Maternal pregnancy weight gain and cord blood iron status are associated with eosinophilia in infancy.

OBJECTIVE: Allergic disease is multifactorial in origin. Because iron nutrition affects immune responses and maternal pregnancy weight gain impairs fetal iron delivery while increasing fetal demands for growth, the study examined maternal pregnancy weight gain, newborn iron status and an index of atopic disease, infant eosinophilia. STUDY DESIGN: Within a larger prospective study of healthy newborns at risk for developing iron deficiency anemia, umbilical cord iron indicators were compared to infant eosinophil counts. RESULT: Infants who developed eosinophilia exhibited higher cord reticulocyte-enriched zinc protoporphyrin/heme ratio, P<0.05 and fewer cord ferritin values in the highest (best) quartile, P<0.05. If cord ferritin was in the upper three quartiles, the negative predictive value for infant eosinophilia was 90%. High maternal pregnancy weight gain predicted infant eosinophil counts, P<0.04, and contributed to cord ferritin predicting eosinophilia, P<0.003. CONCLUSION: Poor fetal iron status may be an additional risk factor for infant eosinophilia.

Neonatal iron status is impaired by maternal obesity and excessive weight gain during pregnancy.

OBJECTIVE: Maternal iron needs increase sixfold during pregnancy, but obesity interferes with iron absorption. We hypothesized that maternal obesity impairs fetal iron status. STUDY DESIGN: Three hundred and sixteen newborns with risk factors for infantile iron deficiency anemia (IDA) were studied to examine obesity during pregnancy and neonatal iron status. Erythrocyte iron was assessed by cord blood hemoglobin (Hb), zinc protoporphyrin/heme (ZnPP/H) and reticulocyte-ZnPP/H, and storage iron by serum ferritin. RESULT: Women with body mass index (BMI) ⩾ 30 kg m(-)(2), as compared with non-obese women, delivered larger offspring with higher reticulocyte-ZnPP/H and lower serum ferritin concentrations (P<0.05 for both). With increasing BMI, the estimated body iron was relatively lower (mg kg(-)(1)) and the ratio of total Hb-bound iron (mg) per total body iron (mg) increased. Maternal diabetes compromised infant iron status, but multivariate analysis demonstrated that obesity was an independent predictor. CONCLUSION: Obesity during pregnancy and excessive weight gain are independent risk factors for iron deficiency in the newborn.

Ovine fetal renal development impacted by multiple fetuses and uterine space restriction.

Intrauterine growth restriction (IUGR) from uteroplacental dysfunction causes impaired nephrogenesis and ultimately hypertension, but it is unknown whether IUGR caused by insufficient space for placental development seen in uterine anomalies and/or multifetal gestation exerts the same effects. Fetal renal development and metabolism were studied in an ovine space-restriction model by combining unilateral horn surgical ligation and/or multifetal gestation. Reduced placental attachment sites and placental weight per fetus defined space-restricted (USR) v. control nonrestricted (NSR) fetuses. Space-restricted fetuses exhibited evidence for decreased plasma volume, with higher hematocrit and plasma albumin at gestational day (GD) 120, followed by lower blood pO2, and higher osmolarity and creatinine at GD130, P < 0.05 for all. By combining treatments, fetal kidney weight relative to fetal weight was inversely related to both fetal weight and plasma creatinine levels, P < 0.05 for both. At GD130, space-restricted fetal kidney weights, cortical depths and glomerular generations were decreased, P < 0.05 for all. Space-restricted kidneys underwent an adaptive response by prolonging active nephrogenesis and increasing maculae densa number, P < 0.05 for both. The major renal adaptations in space-restricted IUGR fetuses included immaturity in both development and endocrine function, with evidence for impaired renal excretory function.

Elevated zinc protoporphyrin/heme ratios in umbilical cord blood after diabetic pregnancy.

OBJECTIVE: Offspring of diabetes patients may suffer from tissue iron deficiency. Erythrocyte zinc protoporphyrin/heme (ZnPP/H) ratios measure impaired iron status. The aim of the study was to examine whether cord ZnPP/H ratios were associated with pregnancy glycemic control. METHODS: ZnPP/H was measured in cord blood from 31 pregnancies with insulin-treated diabetes (diabetes group) and compared to population normal values. Maternal glycemic control was assessed by daily glucose log, glycosylated hemoglobin and birth weight. RESULTS: Median cord ZnPP/H was higher in the diabetes group than the population normal values (106 (65.2 to 146.8) microM/M vs 68.2 (37.6 to 98.8) micro/M, P < 0.0001). Ratios were directly correlated to surrogates of control (glycosylated hemoglobin, P = 0.05, and birth weight, P < 0.04). Cord ZnPP/H ratios from pregnancies with pre-existing and gestational diabetes were similar. CONCLUSION: Because cord ZnPP/H was higher in large offspring of diabetic pregnancy, it might identify greater iron utilization for fetal erythropoiesis.

Roles of erythropoietin in human milk.

UNLABELLED: Erythropoietin (Epo) is one of many biologically active growth factors present in human and animal milk. Accumulating evidence shows important developmental roles for these milk-borne growth factors. Although Epo is present in biologically relevant amounts in mammalian milk, the roles of Epo in milk are incompletely defined. A significant proportion of milk-borne Epo resists proteolytic degradation. Epo receptors (EpoR) have been found on gastric mucosa and intestinal mucosa, and in mesenteric vessel endothelium. Evidence to date shows that intact Epo reaches these local organs, as well as distal organs. After feeding Epo, local gastrointestinal physiological effects are seen in suckling rats. In humans and rats, short-term feeding of high-dose Epo increases reticulocytes, but it is unclear whether sustained treatment increases red cell mass. CONCLUSION: Further work towards understanding the physiological and potential pharmacological roles of enterally administered Epo is necessary.

Enteral absorption of erythropoietin in the suckling rat.

Milk contains biologically relevant concentrations of erythropoietin (Epo), the primary hormone responsible for erythrocyte production. In animals, milk-borne Epo stimulates erythropoiesis. Epo receptors have been found in nonerythropoietic tissues including gastrointestinal tract. We hypothesized that milk-borne Epo is distributed to local gastrointestinal tissues, absorbed intact, and then distributed peripherally via the systemic circulation. Rat milk protected recombinant human Epo (rhEpo) from degradation in the suckling rat gastrointestinal tract. Simulated digestion of (125)I-rhEpo in suckling rat gastrointestinal juices was performed. When measured by acid precipitation and immunoassay, rat milk protected rhEpo from gastrointestinal juices better than saline (p < 0.0001). The fate of enterally administered milk-borne (125)I-rhEpo was examined in 10-d-old rats. RhEpo fed in rat milk was better protected from in vivo proteolytic degradation than rhEpo in saline (p < 0.05). After enteral (125)I-rhEpo dosing, radiolabeled protein from gastric tissue comigrated on SDS-PAGE with intact rhEpo at 36.5 kD. To determine the local and systemic distribution of physiologic intakes of rhEpo, suckling rats were fed (125)I-rhEpo in rat milk, and tissues were harvested 1, 2, and 4 h later. Intact (125)I-rhEpo was found in gastric and small intestinal walls and lumens. Five percent of total administered dose was found intact in the plasma, whereas another 8 to 10% of total administered dose was localized to bone marrow, percentages comparable to those seen after parenteral administration. Radiolabel was also localized to liver and peripheral solid tissues. These patterns of localization and degradation of rhEpo after acute administration support both systemic absorption and gastrointestinal cellular processing.

Iron-deficient erythropoiesis in premature infants measured by blood zinc protoporphyrin/heme.

We measured red blood cell zinc protoporphyrin/heme (ZnPP/H) ratios in premature infants at hospital discharge. ZnPP/heme ratios correlated directly with red blood cell distribution width and reticulocyte number. As in other populations, ZnPP/H ratios may provide a simple measure of iron-deficient erythropoiesis in premature infants.

Absorption of milk-borne insulin-like growth factor-I into portal blood of suckling rats.

BACKGROUND: Insulin-like growth factors (IGFs) are potent mitogens that have been implicated in control of growth and development during the perinatal period. These hormones are also present in biologically significant quantities in mammalian milks. Although one site of action of these IGFs may be at the intestinal level, current information about whether they pass intact into the circulation is conflicting. METHODS: To test the hypothesis that milk-borne IGFs are absorbed into blood in receptor-active form, suckling rats were given either recombinant human (rh)125I-IGF-I or -II (4 x 10(6) counts per minute [cpm]), and the activity present in portal and cardiac blood was examined at 5, 10, 20, and 30 minutes after ingestion for presence of appropriate molecular weight peptides in these samples. In selected samples, purified radioactive samples were tested for their ability to bind competitively to crude membranes bearing IGF receptors. RESULTS: The results of these studies indicate that rh125I-IGF-I is absorbed in receptor-active form into the portal circulation and that maximal amounts are present 20 to 30 minutes after ingestion. Estimation of the presence of intact hormone was made on the basis of the elution profile of samples when run on gel chromatography as well as reversed-phase high-performance liquid chromatography. Isolated samples from portal blood also bound competitively to placental membranes bearing IGF receptors. In contrast, rh125I-IGF-II could not be demonstrated in receptor-active form in portal blood. Chromatography showed appropriate sized peaks with greater activity in portal than cardiac samples, but competitive binding was not appreciated. CONCLUSIONS: It is likely that at least milk-borne IGF-I is absorbed intact and may exert effects on liver and other peripheral tissues. In addition, this study lends further credence to the possibility of an enterohepatic circulation for IGF-I.

Plasma transferrin receptor levels and indices of erythropoiesis and iron status in healthy term infants.

PURPOSE: The goal of this study was to determine if the postnatal changes in plasma transferrin receptor (TfR) levels in healthy infants were associated with changes in erythropoiesis or iron status. SUBJECTS AND METHODS: Longitudinal blood samples were obtained monthly from healthy term infants fed iron-fortified formula for the first 7 months and analyzed for plasma TfR and indices of erythropoiesis and iron status. RESULTS: Plasma TfR level rose during the first 2 months of life (p < 0.002). When examined for its association with indices of erythropoiesis, plasma TfR was negatively associated with hemoglobin (Hb) (p < 0.01), and positively associated with plasma erythropoietin (EPO) concentration (p < 0.005) and absolute reticulocyte count (p < 0.005). Plasma TfR was not associated with erythrocyte protoporphyrin. Although indices of iron status were not suggestive of iron deficiency, plasma TfR was negatively associated with plasma ferritin, Tf saturation, and plasma iron, and positively associated with total iron binding capacity (TIBC) (p < 0.0001 for all). CONCLUSIONS: Increases in plasma TfR levels were observed during normal infancy. The increases in plasma TfR levels correlate with increases in erythropoiesis without evidence for functional iron deficiency.

Human milk as a potential enteral source of erythropoietin.

In addition to its content of traditional nutrients, milk is a rich source of hormones and peptides, which survive digestion in the neonatal gastrointestinal tract secondary to lower proteolytic activity and increased protein permeability. Previous studies have shown accelerated erythropoiesis or elevated serum erythropoietin (Epo) levels in neonatal (suckling) animals after maternal phlebotomy or maternal hypoxia exposure. We sought to determine whether significant quantities of Epo are present in human milk and whether Epo remains intact under physiologic digestion conditions. Immunoreactive Epo concentrations were determined in 409 human milk samples obtained from mothers of term and premature infants. Samples collected between birth and postpartum d 134 were divided into 11 postpartum day groups. Mean milk-borne Epo concentrations were within the normal range for plasma Epo concentrations and rose with postpartum day (F10,398 = 5.82, p < 0.0001). No differences were observed between milk collected from mothers of premature versus term infants. Estimated weekly human milk-borne Epo intakes approximated the lower range of published parenteral therapeutic doses. In simulated digestion at physiologic pH levels of 3.2, 5.8, and 7.4, milk-borne Epo resisted degradation at 1 and 2 h, compared with baseline. Therefore, we conclude that human milk contains considerable amounts of Epo which resist degradation after exposure to gastric juices at physiologic pH levels. These results support continued investigation into the fate and developmental roles of Epo in human milk.

Score for neonatal acute physiology and phlebotomy blood loss predict erythrocyte transfusions in premature infants.

OBJECTIVE: To test the hypothesis that utilization of a previously described measure of acuity (ie, the score for neonatal acute physiology [SNAP]) during the first 7 postnatal days predicts which infants with a birth weight of 1500 g or less received erythrocyte transfusion during the initial hospitalization. DESIGN: Retrospective chart review. SETTING: A regional tertiary care newborn intensive care unit at the Arizona Health Sciences Center, University Medical Center, Tucson. MATERIALS: Medical records of premature infants (birth weight, < or = 1500 g) who were admitted from October 1993 to January 1995. MAIN OUTCOME MEASURES: Occurrence or nonoccurrence of erythrocyte transfusion was determined in 47 infants who were compared for demographic information, phlebotomy blood loss, diagnoses, medications, and the SNAP at 0, 1, 2, and 7 days of life. RESULTS: Infants with a birth weight of 1500 g or less received a mean +/- SD of 1.9 +/- 2.9 transfusions with 22 (47%) of the infants given transfusions Infants who were given transfusions vs those who were not given transfusions were of a lower mean +/- SD birth weight (971 +/- 238 g vs 1272 +/- 144 g; P < .001) and a lower gestational age (27.7 +/- 1.6 weeks vs 30.7 +/- 2.8 weeks; P < .001), and they had a greater mean phlebotomy blood loss (3.3 +/- 1.6 mL/kg per day vs 1.4 +/- 0.5 mL/kg per day; P < .001) during the first postnatal week. The SNAP indexes in those who received transfusions were higher at 1, 2, and 7 days of life (P = .03, P = .001, and P < .001, respectively). Using stepwise logistic regression, phlebotomy blood loss and the SNAP at 7 days of life were significant predictors of the number of transfusions. The logistic model predicted which infants had been administered transfusions with 86% sensitivity and 88% specificity. CONCLUSIONS: The efficacy and cost-effectiveness of recombinant human erythropoietin therapy in premature infants remain under study. As earlier treatment with recombinant human erythropoietin may be more efficacious, early identification of which infants currently undergo transfusion may identify those who will receive the greatest benefit from recombinant human erythropoietin therapy. The SNAP distinguished those infants who were given transfusions from those who did not receive transfusions, even after adjusting for phlebotomy blood loss.

Iron deprivation increases erythropoietin production in vitro, in normal subjects and patients with malignancy.

Although tissue hypoxia is the major stimulus for erythropoietin (EPO) production, serum EPO (sEPO) levels at any given Hb in iron-deficiency anaemia are relatively higher than in other anaemias. Iron chelators stimulate erythropoiesis in anaemia of chronic disease via unknown mechanisms. A recent study suggested that deferoxamine (DFO) regulates steady-state EPO RNA. Here we report that altered intracellular iron balance regulates EPO production both in vitro and in two unique clinical trials. In vitro, both iron chelation with DFO and blockade of Tf-mediated iron uptake with anti-Tf receptor antibody 42/6, stimulated EPO production in serum-deprived hepatoma cells. Conversely, iron repletion by haemin, inhibited EPO production in these cells. In clinical studies, sEPO levels rose in adult volunteers treated with DFO coupled to hydroxyethyl starch (HES-DFO) and in patients with advanced malignancy treated with anti-Tf receptor antibody 42/6, in a time- and dose-dependent manner. These studies indicate intracellular iron balance regulates EPO production in humans.

Serum erythropoietin levels during infancy: associations with erythropoiesis.

OBJECTIVE: To determine plasma erythropoietin levels and their association with hemoglobin and reticulocyte counts in healthy term infants. DESIGN: We compared plasma erythropoietin levels measured in serial blood samples obtained every 4 weeks during the first 6 months of life with one another and with levels in term fetuses and healthy adults. Correlation analysis was applied to examine for associations of erythropoietin with hemoglobin and with reticulocyte count. RESULTS: Plasma erythropoietin levels were lowest in the first and highest in the second postnatal months, a pattern reciprocal to that observed for hemoglobin during the period of physiologic anemia. The erythropoietin level was negatively correlated with hemoglobin (p < 0.0001) and positively correlated with reticulocytes (p < 0.0001). The slope of the inverse relationship of hemoglobin and plasma erythropoietin in infants was similar to those previously reported for anemic fetuses and premature infants, but much less steep than for anemic children and adults. CONCLUSION: This study is the first to report simultaneous patterns of change observed in plasma erythropoietin, hemoglobin, and reticulocytes during normal infancy. These patterns are consistent with postnatal perturbations in tissue oxygenation and suggest a major role for erythropoietin in the regulation of erythropoiesis during normal infancy, but at a lower hemoglobin concentration than for older children and adults with pathologic anemia.

In vitro pharmacology of an angiotensin AT1 receptor antagonist with balanced affinity for AT2 receptors.

L-163,017 (6-[benzoylamino]-7-methyl-2-propyl-3-[[2'-(N-(3-methyl-1-butoxy) carbonylaminosulfonyl) [1,1']-biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine) inhibited specific 125I-[Sar1, Ile8]angiotensin II binding to angiotensin AT1 receptor (Ki = 0.11-0.20 nM) in rabbit aorta, rat adrenal and human angiotensin AT1 receptor in CHO (Chinese hamster ovary transformed) cells and to AT2 receptor (Ki = 0.14-0.23 nM) in rat adrenal and brain receptors. L-163,017 also had a high affinity in the presence of bovine serum albumin (2 mg/ml), for angiotensin AT1 and AT2 receptors on human adrenal (Ki 3.9 and 4.3 nM), aorta (Ki 0.45 and 0.96 nM) and kidney (Ki 3.6 and 2.3 nM). The much higher Ki values in human tissues were likely due to the presence of bovine serum albumin in the binding assay buffer since L-163,017 had Ki values of 0.13 +/- 0.04 and 2.0 +/- 0.04 nM in the absence and presence of bovine serum albumin, respectively, in inhibiting 125I-[Sar1,Ile8]angiotensin II binding to angiotensin AT1 receptor in rat adrenal membranes. Scatchard analysis of 125I-[Sar1,Ile8]angiotensin II binding in the presence of bovine serum albumin (2 mg/ml) in rabbit aorta and bovine cerebellum indicated a competitive interaction of L-163,017 with angiotensin AT1 and AT2 receptors (Ki values 2.5 and 2.1 nM respectively). L-163,017 inhibited angiotensin II-induced aldosterone release in rat adrenal demonstrating that L-163,017 acted as a competitive antagonist (pA2 = 9.9) and lacked agonist activity. L-163,017 also inhibited angiotensin II responses in rat vascular tissues. The specificity of L-163,017 was shown by its lack of activity on the above functional responses produced by other agonists and in several binding assays.

Congenital cutaneous candidiasis: case report and review.

This report describes a preterm infant with congenital cutaneous candidiasis associated with paronychia, dystrophy of the nail plates, and marked, transient leukocytosis.

Pharmacokinetics and pharmacodynamics of erythropoietin during therapy in an infant with renal failure.

We treated an infant with anemia and chronic renal failure with recombinant human erythropoietin (300 to 750 U/kg subcutaneously per week) and iron (6 mg/kg enterally) from 1 to 4 months of age. A suboptimal pharmacodynamic response was seen at the lower dose. This may have been due to developmental erythropoietin pharmacokinetic differences, that is, relatively greater neonatal plasma clearance and steady-state volume of distribution compared with those in adults.

A faculty-house staff retreat.

There has been much discussion regarding the causes of stress in residency training programs and solutions to alleviate the pressure. As a partial solution, we have found discussions of retreats for pediatric interns in the medical literature, but no discussion of department-wide retreats. Since the early 1970s, the University of Wisconsin (Madison) Department of Pediatrics has held a faculty-house staff retreat every 2 years. The more recent retreats used process-oriented discussions in its goals of fostering understanding through group communication to reduce stress. The 1989 agenda was an expansion of previous efforts with extensive faculty and house staff involvement before, during, and after the retreat. The purposes of this article are to review the literature on the use of retreats in various settings, especially residency training programs; describe the past and present use of retreats by the University of Wisconsin Department of Pediatrics; describe the 1989 retreat; and describe the positive and negative aspects relating to retreats as we have used them. We believe our retreat is unique, serves many purposes, and has been a successful tool for relieving residency stress.

A new simple mouse model for the in vivo evaluation of cholecystokinin (CCK) antagonists: comparative potencies and durations of action of nonpeptide antagonists.

A new simple mouse assay for the in vivo evaluation of CCK antagonists which is based upon visual determination of the gastric emptying of a charcoal meal is described. CCK-8 (24 micrograms/kg s.c.) but not various other peptide and nonpeptide agents effectively inhibited gastric emptying in this test system. The effect of CCK-8 was antagonized by established peripheral CCK antagonists but not representative agents of various other pharmacological classes. The rank order of potency of the CCK antagonists were: L-364,718 (ED50 = 0.01 mg/kg, i.v.; 0.04 mg/kg, p.o.) greater than Compound 16 (ED50 = 1.5 mg/kg, i.v.; 2.0 mg/kg p.o.) greater than asperlicin (ED50 = 14.8 mg/kg i.v.) greater than proglumide (ED50 = 184 mg/kg i.v.; 890 mg/kg, p.o.). Duration of action studies based upon ED50 values determined at various time intervals after oral administration showed that L-364,718 and proglumide are considerably longer acting than Compound 16. Asperlicin (ED50 greater than 300 mg/kg, p.o.) was ineffective as a CCK antagonist when administered orally. These data provide the first direct comparisons of the in vivo potencies of current CCK antagonists and demonstrate the utility of a new simple mouse assay for the in vivo characterization of peripheral CCK antagonists.

Thyrotropin-releasing hormone receptors in gut tissues resemble pituitary receptors.

The relative order of activity of thyrotropin-releasing hormone (TRH) and various analogs in contracting the isolated guinea pig antrum and duodenum correlated with their potencies in activating thyroid-stimulating hormone (TSH) release. The action of TRH in both tissues was selectively antagonized by the putative pituitary TRH receptor antagonist, chlordiazepoxide (10 microM). The data indicate that the contractions produced by TRH in these gut tissues are mediated by TRH receptors with similar characteristics as the pituitary TRH receptors responsible for TSH release.

Evidence that cholecystokinin octapeptide (CCK-8) acts as a potent, full agonist on gastrin receptors for acid secretion in the isolated mouse stomach: lack of antagonism by the specific CCK antagonist asperlicin.

Cholecystokinin octapeptide (CCK-8) (EC50 = 5 nM) was considerably more potent than pentagastrin (EC50 = 161 nM) in stimulating acid secretion in the isolated perfused mouse stomach suspended in a medium containing a phosphodiesterase inhibitor. The maximum acid response to CCK-8 was not significantly different from that produced by pentagastrin. The nonselective CCK/gastrin antagonist, proglumide, but not the selective CCK antagonist, asperlicin, antagonized the acid response to both pentagastrin and CCK-8. The data suggest that CCK-8 acts as a potent, full agonist on gastrin receptors for acid secretion in the isolated mouse stomach.