Showing papers in "Pediatric Research in 1968"

The Cells of Human Colostrum. I. In Vitro Studies of Morphology and Functions

Abstract: Extract: The morphology and certain functions of human colostral cells were studied in vitro. Colostrum from 60 human females contained neutrophils, small lymphocytes, macrophages and occasional epithelial cells. The median concentration of neutrophils in colostrum from breast-feeding mothers was 150/mm3 as compared to 7000/mm3 in colostrum from those who did not breast feed. The median concentration of lymphocytes in human colostrum was 205/mm3. Eighty to ninety percent of colostral lymphocytes in culture underwent blastoid transformation after exposure to phytohemagglutinin. Ten to twenty-five percent of cultured lymphocytes were transformed after the addition of specific antigens to the cultures. The synthesis of DNA by blast forms was demonstrated by radioautographic studies with H3-thymidine. The median concentration of macrophages in colostrum was 2100/mm3. Colostral corpuscles (corpuscles of DONNE) were classed with these cells since they displayed identical features. These included glass-adhesive properties, ameboid activity, phagocytosis and presence of abundant lysosomes. Two types of lymphocyte-macrophage interactions were found in fresh and cultured colostrum. These findings suggested that the interactions occurred in vivo as well as in vitro. Speculation: These observations indicate that immunologically active cells are normal constituents of human colostrum. The possibility is advanced that these cells may influence the host response of the neonatal recipient.

Propionicacidemia, a new inborn error of metabolism.

Abstract: Extract: A male sibling who was born of healthy parents and who died at the age of five days with the clinical picture of severe hypotonia, areflexia, hyperventilation, and grunting is described. An older female sibling with identical symptoms had died some years previously. The parents were unrelated and had three other healthy children. The patient exhibited severe metabolic acidosis which was resistant to therapy. This acidosis was caused by the presence in blood of propionic acid in a very high concentration (5.4 mM/l). The high levels of urea and potassium also present were probably the result of a markedly reduced urine production caused by dehydration. The levels of amino acid in plasma revealed low values for one amino acid, normal values for other amino acids, and high values for lysine, histidine, valine, isoleucine, and leucine. At autopsy, except for a right descending aortic arch, no gross anomalies were found, although the liver was enlarged, probably because of increased fat content. Microscopic examination showed a fatty degeneration of liver cells, degeneration of the Purkinje cells and the granular layer in the cerebellum, and macrophages containing debris of blood cells in the bone marrow and in the spleen. Gas chromatography was used to determine the nature of the accumulated fat in the liver. Among the normal constituents of liver triglycerides, three abnormal fractions were observed, two of which contained C15 and C17 straight chain fatty acids. These were not observed in normal liver fat. The combination of propionicacidemia and the storage of fatty acids with an uneven chain number in the liver pointed to a block in the conversion of propionic acid into methylmalonic acid. Speculation: It is suggested that the propionicacidemia found in this patient is due to a metabolic block in the conversion of propionic acid into methylmalonic acid. The increased concentration of odd-numbered fatty acids (C15 and C17) in the liver may arise from either a decreased breakdown of these fatty acids or an increased synthesis initiated by the high concentration of propionyl-CoA. It is proposed that the missing enzyme is propionyl coenzyme A carboxylase. The fact that a sibling with identical symptoms had died forms a strong argument to postulate that a hereditary abnormality of recessive inheritance is the cause of this as yet undescribed syndrome.

Growth and growth hormone. I. Changes in serum level of growth hormone following hypoglycemia in 134 children with growth retardation.

Abstract: Growth and Growth Hormone: I. changes in Serum Level of Growth Hormone Following Hypoglycemia in 134 children with Growth Rctardation

Barbiturate enhancement of bilirubin conjugation and excretion in young and adult animals.

Abstract: Extract: Glucuronide conjugation of bilirubin in mammalian liver is catalyzed by the microsomal enzyme uriding phosphoglucuronyltransefrasc (UDPGT). Enzymic activity as measured in vitro is low in the young of many species. The present study was designed to determine whether UDPGT activity could be modified in adult, young, and newborn animals. Following intraperitoneal injection of saline and sodium barbital in control and experimental mice, respectively, for three consecutive days, the UDPGT activity in liver homogenates was measured on the fourth day. A significant increase in the enzyme acctivity was found in all ages. Results (μg bilirubin conjugated/g protein/20 min) include; newborn of dam trated during pregnancy, 96, vs control, 38; 4 days of age, treated (3 groups with 3 different levels of barbiturate for 3 days) 240, 362, and 533, vs control, 186; adult (treated) 181 vs control, 103. These increases were not influenced by adrenalectomy, hypophysectomy, or orchiectomy. Rabbits also responded with a similar increase in UDPGT activity after pretreatment with phenobarbital given by subcutaneous injection and were utilized in clearance studies. In adult rabbits, following rapid intravenous infusion of bilirubin (8 mg/kg), an enchancement in excretion into bile and an increase in bile flow were observed. Bile flow (μl bile/100 g body weight/min) increased in adult animals following treatment: 2–3 vs control of 1–2. Total bilirubin excreated as a precent of the infused load was: treated, 76% vs control, 33%. In young rabbits, disappearance of bilirubin from serum was faster in the phenobarbital-pretreated animals than in controls. The excretion of bilirubin (Δ bilirubin mg/100 ml serum) in newborn animals was: treated, 3.01; untreated, 1.13. In 4-day-old animals, the excretions was: treated, 3.89 vs controls, 2.61. It is proposed that several mechanisms may be responsible for the barbiturate effect and they may participate differently at various ages. Speculation: Barbiturates were found to be effective enhancers of bilirubin conjugation and excretion in animals. A similar approach may have important threapeutic value in the human. Newborn and premature infants with a deficient glucuronide conjugating mechanism and a probable defect in hepatic transport can benefit from this pharamacologic approach. Applicability to patients with hyperbilirubinemia on an inherited metabolic bases also can be considered.

Changes in nucleic acid and protein content of the human brain during growth.

Abstract: Extract: In order to establish the pattern of cellular growth, nucleic acid and protein content were serially determined in 31 human brains The eraliest-material was obtained from a fetus with a gestational age of 13 weeks; the latest from a 13-month-old infant Weight, protein, and RNA content increased linearly during this period Weight increased from 5 g to 970 g, protein from 193 mg to 53 g, and RNA from 185 to 1384 mg In contrast, increase in DNA content began to level off at about the time of birth and reached a maximum (approximately 900 mg) by five months of age These data indicate that very little cell division occurs in the human brain after five months of age and that further growth occurs by increase in protein, RNA and, perhaps, lipid content of cells

The plasma aminogram. I. Influence of the level of protein intake and a comparison of whole protein and amino acid diets.

Abstract: The Plasma Aminogram. I. Influence of the Level of Protein Intake and a Comparison of Whole Protein and Amino Acid Diets

The syndrome of congenital adrenocortical unresponsiveness to ACTH. Report of six cases.

Abstract: Extract: Six patients with the syndrome of congenital adrenocortical unresponsiveness to ACTH are reported This syndrome is characterized by feeding problems early in life, hypoglycemic episodes and hyper-pigmentation of the skin (table I) Blood pressure and levels of electrolytes in serum were normal (table II) PPD and histoplasmin skin tests were negative, while antibodies to adrenal, thyroid, and gastric tissues were undetectable Urinary excretion of 17-hydroxycorticosteroids and cortisol production rates were low and did not respond to administration of ACTH (table III) While receiving a low sodium diet, the patients were able to conserve sodium (figs 2, 3 and 4) and to increase the rate of aldosterone secretion (tables IV and V) In one case, adrenal pathology showed a normal zona glomerulosa with atrophy of the zonae fasciculata and reticularis This isolated deficiency in cortisol secretion is not due to a defect in pituitary function or a deficiency of one of the enzymes directly involved in steroid biosynthesis The most probable pathogenesis is an abnormality at the site (or one of the sites) of ACTH action on cortisol biosynthesis Speculation: It is probable that some young infants in whom a diagnosis of Addison's disease is made do, in fact, have the syndrome of congenital adrenocortical unresponsiveness to ACTH Studies of cortisol secretion rates prior to and during ACTH administration and a determination of aldosterone secretion rates while receiving normal and low salt diets will permit differentiation of the two disorders

Sweat composition in relation to rate of sweating in patients with cystic fibrosis of the pancreas.

Abstract: Sweat Composition in Relation to Rate of Sweating in Patients with Cystic Fibrosis of the Pancreas

Correlates of low birth weight. Psychological status at eight to ten years of age.

Abstract: Extract: Five hundred low birth weight children and 492 full-term infants were seen when approximately 40 weeks of age for a pediatric-neurologic examination. Of these, 822 provided the data upon which this report is based. To each child, when eight to ten years of age, there was administered ten subtests of the Wechsler Intelligence Test for Children (WISC), the Bender Gestalt Test and the Wide Range Reading and Spelling Achievement Test. In addition, observations were recorded regarding speech articulation and complexity of grammar. The number of perseveration instances and indications of possible comprehension aphasia observed during the examinations were recorded. The Verbal IQ, Performance IQ and Full Scale IQ scores, as well as the independently obtained Bender Gestalt score, showed increasing impairment with decreasing birth weight. Approximately twice as large a proportion of low birth weight children as of control children fell into the IQ category (50–79) which is associated with special medical or educational needs. At the ages of six to seven years the results of the Stanford-Binet Test showed an IQ difference between the low birth weight and full-sized groups of 3.4 points (F = 7.77, 3 and 810 df, p < 0.001), whereas the WISC given at the ages of eight to ten years indicated an IQ difference of 4.9 points (F = 10.87, 3 and 810 df, p < 0.001) for the same samples of children. Of the twenty psychological measures used to assess development of those who had been premature, relative impairment on 16 were significantly associated with birth weight and one was nearly so at the 0.05 level of significance. When the effect of the presence of indicators of possible neurologic abnormality was removed by analysis of covariance, the statistical significance of the association with birth weight was reduced for each of the variables measured, and only six of the twenty remained with significant assocation. Speculation: Future research might profitably consider whether performance by adolescents of low birth weight is relatively impaired in scholastic situations. Also, recent research suggests that a low birth weight occurring in conjunction with long gestational periods, may significantly prejudice intellectual capacity. However, there are little longitudinal data regarding this.

Endogenous insulin and growth hormone response in children with newly diagnosed diabetes mellitus.

Abstract: Extract: Forty-five children with newly diagnosed diabetes mellitus were evaluated in terms of endogenous release of insulin and growth hormone using glucose, tolbutamide, arginine and glucagon as stimuli. The mean concentration of insulin in the plasma obtained from fasting diabetic children was found to be 10.0 μU/ml, a value significantly below the mean level of 15.3 μU/ml in the control group. Essentially no increase in the concentration of insulin in plasma resulted from stimulation with the above agents. The mean concentration of growth hormone in the plasma of fasting diabetics was found to be 3.8 mμg/ml, a value higher than but not significantly different from the value of 2.5 mμg/ml in the contrast patients. Following the intravenous infusion of arginine, however, the mean concentration of growth hormone in the plasma of diabetic children rose to 20.8 mμg/ml, a level significantly higher than the mean peak value of 7.4 mμg/ml in the nondiabetics. Although no change in the concentration of growth hormone followed glucagon injection in the nondiabetic children, a prompt, significant elevation to 9.4 mμg/ml occurred in the diabetics. Glucagon administration has not previously been reported to stimulate the release of growth hormone. Speculation: Insulin deficiency alone will not adequately explain the variability in clinical symptomatology and metabolic derangement seen in children with newly diagnosed diabetes mellitus. These data suggest that growth hormone may play an important role. The finding that glucagon administration stimulates release of growth hormone in the juvenile diabetic may indicate the presence of a previously unrecognized interrelation between glucagon-growth hormone and insulin.

Glucose tolerance and plasma insulin in newborn infants of normal and diabetic mothers.

Abstract: Extract: Infants born to diabetic mothers remove glucose more rapidly from plasma than do infants of normal mothers. The glucose tolerance of normal newborns in the first hour after intravenous injection of glucose is poorer than in the child or adult. Infants of diabetic mothers have higher levels of insulin-like activity in plasma a few minutes after an intravenous glucose load than do normals. The rate of removal of glucose from plasma during the second hour after loading, however, is enhanced in infants of normal mothers; this correlates with the later peak levels of immunologically reactive insulin in the normal baby. Glucose tolerance and levels of insulin in plasma were determined under identical conditions in the infants of 14 normal mothers, of 14 diabetic mothers who had received insulin, of 6 diabetic mothers who had not received insulin, and of one mother who had had glucosuria in pregnancy and whose baby looked like the infant of a diabetic mother. Glucose tolerance was expressed as the ‘total index’ (Kt), the percentage of glucose disappearing from the plasma in one minute. Insulin levels in plasma were determined by the method of Hales and RANDLE [9]. The Kt of infants of normal women (0.44 to 2.31, with a mean of 1.16) during the first hour after a glucose load differed little from that of infants of non-insulin-treated diabetic mothers (1.51 to 1.93, with a mean of 1.31). The Kt of both groups differed significantly from that of infants of insulin-treated diabetic mothers, in whom the Kt was in the range 0.83 to 5.78, with a mean of 3.30. In the second hour, however, the rate of glucose removal in both groups of infants of diabetic mothers appeared to fall, while in infants of normal mothers, the rate appeared to rise. These observations on Kt correlate with changes in insulin levels in plasma of the normal and non-insulin-treated diabetic groups. Although individual differences existed within the groups, the mean for normals rose from 49, μU/ml of plasma before glucose-loading to 139 at two minutes after. The level then fell, but climbed again to reach a value of 229 μU/ml at one hour. In contrast, the mean for the diabetic group rose from a value of 34 prior to loading to one of 208 μU/ml two minutes after loading. There was, however, little if any second peak. The presence of antiinsulin antibodies makes impossible the accurate measurement of insulin levels in plasma of babies of mothers who have been treated with insulin; in one case, however, treatment had been so brief that no antibody was formed. This baby showed a high but ephemeral insulin response to the glucose load. The infant who looked like an infant of a diabetic mother and whose mother was found to have had persistent glucosuria in pregnancy had, in the absence of insulin antibody, the highest insulin response observed. Speculation: In the first hours of life, insulin is released in response to a glucose load, but the size and speed of the response suggest that it simply reflects the glucose levels to which the infant's pancreas has been submitted in utero and has no specific relation to the diabetic status of the mother. Glucose is readily removed from plasma as a result of the release of insulin, yet the opposing mechanisms for increasing plasma levels of glucose are relatively ineffective at this age, although the neonatal liver contains glycogen. Glycogen can be released readily by administering glucagon, suggesting that the appropriate metabolic pathways are functional. When insulin response to glucose is delayed because intrauterine stimulation of the pancreas has been small, the hormone is nonetheless effective in lowering plasma levels of glucose. These observations reported suggest that although the metabolic pathways for glucose homeostasis exist in the newborn, the hormonal mechanisms for controlling these are inappropriately invoked.

Hyperdibasicaminoaciduria: an inherited disorder of amino acid transport.

Abstract: Extract: A dominantly inherited trait, expressed as ‘hyperdibasicaminoaciduria’, has been identified in 13 of 33 members in a French Canadian pedigree (fig. 1). The female proband was 18 months old when first identified. The medical problems which brought her to our attention were her small stature and symptoms compatible with a mild malabsorption syndrome. Neither the small stature nor the intestinal complaints could be linked confidently with the appearance of the inherited trait; it is more reasonable to assume that the incidental appearance of a medical problem in the proband brought the otherwise benign trait to attention. The trait was characterized by abnormally high urinary excretion rates for the diaminomono-carboxylic (‘dibasic’) compounds, lysine, ornithine, and arginine; cystine, which is excreted in abnormal amounts along with the dibasic amino acids in classical cystinuria, was excreted normally in this instance (table I and figs. 2A and 2B). This constitutes the distinctive characteristic of the trait. It allows one to discriminate the carriers of the trait, who presumably are heterozygotes, from carriers of the various cystinuric genotypes. The trait is expressed consistently with regard to interindividual variation (table I) and intraindividual variation (table II). The plasma concentrations of the affected amino acids were normal in carriers of the trait, while the endogenous renal clearance rates were modestly elevated (table III). A defect in net tubular absorption of the relevant amino acids thus existed. The mutant transport trait was apparently also expressed in the intestine. This is assumed because net accumulation of lysine in plasma after loading by mouth was less in carriers of the trait than in normal subjects (fig. 3 and table IV); in contrast, in the single patient tested, intestinal absorption of cystine was not impaired. The characteristics of the trait suggest that the diaminomonocarboxylic amino acids share a transport system in kidney and intestine which excludes cystine. Speculation: The discovery of a mutant trait, in which transport of diaminomonocarboxylic acids alone is impaired, illustrates the specificity of membrane transport systems for amino acids. In this instance, the belief that cystine is not transported on the ‘dibasic’ system is confirmed. Thus, an interpretation of the physical and chemical basis for classical cystinuria, where cystine and ‘dibasic’ amino acids are affected together, still remains a major challenge to the investigator.

Metabolism of Glycine in the Nonketotic Form of Hyperglycinemia

Abstract: Extract: Hyperglycinemia is a disorder of amino acid metabolism characterized by the presence of increased concentrations of glycine in the blood, urine, and cerebrospinal fluid. It is now recognized that there are two forms of hyperglycinemia each representing distinct diseases. These studies were designed to assess the metabolism of glycine in the nonketotic form of hyperglycinemia. Isotope content was assessed in respiratory CO2 and in glycine, serine and the β carbon of serine of plasma after the separate intravenous injections of glycine-I-14C and glycine-2-14C. The specific activities of 14CO2 isolated from expired air after the injection of glycine-1-14C (fig. 2) declined in control subjects from peak values at 10 to 15 minutes in nearly linear fashion over a 2-hour period. In contrast, curves obtained in the patients were rather flat, rising slowly after injection to highest values at about 60 minutes. At 15 minutes, values for the control individuals exceeded those of the patients by a factor of 5− to 10-fold. These data indicate a defect in the formation of 14CO2 from the first carbon of glycine. When the control subjects were infused with nonisotopic glycine to produce pools comparable to those found in the patient, the specific activities of the serine isolated from plasma after the injection of glycine-1-14C (table II) were virtually the same in both groups. The rate of conversion of glycine-2-14C to serine (fig. 3) in the patients was, however, considerably slower than it was in the control subjects for at least the first 30 minutes, and the curves were flat throughout. Degradation of the serine isolated from plasma and precipitation of the β carbon as formaldemethone indicated that the incorporation of the α carbon of glycine into the β carbon of serine was much higher in the controls than in the patients (fig. 4). The curves for the patients approximated the abscissa indicating virtually no conversion. These data indicate that in nonketotic hyperglycinemia there is a defect in the oxidation of carbon 1 of glycine to CO2 and in the conversion of carbon 2 of glycine to carbon 3 of serine. This is consistent with a defect in an enzyme catalyzing the transformation of glycine to CO2, NH3 and hydroxymethyltetrahydrofolate. Speculation: The data obtained indicate that patients with nonketotic hyperglycinemia are unable in vivo to convert the first carbon of glycine directly to CO2 and the second carbon of glycine to the third carbon of serine. This is consistent with a genetic defect in an enzyme which catalyzes decarboxylation and formation of hydroxymethyltetrahydrofolate from glycine. It should be possible to document such a defect at a cellular and subcellular level.

Colonial growth in agar of cells derived from neoplastic and non-neoplastic tissues of children.

Abstract: Colonial Growth in Agar ofcells Derived from Neoplastic and Non-Neoplastic Tissues of Children

Studies on the mechanism of inhibition of sodium transport in cystic fibrosis of the pancreas.

Abstract: Studies on the Mechanism of Inhibition of Sodium Transport in Cystic Fibrosis of the Pancreas

Erythrocyte Lipids in the Neonate

Abstract: Extract: The lipid composition has been characterized in erythrocytes obtained from the cord blood of fullterm normal infants. There is an increase in total lipid, lipid phosphorous and cholesterol per cell (total lipid = 6.45 × 10 -10 mg; Lipid P = 1.54 × 10 -11mg; cholesterol = 1.79 × 10 -10 mg) when compared with adult controls (total lipid = 5.07 × 10 -10 mg; Lipid P = 1.22 × 10 -11mg; cholesterol = 1.33 × 10 -10mg). Despite the increased lipid content, the percentages of total lipid comprised by lipid phosphorous and cholesterol are similar to those found in the adult (P = 2.40% of total lipid in infants, 2.41% in adults: cholesterol = 27.1% of total lipid in infants, 26.0% in adults). Phospholipid fractionation shows minor variations between the two groups. Cord blood erythrocyte phospholipid has 1.0% lysolecithin, 26.0% sphingomyelin, 27.7% phosphatidylcholine, 15.2% combined phosphatidylserine and phosphatidylinositol, and 29.1% phosphatidylethanolamine. Adult erythrocyte phospholipid has 1.2% lysolecithin, 24.1% sphingomyelin, 29.5% phosphatidylcholine, 13.1% combined phosphatidylserine and phosphatidylinositol and 31.2% phosphatidylethanolamine. Phospholipid fatty acid patterns in cord blood erythrocytes show an increased percentage of palmitic acid (cord = 21.3%, adult = 17.0%), stearic acid (cord = 16.3%, adult = 15.3%) arachidonic acid (cord = 19.6%, adult = 17.4%) and combined 22 and 24 carbon fatty acids (cord = 17.6%, adult = 16.3%) associated with decreased percentages of oleic acid (cord = 11.9%, adult = 14.6%) and linoleic acid (cord = 3.4%, adult = 10.9%). Speculation: The erythrocyte lipids of the newborn show deviations from the adult pattern which may have adaptive value for intrauterine life. These same adaptations may render the cell more vulnerable to oxidative damage in postnatal life.

The total energy expenditure and its components in premature infants maintained under different nursing and environmental conditions.

Abstract: The Total Energy Expenditure and its Components in Premature Infants Maintained under Different Nursing and Environmental Conditions

The Effect of LSD-25 on the Chromosomes of Children Exposed in Utero

Abstract: Extract: This paper reports the cytogenetic investigation of nine children exposed to LSD-25 in utero, four children of other LSD users not exposed in utero, the mothers of these children, and six additional adults taking the drug. In comparison with matched controls, significantly elevated frequencies of chromosomal damage were observed in all the individuals exposed. The frequencies of aberrations, however, were markedly reduced in those children not exposed in utero. Eight structural rearrangements were observed, six dicentric chromosomes and two quadriradial formations, among those individuals exposed to the drug, but none was observed in the controls. In spite of obvious chromosomal aberrations, all of the individuals in this study were apparently healthy and showed no obvious birth defects. Speculation: The significance of chromosomal damage produced in utero by pharmacologic agents and observed in the circulating lymphocytes of exposed infants and children remains controversial. Analogies have been drawn which suggest possible consequences of these lesions. The present study documents chromosomal damage in somatic cells of patients lacking any physical abnormality and reemphasizes the necessity for defining the extent to which chromosomal imbalance can be tolerated without phenotypic deviation. One can only speculate on possible biological events were such agents to affect the chromosomes of spermatagonial cells and thus yield defective gamates. Were this to eventuate, drugs with chromosome-breaking potential could act as powerful mutagens and have effects persisting into subsequent generations.

Relation between birth condition and neuro-behavioral organization in the neonate.

Abstract: Extract: The neuro-behavioral organization of three groups of infants who differed in their condition at birth as determined by their Apgar score was examined during the first week of life. At the time of testing, all infants, regardless of birth status, were in good condition according to clinical evaluation. Testing consisted of the presentation of 30 lateralized somesthetic stimuli to the perioral region of each infant (15 to each side). The response measure used was the lateral direction of the first head turn. As a group, normal infants (Apgar scores of 9–10) were found to be more responsive to stimulation of the right than of the left, and to make more ipsilateral responses to stimulation of the right than of the left. Infants whose condition at birth was poor (Apgar scores 1–6) did not show these patterns of response but were equally likely to be preponderantly responsive to stimulation at either side. The degree of lateral differentiation was atypically small even for those infants of poor birth status who exhibited the typical direction of differentiation, i.e., who made more ipsilateral responses to stimulation of the right than of the left. Furthermore, the proportion of infants of poor birth status who made any contralateral responses was higher than the proportion of normal infants who made such responses. Results from a group of infants whose condition at birth was questionable (Apgar scores 7–8) fell between those from the extreme groups with respect to all of the analyses. Speculation: Poor condition at birth has persistent effects on behavioral organization even in babies who, in clinical judgment, have recovered normal functioning. To the extent that early behavioral organization may be relevant to the subsequent development of lateral differentiation, these effects could be related to the association between a variety of disabilities and disturbances in lateral differentiation which has been found in older children and adults.

The free amino acids of serum during development of Macaca mulatta. II. During pregnancy and fetal life.

Abstract: The Free Amino Acids of Serum During Development of Macaca mulatto II. During Pregnancy and Fetal Life

The Clinical Findings in a Patient with Nonketotic Hyperglycinemia

Abstract: Extract: A male infant with hyperglycinemia presented with neonatal seizures and lethargy, but had neither ketosis nor hematologic abnormalities. Treatment with a low protein diet and glycine-binding agents was instituted at the age of 2 ½ months. Although greater alertness and reduced irritability were noted immediately, the treatment failed to prevent severe developmental retardation and persistent seizures. Speculation: The structural and metabolic basis for the severe neurological damage seen in this rare hereditary metabolic defect is unclear. It seems imperative, however, that prompt diagnosis and therapy be instituted if one expects to offer a better prognosis. Attempts to maintain normoglycmemia by using a low-protein diet and glycine-binding agents may be useful if serum glycine levels are monitored carefully.

Transport and intracellular fate of cysteine-35S in leukocytes from normal subjects and patients with cystinosis.

Abstract: Extract: The transport and intracellular fate of cysteine-35S was studied in leukocytes from nine children with cystinosis and nine control subjects of similar age in an attempt to explain the presence of 80 times the normal quantity of free cystine in cystinotic leukocytes. Two differences were observed: the cystinotic cells took up nearly twice as much cysteine-35S as did control cells. Subsequently, almost 40 percent of the 35S was found as the oxidized form, cystine-35S in cystinotic leukocytes, compared with only 2 percent in control leukocytes. Comparison of intracellular and extracellular concentrations of cysteine-35S at steady state showed no differences between normal and cystinotic leukocytes. Both cell types incorporated 30 percent of the intracellular 35S into glutathione and showed the same time course of 35S efflux. Speculation: The increased uptake of cysteine-35S shown by cystinotic leukocytes could be taken as valid conventional evidence for a primary defect in the transport of cysteine in cystinosis. The prompt appearance of the extra 35S transported as intracellular cystine-35S suggests, however, that this rapid conversion may be the primary defect and that the increased uptake of cysteine-35S is but a compensatory mechanism for maintaining the physiological concentration of intracellular cysteine.

Hereditary alterations in the immune response: coexistence of "agammaglobulinemia", acquired hypogammaglobulinemia and selective immunoglobulin deficiency in a sibship.

Abstract: Extract: A longitudinal immunologic study was conducted in a family in which an entire sibship of three males was unduly susceptible to infection. The oldest boy's history of repeated severe infections beginning in infancy and his marked deficiencies of all three major immunoglobulins were compatible with a clinical diagnosis of congenital ‘agammaglobulinemia' (table I, fig. 1). Recurrent severe infections in the second boy did not begin until late childhood, and his serum abnormality involved deficiencies of only two of the major immunoglobulin fractions, IgG and IgM (table I, fig. 1). This phenotype of selective immunoglobulin deficiency is previously unreported. Serum concentrations of the three immunoglobulins in the youngest boy (who also had a late onset of repeated infection) were normal or elevated when he was first studied, but a marked decline in levels of each of these fractions was observed over a four-year period (table I, fig. 1). We could find no previous reports describing apparent congenital and acquired immunologic deficiencies in a sibship. Repeated infections and demonstrated specific immunologic unresponsiveness preceded gross abnormalities in the total and fractional gamma globulin levels in both of the younger boys (tables II–IV). When the total immunoglobulin level in the second boy was 735 mg/100 ml, he failed to respond with a normal rise in titer after immunization with ‘A' and ‘B' blood group substances, diphtheria, tetanus, or Types I and II poliovaccines. When the total immunoglobulin level in the youngest boy was 1564 mg/100 ml, he had absent ‘B' and low ‘A' isohemagglutinins. Later studies showed that he failed to respond with a normal rise in titer after stimulation with ‘A' and ‘B' blood group substances, diphtheria, tetanus, typhoid, and Types I, II and III poliovaccines. Similar studies in family members demonstrated a marked polyclonal IgA hyperglobulinemia and specific immunologic unresponsiveness to ‘B' substance in the mother (tables I and II). She also gave poor circulating antibody responses to immunization with diphtheria and poliovaccines. Two maternal aunts had high normal levels of IgA and low isohemagglutinin titers (table VII). We are unaware of other reports of specific immunologic unresponsiveness and/or antibody deficiency in the apparent heterozygote for what appears to be an X-linked immunologic deficiency. A male maternal first cousin also had a high normal level of IgA, asthma, shortness of stature and repeated respiratory infections. These findings provide direct evidence for a genetic influence in some forms of acquired immunologic deficiency. Speculation: The heterogeneity of immunologic abnormality observed in this family is inconsistent with many of the current hypotheses of the genetic defects in immunologic deficiency. An afferent phase defect seems to offer the best explanation for a single genetic mechanism of immunologic deficiency in this family. The question of a possible contributory role of repeated bacterial infections in the apparent progression and heterogeneity of immunologic deficiency in the members of this sibship is raised.

Cortisone-Induced Growth Failure in Neonatal Rats

Abstract: Extract: Growth failure in two-day-old rats following a single injection of cortisone has been ascribed to thymic destruction. Specific early degeneration of thymus gland, however, has not been demonstrated. Moreover, the cellular changes in other organs accompanying this induced growth failure are unknown. Within 33 hours of injection of cortisone there is marked destruction of thymic and splenic cells, as indicated by a 50-fold reduction in DNA content of these organs. On about the third day following injection, DNA, RNA, and protein content were proportionally reduced in seven other organs studied, and protein: DNA and RNA: DNA ratios remained normal. All organs, therefore, contained fewer cells of normal size. By three weeks of age, the thymus and the spleen were partially regenerated and showed reductions in DNA, RNA, and protein content in proportion to the amount present in other organs. These data demonstrate that the initial event after injection of 1 mg of cortisone in two-day-old rats is the destruction of thymic and splenic cells. This is followed by partial regeneration of these organs. Later, cell division is slowed in other organs, resulting in a stunted animal whose organs contain fewer cells of normal size. Speculation: Injection of a large dose of steroids into young animals will result in selective destruction of lymphoid tissue, subsequent immunologic tolerance, and growth failure. The stunted animal shows a continually reduced number of cells in certain organs. These data reinforce the concept that growth failure after steroid injection is secondary to massive destruction of lymphoid tissue and further support the hypothesis that the thymus may play a role in the regulation of growth during the neonatal period.

Pharmacokinetic Studies with a Long-Acting sulfnamide in Subjects of Different Ages: A Modern Approach to Drug Dosage Problems in Developmental Pharmacology

Abstract: Pharmacokinetic Studies with a Long-Acting sulfnamide in Subjects of Different Ages: A Modern Approach to Drug Dosage Problems in Developmental Pharmacology

Immunologic Amnesia: Study of an 11-Year-Old Girl with Recurrent Severe Infections Associated with Dysgammaglobulinemia, Lymphopenia and Lymphocytotoxic Antibody, Resulting in Loss of Immunologic Memory

Abstract: Immunologic Amnesia: Study of an 11-Year-Old Girl with Recurrent Severe Infections Associated with Dysgammaglobulinemia, Lymphopenia and Lymphocytotoxic Antibody, Resulting in Loss of Immunologic Memory

Lung Tissue Resistance in Healthy Children

Abstract: Extract: In ten healthy children, simultaneous measurements were made of the total pulmonary resistance and the airway resistance. The difference between these two measurements gave the lung tissue resistance which amounted to 1.08 ± 0.32 cm H2O/l/s (range, 0.65 to 1.59), or 29% of the total pulmonary resistance. It was on an average three times higher in children than in healthy adults. An inverse relation was found between lung tissue resistance and the vital capacity. Moreover, the results of measurements made in one child breathing at three different breathing patterns, indicate that with increasing tidal volume, lung tissue resistance increases. These observations suggest that lung tissue resistance itself is the sum of two components; one being due to the flow-dependent frictional forces of lung tissue, and the other, independent of flow resistance, being due to the nonideal elastic properties of the lung. The results obtained can be explained reasonably well on the basis of the latter component which seems to be much more important than the former.

The biosynthesis of cystathionine in patients with homocystinuria.

Abstract: Top of pageAbstract Extract: The synthesis in rat and normal human liver homogenates of cystathionine from homoserine+cysteine was studied. When cystathionine was used as substrate, cyst(e)ine was formed and incubation of liver homogenate with homoserine+cysteine resulted in the formation of cystathionine. Incubation of homogenate prepared from homocystinuric liver with L-homoserine+DL-cysteine-3-14C or DL-cysteine-35S resulted in the formation of labelled cystathionine. The identity of cystathionine was established in three chromatographic separations. Oral loading with homoserine and cysteine or cystine in two patients with homocystinuria resulted in urinary excretion of cystathionine in amounts similar to that reported in normal human subjects without amino acid loading. Speculation: The observation that human and monkey brains contain much larger quantities of cystathionine than those of other species [26] suggests a special relation of this amino acid to the normal development and function of the primate brain. Cystathionine is either absent from or markedly deficient in the brain of untreated homocystinuric patients [2, 9]. Since we have shown that synthesis of cystathionine from homoserine and cysteine does take place in the patient's liver in vitro, supplementation of the diet with homoserine and cysteine may prove effective in raising intracellular cystathionine concentration toward the normal, and may possibly improve the prognosis in this disease. Keywords: Cystathionase; cystathionine; cystine; homocystinuria; homoserine; pyridoxine; serine

Studies in acute iron poisoning. 3. The hemodynamic alterations in acute experimental iron poisoning.

Abstract: Extract: One hour after administration of a lethal dose of ferrous sulfate into the intestine, 10 dogs sustained a sharp decline in cardiac output (mean 57%), a lesser reduction of arterial blood pressure (mean 17%), and a marked elevation of total peripheral resistance (mean 100%). Thereafter, the cardiac output decreased more rapidly than did blood pressure. Total peripheral resistance remained elevated until death.

[Familial congenital hypoaldosteronism caused by 18-OH-dehydrogenase deficiency].

Abstract: Extract: In one case studied from the neonatal period through a follow-up period at almost five years of age, a salt-losing syndrome could be related to a defect in 18-OH-dehydrogenase. In the intial course of the disease, treatment with desoxycorticosterone acetate controlled the salt-losing tendency. At that time, the rate of aldosterone secretion was less than 10 μg/day and that of urinary tetrahydroaldosterone was less than μg/day. In contrast, the rate of corticosterone secretion was 5400 μg/day and the F:B ratio was 0.8. Urinary 18 hydroxytetrahydro A (18 OH-THA) was increased to 128 μg/24 h. There was no cortisol insufficiency; secretion rate was 20 mg m2/day and plasma ACTH 0.24 mU/100 ml plasma. At 20 months of age, treatment was stopped because of hypernatremia. From that time on, the child was clinically normal and received no salt supplement. The hormonal results were as follows: At 22 months of age, the secretion rate of aldosterone was less than 5 μg/day and of corticosterone was 8600μg/day on the sixth day of a well-tolerated salt suppression test. 18 OH-THA was 116μg/day; the F:B ratio for urinary metabolites was low, 0.9. At 3 years and 7 months of age, excretion of urinary tetrahydroaldosterone was 10 μg/day, 18 OH-THA was in the normal range, and the F:B ratio remained low, 0.6 (normal salt intake). At 4 years and six months of age, secretion rate was 19 μg/day and the 18 hydrocorticosterone secretion rate was 470 μg/day (ratio 18 OH-B: aldosterone 24.7). Plasma renin activity was 88.8 ng/l/min. The brother of the propositus was observed when 6 years of age. Urinary tetrahydrosterone was 27 μg/day, 18 OH-THA was 75/μg/day, and the urinary F:B ratio was 0.7 while receiving a normal salt intake. The spontaneous clinical improvement of subjects with the salt-losing syndrome is possibly related to the appearance of a certain amount of aldosterone, an increase in secretion of corticosterone, and modification in salt content of a normal diet during this period. Speculation: A salt-losing syndrome due to 18-OH-dehydrogenase deficiency, probably familial, improved spontaneously. Long-term studies showed persistence of the biosynthetic defect. The data presented raise questions concerning clinical recovery that could be correlated with steroid administration and, possibly, with modifications in sodium homeostasis at that period of life.