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SUMMARY In an infant monkey, prolonged phenylalanine loading has been shown to produce a quantitative deficiency in cerebral cerebroside and in cerebral free amino-acid distribution. RESUME Ľeffet d'une charge prolongee en phenylalanine sur le contenu en amino-acide lihre el on lipide du cerveau du bebe singe Chez le bebe singe on a montre qu'une charge prolongee en phenylalanine provoque une deficience quantitative du cerebroside cerebral et de la distribution de Ľamino-acide libre cerebral. ZUSAMMENFASSUNG Die Wirkung verlangerter Phenylalanin-Ladung auf freie Aminosaure und lipiden Inhalt des Affensaugling-Gehirnes Bei einem Affensaugling erwies sich, dass verlangerte Phenylalanin-Ladung einen quantitativen Mangel an zerebralem Zerebrosid und in der zerebralen freien Aminosaure-Verteilung produzierte. RESUMEN Los resultados de una carga prolongada defenilalanina en el contenido de amino-acidos lihres y de lipidos en el cerebro del mono infante Se ha mostrado que en un mono infante una carga prolongada de fenilalanina ha resultado en una deficiencia cuantitativa de cerebrosido cerebral y de la distribucion de amino-acidos cerebrales libres.

It is not known whether early immunosuppresive treatment can preserve long-term endogenous insulin secretion in subjects with insulin-dependent diabetes mellitus. In the present study, clinical remissions during the first year and C-peptide production for 3 years were followed after 43 subjects with newly diagnosed insulin-dependent diabetes mellitus were randomly assigned to a cyclosporine A treatment group for 4 months or to a control group. Of the six cyclosporine A-treated subjects who had remissions, five were 19 years of age or younger, compared with two of the four in the control group. C-peptide production was present in 98% of all subjects after 4 months, in 88% after 1 year, and in 43% after 3 years. There were no significant differences in numbers of subjects with C-peptide production or in mean hemoglobin A1 levels, between cyclosporine A-treated and control subjects after 3 years. Cyclosporine A treatment of subjects with newly diagnosed insulin-dependent diabetes mellitus for a period of 4 months does not have the ability to preserve residual β-cell function.

Various agents have been tried in subjects with newly diagnosed Type 1 (insulin-dependent) diabetes mellitus in an attempt to preserve Beta-cell function. In this double-blind study, nicotinamide or placebo were given for one year to 35 children and adolescents with newly-diagnosed Type 1 diabetes. All subjects were within six weeks of diagnosis and were between the ages of 6 and 18 years. Nicotinamide, a poly-(ADP-ribose) synthetase inhibitor, was given in a dose of 100 mg/year of age up to a maximum of 1.5 g/day. There were no initial differences between the 17 control and the 18 test subjects in relation to mean age, sex distribution, or severity at onset. Mean insulin dosages and HbA1 values were similar for the two groups during the year of study. Fasting and glucagon-stimulated C-peptide levels were similar for the control and nicotinamide treated groups at the beginning and after 4 and 12 months. There were no differences in remission rates between the two groups. Nicotinamide, at this dosage, does not preserve residual insulin secretion in subjects with newly diagnosed Type 1 diabetes.

To increase knowledge on the predictability of the onset of insulin-dependent diabetes mellitus (IDDM; type I), we followed 38 subjects less than 18 years of age who had positive results on two or more islet-cell antibody tests and one identical twin who had positive results on one islet-cell antibody test. All 39 patients had longitudinal intravenous glucose tolerance tests to determine the first-phase insulin response (FPIR). Insulin dependence has developed in 10 untreated subjects less than 18 years of age. Of the 10 subjects, insulin dependence developed in eight a mean of 4.6 months after their FPIR fell to less than 30 microU/ml and a mean of 14 months after it fell to less than 46 microU/ml. Nine of the untreated subjects had an FPIR less than 67 microU/ml on at least two occasions and became insulin dependent a mean of 19 months after the value first fell below this level (95% confidence limit = 66.4% to 100%). All but one of the 10 subjects in whom IDDM developed initially had islet-cell antibody levels of greater than 80 JDF units. Insulin autoantibody values at onset were available for 9 of the 10 subjects and were positive (greater than 39 nU/ml) in six. We conclude that the combination of positive results on two islet-cell antibody tests and two diminished FPIRs (less than 67 microU/ml) in subjects less than 18 years of age reliably predicts the onset of IDDM. These data should permit intervention studies to be planned.

Kwashiorkor, with typical edema and skin rash is occasionally seen in affluent countries as a result of severe protein restriction. Treatment is with a lactose-free formula after rehydration and sometimes after a period of parenteral alimentation. Complications of therapy included: diarrhea, congestive heart failure, infections, a bleeding tendency, and seizures. Two of the 14 children in this series died.

Although human milk is the optimum form of nourishment for young infants, cows' milk is a valuable substitute and a useful food for older infants and young children. It supplies a large proportion of essential nutrients and calories but it is not an essential component of the diet for anyone whose diet is otherwise adequate. Milk should be eliminated from the diets of children with the rare congenital (hereditary) form of lactase deficiency, those with galactosemia, and those with convincing evidence of milk allergy. Temporary elimination of milk may be beneficial in children with transient lactase deficiency associated with various gastrointestinal disorders. Important racial and age differences in lactase activity are recognized, but our understanding of the etiology and clinical significance of these differences is incomplete. Thus, no firm conclusions can be drawn as yet about the relevance of such differences to the planning of nutritional rehabilitation programs for developing countries and poverty groups, especially in that comparable sources of protein, calories, and other nutrients may not be readily available. The use of skimmed milk is recommended for the approximately one in 150 children born with hereditary hypercholesterolemia as one of the dietary procedures required to lower the blood cholesterol in an attempt to delay the onset and reduce the severity of premature atherosclerosis. Evidence available to date does not support the use of skimmed milk in the child population at large, and such a measure might diminish already inadequate calorie intake in some groups. In infants and young children, the use of skimmed milk may provide an excess of protein and minerals in relation to calories. The amount of milk that should be consumed by healthy older infants and children cannot be stated with convincing accuracy, partly because this will depend to a large extent on economic factors and on the availability of other foods. When a mixed diet is available in adequate quantities, milk consumption should probably not exceed one third of the total daily calorie intake after the latter part of the first year of life (two or three glasses per day). The evidence available at present is insufficient to warrant discouraging programs for increasing the supply and consumption of milk in developing countries where childhood malnutrition is rife, particularly since nutritionally and economically suitable alternatives may not be available in such countries. The distributor of milk under these circumstances should be accompanied by instruction in preparation for feeding to reduce bacterial contamination. If the position stated with regard to some of these issues appears equivocal, it is because the Committee believes that the sum of pertinent, current knowledge does not permit a more dogmatic position. As additional information becomes available, the Committee will review the situation and stands ready to revise its opinions.

A sufficient variety of semisynthetic dietary products is now available to permit control of amino acid imbalance in several inborn errors of metabolism. However, they must be used carefully, and their effects monitored closely. Continuing development of products for this type of special diet—to provide a wider variety—is necessary. Regionalization of treatment programs for patients with inborn errors of metabolism is recommended. Metabolic centers which are accumulating experience and have good laboratory support may be the most efficient way of providing adequate treatment for patients with inborn errors of metabolism.

This statement proposes recommendations toward increasing the practice of breast feeding. Specific recommendations made for standards of infant formulas as to calorie, protein, fat, vitamin, and mineral levels apply to both milk-based and milk-substitute infant formulas. Such formulas, when used in place of breast-feeding, must supply most or all of the nutrients infants require during the first weeks or months of life. The minimum levels of nutrients per 100 kcal recommended for formulas provide good growth and development in healthy, full-term infants; distinct hazards may be encountered at levels below these. However, no significant advantage is to be gained by providing levels in excess of these minima in normal infants. Recommendations for maximum levels are made only where quantities in excess lead to toxicity; generally, levels near the minima recommended are most desirable because they are the most likely to reflect the composition of human milk, and the least likely to result in any undesirable nutrient to nutrient interaction. The recommendations also can be used as reference standards for formulas for special dietary uses of "medical" formulas. The Committee recommends that "medical" formulas be classified by FDA into a special group under the paragraph dealing with infant formulas.

Approximately 20% of children in this country are at risk of developing hypertension as adults. The factors that will induce hypertension are genetic, which cannot be modified, and environmental, which can be modified. Genetic factors assist in identifying the population at risk, i.e., family history of hypertension, myocardial infarction, stroke, or renal disease. The population with a negative family history is less at risk. The role of salt intake as an environmental factor in the induction of hypertension has still to be defined. For 80% of the population in this country, present salt intake has not been demonstrated to be harmful, i.e., hypertension has not developed. Salt intake is likely to be only one of the contributing factors for those whose genetic makeup predisposes them to hypertension. Salt appetite for some is an important expression of personal preference in relation to diet; for others, salt-containing foods have important cultural values. Present evidence does not provide a firm basis for advising a change in the dietary salt intake for the general population. There is a reasonable possibility that a low salt intake begun early in life may protect, to some extent, persons at risk from developing hypertension. Salt consumption today is being determined to an increasing degree by food manufacturers and processors and quick-service food suppliers. To the extent that salt is added to a food prior to its being served, the individual has an obligatory rather than a selected intake of salt. The consumption of presalted foods may be producing significant changes in salt intake which are not perceived at this time.

Human nutrition science and practise to the outsider, at any rate, appears to emphasize the availability, procurement, preparation, and requirement of foodstuffs in man in both health and disease. Special consideration has, of course, been given to defining needs at various ages, the Recommended Dietary Allowances (RDAs), to the biochemistry of nutrients, and to the health problems of too little and too much food. However, adequate nutrition is only achieved when nutrients complete their roles in providing energy and in intermediate metabolism. Any acquired or genetically determined aberration of these processes can thus be construed as a disorder of nutrition. For the nutritionist the special interest of these conditions undoubtedly lies in the opportunities for dietary manipulation as a means of therapy (American Academy of Pediatrics, 1976a,b).

In the United States and Canada, processed infant foods have not been implicated in methemoglobinemia associated with food or water intake in infants. Although raw spinach and beets have a higher nitrate content than do other infant foods, one or more protective factors may prevent the extrinsic or intrinsic formation of toxic levels of nitrite from these foods as commercially processed for feeding of infants. Nitrate contamination of drinking water which may occur from run-off from fields fertilized with nitrates, represents a potential hazard.

The need to consider a primarily metabolic etiology of serious illness in infancy is reviewed. The details of conditions known to present in this manner are summarized and the diagnostic approach outlined.

Using resistance to the action of a crude rat insulinase and the rate of incorporation of intraperitoneally administered14C glucose into rat diaphragm glycogen as indices, it has been shown that there is a difference between immunologically purified insulin from the plasma of juvenile diabetics and the pancreas from certain adult-onset diabetics on the one hand and normal insulin on the other. The difference appears to be inherited as a simple Mendelian factor.

A critical appraisal is presented of 11 clinical chemical methods presently available with the Beckman/Spinco Ultramicro Analytical System. After certain modifications, the suggested technics, with the exception of that for serum bicarbonate estimation, offer acceptable standards of accuracy for clinical work.

Summary The early management of 3 infants with maple syrup urine disease is described with particular reference to variations in daily requirements for branched-chain amino acids. The use of a new dry base mix consisting of a dextrimaltose-corn oil-mineral mix, an iron-vitamin mix, and an amino acid mix as a formula base has facilitated earlier home management of these patients.

A method is described for the isolation of insulin from single human pancreas specimens involving a traditional acid-ethanol extraction, followed by gel filtration and isoelectric focusing.

Workers in the pediatric field have recognized that undernutrition is of major importance in developing countries around the world and have expressed interest in the extent to which efforts have been made in the United States to deal with this problem. This report attempts to bring together information from a wide variety of sources and to summarize the considerable efforts that have been made in dealing with these problems of undernutrition. It may provide a basis for future planning and involvement on the part of those concerned with solutions for the food problems abroad as well as the application of experience with them to situations in this country. The vital importance of nutrition was forcefully described by the President's Science Advisory Committee in its 1968 report on the "World Food Problem." The principal findings and conclusions reached were stated as follows: 1. the scale, severity, and duration of the world food problem are so great that a massive, long-range, innovative effort unprecedented in human history will be required to master it; 2. the solution of the problem that will exist after about 1985 demands that programs of family planning and population control be initiated now. The food supply is critical for the immediate future; 3. food supply is directly related to agricultural development and, in turn, agricultural development and overall economic development are critically interdependent in the hungry countries; and 4. a strategy for attacking the world food problem will, of necessity, encompass the entire foreign economic assistance effort of the United States in concert with other developed countries, voluntary institutions, and international organizations.

Certain milk substitute infant formulas, particularly meat-based and casein hydrolysate based formulas, may be low in vitamin K content in relation to the needs of the infants receiving them. Studies are reviewed of a few infants in which inadequate dietary supply of vitamin K from such sources may have been one factor in the development of hypoprothrombinemia, though this could not be established with certainty. On theoretical grounds it seems reasonable to increase the level of vitamin K1 in milk substitute formulas to 100 µg/l, particularly because these products are often used in treatment of clinical conditions which are associated with diminished absorption of this vitamin. Vitamin K1 (phylloquinone) would seem the most appropriate form to be used for supplementation of formulas. In clinical situations associated with malabsorption of fat, e.g., cystic fibrosis of the pancreas or biliary atresia, and prolonged diarrhea or starvation, vitamin K supplementation of feedings or periodic parenteral administration of vitamin K is recommended. When parenteral vitamin K is necessary, intravenous administration is rarely indicated. Subcutaneous or intramuscular injection is preferred.

Summary 1. The urinary excretion in milligrams per kilogram per 24 hours for creatine, creatinine, free alpha amino acid nitrogen, and total nitrogen have been recorded for a group of premature infants 2 to 12 weeks of age in both single voidings and in 24-hour pools. 2. A considerable range was noted in the excretion coefficients (milligrams per kilogram per 24 hours) of all the components of urinary nitrogen investigated, not only between different infants but between single voidings and 24-hour pools of the same infant. The only significantly constant interrelationship was between free alpha amino nitrogen and total nitrogen in the 24-hour samples. 3. The practice of expressing the urinary excretion of a substance of premature infants in terms of the creatinine ratio is likely to lead to erroneous conclusions, particularly where this is done on single voidings.

The guinea pig, like the human, initiates the period of rapid brain growth in utero and thus provides a model for measuring the effects of maternal malnutrition on intra-uterine brain growth. In these studies the newborn of undernourished guinea pig mothers showed significant reductions in body weight and brain weight, cellularity, protein, cholesterol, cerebroside, and sulfatide contents. The reductions in wet brain weight and protein content were significant for cerebellum but not for cerebrum. Animals undernourished in utero and fed normally after birth showed normal whole brain weight, cerebroside and sulfatide contents, and normal cerebrum cellularity by adulthood. However, the type of cells increasing in the cerebrum during postnatal rehabilitation is unknown. Wet weight and cellularity were still diminished by 22% and 17%, respectively, in the adult cerebella. The results suggest that adequate postnatal nutrition will offset some, though not all of the brain biochemical changes resulting from fetal undernutrition.

Normal values for both total body water and extracellular water have been determined in 86 premature infants aged 1 to 90 days and weighing 940 to 2,435 gm, with use of the techniques of deuterium oxide and bromide dilution. Nine full-term infants aged 1 to 6 days and weighing 2,590 to 4,985 gm were similarly studied. Nine infants with the respiratory distress syndrome and eight infants of toxemic mothers studied in the first 24 hours of life showed no significant difference in their body water compartments in comparison to a control group of normal infants matched for age and weight. Seven infants of diabetic mothers studied in the first 24 hours of life showed a significant decrease in total body water, expressed as percentage of body weight, with a normal intracellular to extracellular water ratio. These data indirectly support other evidence that there is an increase in body fat in these infants at birth. See Table in the PDF file

Urinary excretion coefficients (µg/kg/24 hr) for 3-methoxy-4-hydroymandelic acid (VMA) have been measured for the first third, and fifth days of life in 6 infants with the respiratory distress syndrome and in 20 normal control infants. No significant differences could be detected between the two groups. Present understanding of pressor amine metabolism in this condition is discussed.

The nutrient medium of a series of cultures inoculated simultaneously with mouse fibroblasts of the 3T6 strain was replaced by fresh medium containing Uridine-2-C-14 and 5,000 μunits of insulin from four normal and two diabetic pancreases. After a twelve-hour incubation period the cellular monolayer was subdivided by conventional chemical methods and the specific activity of the RNA fraction estimated. A consistent difference was observed between RNA specific activity of the cellular monolayers treated with diabetic pancreatic insulin and normal pancreatic insulin. These data constitute a further argument strengthening the case for an “abnormal insulin in diabetes mellitus.”

The association of mottled enamel and dental fluorosis with community drinking water was detected before 1920 and was specifically related to the fluoride content of the water when Churchill, in 1931,1 was able to measure trace amounts of fluoride in drinking water. Also, in areas with communal water supplies naturally contaming increased amounts of fluoride, the occurrence of dental caries was lower than that seen in the general population.2 These observations and subsequent studies3 led to the practice of adding fluoride to communal waters, with a consequent significant reduclion in the incidence of dental caries. Nearly 90 million persons in 7,500 communities4 use water supplies containing an amount of fluoride effective in reducing the dental caries rate. Fluoride is present in the customary diet and in most potable water sources in amounts that vary from 0.1 to 0.5 parts per million (ppm).5 The average dietary intake of fluoride is approximately 0.5 mg daily from these two sources. In the temperate zone, fluoridated community water supplies are increased in fluoride content to a level of 1.0 ppm, thus providing, on the average, a total fluoride ingestion of 1.5 mg per day. A lesser level of fluoridation may be sufficient in warmer climates conducive to a higher water consumption. Fluoride is regarded as an essential nutrient6 and it is now well known to be effective in the maintenance of a tooth enamel that is more resistant to decay. Fluoride is a normal component of tooth enamel and bone. Studies in vivo and in vitro demonstrate that the calcified tissues of both enamel and bone are made up of a combination of hydroxy- and fluor-apatites of varying composition, depending on the abundance of fluoride at the site of formation.

SINCE the first descriptions in 1952, idiopathic hypercalcemia of infancy has come to be a well-recognized and not uncommon entity in Europe, especially in the United Kingdom—a contrast to the sparse and more recent observations from North America. The clinical features of the disease first appear between the second and eighth months of age and are commonly described as developing into mild and severe forms. In the benign type, where full recovery can usually be expected after a few weeks of treatment, the early signs are not specific: an insidious onset of vomiting, loss of appetite, constipation and irritability. The infant becomes listless and hypotonic and plainly fails to thrive; the appearances indeed are indistinguishable from those of hyperchloremic renal acidosis which is an occasionally associated complication. Bands of increased density are sometimes seen in roentgenograms at the metaphyseal margins of the long bones and metacarpals.

A double-blind controlled study to determine the effect on infections of repeated administration of large doses of gamma-globulin to premature infants revealed that significantly more of these infants had no infections and fewer had mild infections during the first year of life. The data also suggests that gamma-globulin afforded some amelioration of serious but nonfatal infections. Deaths from infection showed a similar trend in favor of the gamma-globulin group, but this difference on its own was not significant.

Understanding of diabetes in molecular terms has advanced very little. The possibility that a structural difference exists in the circulating and pancreatic insulin moiety of diabetics is supported by three lines of evidence obtained in the authors' laboratory. — Immunologically purified circulating insulin from diabetic subjects untreated with insulin was noted to be relatively resistant to degradation by a crude muscle insulinase preparation. The pancreatic insulin of five diabetic pancreases was found to have a decreased biological activity in its ability to enhance glycogen synthesisin vivo and in its capacity to stimulate RNA turnover in tissue culture. — The nature of this “abnormal insulin” and its hypothetical role in the physiopathology of diabetes are discussed in the light of the need for a specific definition of the precise molecular change.

There is still much ignorance and un certainty as to the relative merits of strict vs. free diets, oral vs. injectable drugs, the basic physiologic faults, the useful ness of the sugar tolerance and related tests, etc. Here is a straightforward ex position of the newer insights into patho genesis which are pertinent to the best care of the child with diabetes.

1. The iron endowment of the newborn is proportional to the initial hemoglobin mass. This in turn depends upon the birth weight and initial hemoglobin level. The presence of low birth weight or decreased hemoglobin level in the first few days of life may identify infants with special iron requirements during the first 18 months of life. 2. It is recommended that the diet of normal term infants provide 1.0 mg/kg/day of iron by 3 months of age to a maximum intake of 15 mg/day. This requirement can be easily met by inclusion in the diet of appropriate amounts of foods which have been enriched with iron, such as infant cereals or milk formulas. 3. Infants with low birth weight and others with reduced iron endowment require as much as 2.0 mg of iron per kilogram per day beginning by 2 months of age. This amount of iron will not ordinarily be provided by the diet, even if iron-supplemented cereals are given. Attainment of these larger amounts requires the use of medicinal iron or iron-supplemented milk formula. 4. Attention should be directed to providing a variety of iron-enriched dietary staples to be used routinely for feeding American infants during the period of life from 3 to 18 months of age and to more precisely determining the best form of iron supplementation. At the present time iron fortified baby cereals and milk formulas are the iron supplemented foods most generally available. These are not utilized by the segments of the American population which have the greatest need for them.

The sodium, potassium and nitrogen balances of 24 small premature infants during the first 3 weeks of life have been determined. During the first week of life there was a sodium deficit of 6 to 16 meq/kg in clinically well infants. Prior to milk feeding there was a loss of potassium and nitrogen, followed by change to retention once milk feedings were started. See Image in the PDF file Some sick infants showed a similar pattern; others showed a relative salt retention during illness or during moderate increases in sodium intake. Three infants were treated with cortisone during the first week of life. Two retained potassium as well as sodium during that time. Another demonstrated an apparent migration of sodium into the cells while receiving the cortisone. Low and more labile sodium values in serum were noted more often in the ill infants, while higher potassium levels in serum were more frequently encountered in the same infants, although these two phenomena were not necessarily associated. During the second and third weeks of life, all babies studied began to retain sodium irrespective of the degree of immaturity at birth and the positive nitrogen and potassium balance continued. See Image in the PDF file It is conjectured that the sodium diuresis observed during the first week of life may represent a physiologic reduction of the total body water.

(1) The technique of treatment of soft tissue injuries by the two-stage method is described, and the results considered in relation to those of other methods still practised. (2) Primary surgery is directed principally to the removal of conditions favourable to the development of bacteria, rather than to an attempt to produce an aseptic field. (3) Subsequent treatment is directed to the exclusion of possible secondary infection, by occlusive dressings, rigid aseptic technique, and early closure of wounds in one or more stages, by suture or by skin grafting. Emphasis must constantly be laid on early restoration of function in the affected part, and preservation of function in the uninjured parts. (4) Infected wounds may be sutured with a high proportion of successful results, provided there is no invasive cellulitis, and no sloughs, haematomata, or irritant foreign bodies are left in the wound. Under the heading of infected wounds one may probably include a considerable number of simple abscesses which are normally always left to heal by granulation.

The effects of progressive protein deprivation have been studied in the monkey to determine which laboratory tests are affected early and which laboratory tests reflect the severity of protein deprivation. BUN levels and serum amylase activity were significantly reduced after 2 weeks, and hematocrit values after 4 weeks of protein deprivation. They continued to be decreased in poorly nourished animals thereafter, but did not reflect progressive protein deprivation. Total serum protein, albumin, and transferrin were affected later in the course of protein deprivation and appeared to reflect the severity of deprivation. Five of seven measured essential amino acids showed statistically significant reductions in serum concentrations after 8 weeks of low protein diet but did not show further diminution after 14 weeks. The ratio of nonessential to essential serum amino acids was also increased after 8 weeks of protein deprivation but was not further decreased after 14 weeks. Serum alkaline phosphatase and cholesterol levels were variable throughout the 20 weeks of deprivation and did not appear to be good screening tests for protein malnutrition.

The hydrolytic products of the fetuin fraction of fetal calf scrum, which is active in causing glass attachment and reproduction of mammalian cells, have been determined. The absence of methionine is noteworthy. Fetuin which has lost its biological activity as a result of chromatography on DEAE-cellulose columns, displays little or no change in its hydrolytic products. The hydrolytic products of another glycoprotein, orosomucoid, are also presented. The various possible relationships between the biological activity and the molecular constitution of the fetuin fraction are discussed.

In recent years it has become apparent that hyperphenylalaninemia in newborn infants may be caused by a variety of defects in the enzyme phenylalanine hydroxylase or by an abnormality in either the enzyme dihydropteridine reductase (DHPR) or the synthesis of dihydrobiopterin (BH2) (Figure). Despite the rarity of the latter conditions1 there are important implications for management in making this diagnosis. It has been suggested that all new cases of hyperphenylalaninemia now be screened for these variants.2 The purpose of the Task Force was to define the feasibility of this course at the present time. BACKGROUND The hepatic system for conversion of phenylalanine to tyrosine is complex and consists of at least two essential enzymes, phenylalanine hydroxylase (catalyzing reaction 1) and dihydropteridine reductase (catalyzing reaction 2), and an essential, nonprotein cofactor, tetrahydrobiopterin3: (1) Phenylalanine + O2 + tetrahydrobiopterin → tyrosine + H2O + quinonoid dihydrobiopterin; (2) nicotinamide adenine dinucleotide (reduced form) + H+ + quinonoid dihydrobiopterin → nicotinamide adenine dinucleotide (oxidized form) + tetrahydrobiopterin. Most cases of hyperphenylalaninemia detected by newborn infant screening programs are caused by deficiencies of phenylalanine hydroxylase ranging from the severe "classic phenylketonuria (PKU)" to the more benign "hyperphenylalaninemic variant." The patients with classic PKU usually respond to a diet low in phenylalanine. However, of the estimated 400 cases of classic PKU detected annually in the United States, up to 3% may show progressive neurologic deterioration despite adequate dietary treatment. The elevated phenylalanine in these infants may be caused by either DHPR deficiency or a deficient synthesis of BH2 or to other still unidentified causes.

Vitamins have long been recognized for their unique role in human nutrition. Most of these low-molecular weight, organic substances are precursors of coenzymes, and adequate amounts to meet the known nutritional needs of healthy persons of all ages have been defined by the Food and Nutrition Board of the National Academy of Sciences as the "Recommended Dietary Allowances" (RDA). The consistent opinion of the Committee on Nutrition of the American Academy of Pediatrics has been that normal children receiving a normal diet do not need vitamin supplementation1 over and above RDA levels. However, there are a variety of clinical entities in which the daily intake of vitamins needs to be significantly increased. This is true, for example, with the fat-soluble vitamins A, D, E, and K in the steatorrhoeas2 and in the autosomally recessive selective malabsorption of vitamin B12.3 Rarely, children treated with isoniazid require increased pyridoxine; and, when treated with diphenylhydantoin sodium (Dilantin), they need increased folic acid and vitamin D.4 Finally, there are a number of rare inborn errors of metabolism affecting the apoenzyme at the cofactor binding site or involving the metabolism of the vitamin itself to its biologically active derivative.5 In these so-called dependency syndromes, the metabolic defect may completely or partially be overcome by greatly increasing vitamin or cofactor availability. Set against a background of wide public belief in the benefits of vitamins, the accounts of dramatic amelioration of deficiency states, the easy and relatively inexpensive availability of these substances, and the occasional, remarkable benefit of large doses (both in the dependency syndromes and in certain other clinical situations), it is not surprising that a cult developed in the use of large doses of water-soluble vitamins to treat a wide spectrum of disease states.

A subcommittee of the Inter-Society Commission for Heart Disease Resources recently recommended an immediate, nationwide change in dietary habits to reduce the risk of coronary heart disease in later life.1 Specifically, the Commission urges that people eat less than 300 mg of cholesterol each day, that the total calories from fat be less than 35% of the diet, and that the fat calories essentially be divided equally among saturated, monounsaturated, and polyunsaturated sources. (A commentary on these recommendations appears in this issue of Pediatrics.2) The Committee on Nutrition, realizing that pediatricians will increasingly be asked about diets for children to reduce the risk of heart disease in later life, has evaluated the Commission's report for its application to pediatric practice. The Committee stresses that such dietary intervention is, at present, experimental and recommends against dietary changes for all children. Dietary intervention may be warranted in special circumstances, but not before 1 year of age. Reasons for these recommendations will be given in this report. The evidence relating dietary cholesterol to coronary heart disease is summarized as follows: 1. Some inborn or acquired diseases with hypercholesterolemia are associated with premature atherosclerosis. 2. Serum cholesterol levels are higher than usual in persons with coronary heart disease. 3. Persons with high cholesterol levels in prospective studies developed coronary heart disease more often than those with normal levels. 4. The mortality rate from coronary heart disease in different countries varies in relation to the average blood cholesterol values (or dietary fat intake). 5. Experimentally induced hypercholesterolemia in animals is associated with atherosclerotic deposits.

Islet cell antibodies were found in 71 of 1169 first-degree relatives (6.1%) from 448 families who had a proband with type I diabetes. Seven children have since become insulin dependent. All had islet cell antibodies and were followed up prospectively with measurement of first-phase insulin production during intravenous glucose tolerance testing. In this group the statistical probability of developing type I diabetes within 12 months with 95% confidence was found to be 59% to 100% when the first-phase insulin secretion was less than 25 microU/mL. The identification of the prediabetes time period should allow an opportunity for intervention in the underlying disease process to determine if the onset of type I diabetes can be altered.

A technic is described for the isolation of insulin from serum using a series of gel nitrations in combination with an interim complexing with guinea pig anti-insulin serum. Insulin thus derived from the serum of juvenile diabetic subjects was shown to be significantly more resistant to insulinase than that from normal persons. It is suggested that there is a genetically determined structural difference in the insulin of diabetic children which contributes importantly to the underlying biochemical disorders of the disease.

Insulin isolated from normal and diabetic pancreas was isolated and injected intraperitoneally into rats together with C-14 glucose. Measurement of C-14 incorporation into the diaphragm showed a significantly lesser biologic activity for diabetic insulin. These results are in accord with earlier work on the resistance of diabetic insulin to insulinase and on the inheritance of diabetes in terms of the abnormal insulin. The possibilities for a mutation site in the insulin molecule are discussed in relation to known molecular variations.