Showing papers in "Pediatric Research in 1971"

Gaps in Doctor-Patient Communication: Doctor-Patient Interaction Analysis

Abstract: Extract: As one of several approaches to scientific analysis of doctor-patient communication 285 visits to a pediatric walk-in clinic were scrutinized using an expanded version of Bales' Interaction Process Analysis Data analysis consisted of individual case studies and computer programs for descriptive summaries of cases and index scores. Factor analysis and chi-square calculations were among the methods used to test significant relations between attributes of the doctor-patient interaction and the dependent variables, patient satisfaction, compliance, and demography. As hypothesized, a distinctive behavior pattern emerged for doctor, parent, and child. Doctors were found to talk more but show less emotion than mothers. Almost two-thirds of the mother's communication related to medical history, while the doctor discussed history and treatment but gave little reassurance or friendlines to the mother, almost half of his conversation with the child consisited of friendly statements. In general, outcome of the medical consultation was found to be favourably influenced by having physician who was friendly, expressed solidarity, took some time to discuss nonmedical, social subjects, and gave the impression of offering information freely without the patients having to request it or feeling excessively questioned. Speculation: Because of the complicated nature and limited methods available for study, the doctor-patient relation has rarely been subjected to scientific inquiry or attempts at quantification. It is hoped that the present effort as well as other ongoing studies will contribute to a body of scientific information which in itself may have application for pediatric education and practice and which ultimately might contribute one approach in urgently needed studies of the quality of medical care.

Postnatal Changes in Oxygen Transport of Term, Premature, and Sick Infants: The Role of Red Cell 2,3-Diphosphoglycerate and Adult Hemoglobin

Abstract: Extract: In view of previous studies which did not show a precise relation between the percentage fetal hemoglobin and the position of the oxygen hemoglobin equilibrium curve, this problem was reexamined taking into account both the concentration of fetal hemoglobin and the 2,3-diphosphoglycerate (2,3-DPG) content of the cell. Forty-eight normal infants weighing 2500 g or more at birth were studied on days 1 and 5 of life and then at 3 and 6–9 weeks, and at 3–4, 5–6, and 8–11 months of age. Fifty-six ingfants ranging in birth weight from 900 to 2420 g were studied during the first 8 days of life and then at 2− to 3-week intervals until approximately 16 weeks of life. Twelve premature infants who were ill with the respiratory distress syndrome were also studied. Laboratory procedures consisted of measurement of total hemoglobin, fetal hemoglobin, red cell 2,3-DPG, and oxygen equilibrium curves. The “functioning DPG fraction” in millimicromoles per milliliter red blood cells (RBC) was obtained by multiplication of the total red cell DPG content (millimicromoles per milliliter RBC) by the percentage of adult hemoglobin. These studies confirm previous observations that the term infant begins life with blood that has an increased affinity for oxygen. During the first few months of life the oxygen-hemoglobin equilibrium curve gradually shifts to the right and between 4 and 6 months of age becomes similar to that observed in the normal adult. The change in P60 in these infants correlated neither with the change in red cell DPG content alone nor with the decline in fetal hemoglobin alone. Instead, the progressive decrease in oxygen affinity during the first 6 months of life correlated significantly (r = 0.876, P < 0.001) with the functioning DPG fraction. The term “functioning DPG fraction” is suggested to reflect the fact that both the DPG concentration and the adult hemoglobin concentration within the cell, with which the DPG interacts, are necessary factors in determining the position of the oxygen equilibrium curve. Infants with respiratory distress appear to have P50 s that are lower than those of healthy infants of similar gestational age and birth weight. This appears to be primarily a result of a decrease in red cell DPG concentration. It is this type of infant who may benefit from exchange transfusion with fresh adult blood.

Chemotactic Function in the Human Neonate: Humoral and Cellular Aspects

Abstract: Extract: The cellular and humoral components of the chemotactic response in neonates have been compared with those in adults. Leukocytes from neonates were compared with those from adults in their ability to movetoward chemotactic factors (CF) generated from pooled, normal serum. Neonatal leukocytes showed a consistent and highly significant deficiency in their response to chemotactic factor generated from Staphylococcus aureus, Escherichia coli, or albumin-antialbumin (Table I). Chemotactic factor generated from neonatal and adult sera was compared for its ability to stimulate migration of a standardized, normal leukocyte pool. A small but highly significant difference was seen between the amounts of effective CF generated from neonatal sera and that from adult sera. The difference was found with all three generating agents (Table II). The mechanism by which leukocytes undergo chemotactic migration is presently unclear. It is possible that in neonates cellular defects in leukocyte phagocytosis and leukotactic chemotaxis may be related to developmental immaturity of common biologic mechanisms. Although other serum factors may be involved, it appears that the separate deficiencies of neonatal sera in generation of CF and enhancement of phagocytosis may both be related to deficiencies of C3 and C5. The enhanced susceptibility to infection in neonates cannot be explained simply by a selective deficiency of IgM. Addition of IgM failed to correct the humoral deficiencies of chemotaxis and phagocytosis in vitro. Further, a deficiency of IgM would not explain the cellular deficiencies demonstrated. It is only by a sequential analysis of the entire inflammatory response in the neonate that these relations will become clear. Speculation: It has become apparent that the relative susceptibility of the neonate to bacterial infections is the result of a number of deficiencies involving both humoral and cellular aspects of the neonatal inflammatory response. The future delineation of these individual defects may lead to improved therapeutic approaches in neonatal septicemia and, also, provide valuable information on the mechanisms involved in the normal inflammatory response.

Skeletal Muscle Cell Mass and Growth: The Concept of the Deoxyribonucleic Acid Unit

Abstract: Speculation: Two important predictions, contradicting current opinion, arise from his review: Removal of the pituitary causes loss of muscle deoxyribonucleic acid (DNA) in the weanling rat. Exercise causes increase in muscle tissue with a commensurate increase in DNA and protein. Therefore, some of the muscle DNA must be in a dynamic state. Calorie restriction (without protein restriction) imposed during the postweanling period of growth in rats does slow cell multiplication but does not cause permanent growth retardation. Therefore, protein restriction, per se, is probably responsible for permanent growth retardation in the experimental animal.

Studies on the Circulation of the Previable Human Fetus

Abstract: Extract: The circulation was studied in 33 previable human fetuses (12–272 g) delivered by hysterotomy, while the placenta was still attached. The umbilical vein (UV) and in some instances umbilical or carotid artery (FA) were cannulated. Fetal and maternal pH, PO2, and PCO2 were measured. Radionuclide-labeled microspheres (50 μ in diameter) were injected into the UV on one or more occasions from 1 to 36 min after delivery of the fetus. The distribution of the cardiac output (CO) was calculated from the relative amounts of radioactivity in each organ. In 11 fetuses, FA blood samples were withdrawn during microsphere injection, and CO and actual organ blood flows were measured. With advancing gestational age (10–20 weeks) there was an increase in total inferior vena caval return from 64 to 75% of CO. The proportion of CO to the placenta increased from 17 to 33% and to the gut from 5.5 to 9.2%. Superior vena caval return decreased from 32 to 23%, and the percentage of CO to the kidneys fell from 6.5 to 3.2%. In those fetuses in which repeated observations were made, there was a fairly uniform decrease in proportion of CO distributed to the placenta, probably owing to umbilical vessel constriction. This deterioration was not reflected by UV blood gases which in fact showed a decrease in PCO2 and rise of PO2, when FA showed a rise of PCO2 and fall in PO2 and pH. Associated with the fall in FA pH there was an increase in the proportion of CO to the brain, myocardium, and adrenals. The proportion of CO to the brain increased significantly with increase of FA PCO2. Speculation: The circulation of the previable human fetus may be studied at the time of hysterotomy. It is most important to realize that, even though umbilical venous blood gases may appear to reflect good physiological function, umbilical flow may be markedly decreased. This must be taken into account in all attempts to study placental function.

Intrarenal blood flow distribution in canine puppies.

Abstract: Extract: The present study was designed to examine the developmental changes in renal blood flow distribution in canine puppies utilizing the techniques of xenon-133 (133Xe) washout, anatomic measurements, and para-aminohippuric acid (PAH) clearances and extractions. The distribution patterns determined by analysis of the xenon washout curves were confirmed by studies of the intrarenal distribution of injected radioactive microspheres. The mean total blood flow was 1.2 ml/g kidney/min at 6 weeks of age and rose progressively to the adult value of 3.5 ml/g kidney/min at 14–16 weeks of age. The mean Component I flow, 1.7 ml/g/min at 6 weeks, increased to 4.7 ml/g/min at 14–16 weeks of age. The increase in Component I flow was associated with an increase in PAH extraction ratio. The low renal blood flow observed in the puppy less than 6 weeks of age appears to be due in large part to a small cortical volume. Anatomically, the amount of cortex/medulla ratio was less in the puppy than in the adult, and this was supported by the relatively low cortical volume of distribution noted in the washout studies. At 10 and 12 weeks of age, when the relative cortical mass approximated that found in the adult, the Component I flow rate was still low, but from age 12 weeks, Component I flow and total renal blood flow increased markedly. Renal blood flow increased during a period when cardiac output per kilogram body weight was constant and total peripheral resistance was rising. The progressive age-dependent increase that was noted in total renal blood flow was primarily due to an increase in cortical flow. The increased cortical flow was in part a consequence of cortical growth; change in sympathetic tone may also have contributed.

The ToRCH complex-perinatal infections associated with toxoplasma and rubella, cytomegol- and herpes simplex viruses

Abstract: The ToRCH complex-perinatal infections associated with toxoplasma and rubella, cytomegol- and herpes simplex viruses

Postnatal Changes in the Chemical Heterogeneity of Human Fetal Hemoglobin

Abstract: Extract: The fetal hemoglobin (Hb-F) of blood samples from 11 newborn babies (two normal infants, two sickle cell trait carriers, two Hb-C heterozygotes, two infants with Hb-SG disease, one infant with Hb-Richmond heterozygosity, one β-thalassemia heterozy-gote, and one infant with a heterozygosity for the hereditary persistence of fetal hemoglobin) and from 16 adults (eight normals, two Hb-S heterozygotes, one Hb-C heterozygote, and five SC patients) has been examined to determine the ratio of the two structurally different γ chains, namely the Gγ and Aγ chains. This ratio is about 2:3 in the Hb-F of the adults and, therefore, significantly different from the 3:1 ratio in the Hb-F of the newborn. This newborn ratio undergoes a considerable change between the 3rd and 4th months of life, at which time it approaches that of the Hb-F of adults. Speculation: The mechanism by which the gradual change from γ chain synthesis to β and δ chain synthesis is controlled remains unclear. However, the change in the ratio of production of structurally different γ chains as a function of postnatal age indicates a rather complex mechanism which probably involves an unequal repression of the γ chain structural genes. Any explanation of the mechanism must take into account the fact that the production of two genes, the Gγ and Aγ, is greatly decreased, whereas that of two other genes, the β and δ, is started. Perhaps a closely related or even identical mechanism controls not only the ratio of production of the Gγ and Aγ genes but also that of the β and δ genes.

Primary and Secondary Bile Acids in Meconium

Abstract: Extract: Meconium, newborn stool, and fetal bile were examined for bile acids by the techniques of gas liquid chromatography, thin layer chromatography and colorimetric spectrometry. Cholic, chenodeoxycholic, deoxycholic, and lithocholic acid were detected in meconium. Secondary bile acids were not present in significant amounts in either stool or fetal bile from newborns. During fetal development more cheno-deoxycholate than cholate is formed. The presence of secondary bile acids in meconium is suggestive of maternal-to-fetal transfer via the placenta. Speculation: The number of hydroxyl groups on the basic sterol nucleus may influence bile duct development. Excess quantities of bile acids, particularly lithocholic acid, may alter the developing fetal hepatic stucture.

Metabolic and Hormonal Responses to Glucose and Glucagon in Patients with Infantile Malnutrition

Abstract: Extract: The interrelations of plasma levels of glucose, free fatty acids (FFA), α-amino nitrogen (α-aaN), insulin, and growth hormone (GH) were studied in 26 malnourished infants shortly after admission to the hospital and again several weeks later when they had recovered. In the sick children (SC) fasting levels of FFA and GH were high, and insulin and α-aaN were low; with recovery FFA, α-aaN and insulin levels became normal, and GH levels fell. No change occurred in glucose levels. Ten infants were given glucose (0.5 g/kg body weight) intravenously on the 1st or 2nd day after admission and again 6–12 weeks later. Glucose tolerance was impaired in the sick group and, although improved, was not normal when the children had recovered from the nutritional insult. Insulin secretion was stimulated by glucose in those that had recovered (RC), but not in the SC. No significant change occurred in either FFA or α-aaN levels in these groups. Nine infants received glucagon (0.1 mg/kg body weight) intravenously on the 2nd to 6th day after admission and again 6–12 weeks later. Glucagon caused a rise in glucose levels that were greater in RC than in SC but did not cause a significant change in insulin levels in either group. Free fatty acid levels were higher in SC throughout the test, but in both groups FFA levels responded similarly to glucagon administration, falling 10 and 60 min after the injection. Changes in GH levels in plasma after glucose or glucagon administration were compared with the changes caused by five venepunctures in RC. Venepunctures and glucose caused similar rises in GH levels, but glucagon caused a greater rise than either. It was concluded that the stress of repeated venepunctures caused a rise in GH levels in plasma in all three tests, but that, independent of this, glucagon stimulated GH secretion. Speculation: Insulin secretion is impaired in infantile malnutrition and does not improve at the same rate as clinical recovery occurs, suggesting that normal β cell function is not essential for rapid growth. The role of growth hormone in malnutrition is not clear, but it appears to be involved more in the metabolic adaptation to malnutrition than in the control of growth.

Bilirubin Uridine Diphospho-glucuronyltransferase in Rat Liver Microsomes: Genetic Variation and Maturation

Abstract: Extract: Optimal conditions for the in vitro assay of bilirubin uridine diphospho- (UDP) glu-curonyltransferase activity in rat liver microsomes are described. Solvent partitioning was used to separate the conjugated from nonconjugated bilirubin, thus avoiding dependency on the rate of coupling with diazotized sulfanilic acid for the distinction between bilirubin and its conjugated form. The inclusion of uridine diphospho-N-ace-tylglucosamine (UDPNAG) in the reaction mixture permitted the rate of conjugation of bilirubin by fresh rat liver homogenates and microsomes to occur at greater saturation of the available enzyme with the substrates bilirubin and UDP-glucuronic acid. Liver microsomes, isolated in 0.15 M KC1, increased their activity for bilirubin conjugation and decreased their dependency on UDPNAG during the first 10 days of storage at — 15°. Chromatographic separation of the azo pigments of the conjugated bilirubin gave evidence to suggest that bilirubin monoglucuronide was the initial product and bilirubin diglucuronide appeared in increasing amounts in more prolonged incubations. These results suggested that bilirubin monoglucuronide can be intermediate to the formation of bilirubin diglucuronide. Bilirubin UDP-glucuronyltrans-ferase activity in hepatic microsomes of adult homozygous Gunn rats was not demonstrable. In microsomes of heterozygous Gunn rats and normal Wistar and Sprague-Dawley rats bilirubin UDP-glucuronyltransferase activity was found to be 31.0 and 58.0 μg bilirubin conjugated/mg microsomal N/30 min, respectively. Measurements in developing rats indicated that the maturation in enzyme activity occurred by at least two distinct means: increase of specific activity of the microsomes, and an increase in the content of microsomes per gram of liver (Table IV). Speculation: A method for quantitative measurement of bilirubin UDP-glucuronyltransferase activity applicable to samples obtained by needle biopsy has been needed. The method described in this report meets this need and may permit more precise differential diagnosis of retention jaundice of infancy and childhood and especially the “physiologic” jaundice of the newborn.

Metabolic Studies in a Patient with Hepatic Cytosol Tyrosine Aminotransferase Deficiency

Abstract: Extract: Metabolic studies on a patient having multiple congenital anomalies and defective hepatic soluble tyrosine aminotransferase activity are presented. The activities of hepatic mitochondrial tyrosine aminotransferase and soluble p-hydroxyphenylpyryvate hydroxylase were normal. When untreated, levels of tyrosine in plasma rose as high as 62 mg/100 ml. He had phenolic aciduri (3.1–4.9 mg/mg creatinine) with p-hydroxyphenylpyruvic acid (0.6-1.8 mg/mg creatinine), p-hydroxyphenylacetic acid (0.7–1.2 mg/mg creatinine), p-hydroxyphenyllactic acid (1.0–1.7 mg/mg creatinine), and N-acetyltyrosine (0.9–1.6 mg/mg creatinine). These metabolites were identified by gas chromatography-mass spectrometry. Excretion of p-tyramine was grossly elevated (17–44 μg/mg creatinine) and was not reduced by orally administered antibiotics. Oral tolerance tests showed rapid conversion of phenylpyruvic acid to phenylalanine and of phenylalanine to tyrosine. Speculation: The results described suggest the need to reexamine subcellular distribution of enzymes both in normal subkects and in patients with inborn errors of metabolism. When methods are developed to fractionate tyrosine aminotransferase, it may become apparent that there are several isozymes under individual genetic control. Accumulation of an intermediary metabolite should not be taken as conclusive evidence of a primary abnormality of its catabolism. The similarity of the findings in the urine of a patient with hepatic soluble tyrosine aminotransferase deficiency and in tyrosyluric neonates suggests that delayed maturation of soluble tyrosine aminotransferase rather than p-hydroxyphenylpyruvate hydroxylase might be present in at least some of these infants.

Relation of Kwashiorkor in Early Childhood and Intelligence at School Age

Abstract: Extract: Measured intelligence at school age was compared in 37 previously severely malnourished children and their siblings. The malnourished children all had been hospitalized for kwashiorkor (severe infantile malnutrition with edema) when they were between 6 and 30 months of age. The siblings had never experienced a bout of severe malnutrition requiring hospitalization. The sibling controls were all within 3 years of age of the index cases. Full scale WISC IQ of the index cases was 68.5 and of the controls 81.5. Verbal and performance differences were of similar magnitude and in the same direction. All mean IQ, differences were significant at less than the 5% level of confidence. If an IQ score of below 70 is considered a customary cut-off point for the definition of mental retardation then twice as many of the previously malnourished children as their sibs functioned below this level; 18 malnourished, compared with 9 of the control subjects, had an IQ below 70. Moreover, of those with a low IQ, 10 of the index cases were below 60, contrasted with only 2 of the control subjects. At the other extreme of the distribution, in the conventionally normal range, the reverse picture obtains; 10 of the control subjects compared with 4 of the index cases had an IQ. of 90 or higher (Table III). Speculation: The long term effect of severe malnutrition in infancy has been suggested but not unequivocally demonstrated in comparative studies of malnourished children with controls drawn from the general population. To demonstrate the relation more convincingly it is necessary that children who have experienced such severe malnutrition be compared with their own sibs raised in the same family environment but not experiencing the same severity of nutritional insult. If differences in intellectual outcome exist between sib groups at school age the source of these differences may be more clearly related to the antecedent episode of severe malnutrition and hospitalization.

Newborn urimary cyclic. AMP and developmental renal responsiveness to parathyroid hormone

Abstract: Since the renal action of parathyroid hormone (PTH) is known to be mediated via 3′, 5′-adenosine monophosphate (cyclic AMP), urinary cyclic AMP studies were used to determine proximal tubular maturation. Ten formula fed full-term male infants showed a 30 to 60 fold increase in phosphate clearance and excretion with a 3–4 fold increase in urinary cyclic AMP comparing their first and third day 24-hour urines. This 3–4 fold increase in cyclic AMP could reflect increasing pTH renal responsiveness and/or increasing secretion of PTH. One and 3 day old infants and adults were given a one hour PTH infusion (5 μ/kg/hr) measuring urinary cyclic AMP in time periods before and after the infusions. Peak increases in responses from baseline of cyclic AMP were 1.64 ± 0.34, 7.15 ± 1.15 and 36.30 ± 0.73 μmoles/gm creatinine mean ± range on first day, third day and adults respectively with similar relationships of increasing phosphate excretion and decreasing % TRP. Thus, the development of newborn renal responsiveness to parathyroid hormone is on the cellular cyclic AMP level suggesting increasing maturation of the enzyme adenyl cyclase which forms cyclic AMP from ATP.

Onset of Lymphocyte Function in the Developing Human Fetus

Abstract: Extract: Lymphocytes capable of responding to phytohemagglutinin (PHA) were present in human fetal thymus tissue by 12-week gestational age and in spleens 2–4 weeks later. In spleens, establishment of the PHA response was associated with the appearance of small lymphocytes in cuffs surrounding central arterioles. Speculation: Onset of PHA responsiveness in lymphocytes obtained from the embryonic thymus precedes that of the spleen. It would be of particular interest to know when bone marrow cells and lymph node lymphocytes start to show this function.

Isovaleric Acidemia Presenting with Altered Metabolism of Glycine

Abstract: Extract: A 7-year-old girl with periodic acidosis, lethargy, and coma beginning during the 1st year of life was studied. Episodes of ketoacidosis usually occurred with minor respiratory or gastrointestinal infections. There was history neither of peculiar body odor nor characteristic smell like that of sweaty feet. Hyperglycinemia, 4.2 mg/100 ml, and hyperglycinuria, 361 mg/liter, were found at times of illness with acidosis. A clinical diagnosis of ketotic hyperglycinemia was made in 1966. Glycine metabolism was therefore investigated in vivo using 14C-labeled glycine. The oxidation of glycine to respiratory CO2 and formation of serine from glycine were found to be normal. The labeling of urinary hippurate, however, the largest component of the labeled products of glycine in the urine in normal individuals, was virtually zero. An abnormal, labeled product of glycine was found in the urine and identified as isovalerylglycine. As much as 6% of the 14C-glycine administered was incorporated into urinary isovalerylglycine within 24 hr. Isovalerylglycine in urine was 2880 mg/24 hr, while normal individuals excrete less than 2 mg/24 hr. Isovaleric acid was found in both urine and plasma. Isovaleric acid in the plasma and urine, 2.86 mg/liter and 2.56 mg/day, respectively, was only five to six times larger than that found in normal individuals. Formation and excretion of isovalerylglycine may be a compensatory mechanism for the elimination of toxic amounts of isovaleric acid from the body. Biosynthesis of such huge amounts of isovalerylglycine may alter the overall metabolism of glycine. Isovaleric acidemia may present with hyperglycinemia and hyperglycinuria. Examination of the urine for isovalerylglycine is a convenient method for detecting the syndrome of isovaleric acidemia. Speculation: Isovaleric acidemia, in common with propionic acidemia with ketotic hyperglycinemia and methylmalonic acidemia, produces dramatic episodes of ketoacidosis. It is now clear that, like these conditions, isovaleric acidemia can also produce leukopenia and elevated concentrations of glycine in body fluids. The mechanisms causing these abnormalities are unknown. Elucidation of metabolic interfaces among these conditions could lead to understanding of the pathophysiology involved.

Thrombocytopenia in murine cytomegalovirus infection

Abstract: The pathogenesis of cytomegalovirus-induced thrombocytopenia in neonatal cytomegalic inclusion disease is obscure, and the phenomenon has not previously been described in cytomegalovirus infections of other species. In these studies, 4-week-old female HA-ICR mice were infected i.p. with 105.0 plaque-forming units of murine cytomegalovirus (MCMV) and their hemograms were serially determined over the succeeding 14 days. Mice infected similarly were sacrificed on appropriate days for histopathologic and fluorescent microscopic study of their spleens. Significant thrombocytopenia occurred uniformly on the 4th day of infection. This was correlated with distinctive histopathologic changes in megakaryocytes which included decrease in ratio of cytoplasm to nucleus, vacuolization of the nucleus, and appearance of markedly basophilic megakaryocytes suggesting increased turnover. Direct immunofluorescent staining for MCMV antigen, using hyperimmune anti-MCMV mouse serum, revealed positive megakaryocytic intranuclear fluorescence on days 4 and 5 of infection. These pathologic alterations gradually reverted to normal between days 7 and 14, concomitant with a return to normal control levels of circulating platelets. MCMV-induced megakaryocyte destruction is suggested as a useful model for exploration of the pathogenesis of human virus-induced thrombocytopenia.

Relation of Poverty and Race to Birth Weight and Organ and Cell Structure in the Newborn

Abstract: Extract: Based on studies of birth weights, there has long been speculation that poverty, inadequate maternal nutrition, and race might alter prenatal growth by influencing fetal nutrition. In the present study, undernutrition was identified as the cause of low birth weight in a group of infants born to poor urban mothers in the United States. A postmortem, quantitative, morphological study of body size, organ size, and cellular structure demonstrated that the infants of 83 poor mothers had many anatomic abnormalities recognized as characteristic of undernutrition. Such abnormalities were not found in infants from 386 families with incomes above the poverty line. There were almost no differences in body or organ growth among various racial groups when the comparisons were between families of similar economic status. Speculation: Is the low birth weight in infants born to poor urban mothers due to abnormal nutrition during pregnancy, the mother's earlier development, or uterine or placental abnormalities? If maternal malnutrition is responsible, the exact nutritional deficiencies should be promptly identified so that preventive programs can be developed. There is also a pressing need to know whether or not the moderate undernutrition observed in the present study alters brain composition and subsequent mental and motor performance.

Fetal Homeostasis in Maternal Malnutrition. II. Magnesium Deprivation

Abstract: Extract: In rats, supplied with an adequate dietary intake of magnesium, the mean fetal magnesium concentration in plasma was 2.4 mEq/liter compared with a maternal concentration of 1.6 mEq/liter. Equilibrium dialysis experiments resulted in a disappearance of the fetal to maternal gradient, with maternal levels becoming slightly higher than fetal levels. Determination of ultrafiltrable magnesium concentrations also demonstrated a slightly lower binding capacity for magnesium in fetal plasma so that the fetal to maternal gradient reflected the unbound magnesium. When a diet containing magnesium in a concentration of 0.88 mEq/kg (compared with a control diet containing 120 mEq/kg) was introduced on day 2 of gestation, only one of eight pregnant rats bore a litter to term. If the diet was introduced on day 10 of gestation, pregnancy continued until term but there was an increased resorp-tion rate and the surviving fetuses were small, weak, and anemic. Analyses of maternal muscle for magnesium, calcium, sodium, and potassium revealed normal concentrations, even though magnesium concentrations in plasma rapidly fell to 20% of the normal level. There appeared to be a reduction in bone magnesium. The significant changes in the fetus were a reduction in magnesium levels in plasma with a disappearance of the fetal to maternal gradient and an elevation in sodium levels. Analysis of the total fetus demonstrated a reduction in magnesium and potassium and an increase in calcium concentrations. The last was also evident in the placenta. Speculation: “Fetal parasitism” as a general concept appears to be. an over-simplification which can be denned with accuracy only by the study of deprivations of specific nutrients, and eventually by the interaction of such nutrients.

Antipyrine Space Studies and Cell Water Estimates in Infants of Low Birth Weight

Abstract: Extract: Antipyrine space (APS) studies in 44 normally grown (NG) neonates revealed estimates of total body water (TBW) comparable to those found by earlier investigators utilizing desiccation analyses. Body water per kilogram of body weight was higher in the 32 premature infants than in the 12 mature neonates, even after correction for presumed changes in body fat during growth (mean APS/lean mass was 846 ml/kg in premature and 782 ml/kg in mature infants, P 0.10). Prompt decrease in cell water was evident in the mature NG infants (correlation coefficient for ICW/APS versus study age: r = −0.76; ICW versus study age: r = −0.58), whereas such changes were absent in the premature infants (ICW/APS versus study age: r = −0.08; ICW versus study age: r = −0.16). Total water and cell water estimates in 23 intrauterine growth-retarded (IGR) neonates also studied were comparable to those of weight peers (mean APS, 790 ml/kg and ICW, 379 ml/kg in IGR; mean APS, 809 ml/kg and ICW, 375 ml/kg in NG prematures) but considerably in excess of values seen in gestational peers (mean APS, 688 ml/kg and ICW, 324 ml/kg in NG mature infants). The high total body water and cell water values were particularly prominent in the earlier-studied IGR infants (mean APS, 841 ml/kg and ICW, 494 ml/kg); a notable finding was the rapid downward adjustment of cell water to values similar to those in NG mature infants (ICW, 335 ml/kg in later-studied IGR infants and 314 ml/kg in later-studied NG mature neonates). This expansion of cell water in earlier-studied IGR infants persisted despite correction for a presumed total depletion of body fat (ICW/lean mass, 494 ml/kg in IGR infants, and 389 ml/kg in NG mature babies; ICW/APS was 0.56 in IGR neonates and 0.50 in NG mature infants, P < 0.001 for both). These findings indicate a real increase in cell water at birth in the IGR infant. Speculation: Changes in body composition in infants with intrauterine growth retardation (IGR) include sizable expansions, on a per kilogram basis, of all body water compartments. Although these findings resemble those observed in chronic protein-calorie malnutrition, rapid adjustments toward normal in the early hours after birth suggest a more transient, acute expansion, primarily of cell water, in the IGR neonate. These changes may reflect impaired cellular metabolism and increased cell acidity consequent to an increased asphyxial stress of labor and delivery in these infants

Adenine Therapy for Lesch-Nyhan Syndrome

Abstract: Extract: A child with the Lcsch-Nyhan syndrome was identified at birth by demonstrating a gross deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) in cord blood. Therapy with adenine, begun during the 1st month of life, failed to prevent the development of the severe neurological damage characteristic of this disease. Speculation: Since this work was completed, Dr. Grant Bartlett of San Diego has found (unpublished work) a very poor uptake of intravenously administered adenine-14C in the brain of rabbits. This raises a possible reason for the failure of adenine to prevent the neurological dysfunction in this disease. A purine compound that is more readily taken up by brain tissue might, therefore, offer a more reasonable approach to treatment.

Sex Differences in Immunologic Reponse: Studies of Antibody Production by Individual Spleen Cells after Stimulus with Escherichia coli Antigen

Abstract: Extract: Specific antibody production by spleen cells of male and female mice during a noninvasive enteric infection with Escherichia coli and after parenteral injection of heat-killed E. coli was studied by use of the Jerne-Nordin agar plaque technique. Following experimental enteric colonization with E. coli 0127 significantly greater proportions of spleen cells produced specific anti-0 antibody in immature weanling female mice than in their male littermates. Anti-E, coli 0127 plaque-forming cells were also found in significantly greater numbers in the spleens of immature females than in males following intraperitoneal injection of small numbers of heat-killed E. coli. Although many spleens from male mice produced no cell plaques after a small dose of antigen, responses by the sexes were comparable after injection of large numbers of heat-killed bacteria. Production of plaques by spleen cells from female animals after injection of small amounts of antigen increased significantly with age, but the responses observed in adult male mice were only slightly and insignificantly greater than those of male weanlings. Studies of the sizes of plaques produced by spleen cells of male and female animals showed no statistical differences. Young ovariectomized females responded in the same way as their sham-operated male littermates to small amounts of E. coli antigen. Administration of small doses of estrogen increased plaque formation by spleen cells of weanling males. It appears that an effect of female sex hormones is production of greater numbers of antibody-producing cells; yet in the final phase of antibody production, individual cells from each sex produce on the average the same amounts of antibody. Speculation: The better ability of the immature female to respond immunologically to a small amount of E. coli 0 antigen may be a significant factor in her superior resistance to invasive disease with E. coli. Differences in the immune response of the two sexes appear to occur in the proliferative phase of antibody-producing process or steps leading up to this phase, but not in the final phases of antibody production by the cell. By mechanisms not yet defined, estrogen appears to enhance the proliferation of immunocompetent cells, and secretion of estrogen by the female may explain her superior immunologic responsiveness.

Effect of Hyperoxia on the Cerebral Ciculation of the Newborn Puppy

Abstract: Extract: Local cerebral blood flow (CBF) in the 2-day-old puppy ranged between 0.58 (superior olive) and 0.07 ml/g/min (centrum ovale), with average values in gray matter of the cerebral cortex, deep cerebral structures, and brain stem equal to 0.34, 0.38, and 0.45 ml/g/min, respectively. Animals of the same age, after being placed in oxygen for 1 hr, had a mean arterial oxygen tension (Pao2) of 349 mm Hg; arterial carbon dioxide tension (Paco2) did not change from the level seen in animals kept in air. The CBF of nearly all structures was 20-30% lower in the hyperoxic newborns than in control animals. In 3-week-old puppies, CBF ranged between 1.41 (inferior colliculus) and 0.20 ml/g/min (centrum ovale), with average values for gray matter in the cerebral cortex, deep cerebral structures, and brain stem equal to 0.61, 0.72, and 0.93 ml/g/min, respectively. Puppies at this age breathing oxygen attained a mean Pao2 of 357 mm Hg; again, PaCo2 values were not different from those in air. The oxygen effect on CBF in the 3-week-old animals was less than had been found at 2 days, there being far fewer structures in which the difference was significant. The smallest differences were in white matter ( – 11%). Continuous exposure to oxygen for 1 week, followed by removal of the puppies to air for 2–3 days, resulted in values for CBF which were comparable with those found in control animals. Speculation: Fligh concentrations of oxygen at ambient pressure alter a number of growth processes of the cell. The vasoconstrictive action of oxygen on cerebral vessels, which is exaggerated in early postnatal life, may be part of a homeostatic mechanism to limit oxygen concentration in the brain when the arterial Po., is elevated.

The effect of vitamin D on renal inorganic phosphate reabsorption of normal rats, parathyroidectomized rats, and rats with rickets.

Abstract: The Effect of Vitamin D on Renal Inorganic Phosphate Reabsorption of Normal Rats, Parathyroidectomized Rats, and Rats with Rickets

The Renin-Angiotensin-Aldosterone System in Patients with Cystic Fibrosis of the Pancreas

Abstract: ExtractPatients with cystic fibrosis of the pancreas (CFP) have elevated plasma renin activity,supine renin 497-595 compared with a normal value of 228 ± 133 ng/100 ml plasmaon 109 mEq sodium intake/24 hr, but have normal renin release mechanisms as faras postural changes are concerned, since the renin activity increases normally withthe upright posture; upright renin, 594-875 compared with a normal value of 359 ±210 ng/100 ml plasma on the same sodium intake. The high aldosterone secretion rates(ASR), 161 —4-45 compared with a normal value of 90 ± 31 /jg/24 hr, seen on 109mEq sodium intake were probably secondary to the abnormally high renin release.The same can be said for the lack of adequate suppression to normal of both renin andASR on 249 mEq sodium intake/24 hr, supine renin 205-544 compared with a normalvalue of 97 ± 71 ng/100 ml plasma; upright renin 845-893 compared with a normalvalue of 212 ±61 ng/100 ml plasma; ASR on the same intake, 93-333 compared witha normal value of 62.15 ± 27.8 /ug/24 hr. The low metabolic clearance rates and thehigh calculated plasma aldosterone concentrations on the 109 mEq sodium intakeindicate that a state of secondary hypcraldosteronism exists in patients with CFP,probably as an adaptation to frequent, excessive sodium losses via the sweat and con-sequent contraction of intravascular volume.SpeculationIn all the patients that we studied with cystic fibrosis of the pancreas a state of secon-dary hyperaldosteronism appears to exist. This state of hyperaldosteronism, secondaryto increased renin release, probably results from adaptation to frequent, excessivesodium losses via the sweat, leading to depletion of extracellular fluid volume.Introduction present in most patients. The sweat electrolyte abnor-Cyslic fibrosis of the pancreas (CFP) is a hereditary »'

Correlative studies in obese children and adolescents concerning body composition and plasma insulin and growth hormone levels.

Abstract: Extract: Levels of plasma insulin, growth hormone (HGH), glucose, and free fatty acids (FFA) were investigated in 17 obese, nondiabetic children or adolescents after administration of intravenous arginine, oral glucose, and a protein-glucose meal. These results were compared with those obtained in eight normal adolescents. Four of the obese patients had a family history of diabetes but had hormonal responses identical with those observed in obese subjects with a negative family history of diabetes. Subjects were arbitrarily separated into two groups depending on duration of obesity (Table I) (age of onset was different: infancy or early childhood for group B, 5–8 years for group A). Subjects in group B (longstanding obesity) all had a strong family history of obesity with marked increases in body weight, body fat, and excess fat. Fasting levels of insulin were greater than normal (P < 0.001 (Table II)). Patients in group A (short duration), with lesser increments in body weight and body fat, had normal fasting levels of insulin and normal response to intravenous arginine (Fig. 4). All obese subjects had hyperinsulinemia in response to other stimuli, but patients in group B achieved the highest insulin levels (Figs. 2, 3, and 4). All obese patients had significantly decreased levels of HGH during tests and elevated fasting levels of FFA. Patients in group B exhibited a reduced mean decrement in FFA during the oral glucose tolerance test. Whether or not responses seen in patients in group A represent an early stage of the conditions observed in patients in group B cannot be determined by this study, but the biochemical changes reported in established obesity of childhood mimic those found in the adult. Speculation: Obesity in children is associated with excess lipogenesis and hyperinsulinemia, which are interdependent and initiated through maximal nutritional intake in infancy. Eventually muscle becomes resistant to insulin with decreased transport of glucose into the cell and decreased protein synthesis relative to DNA. The reduced levels of growth hormone in the circulation may indicate excessive uptake by muscle, which is followed, in some instances, by an associated proliferation of nuclei.

Pathogenesis of Osteopetrosis: A Comparison of Human and Animal Spectra

Abstract: The term osteopetrosis was introduced to describe a human condition characterized by generalized sclerosis of the skeleton with multiple fractures [l, 401. Subsequently, several isolated reports have described the clinical spectrum of the human disease, genetic variants, and histological correlates in bone. The occurrence in several animal species of diseases involving increased bone density has suggested that satisfactory models of the human disease might exist which would permit evaluation of pathogenic mechanisms under a variety of experimental conditions. This review compares the human forms of the disease with those animal syndromes which have been termed osteopetrosis on the basis of gross and radiological observations.

Pulmonary Gas Trapping in Premature Infants

Abstract: Extract: Measurements of thoracic gas volume and functional residual capacity were performed serially from birth on 26 premature infants to determine the presence and time course of gas trapping. Nitrogen washouts were carried out on 16 of these infants and urinary-alveolar nitrogen gradients (uADN2) were measured in 7. The infants were divided into two groups, those above and those below 1750 g birth weight. Trapped gas was documented in both groups, but in the smaller infants the condition persisted for a longer time. The mean thoracic gas volume (TGV) in infants over 1750 g birth weight was 2.0 ± 0.7 ml/cm at birth, with a mean functional residual capacity (FRC) of 1.3 ± 0.4 ml/cm; by day 9, the TGV and FRC were 1.5 ± 0.3 and 1.2 ± 0.2 ml/cm, respectively. Infants under 1750 g birth weight had a mean TGV of 1.7 ± 0.2 ml/cm at birth with an FRC of 0.9 ± 0.2 ml/cm; by week 2 of life, mean TGV and FRC were 0.9 ± 0.2 and 0.8 ± 0.2 ml/cm, respectively. When gas trapping was present, nitrogen washouts and uADN2 indicated that the lung was a single well ventilated space with no evidence of an abnormal distribution of ventilation. This indicated that ventilation of the trapped areas was so small that it could not be measured. The possibility that gas trapping is related to the presence of lung fluid and very compliant airways is considered. Speculation: Low birth weight infants have been shown to have high airway resistance, compliant airways, and low lung volume. This combination of findings has been associated with airway closure in adults. The possibility arises that a volume of gas is “trapped” with each expiration until airways are sufficiently stiff and remain patent with every breath.

Role of bile acids in fat absorption in low birth weights infants

Abstract: Low birth weight (LBW) infants absorb fats with greater difficulty than normal term infants The possible role played by intestinal bile acid concentrations (BAC) in this defect was studied Seventeen LBW infants aged 10 to 34 days weighing 1540–2300 Gm (mean-1790) were intubated and duodenal contents were aspirated for a period of one hour starting between 2–3 hours after feedings of unsaturated fat formula Aspirates were kept on ice and were subsequently assayed for lipase activity and total BAC (Method of Iwata) Concurrent 48 hr stool collections were analyzed for fat Lipase activity was normal in all infants (65–16 IU/ml) In infants with duodenal BAC below 2mM/L (critical micellar concentration) coefficients of fat absorption were 48%-77% (normal 80%) In 7 of 8 infants with levels greater than 2mM/L, fat absorption was above 80% Attempts to correlate ages or weights of the infants with levels of fat absorption did not yield consistent relationships However, when age of the infants was related to total BAC, 10–19 day old infants (12) showed a mean value of 207 ± 13 mM/L, compared to 20–34 day old infants (7) with a mean of 58 ± 27 mM/L Control babies of three weeks to 8 mos of age (8) had a mean BAC of 68 ± 27 Four younger LBW infants were restudied after 2–3 weeks and showed a three-fold rise in BAC Conclusions from these preliminary studies indicate that LBW infants display lower levels of duodenal BAC than do older and larger infants There is a good inverse correlation between BAC and steatorrhea

A Child with Lactacidemia and Fructose Diphosphatase Deficiency in the Liver

Abstract: Extract: A female infant with a progressive liver disorder associated with persistent lactacidemia and a tendency toward hypoglycemia was studied. The disorder appeared to be hereditary since the parents were consanguinous and there had been two siblings with the same disease. The existing fasting lactacidemia increased after administration of oral hexose or casein (Figs. 1 and 2). Levels of blood glucose declined to 26 mg/100 ml after casein challenge but the leucine tolerance test was normal. In a liver sample obtained postmortem at 6 months of age as well as in liver tissue from a control subject, pyruvatc carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-diphos-phatase, and glucose 6-phosphatase activities were measured (Table I). Fructose-1,6-diphosphatase activity was found to be very low. Blocked gluconeogenesis due to a deficiency of fructose-1,6-diphosphatase is assumed to be the cause of this inborn error of metabolism. Speculation: Some cases of congenital lactacidemia may be due to defective gluconeogenesis caused by a deficiency of one of the key enzymes of gluconeogenesis.