus 5 per cent L-tyrosine and 5 per cent DL-phenylalanine resulted in the death of newborn or suckling animals when this diet was fed to the pre-parturient and lactating mothers. The same diet caused death when fed to 21-day-old animals, although animals of the same age grew normally when fed 5 per cent of either amino-acid alone. Reduction of the levels to 2.5 per cent of each amino-acid (and in a later experiment to 3.75 per cent each) caused no difficulty since animals fed this diet gained weight at a rate comparable to that of rats on the commercial diet alone. The methods used for the amino-acid analyses and for enzyme assays have been previously listed1. The urinary and blood data are given in Table 1, and the enzymatic data concerned with phenylalanine and tyrosine metabolism are given in Table 2.

Summary The biochemical findings in blood and urine are presented in a child who failed to thrive in the first month of life and in whom the enzyme system which converts p-hydroxyphenylpyruvic acid to homogentisic acid did not mature until 2 months of age. Spontaneous correction of this abnormality of tyrosine metabolism was followed by dramatic changes in the patient's biochemical status.

The administration of 3-amino-1,2,4-triazole to rats inhibited the hepatic porphyrin-containing enzymes tryptophan peroxidase-oxidase and catalase. The effect of 3-amino-1,2,4-triazole on tryptophan peroxidase-oxidase was shown to be due to decreased synthesis of the enzyme and not due to inhibition of a given amount of enzyme. This action on tryptophan peroxidase-oxidase is presumably due to the inhibition by 3-amino-1,2,4-triazole on one of the enzymes involved in porphyrin synthesis.

— The effect of phenylalanine and phenylpyruvate on the metabolism of pyruvate by homogenates of human brain was investigated. In the presence of 5 mM pyruvate as substrate homogenates of human cerebral cortex fixed about 1 μmol of H14CO3-- per g of tissue in 30 min. Phenylpyruvate at a concentration of 5 raw inhibited the fixation of H14 CO3-- by homogenates of human brain by approximately 50 per cent, whereas 5 mM phenylalanine had no effect. The inhibition of pyruvate carboxylation by phenylpyruvate was dependent upon the concentration of the inhibitor. The activity of pyruvate carboxylase (EC 6.4.1.1) in human cerebral cortex was 02–0.4 units, with a Km for pyruvate of about 0.2 mM. Homogenates of human cerebral cortex decarboxylated [1-14C]pyruvate to 14CO2 at a rate of about 5 μmol per g of tissue per 15 min, with a 20–50 per cent reduction in the presence of 5 mM phenylpyruvate; phenylalanine at the same concentration had no effect. The possible toxic effect of phenylpyruvate on the metabolism of pyruvate in the brains of untreated phenylketonuric patients is discussed.

SINCE the original description of leucine-induced hypoglycaemia in 19561, much interest has been aroused concerning the mechanism by which the administration or ingestion of L-leucine or leueine-containing proteins produces a profound lowering of blood sugar-levels in susceptible individuals. Our previous experiences with two leucine-sensitive children have been reported in detail elsewhere2,3; the present communication deals with new and pertinent observations.

Serial serum zinc (Zn) concentrations were measured from birth to a mean age of 16 weeks in 17 well, AGA, singleton, premature infants (mean GA=30 wks., mean B.W.=1253gms.) and compared to serum Zn concentrations in 4 sets of premature twins (mean GA=30 wks., mean individual B.W.=1104gms.) who were followed to a mean age of 18 weeks. All infants were fed standard infant formulas. Average weekly daily weight gain, linear growth, caloric, protein, and Zn intake were not significantly different between the two groups. Serum Zn concentrations measured in the first 72 hrs. of life averaged 170μg/dl in the singleton infants and 144μg/dl in the twins (p=.3). Hypozincemia (serum Zn

Psychogenic water drinking has been reported only in older children and adults. We shall report successful management of three young children with psychogenic water drinking. One infant, 2½ mo. old was extremely irritable unless the oral fluid intake ranged from 1200-2100 ml/day. Urine Osm. was 42 mOsm/L and serum Osm. was 272 mOsm/L. Urine output was 1705 ml/day. Serum Na was 132 mEq/L;serum K 5.2 mEq/L;BUN 8 mg%;serum Ca 10.5 mg% and 24 hr. Ca excretion less than 3 mg/kg/24 hr. During the water loading portion of a modified Carter Robbin's Test, CH2O was +10.9 ml/min/1.73m2. CH2O fell to -0.37 ml/min/1.73m2 when 3% NaCl was infused. A 6 mo. old and a 2½ yr. old had polydipsia and polyuria without dehydration and were able, after overnight water deprivation,to concentrate their urines. An abnormal maternal child relationship in two patients, and a prescribed fluid diet in the third had led to excessive water ingestion through inappropriate maternal responses. Appropriate psychological advice coupled with restriction of fluid to estimated insensible water loss plus 25-35% of expected normal urine output resulted in a “cure” in all patients within 6 weeks. In summary: Psychogenic water drinking in the very young appears to be a real entity and responds to parental counseling along with carefully monitored water restriction. Supported in part by NIH grant RR-75, RR-5624.

Serum zinc (Zn), copper (Cu), and 24 hour urine collections for Zn, Cu, and amino acid excretion were measured in 12 primarily intravenously nourished premature infants (mean GA=30.6 wks., mean birth wt=1067gms.). Five infants had two or more serial measurements. All infants were clinically stable, non post-op, and not infected at times of study. Mean age at time of first study = 3.3 wks. Serum Zn and 24 hr. urinary Zn excretion were positively correlated (r=.74 p

Serial serum zinc (Zn) and copper (Cu) concentrations were measured in 4 intravenously fed, non-Zn, non-Cu supplemented premature infants all of whom had culture proven bacterial septicemia in the 3rd to 4th weeks of life. (Mean G.A. = 28.7 wks., mean birth wt.=1115gms.). Mean serum Zn and Cu concentrations in the infected group were compared to 9 non-Zn and non-Cu supplemented, age matched, IV nourished controls. The data suggests that the premature infant, similar to the adult, (J Infect Dis 126:77, 1977), is capable of sequesting Zn as a host response to infection from early in gestation. Serum Zn concentrations may be helpful in monitoring onset of infection and adequacy of antibiotic therapy in the newborn. No statistically significant changes in Cu in response to infection were seen.

Renal blood flow has been measured in children of age 1½ to 16 years, by injecting 133Xe into the renal artery at the time of aortography or surgery. The rate of washout of radioactivity was monitored on magnetic tape and the resultant data analyzed by graphic analysis using a semi-automatic method of plotting and computing the rates and fraction of blood flow perfusing the outer and inner cortical regions of the kidney. The number, type, and results of the studies follows: 1) In 8 normal kidneys, RBF's were similar to adult values. 2) In 53 studies of RBF in children with congenital heart disease, RBF's were reduced in both cyanotic and acyanotic heart disease, were further reduced when heart failure was present (8 patients) and fell after angiography (19 patients). 3) Following renal biopsy drops in RBF may occur in intact kidneys, but not in the transplanted kidney (4 patients). 4)In chronic renal disease outer cortical blood flow is diminished. 5) 31 measurements of RBF in donor kidneys upon insertion and/or following transplantation suggest that this technique may have some value in predicting both the immediate and subsequent function of the graft. 6)In 5 patients with renal vascular hypertension, 133Xe measurements of RBF were helpful in determining secretory rates of renin in both kidneys. Supported NIH grants RR-75, RR-5624 and HE-12651.

Serial serum copper (Cu) and ceruloplasmin (Cerlp) concentrations were followed for an average of 14 weeks in 25 well, growing AGA premature infants (mean GA=30 wks., mean B.W.=1181gms.) fed standard infant formulas. Serum Cu and Cerlp, low at birth, gradually increased over the first 5 months of life. No relationship between Cu intake (μg/kg) and serum Cu concentrations was seen as serum Cu was lowest when intake was highest. The ratio of Cerlp/Cu was constant (x=.28) except for the first 72hrs. of life when the ratio was significantly lower (p=.00007). The data suggests: 1. serum Cu is controlled by factors other than dietary intake; 2. Cerlp production relative to serum Cu increases significantly over the first week of life; 3. Changes in serum Cu are paralleled by proportional changes in Cerlp after the first 72 hrs. of life.

The renal mechanisms involved in sustaining hypertension were evaluated in 7 children ages 5-11 with coarctation. IRBFD was determined following renal artery injections of 133Xe which measures rates of flow and the fraction of total renal blood flow to the outer cortical (OC) nephrons in which renin is produced. RRSR was calculated by multiplying OC flow by the renal venous minus arterial difference in immunoreactive plasma renin activity (PRA). When measurements were made in both kidneys (4 children), results between the kidneys were averaged. when compared to data obtained in 8 normal kidneys the following was found in the 7 children with coarctation and 5 patients with L-R shunts. OC flow was reduced in children with shunts or coarctation (p < 0.01). Fractional flow to the OC was reduced only in children with shunt lesions (p

Peritoneal dialysis was performed in 7 uremic children (4 months to 18 years). Rates of diffusion of Na, K, Cl, PO4, urea, creatinine, and uric acid were similar to adult diffusion curves. With the exception of uric acid diffusion, no age related differences were found. Peritoneal urea and creatinine clearnces paralleled the rate of exchage of dialysis fluid. Actual urea clearance values were within the range of clearance values obtained in adults dialysed at similar rates. Data to compare creatinine clearances in adults to children is not avialble over the range of dialysis volumes utilized in their studies. Estimation of urea production based on the average daily rise in BUN revealed similar production rates per kg body weight in all ages. These studies demonstrate no intrinsic age-related differences in the kinetics of peritoneal dialysis. Thus, there is no necessity to correct peritoneal clearances to cither 70 kg body weight or 1.73 M2, in order to compare children to adults. The greater ‘efficiency’ of peritoneal dialysis in children can be ascribed to a smaller body pool size in children relative to adults. Therefore, at a give clearance rate, the amount of material in the pool diminishes at a faster rate in children than in adults. Moreover, since peritoneal clearance increases as the rate of dialysis increases, no single clearance value for a given individual exists but rather a family of values related to the rate of dialysis. (Supported in part by NIH grants RR-5624. HD-2870 and FR-75.)