Ian R. Holzman

Effects of butyrate on intestinal barrier function in a Caco-2 cell monolayer model of intestinal barrier.

Production of short-chain fatty acids (SCFA) in the intestinal lumen may play an important role in the maintenance of the intestinal barrier. However, overproduction/accumulation of SCFA in the bowel may be toxic to the intestinal mucosa and has been hypothesized to play a role in the pathogenesis of neonatal necrotizing enterocolitis (NEC). By using a Caco-2 cell monolayer model of intestinal barrier, we report here that the effect of butyrate on the intestinal barrier is paradoxical. Butyrate at a low concentration (2 mM) promotes intestinal barrier function as measured by a significant increase in transepithelial electrical resistance (TER) and a significant decrease in inulin permeability. Butyrate at a high concentration (8 mM) reduces TER and increases inulin permeability significantly. Butyrate induces apoptosis and reduces the number of viable Caco-2 cells in a dose-dependent manner. Intestinal barrier function impairment induced by high concentrations of butyrate is most likely related to butyrate-induced cytotoxicity due to apoptosis. We conclude that the effect of butyrate on the intestinal barrier is paradoxical; i.e. whereas low concentrations of butyrate may be beneficial in promoting intestinal barrier function, excessive butyrate may induce severe intestinal epithelial cell apoptosis and disrupt intestinal barrier.

Cause of hearing loss in the high-risk premature infant

Bilateral hearing loss occurred in 9.7% of infants who survived despite very low birth weight (less than or equal to 1500 gm), 16.7% of infants who survived neonatal seizures, and 28.6% of infants who survived both low birth weight and neonatal seizures. All neonates received treatment in a single neonatal intensive care unit between 1976 and 1980. Twenty-two of 36 hearing-impaired children were normal physically and mentally, with IQ scores of greater than or equal to 85. Significant neonatal predictors of hearing loss in high-risk premature infants (less than or equal to 36 weeks gestation), as determined by multivariable testing, were prolonged respirator care, high serum bilirubin concentration, and hyponatremia. Exchange transfusions were associated with a decreased risk of hearing loss.

Effect of labor epidural analgesia with and without fentanyl on infant breast-feeding: a prospective, randomized, double-blind study.

Background:The influence of labor epidural fentanyl on the neonate is controversial. The purpose of this study was to determine whether epidural fentanyl has an impact on breast-feeding. Methods:Women who previously breast-fed a child and who requested labor epidural analgesia were randomly assigned in a double-blinded manner to one of three groups: (1) no fentanyl group, (2) intermediate-dose fentanyl group (intent to administer between 1 and 150 &mgr;g epidural fentanyl), or (3) high-dose epidural fentanyl group (intent to administer > 150 &mgr;g epidural fentanyl). On postpartum day 1, the mother and a lactation consultant separately assessed whether the infant was experiencing difficulty breast-feeding, and a pediatrician assessed infant neurobehavior. All women were contacted 6 weeks postpartum to determine whether they were still breast-feeding. Results:Sixty women were randomly assigned to receive no fentanyl, 59 were randomly assigned to receive an intermediate dose, and 58 were randomly assigned to receive high-dose fentanyl. On postpartum day 1, women who were randomly assigned to receive high-dose fentanyl reported difficulty breast-feeding (n = 12, 21%) more often than women who were randomly assigned to receive an intermediate fentanyl dose (n = 6, 10%), or no fentanyl (n = 6, 10%), although this did not reach statistical significance (P = 0.09). There was also no significant difference among groups in breast-feeding difficulty based on the lactation consultant’s evaluation (40% difficulty in each group; P = 1.0). Neurobehavior scores were lowest in the infants of women who were randomly assigned to receive more than 150 &mgr;g fentanyl (P = 0.03). At 6 weeks postpartum, more women who were randomly assigned to high-dose epidural fentanyl were not breast-feeding (n = 10, 17%) than women who were randomly assigned to receive either an intermediate fentanyl dose (n = 3, 5%) or no fentanyl (n = 1, 2%) (P = 0.005). Conclusions:Among women who breast-fed previously, those who were randomly assigned to receive high-dose labor epidural fentanyl were more likely to have stopped breast-feeding 6 weeks postpartum than woman who were randomly assigned to receive less fentanyl or no fentanyl.

Blood flow and oxygen delivery to fetal organs as functions of fetal hematocrit

The purpose of our experiments was to relate blood flow and oxygen delivery (blood flow x arterial blood oxygen concentration) to fetal organs as functions of fetal hematocrit. In 12 chronically catheterized fetal lambs, we observed two patterns of responses of fetal organs and tissues to isovolemic alterations in fetal hematocrit from 12% to 55%. In group 1 organs (brain, heart, adrenal glands), blood flows increased as hematocrit was either raised or lowered from normal such that oxygen delivery to these organs was stable over the entire range of hematocrits studied. In group 2 organs (gastrointestinal tract organs, spleen, kidneys, placenta, and carcass), blood flows varied little over the range of hematocrits from 12% to 40% or 45% but decreased at hematocrits greater than or equal to 40% to 45%. Because of these flow responses, oxygen delivery to these organs and tissues was maximal at hematocrits ranging from 32% to 38%. Our data indicate that the various organs of the unanesthetized fetal lamb respond in different ways to alterations in hematocrit. It is of particular interest that, in the great majority of the organs of the fetus, oxygen delivery is maximal at hematocrits considered normal for the fetal lamb in utero.

Metabolic correlates of neurologic and behavioral injury after prolonged hypothermic circulatory arrest

Thirty-two inbred weanling puppies were divided into four groups to study the effect on cerebral blood flow and metabolism of different hypothermic strategies for cerebral protection similar to those used during cardiac operations in infancy. All animals were cooled to 18 degrees C. The animals in the hypothermic control group were immediately rewarmed. One group underwent 30 minutes of hypothermic circulatory arrest at 18 degrees C; another group had 90 minutes of hypothermic circulatory arrest at 18 degrees C, and the final group had low-flow cardiopulmonary bypass (25 ml/kg per minute) at 18 degrees C for 90 minutes. All animals had preoperative and postoperative neurologic and behavioral evaluation and extensive intraoperative monitoring of cerebral blood flow, cerebral vascular resistance, and oxygen and glucose uptake and metabolism: quantitative electroencephalography was also monitored before, during and after operation, but those results are reported separately. Two animals in the 90-minute arrest group died, and all the survivors showed evidence of clinical, neurologic, and behavioral impairment on postoperative day 1, with residual abnormalities in all but one animal on day 6. In contrast, the survivors in all the other groups showed no significant clinical or behavioral sequelae. Cerebral metabolism was reduced only to 32% to 40% of baseline values at 18 degrees C in all groups, although systemic metabolism was only 16% of normal. Cerebral metabolism returned promptly to baseline in all groups during rewarming and remained at baseline levels throughout the 8 hours of follow-up. Cerebral blood flow showed marked hyperemia in the hypothermic arrest groups during rewarming but then significant reductions below baseline values in all groups except the controls at 2 and 4 hours after the operation, lasting as late as 8 hours after the operation in the 90-minute arrest group. Cerebral vascular resistance showed increases in all groups at 2 and 4 hours after the operation, which persisted in the 90-minute arrest group at 8 hours. Cerebral metabolism was maintained at baseline levels despite postoperative decreases in cerebral blood flow and increases in cerebral vascular resistance by increases in oxygen and glucose extraction. The result was very low sagittal sinus oxygen saturations in all groups, most marked in the 90-minute arrest groups, which had a saturation of only 24% 8 hours after the operation. Our data show a severe, prolonged disturbance in cerebral blood flow and cerebral vascular resistance after 90 minutes of hypothermic circulatory arrest at 18 degrees C, which correlates with clinical evidence of cerebral injury.(ABSTRACT TRUNCATED AT 400 WORDS)

Selective fetal malnutrition: The effect of ethanol and acetaldehyde upon in vitro uptake of alpha amino isobutyric acid by human placenta

Abstract Uptake of alpha amino isobutyric acid was measured in human placental villus tissue exposed in vitro to ethyl alcohol (ethanol) (0.3 g/dl–2 g/d1) or acetaldehyde (50 μM-20 mM). Ethanol and acetaldehyde significantly inhibited uptake of amino acid at higher, pharmacologic concentrations (2 g/dl and 2–20 mM respectively). Inhibition by 10 mM acetaldehyde was partially reversible. The results suggest that the human placenta is resistant to acute ethanol-associated effects upon amino acid transport in vitro . However, both ethanol and its major circulating metabolite, acetaldehyde, may still alter placental function during in vivo chronic exposure.

Expression of Intestinal Trefoil Factor in Developing Rat Intestine

Intestinal trefoil factor (ITF or TFF3), a small peptide secreted at the mucosal surface by goblet cells throughout the mature intestine, appears to play important roles in the maintenance and repair of the intestinal mucosal barrier. To study the expression of TFF3 during development, intestinal tissues were collected from rats at different development stages and examined by Northern blot analysis, Western blot analysis and immunohistochemical staining for TFF3 mRNA and protein expression. The results demonstrate that rat TFF3 mRNA is not detected until the 17th gestational day (term = 22 days), the expression is greater on gestational day 20 and increased further postnatally. TFF3 protein is first detected by Western blotting and immunohistochemical staining on gestational day 20. Further increases in TFF3 protein expression are demonstrated at around the weaning period. In conclusion, significant expression of rat TFF3 commences late in gestation and its expression is relatively deficient in immature rats. Expression of TFF3 may be deficient in premature infants and, therefore, may have a role in the development of necrotizing enterocolitis.

Pulse Oximetry Saturations in the First 6 Hours of Life in Normal Term Infants

The pulse oximetry saturation values and the average percentage of time that normal newborns spend at different saturation ranges in the first 6 hours of life were determined in a cross-sectional study. Pulse oximetry saturation values were measured for a single 20-minute period in 101 normal term newborns between 20 minutes and 6 hours of age. The 25th percentile saturation values in the first postnatal hour (range 91%-100%) were lower than those from the second postnatal hour (range 96%-100%) onward. There was no significant difference between the 50th percentile (range 96%-100%) and the 75th percentile (range 97%-100%) saturation values in all postnatal hours. The babies spent a majority of time with saturations?96% in all postnatal hours. A newborn more than 20 minutes old who does not achieve a pulse oximetry saturation value of 96% over several minutes of observation may need evaluation or continuous monitoring.

Late rise of thyroid stimulating hormone in ill newborns.

OBJECTIVES To determine the frequency and characteristics of late rise of thyroid stimulating hormone (LRT) among ill newborns. INFANTS AND METHODS Data were retrospectively analyzed from infants in intensive care settings with abnormal thyroid tests over 13 months. Thyroid tests were performed by filter paper if neonatal intensive care >4 weeks or serum if clinically indicated. LRT was defined as thyroid stimulating hormone (TSH) >10 microIU/ml after normal TSH on initial newborn screen. RESULTS LRT was identified in 13 infants. Of 736 admissions to the neonatal intensive care unit (NICU), 10 (1.4%) had LRT. Excluding 3/10 with diagnosis at <1 week of age the frequency is 0.95%. Three additional cases occurred in other ICUs. TSH elevation resolved in 6/13 (group A, TSH 10.6-20.6 microIU/ml) and persisted in 7/13 necessitating treatment (group B, TSH 10.5-1326 microIU/ml). 7/13 had birth weights <1500 g. 11/13 had gestational ages <37 weeks. LRT was associated with surgery, sepsis workup, dopamine, and gastrointestinal disorders. CONCLUSIONS LRT was not infrequent in ill newborns. Most were premature and half were not very low birth weight. We recommend monitoring of thyroid function by serum specimen in ill newborns with prolonged ICU care regardless of birth weight.

Blood flow and oxygen delivery to the organs of the neonatal lamb as a function of hematocrit.

ABSTRACT. We chronically catheterized 15 newborn lambs (9.5 ± 2.8 days) and measured the distribution of cardiac output by the radionuclide-microsphere technique at hematocrits ranging from 10 volumes % to 55 volumes %. Seven animals were made progressively anemic and eight polycythemic by means of exchange transfusions. Cardiac output and heart rate increased with decreasing hematocrit while whole body oxygen consumption showed a small decrease during severe anemia. Both cerebral and cardiac blood flow markedly increased during anemia which assured a relatively stable oxygen delivery to both organs. The changes seen for blood flow to the carcass (skin, bones, and muscle) were predictable from the effects of blood viscosity: small decreases in flow at the highest hematocrits and small increases in flow at the lowest hematocrits. Consequently, oxygen delivery was as low as 1 ml of oxygen/min/100 g at a hematocrit of 10 volumes %. Renal blood flow remained unchanged while oxygen delivery fell when hematocrit was decreased. Hepatic oxygenation was measured using a modification of the Fick principle. Hepatic blood flow showed only a small decrease as hematocrit increased and changed minimally during anemia resulting in a falling delivery of oxygen with anemia. A stable hepatic oxygen consumption was assured by a marked increase in oxygen extraction during anemia. Two differing organ responses to changes in hematocrit can be seen in the newborn: the brain and heart vary blood flow to assure an adequate delivery of oxygen while a number of other organs show less blood flow regulation and, most likely, vary oxygen removal from blood. Over a wide range of hematocrits, compensatory responses occur in the newborn which effectively prevent the development of tissue hypoxia.