Human chorionic gonadotropin: its possible role in maternal lymphocyte suppression.

Human chorionic gonadotropin completely inhibits the response of lymphocytes to phytohemagglutinin. The effect is both reversible and noncytotoxic. These observations support the theory that the fetus is accepted because human chorionic gonadotropin represents trophoblastic surface antigen and blocks the action of maternal lymphocytes.

Umbilical uptake of amino acids in the unstressed fetal lamb.

The whole blood concentrations of 22 amino acids were measured in a chronic, unstressed fetal lamb preparations. Samples were taken daily from the umbilical artery, umbilical vein, and maternal artery over the latter quarter of gestation. 73 sets of samples (from the umbilical artery and vein and the maternal artery) from 13 animals were analyzed for amino acid levels. Oxygen contents were determined simultaneously in 48 sets (umbilical artery and vein) to relate fetal oxygen consumption to amino acid uptake via the umbilical circulation. The results indicate that there is no umbilical uptake of the acidic amino acids, glutamate and aspartate; there is, in fact, a net flux of glutamate out of the fetus into the placenta. As both of these amino acids are major constituents of body proteins, the data indicate that they are formed within the fetus. The umbilical uptake of some neutral and basic amino acids (e.g., valine, leucine, isoleucine, arginine, phenylalanine, and tyrosine) is in considerable excess of estimated growth requirements, suggesting that some amino acids undergo extensive transamination and oxidative degradation in the fetus. Finally, the net uptake of nitrogen, carbon, and calories by the growing ovine fetus in the form of amino acids, glucose, and lactate is compared to estimated requirements as determined in previous studies.

Lithocholate glucuronide is a cholestatic agent.

Lithocholic acid and its taurine, glycine, and sulfate derivatives are potent cholestatic agents. Lithocholate glucuronide is present in the plasma and urine of patients with cholestatic syndromes, but little is known of its metabolism, excretion, and cholestatic potential. [3 beta-3H]lithocholate 3-O-beta-D-glucuronide was synthesized, and chemical and radiochemical purity were established. The aqueous solubility of lithocholate glucuronide was determined and found to be greater than that of lithocholic acid or several of its derivatives. In the range of concentrations examined, calcium ions precipitated lithocholate glucuronide stoichiometrically. The material was administered to rats prepared with an external biliary fistula. When 17-25 micrograms quantities were administered, 89.1 +/- 4.5% (mean +/- SEM) of the radiolabel was secreted in bile within the first 20 h after administration, the major fraction being secreted in less than 20 min. Four-fifths of the radiolabeled material in bile was the administered unaltered parent compound, while a minor fraction consisted of a more polar derivative(s). We showed that increasing biliary concentrations of more polar derivatives were observed with milligram doses of [3H]lithocholate glucuronide, and with time after the administration of these loading doses. Milligram doses of [3H]lithocholate glucuronide resulted in partial or complete cholestasis. When induced cholestasis was partial, secretion in bile remained the primary excretory route (82.5-105.6% recovery in bile), while, when complete cholestasis was induced, wide tissue distribution of radiolabel was observed. Cholestasis developed rapidly during infusion of [3H]lithocholate glucuronide. Bile flow was diminished within 10-20 min of the start of an infusion of 0.05 mumol, 100 g-1 body weight, minute-1, administered concomitantly with an equimolar infusion of taurocholate. The results establish that lithocholate glucuronide exerts cholestatic effects comparable to those exerted by unconjugated lithocholic acid.

Bile salt-induced calcium fluxes in artificial phospholipid vesicles.

The ionic permeability of selected biological membranes is increased by bile salts. To examine changes in calcium permeability during the exposure of artificial membranes to bile salts, we investigated calcium uptake by unilamellar and multilamellar phospholipid vesicles. In the presence of 750 microM taurodeoxycholate, uptake of radiolabelled calcium by unilamellar vesicles increased 2.5-fold over control values. Calcium uptake by multilamellar vesicles as measured with a free calcium indicator, arsenazo III, increased 2.2- or 21-fold in the presence of 60 microM lithocholate or 3 beta-hydroxy-5-cholenoate, respectively. Results were directly influenced by experimental variables such as bile salt hydrophobicity, external calcium concentration, and the bile salt/lipid molar ratio. Observed membrane solubilization was minimal despite increased calcium permeability. Comparison of radiolabelled calcium uptake with radiolabelled sodium or radiolabelled rubidium uptake indicated that bile salt-dependent calcium uptake was 60-140-times greater than bile salt-dependent uptake of either monovalent cation. In an effort to delineate forces affecting calcium translocation, vesicles were exposed either to valinomycin, which induced an electrochemical gradient across the membrane, or to nigericin, which induced a proton gradient. Exposure to valinomycin minimally influenced bile salt-induced calcium uptake while exposure to nigericin significantly promoted uptake by 40-70%. The results suggest that bile salts promote calcium uptake by a mechanism which may be similar to those of other carboxylic ionophores.

Prospective observations of 100 high-risk neonates by high-field (1.5 Tesla) magnetic resonance imaging of the central nervous system: I. Intraventricular and extracerebral lesions.

The results of observations of the first 100 neonates at the University of Texas Health Science Center (Houston) who received magnetic resonance imaging of the central nervous system by means of a high-field image (1.5 T) are reported. All were assessed prospectively to be at risk neurodevelopmental delay. This first report specifically addresses the appearance of primarily hemorrhagic intracranial lesions, including intraventricular hemorrhage (n = 28), and extracerebral lesions, which include 3 cases of venous sinus thrombosis (n = 20). The signal intensities of hemorrhage underwent a characteristic evolution with time with only minor variations in the study group. Magnetic resonance imaging detected direct evidence of hemorrhage for up to 2 months, but hemosiderin was detected as a late indicator of hemorrhage for up to 9 months. Magnetic resonance imaging was equal in benefit to head ultrasonography and computed tomography for the diagnosis of intraventricular hemorrhage, but magnetic resonance imaging was also able to approximate the time of onset of hemorrhage. Magnetic resonance imaging was superior for the evaluation of extracerebral hemorrhage; ultrasonography failed to detect any of these lesions and computed tomography detected only 3 of 7. Short-term neurological abnormality was assessed, but the ability of magnetic resonance imaging to predict long-term neurodevelopmental delay is unknown and is the subject of an ongoing project.

Prospective observations of 100 high-risk neonates by high-field (1.5 Tesla) magnetic resonance imaging of the central nervous system. II. Lesions associated with hypoxic-ischemic encephalopathy.

One hundred neonates determined prospectively to be at risk for neurologic handicap underwent magnetic resonance imaging with a high-field (1.5 T) imager. Thirty-three demonstrated a total of 37 lesions consistent with hypoxic-ischemic encephalopathy, including periventricular leukomalacia (n = 12), basal ganglia hemorrhage (n = 5), multicystic encephalomalacia (n = 5), and focal parenchymal hemorrhage (n = 15). Diagnoses by ultrasonography and computed tomography were compared with those by magnetic resonance imaging in 29 and 17 infants, respectively. Ultrasonography agreed more frequently with magnetic resonance imaging than did computed tomography. Ultrasonography detected 79% of lesions demonstrated by magnetic resonance imaging whereas computed tomography detected only 41%. Periventricular leukomalacia was seen most often in preterm infants, basal ganglia hemorrhage and multicystic encephalomalacia primarily occurred in term infants, and focal parenchymal hemorrhage occurred at all gestational ages. Basal ganglia hemorrhage and multicystic encephalomalacia were strongly associated with histories of perinatal asphyxia, seizures, and early abnormal neurological status. All infants with basal ganglia hemorrhage (5/5) and multicystic encephalomalacia (5/5) and the majority with periventricular leukomalacia (9/12) and focal parenchymal hemorrhages (9/15) had developmental abnormalities at discharge.

Endocarditis in high-risk neonates.

The clinical spectrum of neonatal endocarditis, including bacterial and nonbacterial types, is examined in five case reports that were drawn from nursery experiences over a recent 2-year period. In contrast to previous reports of 100% mortality from neonatal endocarditis, one patient survived. Changing heart murmur and hematuria were most frequently associated with bacterial and nonbacterial endocarditis in four of the five cases. Pulmonary hypertension, thrombocytopenia, and coagulopathy were also associated with nonbacterial endocarditis. Echocardiograms were performed on four of the patients; only one was suggestive of endocarditis. Staphylococcus aureus was isolated from both cases of bacterial endocarditis, including the single survivor. Thus, it is suggested that the initial antibiotic coverage of any neonate with the clinical syndrome of sepsis, hematuria, and a heart murmur include antistaphylococcal coverage for the possibility of bacterial endocarditis.

Retinol (vitamin A) and riboflavin (vitamin B2) administration and metabolism in very low birth weight infants.

The combination of marginal hepatic retinol stores at delivery and the reduction of daily retinol dose due to complications with the delivery system places the VLBW infant receiving parenteral nutrition at high risk for retinol deficiency during the first month of life. This has serious health implications because retinol is essential during this period for normal growth and repair of the pulmonary tissue in VLBW infants. Enterally fed VLBW infants, on the other hand, receive relatively higher doses of retinol from vitamin-supplemented premature infant formula and fortified breast milk. Equally serious is the problem of monitoring vitamin A status in infants receiving supplemental doses of vitamin A. It seems clear that while plasma vitamin A levels are the most easily available method of monitoring vitamin A status, further studies are necessary to determine if these levels correlate with hepatic content. This is of particular concern since liver disease is common in VLBW infants and vitamin A hepatotoxicity has been described in a cohort of 41 patients receiving therapeutic doses of the vitamin. While further research of daily enteral and parenteral retinol requirements of VLBW infants should continue, formulation of a specific VLBW parenteral vitamin supplement should also be developed.

Twenty-four hour in-house coverage for neonatal intensive care units in academic centers: who, how, and why?

Twenty-four-hour in-house coverage by attending physicians is becoming more common in academic centers in certain subspecialties in pediatrics. The actual percentage of programs providing this coverage in most subspecialties is not documented. We report the results of a survey of in-house coverage by attending physicians in neonatal intensive care units at academic centers in the United States. Of the 238 surveys distributed, 204 (86%) were returned and completed. At the time of the survey, 47 of 204 programs (23%) provided 24-hour in-house coverage for their neonatal intensive care units. These programs had more manpower than those programs not providing this coverage. If this trend continues, it will significantly alter projections for neonatal manpower needs in the United States.

Intracranial hemorrhage in term or near-term newborns with persistent pulmonary hypertension.

To substantiate the clinical impression of an increased incidence of intracranial hemorrhage (ICH) in term and near-term infants with persistent pulmonary hypertension (PPH), a retrospective chart review of 35 affected patients was performed. ICH was diagnosed in 40 percent of the patients. Multiple regions of the brain were affected; in many patients, at more than one location. In addition, 43 percent of ICH victims had hemorrhages of the type associated with periventricular bleeding in preterm newborns. Of multiple obstetric and neonatal factors analyzed, many of which are identified risk factors for periventricular hemorrhage, only thrombocytopenia (p = 0.02) was significantly associated with ICH. We conclude that the risk of ICH in newborns with PPH is significant and warrants consideration by clinicians caring for this population. Risk factors (except thrombocytopenia) previously implicated in other types of neonatal ICH, particularly periventricular hemorrhage, do not significantly correlate with ICH in infants with PPH.

The relationship of lactic dehydrogenase to epithelial cells in the urine of normal neonates.

Urinary lactic dehydrogenase (LDH) isoenzyme assays in 20 female and 15 male normal newborn infants during the first 3 days of life revealed higher levels than in older populations and a tendency toward a "slow zone pattern" (predominance of isoenzymes 4 and 5). Total LDH and LDH-5 activities were higher in the female (33.2 +/- 5.2 and 12.4 +/- 2.8 mU/mL, respectively), than in the male population (9.7 +/- 2.2 and 1.0 +/- 0.3 mU/mL, respectively). The amount of LDH correlated with the presence of epithelial cells in the urine that also were prominent in female patients and were apparently derived from the vagina. Separation of epithelial cells by centrifugation and filtration decreased total LDH and isoenzyme activities in the remaining sample, while sonification of the resuspended cells increased TLDH and LDH-5 activities by 6- and 12-fold respectively. Saline washings of the perineum and vagina revealed large numbers of epithelial cells and similar LDH isoenzyme patterns suggesting that contamination of the urine with these cells is a frequent occurrence during collection of voided and/or bag urine samples, and that these cells are responsible for much of the LDH activity found in the urine. We conclude that epithelial cells can increase both total LDH and isoenzyme activity in voided urine samples from otherwise normal female neonates. In this age group, urine collected by other methods (catheterization or suprapubic aspiration) must be studied to minimize the possibility of contamination of the sample with epithelial cells from the vagina or the perineum or both.

The care by parent unit. A tool for decreasing anxiety in mothers of high risk infants.

The delivery of a premature infant, especially one of very low birth weight, represents a crisis for a family. Bidder et al. have determined through a series of interviews that mothers of preterm infants are anxious at two particular points in their infant's neonatal course: the time of birth and the time of discharge. The Care By Parent Unit (CBPU) was developed at Hermann Hospital in Houston, Texas, to provide a transition from the specialized care of the Neonatal Intensive Care Unit (NICU) to home and to aid the parents in viewing their infant as a normal, "safe" child to take home. To evaluate the impact of a CBPU on maternal anxiety, the mothers' responses before and after the CBPU experience were evaluated.

Osmolalities of infant formulas.

The osmolalities of breast milk and of 36 products that may be fed to infants were determined by the freezing-point depression method. A wide range of osmolality was observed among formulas that provide 67 kcal/100 ml, and many have osmolalities greater than 400 mOsm/kg of water. Reconstituted powdered formulas have osmolalities that are widely varied from batch to batch, are greater when prepared by scoop measures when the osmolalities of corresponding ready-to-feed formulas, and are greater than the osmolalities of the formulas prepared by weighed measures from the manufacturer's formulation. The osmolality of products for oral consumption should be considered in the selection of formulas for preterm infants.

Effect of uterine artery insulin infusions on umbilical glucose uptake in sheep.

Although glucose is an important fuel for fetal oxidative metabolism, regulation of its availability to the mammalian fetus is poorly understood. This study was performed to determine the effect of infusions of insulin into the uterine arterial circulation on umbilical uptake of glucose in chronically instrumented, unstressed sheep. Twenty-eight determinations of umbilical glucose uptake and diffusion clearance of glucose by the placenta were made in four ewes. Immediately following a control study during which saline was infused into the uterine artery, porcine regular insulin diluted in saline was infused at 0.05 to 8.1 mU/min . kg uterine weight for 20--30 min and the determinations were repeated. Subsequent studies were performed at the conclusion of additional infusions of insulin to a maximum of 21.6 mU/min . kg. There was a significant increase in umbilical glucose uptake during initial insulin infusions (4.47 +/- 0.6 mg/min . kg fetus) compared to the control studies (3.08 +/- 0.6 mg/min . kg) associated with an increase in diffusion clearance (13.8 +/- 1.9 ml/min . kg fetus vs. 8.99 +/- 1.8 ml/min . kg). When the total cumulative dose of exogenous insulin, It, was 162 mU/kg uterine weight or less, the umbilical uptake of glucose, Q, may be expressed as a function of maternal arterial blood glucose concentration in milligrams per dl, [A], and of It.

Hydrolysis of dipeptides by human and ovine placentas.

Human and ovine placental tissue homogenates were assayed for dipeptidase activity in vitro. Glycyl-L-leucine, L-leucyl glycine, glycyl-L-lysine, and L-lysyl glycine were hydrolyzed by placental homogenates. The pH optimum for the reaction was 8.0. The relationship between enzyme activity and concentration was linear for placental homogenate concentrations between 0.01 and 0.10 mg protein/ml of reaction mixture. Enzyme activities were 1.92 +/- 0.12 (S.E.) micromoles/min/mg protein for hydrolysis of glycyl-L-leucine, 0.34 +/- 0.06 (S.E.) micromoles/min/mg protein for hydrolysis of glycyl-L-lysine by human placenta, and 2.79 +/- 0.80 micromoles/min/mg protein and 0.41 +/- 0.25 micromoles/min/mg protein, respectively, by ovine placenta. The infusion of glycyl-L-leucine into the uterine artery of unstressed catheterized pregnant ewes yielded increased concentrations of both component amino acids in uterine venous blood and of leucine in umbilical venous blood.

Development of gluconeogenic enzymes in fetal sheep liver and kidney.

In the sheep, the system of enzymes necessary for conversion of nonhexose substrates to glucose becomes active during late fetal life. Glucose-6-phosphatase and fructose-1,6-diphosphatase, two of the four key gluconeogenic enzymes, appear in significant amounts between 100 and 120 days gestation. Phosphoenolpyruvate carboxykinase activity is comparable to mature animals as early as 45 days gestation. Two aminotransferases, necessary to allow amino acid access to the gluconeogenic pathway, likewise have substantial activity as early as 45 days gestation. Hence, the surge of glucose-6-phosphatase and fructose-1,6-diphosphatase at 100-120 days gestation makes possible the endogenous production of new glucose by fetal sheep at a time when the amount of glucose transferred from the maternal circulation is less than the total aerobic substrate utilized by the fetus. Both renal cortex and liver have similar developmental patterns for the gluconeogenic enzymes, although renal cortex generally shows greater activity than liver. This observation holds true for tissue from both fetal and mature animals.

Effects of fasting on uterine blood flow and substrate uptake in sheep.

Twelve chronically instrumented late-gestation ewes fasted for 5 days were found to have a 25% decrease in total uterine blood flow and a 20% decrease in placental blood flow. Cardiac output was unchanged but was redistributed, as measured by radiolabeled microspheres, in a pattern similar to that produced by catecholamines. Fasting also was associated with hypoglycemia and altered whole blood amino acid concentrations. Uterine uptakes of glucose, oxygen, essential amino acids and glutamine, an important uterine and fetal nutrient, were decreased significantly during fasting. The increased hepatic blood flow and decreased arterial concentrations of glucogenic amino acids observed during fasting are consistent with a redistribution of maternal cardiac output to support maternal hepatic gluconeogenesis at the expense of nutrient supply to the gravid uterus.

Plasma and urine riboflavin and pyridoxine concentrations in enterally fed very-low-birth-weight neonates.

Preterm infant formulas (PIFs) for very-low-birth-weight (VLBW) infants (birth weight, < 1,500 g) are augmented to provide daily riboflavin and pyridoxine at levels up to five-fold greater than in term infant formula and 18-fold greater than in human milk. We evaluated plasma riboflavin and pyridoxine concentrations in VLBW infants who received PIF during their first postnatal month. Eighty-eight plasma and 124 urine samples were collected for riboflavin- and pyridoxine-concentration measurements from 57 clinically healthy VLBW infants weekly during their first postnatal month. Concentrations were measured using high-performance liquid chromatography. At the time of the sample, patients were receiving > or = 80% of their total calories via enteral feedings. Plasma riboflavin concentrations rose from 45.3 +/- 7.3 ng/ml at baseline (mean +/- SEM) to 173.5 +/- 20.3 ng/ml by 1 week of age and remained at 177.3-199.7 ng/ml during the following three weekly measurements; values were up to 14-fold above baseline concentration. Urine riboflavin concentration increased from 534 +/- 137 ng/ml at baseline to 3,521 +/- 423 ng/ml by 1 week of age and remained at 4,451-5,216 ng/ml during the next 3 weeks. In a similar pattern, baseline plasma (69.4 +/- 10.4 ng/ml) and urine (145 +/- 30 ng/ml) pyridoxine concentrations were significantly increased by 1 week postnatal age; they remained at 163-248 ng/ml (plasma) and 1,573-2,394 ng/ml (urine) through the first postnatal month. Plasma and urine riboflavin and pyridoxine concentrations in enterally fed VLBW infants increased from baseline concentrations by 1 week of postnatal age and remained elevated for the first postnatal month. High daily intake and immature renal development are probable contributing causes of the elevated plasma riboflavin and pyridoxine concentrations. We suggest that lower daily enteral administration of riboflavin and pyridoxine should maintain adequate blood concentrations and minimize potential toxicity.

What is meant by the term "bile acid"?

The bile acids are a set of acidic steroids. Many conventional bile acids share a common derivation and have functional characteristics in common. Exceptions exist, however, to virtually all of the rules that can be applied to a definition of bile acids. The term is thus best applied to those steroids with a side chain at C-17, which contains a carboxylic acid group, and to acidic derivatives of such compounds. Naturally occurring bile acids are a more numerous and diverse group than has been generally recognized. The site of origin, synthetic pathways, metabolism, and bioactivity of recently recognized unconventional bile acids are under intensive investigation.