Showing papers in "Pediatric Research in 1992"

Enhancement of the circulating antibody secreting cell response in human diarrhea by a human Lactobacillus strain.

Abstract: Human Lactobacillus sp strain GG (Lactobacillus GG) administered during acute rotavirus diarrhea has been shown to promote clinical recovery. To elucidate the immune mechanisms behind such a favorable outcome, the ELISPOT (solid phase enzyme-linked immunospot) assay of Ig- and specific antibody-secreting cells among circulating lymphocytes was used, giving indirect evidence of the immunologic events in the gut. After rehydration, 39 children with acute rotavirus diarrhea, mean age 16 (SD 6) mo, randomly received either a Lactobacillus GG fermented milk product (study group) or a pasteurized yogurt (placebo group). The duration of diarrhea was significantly shorter in the study group than in the placebo group [mean 1.1 (SD 0.6) versus 2.5 (SD 1.4)d, p = 0.001]. Lactobacillus GG therapy was associated with a significantly enhanced nonspecific humoral response during the acute phase of the infection, reflected in the IgG, IgA, and IgM Ig-secreting cell numbers. At convalescence, 90% of the study group versus 46% of the placebo group had developed an IgA specific antibody-secreting cell response to rotavirus (p = 0.006). The results indicate that Lactobacillus GG promotes recovery from rotavirus diarrhea via augmentation of the local immune defense. Furthermore, specific IgA response to rotavirus is endorsed, which is possibly relevant in protection against reinfections.

Mutations within the S gene of hepatitis B virus transmitted from mothers to babies immunized with hepatitis B immune globulin and vaccine.

Abstract: A variant of hepatitis B virus (HBV) having a specific mutation within the S gene has been found to infect vaccinees. To know whether similar variants were involved in Japan, we analyzed two cases of maternal transmission of HBV in infants immunized with hepatitis B immune globulin and hepatitis B vaccine. DNA clones of HBV S genes were propagated from patients and family members and sequenced. In one family, the DNA clones from the baby patient had a Gly-to-Arg mutation at the 145th codon of the S gene, whereas those from her mother had no such mutations. In the other family, all the DNA clones obtained from the two infected children had the 145th codon intact, but they had a missense mutation at the 126 th codon of the S gene, causing an amino acid substitution of Asn for Thr or Ile. This same mutation was observed in 12 of 17 clones of DNA obtained from their mother. In comparison with the wild type HBV-derived hepatitis B surface antigen, the two types of S gene mutations, either at the 145th or the 126th codon, were associated with a significant decrease in the antigenicity of some determinants on the hepatitis B surface antigen, measured by MAb. Amino acid substitution at these sites, therefore, would have induced the escape from conventional vaccines that were S gene products of wild type HBV and also from hepatitis B immune globulin, whose main components were probably also antibodies against the S gene products expressed by wild type HBV.

Dynamic analysis of cardiac R-R intervals in normal infants and in infants who subsequently succumbed to the sudden infant death syndrome.

Abstract: Infants who subsequently succumb to the sudden infant death syndrome (SIDS) have higher heart rates and reduced heart rate variation compared with other infants. We examined dynamic changes in cardiac interbeat intervals to explore these differences in cardiac control. Recordings of electrocardiographic activity and respiratory movement were acquired from 13 SIDS victims before their deaths. Moment-to-moment changes in R-R intervals during quiet sleep, rapid eye movement sleep, and waking were compared with values of 13 matched control infants. For each sleep-waking state, every R-R interval was plotted against the previous interval (Poincare plots), and each change in interbeat interval was plotted against the previous change. Dispersion of interbeat intervals at different heart rates was reduced in SIDS victims, resulting in Poincare plots markedly different from those of controls. The dispersion, sampled at the 10th and 90th percentiles of heart rates, was reduced across all sleep-waking states in SIDS victims. At high heart rates, the difference between groups disappeared after correcting for basal rate; however, the reduced range at low heart rates was independent of basal rate. SIDS victims also showed smaller beat-to-beat changes in heart rate and fewer sustained runs of consistent heart rate changes during waking relative to controls. The differences in cardiac rate dynamics suggest altered autonomic control in infants who succumb to SIDS. We speculate that the autonomic disturbance may lead to cardiac instability or may indicate CNS alterations with the potential to affect other vital functions.

Cerebral Histologic and Electrocorticographic Changes after Asphyxia in Fetal Sheep

Abstract: Asphyxia can cause neurologic damage in the fetus, hot there are few data relating severity or duration of asphyxia to the degree of cerebral damage. We report cerebral histologic and electrophysiologic changes after asphyxia in chronically instrumented late-gestation fetal sheep. We reduced uterine blood flow to produce an ascending aortic blood oxygen content 7.0 in five of six without damage (p < 0.05). We conclude that severe intrauterine asphyxia for periods of 30 to 120 min can cause predominant parasagittal neuronal death and that this is associated with hypotension, severe metabolic acidosis, and suppression of EEC during the insolt. These data are consistent with the suggestion that impairment of cerebral perfusion is a critical event in localizing cerebral damage during perinatal asphyxia.

Heart rate variability in congenital central hypoventilation syndrome

Abstract: Heart rate variability was assessed in 12 patients with congenital central hypoventilation syndrome (CCHS) and in age- and sex-matched controls using SD of time intervals between R waves (R-R intervals), R-R interval histograms, spectral analysis, and Poincare plots of sequential R-R intervals over a 24-h period using ambulatory monitoring. Mean heart rates in patients with CCHS were 103.3 +/- 17.7 SD and in controls were 98.8 +/- 21.6 SD (p greater than 0.5, NS). SD analysis of R-R intervals showed similar results in both groups (CCHS 102.2 +/- 36.0 ms versus controls 126.1 +/- 43.3 ms; p greater than 0.1, NS). Spectral analysis revealed that, for similar epochs sampled during quiet sleep and wakefulness, the ratios of low-frequency band to high-frequency band spectral power were increased for 11 of 12 patients with CCHS during sleep, whereas a decrease in these ratios was consistently observed in all controls during comparable sleep states (chi 2 = 20.31; p less than 0.000007). During wakefulness, the ratios of low-frequency band to high-frequency band spectral power were similar in both patients with CCHS and controls. Poincare plots displayed significantly reduced beat-to-beat changes at slower heart rates in the CCHS patients (chi 2 = 24.0; p less than 0.000001). The scatter of points in CCHS Poincare plots was easily distinguished from controls. All CCHS patients showed disturbed variability with one or more measures. The changes in moment-to-moment heart rate variability suggest that, in addition to a loss of ventilatory control, CCHS patients exhibit a dysfunction in autonomic nervous system control of the heart.

The frequency of revertants in mdx mouse genetic models for Duchenne muscular dystrophy.

Abstract: The mdx mouse has been used for the development of cellular and gene therapies for Duchenne muscular dystrophy. The relatively frequent occurrence of dystrophin-positive muscle cells called revertants has hampered these efforts by interfering with data interpretation. The mdx4cv and mdx5cv dystrophin mouse mutants have approximately 10-fold fewer revertants than the mdx mutant at both 2 and 6 mo. The mdx3cv dystrophin mouse mutant may be a useful model for some types of human dystrophin deficiencies in which the levels of dystrophin are low but not completely absent.

The mammalian glucose transporters.

Abstract: We have described the properties of glucose transporters expressed in several mammalian tissues and have summarized some of the adaptations that take place involving these molecules in various normal and abnormal states. With the exception of a few cell types, such as adipocytes and skeletal muscle, glucose transport is not a rate-limiting step in cellular glucose metabolism, and other substrates may be equally important for cellular metabolism. Nevertheless, an understanding of the mechanisms behind the regulation of glucose transport in individual tissues may facilitate an understanding of in vivo glucose utilization and clearance processes as they relate to normal and disease states. Although adult studies provide an impetus toward a mechanistic approach in preventing and treating various disease states involving derangements in glucose homeostasis, there remains a need for similar studies in the fetus and newborn. These developmental studies should help unravel the fetal/neonatal responses to normal and abnormal hormonal and substrate milieu.

Gaucher disease in the neonate: a distinct Gaucher phenotype is analogous to a mouse model created by targeted disruption of the glucocerebrosidase gene.

Abstract: A group of neonates with Gaucher disease with a particularly devastating clinical course is described. The phenotype of these infants is analogous to that of a Gaucher mouse, which was created by targeted disruption of the mouse glucocerebroside gene. Similar to the homozygous mutant mice with glucocerebrosidase deficiency, these infants present at or shortly after birth, have rapidly progressing fulminant disease, and many have associated ichthyotic skin and/or hydrops fetalis. This transgenetic mouse model of Gaucher disease has helped us to appreciate a distinct Gaucher phenotype. Potentially, as this technology is applied to create other animal models of metabolic diseases, it may enable the recognition of other, as yet unappreciated presentations of inherited disorders.

Intrauterine growth retardation: fetal glucose transport is diminished in lung but spared in brain.

Abstract: "Uteroplacental insufficiency" often causes asymmetric fetal growth retardation. Glucose transporters control cell glucose utilization and thus may be critical in the control of fetal growth. We hypothesized that uteroplacental insufficiency might alter glucose transporter activity, protein, and gene expression and thereby affect discordant organ growth in small-for-gestational-age (SGA) fetuses. We performed bilateral uterine artery ligation in pregnant rats on d 19 of gestation (term-21.5 d) to cause uteroplacental insufficiency and obtained fetal brain and lung tissue on d 20. The brain mass of SGA fetuses did not differ from that of sham and normal fetuses, but lung mass was significantly diminished. Glucose transport, measured with [3H]2-deoxyglucose, was similar in glial cells and brain tissue of SGA, sham, and normal fetuses. In contrast, type II pneumocytes, lung fibroblasts, and lung tissue of SGA fetuses had significantly decreased glucose transport. The intrinsic activity of the glucose transporter (Km) was not altered in the brain or lung of SGA fetuses. Total glucose transporter protein measured by cytochalasin-B binding and glucose transporter 1 mRNA was diminished in SGA lung tissue and type II pneumocytes, but not in SGA brain tissue or glial cells. We could not detect glucose transporter 3 mRNA in significant quantity in any tissue. With uteroplacental insufficiency, glucose transport is differentially altered in lung and brain. Glucose transporter protein and gene expression are diminished in the lung and normal in the brain of SGA fetuses. These changes may contribute to fetal growth retardation and the phenomenon of "brain sparing."

Docosahexaenoic Acid Status of Term Infants Fed Breast Milk or Infant Formula Containing Soy Oil or Corn Oil

Abstract: Docosahexaenoic Acid Status of Term Infants Fed Breast Milk or Infant Formula Containing Soy Oil or Corn Oil

Effect of insulin-induced and fasting hypoglycemia on perinatal hypoxic-ischemic brain damage.

Abstract: Experiments in adult animals have indicated that hyperglycemia accentuates whereas hypoglycemia ameliorates hypoxic-ischemic brain damage. To determine whether hypoglycemia is protective or deleterious to the perinatal brain subjected to hypoxia-ischemia, 7-d postnatal rats were rendered hypoglycemic either by receiving an s.c. injection of insulin or fasting for 12 h. All rat pups underwent unilateral common carotid artery ligation followed by exposure to 8% oxygen-balance nitrogen at 37 degrees C for 2 h. Control animals (no insulin or fasting) received s.c. injections of normal saline. Mean blood glucose concentrations were 5.4 +/- 0.1, 4.3 +/- 0.2, and 3.4 +/- 0.1 mmol/L for control, insulin, and fasted animals, respectively. Blood beta-hydroxybutyrate concentrations were identical (0.5 +/- 0.1 mmol/L) for control and insulin-treated animals, but more than doubled in concentration in the fasted animals (p less than 0.001). Mortality rates during hypoxia-ischemia were higher in the insulin-treated animals (30%) than in either the fasted (4%) or control (0%) animals (p less than 0.05). Fasted animals showed a significant reduction in hypoxic-ischemic brain damage as compared with either the insulin-treated or control animals. Insulin-treated animals were not significantly different from controls. The findings indicate that 1) insulin induced hypoglycemia does not provide a protective effect on perinatal hypoxic-ischemic brain damage, as in adults; and 2) fasting adequate to produce hypoglycemia and ketonemia improved neuropathologic outcome.

Polyamine concentration in rat milk and food, human milk, and infant formulas.

Abstract: The polyamine concentration in rat milk and food, human milk, and infant formulas was estimated by HPLC. In rat milk, the concentration of putrescine and spermine was low (generally under 2.5 nmol.mL-1 for putrescine and under 1 nmol.mL-1 for spermine). The spermidine concentration was higher and seemed to increase during lactation. The rat food was richer in polyamines than the rat milk (about 150 times for putrescine and spermine, about 30 times for spermidine). We already proved that ingestion of spermine or spermidine can induce precocious maturation of the rat intestine. The present observations suggest that polyamines contained in rat food could play an important role in postnatal maturation of the rat intestine. The polyamine concentration of human milk was measured from 60 different mothers during a period extending from the 1st wk to the 6th mo of lactation. Great variation was observed. During the 1st mo of lactation, the general pattern was as follows: putrescine concentration generally varied little (from 1 to 3 nmol.mL-1), spermine and spermidine concentrations showed a similar pattern (the highest values appeared at the end of the 1st wk of suckling). After the 4th mo of lactation, putrescine concentration increased slightly, whereas spermine and spermidine concentration stayed almost stable. The concentrations of polyamines in 18 powdered milks for babies were estimated. Spermine and spermidine contents were lower than those in human milk. A protective effect of spermine or spermidine against alimentary allergies is suggested.

Tumor Necrosis Factor-α in Human Milk

Abstract: We previously demonstrated that certain biologic activities in human milk were partially blocked by antibodies directed against human tumor necrosis factor-α (TNF-α). In this study, immunochemical methods were used to verify the presence of TNF-α in human milk obtained during the first few days of lactation. Gel filtration revealed the presence of TNF-α by RIA in molecular weight fractions between 80 and 195 kD. TNF-α could not be detected consistently by conventional Western blotting or cytotoxic assays. Although immunoreactive bands were detected by a Western blot-125I protein A technique in TNF-α-positive fractions from gel filtration, those bands proved to be nonspecific. TNF-α in milk was reliably quantified by the competitive RIA. Those studies revealed that the concentrations of TNF-α in milk were 620 ± 183 pg/mL. Although RNA to TNF-α was detected in milk leukocytes by Northern blotting, little TNF-α was found in those cells before or after stimulation with N-formyl-l-methionyl-l-leucyl-l-phenylalanine or 4β-phorbol-12β-myristate-13α-acetate. The origin of this cytokine in human milk remains unclear. Nevertheless, this study suggests that TNF-α is present in early human milk in sufficient quantities to exert possible biologic effects upon the mammary gland of the mother or the immune system of the infant.

Hypoxemia and Reoxygenation with 21% or 100% Oxygen in Newborn Pigs: Changes in Blood Pressure, Base Deficit, and Hypoxanthine and Brain Morphology

Abstract: To study whether room air is as effective as 100% O2 in resuscitation after hypoxia, hypoxemia (Pao2 2.3–4.3 kPa) was induced in newborn pigs (2–5 d old) by ventilation with 8% O2 in nitrogen. When systolic blood pressure had fallen to 20 mm Hg, animals were randomly reoxygenated with either 21% O2 (group 1, n = 9) or 100% O2 (group 2, n = 11) for 20 min followed by 21% O2 in both groups. Controls (group 3, n = 5) were ventilated with 21% O2 throughout the experiment. Base deficit peaked at 31 ± 5 mmol/L (mean ± SD) for both hypoxic groups at 5 min of reoxygenation and then normalized over the following 3 h. There were no statistically significant differences between the two groups during reoxygenation concerning blood pressure, heart rate, base deficit, or plasma hypoxanthine. Hypoxanthine peaked at 165 ± 40 and 143 ± 42 μmol/L in group 1 and 2 (NS), respectively, and was eliminated monoexponentially in both groups with an initial half-life for excess hypoxanthine of 48 ± 21 and 51 ± 27 min (NS), respectively. Blinded pathologic examination of cerebral cortex, cerebellum, and hippocampus after 4 d showed no statistically significant differences with regard to brain damage. We conclude that 21% O2 is as effective as 100% O2 for normalizing blood pressure, heart rate, base deficit, and plasma hypoxanthine after severe neonatal hypoxemia in piglets and that the extent of the hypoxic brain damage is similar in the two groups.

Development of intestinal mucosal immunity in fetal life and the first postnatal months.

Abstract: Nine premature infants who were either stillborn or who died shortly after delivery (gestational age, 24-32 wk), eight full-term infants who died during the first 3 postnatal wk, and four infants who died in the postneonatal period were studied by immunohistochemistry for duodenal expression of secretory component (SC) and epithelial HLA class I and II determinants and for the presence of IgA-, IgM-, and IgG-producing immunocytes. Only small amounts of SC appeared before the 29th gestational wk, but thereafter it increased rapidly; 1 wk after birth, SC showed an adult distribution pattern. Epithelial class I was expressed throughout the period investigated, whereas class II (HLA-DR) determinants were absent on the duodenal villi until 1 wk after birth. HLA-DP and -DQ were not expressed by the epithelium. No IgA immunocytes were seen before 1 wk after birth, whereas a few IgM- and IgG-producing cells were present throughout the period studied. The intense epithelial HLA-DR expression from the 2nd postnatal wk, along with SC and the appearance of IgA immunocytes, suggests that the intestinal immune system is modulated in response to environmental factors shortly after birth.

Dual energy x-ray absorptiometry measurement of bone mineral content in newborns: validation of the technique.

Abstract: Dual Energy X-Ray Absorptiometry Measurement of Bone Mineral Content in Newborns: Validation of the Technique

Bioavailability in man of iron in human milk and cow's milk in relation to their calcium contents.

Abstract: Iron absorption from human milk and cow's milk was compared in the same subjects using two radio-iron tracers and extrinsic labeling of the iron. Previously observed higher iron absorption from human milk was confirmed as 19.5 +/- 17.3% (mean +/- SD) in cow's milk versus 48.0 +/- 25.5% in human milk; mean individual absorption ratio was 0.39 +/- 0.18 (p less than 0.0001). Cow's milk has a several times higher content of calcium, recently established to be a potent inhibitor of iron absorption. Adding calcium chloride to human milk in amounts to equate the calcium content of cow's milk significantly reduced iron absorption [39.1 +/- 17.8% (mean +/- SD) versus 21.3 +/- 10.6%]; mean individual absorption ratio with or without added calcium was 0.58 +/- 0.12 (mean +/- SD) (p less than 0.0001). Differences in calcium content could explain at least 70% of the difference in iron bioavailability between milks. It is suggested that the remaining 30% difference may mainly be an artifact related to inhomogeneous radioiron-labeling of milk iron compounds, especially in human milk, and that the main difference in true iron absorption between human and cow's milk is related to their different calcium contents. The rather high fractional iron absorption from human milk can be explained by its low iron content. There is nothing to indicate that human milk contains any enhancer of iron absorption. The marked inhibiting effect of calcium on iron absorption should be considered in the design of infant formulas to achieve an optimal balance in the contents of calcium and iron.

Defective production of interleukin-6 by monocytes: a possible mechanism underlying several host defense deficiencies of neonates.

Abstract: Several deficiencies in antibacterial defense have been described in neonates. Among those best characterized are delayed maturation of B cells into antibody producing cells, deficient T-cell maturation, and delayed cycling of hematopoietic progenitor cells after an infectious challenge. No unifying theory has been forwarded, however, to explain the concomitance of these three developmental deficiencies. IL-6, a cytokine produced primarily by monocytes and macrophages in response to stimulation by IL-1, is involved in the regulation of these three processes. Thus, we postulated that defective production of IL-6 could be a mechanism underlying these immune deficiencies of neonates. Indeed, we observed that at peak production, cells of five term neonates produced only one half as much IL-6 (14 120 ± 2590 pg IL-6/108 monocytes) as those of five adults (28 940 ± 1680 pg, p < 0.001). Peak production was lower still by monocytes of six preterm neonates (7190 ± 1400 pg, p < 0.001 versus term). Production of IL-6 protein was inhibited by actinomycin D and the IL-6 mRNA content of monocytes from neonates, as assessed by competitive polymerase chain reaction, was less than that of adult monocytes. We speculate that defective IL-6 transcription might underlie some of the defects in immune regulation observed in neonates.

Enzyme augmentation in moderate to life-threatening Gaucher disease.

Abstract: Gaucher disease type 1 (GD type 1) is the most prevalent lysosomal storage disease and has its highest frequency in the Ashkenazi Jewish population. Deficiency of the enzyme, acid beta-glucosidase, results in the deposition of glucocerebroside primarily in macrophages. The accumulation of such "Gaucher cells" leads to visceromegaly, hepatic and bone marrow dysfunction, hypersplenism, and bony disease. Eleven GD type 1 patients, ages 4-52 y, with moderate to life-threatening manifestations, received 6-12 mo of enzyme augmentation with a macrophage-targeted acid beta-glucosidase preparation. Within 6 mo, substantial increases in Hb levels (mean = +30%) and platelet counts (mean = +39%) were observed. Hepatic and splenic volumes decreased by approximately 20% (range = 3-35%) and approximately 35% (20-52%), respectively. Hematologic and hepatic volume improvements were similar in the splenectomized (n = 4) and nonsplenectomized (n = 7) patient groups. In this patient population, no major differences were observed in the hematologic and visceral improvements with enzyme doses of 30, 50, or 60 IU/kg administered every 2 wk. Normal levels of acid beta-glucosidase activity were present in hepatic autopsy samples from one patient 11 d after enzyme infusion. In comparison, exogenous activity was absent from brain and lung specimens of the same patient. High levels (approximately 10-fold normal) were present in bone marrow samples from two patients obtained at 1 and 11 d after infusions. These studies demonstrate biochemical and clinical improvements by targeted enzyme augmentation in GD type 1, even in far advanced, life-threatening involvement.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased G-CSF and IL-3 Production and Gene Expression from Mononuclear Cells of Newborn Infants

Abstract: Newborns are predisposed to neutropenia and thrombocytopenia during bacterial sepsis. The presence of peripheral cytopenias during overwhelming infection may be secondary to decreased hematopoietic growth factor production during states of increased demand. We therefore examined circulating levels of granulocyte-colony stimulating factor (G-CSF) and IL-3, production of G-CSF and IL-3 from unstimulated and stimulated mononuclear cells (MNC), expression of G-CSF and IL-3 genes during unstimulated and stimulated conditions, and equilibrium and binding of G-CSF receptors on mature effector peripheral blood cells of adults and neonates. Serum from cord and adult peripheral blood contained negligible amounts of both G-CSF (less than or equal to 50 pg/mL) and IL-3 (less than or equal to 5 pg/mL). Constitutive supernatant levels of G-CSF and IL-3 from cord and adult unstimulated MNC were also undetectable. However, there was a significant difference in G-CSF and IL-3 production from stimulated cord and adult MNC. Supernatants from stimulated adult MNC had significantly more G-CSF (p less than 0.007) and IL-3 (p less than 0.02). Additionally, Northern blot hybridization and densitometry of autoradiographs demonstrated significantly more G-CSF and IL-3 mRNA transcripts from adult than from cord MNC. Lastly, affinity, binding, and number of G-CSF receptors on cord and adult peripheral effector cells were equal. These data suggest that, during states of increased demand, cord MNC produce less G-CSF and IL-3 than do adult MNC and have an associated reduction in their respective mRNA transcripts. These findings may have implications in the pathogenesis of neonatal cytopenias during states of increased demand, such as sepsis.

The relationship between rhythmic swallowing and breathing during suckle feeding in term neonates.

Abstract: S: Little is known of the development of efficient coordination between suckle feeding and breathing in human infants. To establish baseline data, we recorded breathing and swallowing activity during bottle feeds in 23 infants at 14–48 h postnatal age. Most swallows (overall mean 68%) were organized into runs, with intervals starting at 0.6–0.8 s and slowing to 1–1.3 s after 30–40 s. The proportion of run swallows to total swallows increased significantly with age. Swallow intervals were regular (coefficient of variation = 18–38%) compared with breathing (coefficient of variation = 50%). Both breathing rate and tidal volume were significantly reduced by the onset of suckle feeding, and the pattern of respiratory airflow became markedly irregular. Mild transient desaturation was common, but was not accompanied by changes in heart rate. Swallows could occur in all phases of breathing. Overall, equal numbers of swallows were preceded by expiration and inspiration, but twice as many were followed by expiration compared with inspiration. Swallows were classified by the respiratory phases both preceding and following the swallow. Swallows occurred in all possible classifications in each of the infants studied. The incidence of the most frequent classification (inspiration-swallow-expiration), was 24% overall (individual range 5–50%). The phase relation between swallows and breaths changed frequently but showed occasional short periods of stability during which the breathing became regular and tidal volume increased. We conclude that at <48 h the normal infants has little coordination between swallowing and breathing rhythms and maintains rhythmic swallowing at the expense of eupnea.

Pulsatile and sexually dimorphic secretion of luteinizing hormone in the human infant on the day of birth

Abstract: Experimental evidence indicates that the hypothalamic-pituitary-gonadal axis is operational and sexually dimorphic in the mammalian fetus and newborn. We examined the dynamics of human luteinizing hormone (LH) secretion in five male and three female infants on the day of birth, after 34–41 wk of gestation. The infants were polycythemic, and blood samples were obtained every 20 min for 160 to 360 min during a therapeutic, standardized, isovolumetric, partial exchange transfusion. Serum LH was measured by an immunoradiometric assay that does not cross-react with human chorionic gonadotropin. The serum profiles of LH presented a striking sex dimorphism with elevated LH levels in male compared with female newborns. Deconvolution analysis of all male LH profiles was consistent with a high-frequency, pulsatile secretory pattern. Testosterone, measured in a pooled serum sample of each infant, was 10-fold higher in male than in female newborns. These results document pulsatile and sexually dimorphic secretion of LH in the human infant as early as the first day of postnatal life. It is possible that the augmented LH secretion in the male newborn participates in the neonatal rise of the serum testosterone concentration.

Surfactant lavage in a piglet model of meconium aspiration syndrome.

Abstract: S: Meconium aspiration continues to be a major cause of morbidity and mortality in newborn infants and is one of the most common indications for extracorporeal membrane oxygenation. Lab studies have suggested that meconium inactivates surfactant and displaces surfactant from the alveolar surface. A recent report has suggested a clinical role for surfactant therapy in human infants with meconium aspiration. We evaluated the effect of surfactant (Survata) lavage on a piglet model of meconium aspiration. Meconium pneumonitis was created by administration of 4 mL/kg of a 20% slurry of human meconium via endotracheal tube. Twenty-four newborn piglets were then randomly assigned to one of three groups: I) suction only (n = 7), 2) saline lavage (n = 5), or 3) surfactant lavage (n = 7). Five piglets were excluded from analysis due to death from pneumothorax during meconium administration (n = 3), death from pneumothorax during saline lavage (n = 1), and death from pneumothorax during surfactant lavage (n =1). The surfactant group had a statistically significant (p < 0.05) improvement in arterial to alveolar oxygen ratio gradient versus both control groups for the first 3 h. The oxygenation index was statistically significant versus the suction only group at 1, 3, and 4 h. Surfactant levage of meconium aspiration in piglets results in short-term improvement of oxygenation and warrants further study.

Mitochondrial myopathy studies on permeabilized muscle fibers.

Abstract: Respiratory parameters of skeletal muscle were determined in permeabilized muscle fibers by adapting a technique described by Veksler et al. for cardiac fibers (Biochim Biophys Acta, 892:191–196, 1987). This method consists of the permeabilization of muscle fibers by saponin by allowing respiratory substrates and inhibitors to reach the mitochondria. In this way, the mitochondria may be studied inside the fibers as if they were isolated. We have verified, using various techniques, that the mitochondria remain intact during this procedure. This method has been applied to the study of six newborn infants for whom a diagnosis of a mitochondrial defect was suspected. In all cases, the defect was to be found on the permeabilized fibers, and this was confirmed by an enzymatic study. The advantage of this new method, associated with the measurement of the enzymatic activities on a crude homogenate, is to enable a simple and rapid diagnosis on a small amount of sample without damaging the mitochondria during the isolation procedure.

Ontogeny of the epidermal barrier to water loss in the rat: correlation of function with stratum corneum structure and lipid content.

Abstract: The mammalian epidermal permeability barrier is provided by highly hydrophobic lipids forming multiple membrane bilayers within the extracellular domains of the outer, cornified cell layers. To characterize the critical events associated with barrier maturation, we correlated the emergence of a competent barrier to transepidermal water loss with development of the lamellar body secretory system, the organization of stratum corneum membrane bilayers, and the lipid composition of these membranes in the perinatal rat. Whereas pups of 19 d estimated gestational age had no measurable barrier (transepidermal water loss greater than 10 mg/cm2/h), by 21 d the barrier was well established (mean transepidermal water loss 0.41 mg/cm2/h). Development of a functional barrier correlated with increasing thickness of the stratum corneum, as well as with development of a membrane pattern of lipid deposition, visualized with the hydrophobic fluorescent probe nile red. At 19 d estimated gestational age, the stratum corneum intercellular domains exhibited an abundance of secreted lamellar body contents, but they were not organized into basic bilayer unit structures. Lamellar unit structures became evident by 20 d and extended throughout the stratum corneum interstices by 22 d (term). The quantity of lipid in isolated stratum corneum increased significantly between 19 and 20 d (34.08 versus 50.08 mean micrograms lipid/cm2, respectively; p less than 0.02) and still further between 20 and 21 d estimated gestational age (74.49 micrograms lipid/cm2; p less than 0.001). This increase was due to progressive accumulation of neutral lipids, particularly cholesterol, as well as nonpolar ceramides, as shown by thin-layer chromatography/scanning densitometry. These studies imply that in the development of cutaneous barrier function in the fetal rat both the generation of sufficient quantities of hydrophobic lipids and the organization of these lipids into bilayer unit structures are required.

A Human Milk Factor Inhibits Binding of Human Immunodeficiency Virus to the CD4 Receptor

Abstract: Perinatal transmission of human immunodeficiency virus (HIV) from infected mothers to their children occurs at rates reported as 20-50%. The role of breast feeding in perinatal transmission of viral infections has not been well established. We studied 34 milk and colostral samples obtained from HIV-seropositive and HIV-seronegative women to determine if they contained anti-HIV activity. We found that all the samples contained a factor that inhibited the binding of HIV epitope-specific MAb to recombinant CD4 receptor molecules. The titers of inhibitory activity ranged from 1:200 to 1:10,000 and did not differ between HIV-seropositive and HIV-seronegative mothers. This milk factor also inhibited the binding of gp120 to CD4. Neither human sera nor bovine milk exhibited appreciable inhibitory activity. Fractionation of human milk indicated that the inhibitory activity was confined to the macromolecular fraction; little activity was found in isolated milk lipids or oligosaccharides. Chromatographic procedures indicated that the active macromolecule has an isoelectric point of 9.3-9.6. The active material did not bind to concanavalin A; however, the activity was partially destroyed by chemical and enzymatic treatments that removed sulfated residues. The active material may thus be a sulfated protein, glycoprotein, mucin, or glycosaminoglycan that inhibits the binding of CD4 to HIV envelope glycoproteins. The role of this factor in the natural history of HIV infection in infants and children should be the subject of additional investigations.

Bone mineralization outcomes in human milk-fed preterm infants.

Abstract: S: We evaluated bone mineralization by single photon absorptiometry at 2 y in a cohort of preterm infants studied since birth. Infants were fed human milk fortified with Ca [to achieve 80 mg/dL (19.96 mmol/L)] and P [40 mg/dL (12.91 mmol/L)] from wk 2 through 8 after birth. After hospital discharge, infants were divided into two groups (HM and F) determined by the timing of the introduction of cow milk-based formula. Mid-radius bone mineral content (BMC) was assessed in 10 infants who were breast-fed (HM) for a minimum of 2 mo after hospital discharge and 11 who were bottle-fed (F). The mean duration of human milk-feeding differed by design between HM and F groups (31 ± 15 versus 11 ± 3 wk, respectively). Although we had observed previously that group F had significantly greater BMC values at 16, 25, and 52 wk compared with values in group HM, we found similarities in BMC values (180 ± 30 mg/cm) between groups at 2 y. The 2-y cohort comprised healthy infants and the groups had similar birth weights, lengths of gestation, and values for weight (10.8 ± 1.1 kg), length (82 ± 2 cm), and bone width (7.8 ± 1.1 mm). Follow-up outcomes at 2 y in preterm infants fed fortified human milk in hospital suggest that if they continue to receive human milk after hospital discharge, radios BMC will “catch-up” to that of similar infants given formula in the posthospitalization period.

Glycerol metabolism and triglyceride-fatty acid cycling in the human newborn: effect of maternal diabetes and intrauterine growth retardation.

Abstract: Kinetics of glycerol metabolism and triglyceride/fatty acid cycling were quantified in 12 healthy, normal, appropriate-for-gestational-age (AGA) infants, eight small-for-gestational-age (SGA) infants, and five infants of insulin-dependent diabetic mothers (IDM) at less than 48 h of age. Stable isotope-labeled [2-13C]glycerol and [6,6-2H2]glucose in combination with indirect respiratory calorimetry were used. The tracers were used as constant rate infusion and steady state isotopic enrichment of glucose, glycerol, and bicarbonate was measured by mass spectrometric methods. After a 7- to 9-h fast, the plasma glucose, glycerol, and FFA concentrations were similar in the AGA and IDM groups. In the SGA group, the plasma glucose concentration was significantly lower than that in the AGA group throughout the study, but plasma FFA and glycerol concentrations were not different from those in the AGA infants. Plasma betahydroxybutyrate concentration was significantly elevated in the AGA group compared with IDM and SGA infants (AGA 0.59 +/- 0.39, SGA 0.35 +/- 0.09, IDM 0.33 +/- 0.21 mmol/L; mean +/- SD). The rate of appearance of glycerol was significantly elevated (p less than 0.05) in SGA infants (AGA 9.47 +/- 2.11, IDM 9.55 +/- 2.14, SGA 12.15 +/- 3.87 mumol/kg.min). Between 80 and 90% of glycerol turnover was converted to glucose, accounting for 20% of glucose turnover with no significant difference in the three groups. Approximately 35% of glycerol carbon was recovered in the bicarbonate (CO2) pool. Less than 5% of CO2 carbon was derived from glycerol. Estimation of triglyceride-fatty acid cycle revealed that the triglyceride energy mobilized was increased in SGA infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Decline of exocrine pancreatic function in cystic fibrosis patients with pancreatic sufficiency.

Abstract: Decline of Exocrine Pancreatic Function in Cystic Fibrosis Patients with Pancreatic Sufficiency

Fetal alcohol syndrome and fatty acid ethyl esters.

Abstract: Fetal alcohol syndrome is the leading known cause of mental retardation. The syndrome, defined as growth retardation, midface hypoplasia, and neurologic dysfunction, represents only part of the spectrum of fetal alcohol effects. The biochemical mechanism of teratogenesis is unknown. In adults, metabolites of ethanol, FAEE, are known to accumulate in major organs. The formation of FAEE is catalyzed by a family of enzymes, FAEE synthases. Our hypothesis is that accumulation of FAEE in the embryo results in fetal alcohol syndrome. We have developed assays for FAEE and FAEE synthase activity using mg of tissue. Using these assays, we have shown the following: Human placenta, mouse placenta, heart, and liver are active in catalyzing the formation of FAEE. One h after maternal ethanol administration on gestational d 14, mouse placenta and fetuses accumulated significant quantities of FAEE. The fatty acid incorporated into FAEE was tissue dependent. Tissues from pregnant animals given ethanol on gestational d 7 showed persistence of FAEE on gestational d 14. We conclude that: 1) human and mouse placentas have significant FAEE synthase activity, 2) mouse heart, liver, placenta, and fetal tissues accumulate significant amounts of FAEE after maternal ethanol exposure, 3) there is tissue specificity for the fatty acid incorporated into FAEE, and 4) FAEE may persist for 7 d in placentas. These results provide a basis for further research into the role of FAEE in the development of fetal alcohol syndrome.