Immature Fetuses Research Articles

Developmental regulation of hepatic and renal gluconeogenic enzymes by thyroid hormones in fetal sheep during late gestation.

Tissue glucose-6-phosphatase (G6P) and phosphoenolpyruvate carboxykinase (PEPCK) activities were investigated in sheep fetuses after experimental manipulation of thyroid hormone status. Increments in hepatic and renal G6P and PEPCK activities seen between 127-130 and 140-145 days of gestation (term, 145 +/- 2 days) were abolished when the normal prepartum rise in plasma triiodothyronine (T3), but not cortisol, was prevented by fetal thyroidectomy (TX). At 127-130 days, hepatic and renal G6P, and renal PEPCK, activities were similar in intact and TX fetuses; however, hepatic PEPCK was increased by TX. At 140-145 days, tissue G6P and PEPCK activities in TX fetuses were lower than in intact fetuses. In immature fetuses infused with cortisol (2-3 mg (kg body wt)-1 day-1) for five days, hepatic and renal enzyme activities were increased to those seen in mature fetuses near term. After five days of T3 infusion (8-12 microg (kg body wt)-1 day-1), G6P and PEPCK activities in the liver and kidney were greater than in saline-infused fetuses, but only renal G6P and PEPCK increased to the level seen close to term. Therefore, in fetal sheep, thyroid hormones are important for the prepartum rises in G6P and PEPCK activities in the liver and kidney and may mediate, in part, the maturational effects of cortisol.

The Effects of Cortisol on the Binucleate Cell Population in the Ovine Placenta During Late Gestation

Large granulated binucleate cells (BNCs) producing placental lactogen (PL) and pregnancy-associated glycoproteins (PAG) are present in all ruminant placentae throughout pregnancy. These BNC account for 15–20% of the cells in ovine trophectoderm for most of gestation but decrease in number close to term at the same time that fetal cortisol levels rise. The present study investigated the effects of cortisol on the BNC population using immunohistochemistry to count BNCs in ovine placentomes during late gestation and after experimental manipulation of the fetal cortisol level by fetal adrenalectomy and exogenous cortisol infusion. Abolition of the prepartum rise in fetal cortisol prevented the normal decline in BNC numbers towards term. Conversely, raising cortisol levels in immature fetuses to prepartum values prematurely reduced placental BNC numbers. However, a small population of BNC remained, even at the highest cortisol concentrations. When all the data were combined irrespective of treatment or gestational age, there was a significant inverse correlation between fetal plasma cortisol and the number of BNCs in the ovine placenta. These findings show that cortisol regulates the BNC population in ovine placenta during late gestation. They also have important implications for the production of PL and PAG during ovine pregnancy.

Regulation of 11 beta-hydroxysteroid dehydrogenase type 2 activity in ovine placenta by fetal cortisol.

The effect of fetal cortisol on the activity of the type 2 isoform of the enzyme, 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD2), was examined in ovine placenta and fetal kidney by measuring tissue 11 beta-HSD2 activity during late gestation when endogenous fetal cortisol levels rise and after exogenous cortisol administration to immature fetuses before the prepartum cortisol surge. Placental 11 beta-HSD2 activity decreased between 128-132 days and term (approximately 145 days of gestation) in association with the normal prepartum increase in fetal plasma cortisol. Raising fetal cortisol levels to prepartum values in the immature fetus at 128--132 days of gestation reduced placental 11 beta-HSD2 activity to term values. In contrast, 11 beta-HSD2 activity in the fetal renal cortex was unaffected by gestational age or cortisol infusion. When all the data were combined, there was an inverse correlation between the log fetal plasma cortisol level at delivery and placental 11 beta-HSD2 activity, expressed both on a weight-specific basis and per mg placental protein. Fetal cortisol therefore appears to be a physiological regulator of placental, but not renal, 11 beta-HSD2 activity in fetal sheep during late gestation. These findings have important implications, not only for glucocorticoid exposure in utero, but also for the local actions of cortisol within the placental tissues that are involved in initiating parturition in the sheep.

Erythrocyte and erythropoietin responses to hemorrhage in the immature and near term ovine fetus

Objective: Previous reports suggested that immature ovine fetuses have a greater erythropoietin response to hemorrhage than those near term. This study tested the hypothesis that immature ovine fetuses would expand their red cell mass more rapidly than near term fetuses after hemorrhage. Study Design: Chronically catheterized immature ovine fetuses at 109.5 ± 0.3 (mean ± SE) days' gestation (term = 150 days) were studied over a 10-day period. They either underwent hemorrhage of 40% of their measured blood volume on day 3 or were in a time control group monitored without hemorrhage. Red cell mass, hematocrit, blood volume, plasma volume, and plasma erythropoietin concentrations were measured at 24- and 48-hour intervals. Responses in the immature fetuses were compared with responses in near term fetuses. Results: In the control group red cell mass, hematocrit, blood, and plasma volumes increased significantly, whereas plasma erythropoietin concentration decreased significantly with advancing gestational age. In immature fetuses that underwent hemorrhage, the relative changes in red cell mass, hematocrit, and plasma erythropoietin concentration were not significantly different from those seen in the near term fetuses. The only significant posthemorrhage difference was that the increases in blood and plasma volumes were greater in the immature compared with the near term fetuses. Conclusion: Immature and mature fetuses have similar erythrocyte and erythropoietin responses to moderately severe hemorrhage. The larger blood and plasma volume responses in the immature fetuses are consistent with the concept that they have a greater extracellular fluid volume. (Am J Obstet Gynecol 2001;185:501-6.)

Ontogeny of Toll-like receptors Tlr2 and Tlr4 in mice.

Toll-like receptors (TLR:) have recently been linked to the immunostimulatory function of microbial toxins in human and mice. TLR: signals activation of nuclear factor kappaB that leads to the production of a number of proinflammatory mediators. TLR:4 mediates the endotoxin-induced inflammatory response, whereas TLR:2 may be involved in the response to yeast and Gram-positive bacterial products. To better understand age-related changes in acute inflammatory response, we studied the ontogeny of TLR:2 and TLR:4 mRNA in murine fetal lung, liver, and placenta by quantitative reverse transcriptase-PCR. Different expression patterns were seen between the tissues and between the TLR: This is in accordance with the evidence that there are differences in the receptors for different microbial toxins and that the response is organ specific. We additionally show that the expression of TLR: was dependent on the stage of differentiation. In the liver, the levels of Tlr2 and Tlr4 were high regardless of the age. In the lung, Tlr2 and Tlr4 expression levels were barely detectable in immature fetus (d 14-15). Tlr2 and Tlr4 were increased several-fold during prenatal development and further increased after birth. The present results support the finding of a deficient inflammatory response of the immature lung to microbial toxins.

Corticotropin-releasing hormone type I receptor messenger ribonucleic acid and protein levels in the ovine fetal pituitary: ontogeny and effect of chronic cortisol administration.

In sheep, the ACTH secretory response to CRH in vivo or in vitro changes as a function of development, with peak responses occurring several weeks before term (145 days of gestation). CRH-stimulated ACTH secretion is mediated via the G protein-coupled CRH type I (CRH R1) receptor. We used a quantitative ribonuclease protection assay and Western immunoblotting to determine messenger RNA (mRNA) and protein levels of the CRH R1 receptor in immature and mature fetuses and adults. In addition, we precociously elevated fetal plasma cortisol levels to determine whether the fetal CRH R1 receptor is sensitive to increases in plasma cortisol. CRH R1 receptor mRNA levels decreased markedly throughout gestation and into the transition to adult life (immature fetus, 1.24+/-0.17; mature fetus, 0.75+/-0.13; adult, 0.18+/-0.093 pg/microg total anterior pituitary RNA). Also, continuous cortisol infusion in immature fetuses significantly decreased CRH R1 mRNA levels by 41%. Similar decreases were noted in protein levels. Thus, the decreased ACTH response to CRH stimulation during late gestation may be related to decreased CRH R1 receptor expression. In addition, plasma cortisol levels may influence corticotroph responsiveness to CRH by decreasing CRH R1 receptor expression.

Effect of Repetitive Umbilical Cord Occlusions on Neuronal Brain Activity Measured by the Cerebral Function Analyzing Monitor and Histologic Outcome in Immature Fetal Sheep

To examine the effect of repetitive total umbilical cord occlusions on electrocortical brain activity as measured by cerebral function analyzing monitoring (CAFM) and the histologic outcome in immature sheep fetuses. We performed brief repeated total umbilical cord occlusions, two every 5 minutes, in 12 immature sheep fetuses (at 90 days of gestation, term 147 days) until fetal mean arterial pressure dropped below 50% of baseline value during two successive occlusions. A pair of electrodes was inserted on the parietal dura for recording of electrocortical brain activity (ECoG). Off-line ECoG signal processing consisted of amplitude integrated analysis (CFAM) and spectral analysis. Fetal blood gas analyses were performed at regular intervals just before subsequent umbilical cord occlusions. Three days after the occlusion neuronal damage was evaluated histologically in three regions of the fetal brain. CFAM amplitide parameters decreased significantly during the first occlusion and remained so during the entire repetitive occlusion period (analysis of variance [ANOVA]; P <.05). Spectral analysis of the ECoG signal demonstrated no changes in the distribution of frequency bands. Progressive acidemia and hypotension developed with ongoing occlusions. Five fetuses died at the end or shortly after the entire repetitive occlusion period. No neuronal damage or macroscopic intraventricular and/or germinal matrix hemorrhage was observed in the surviving fetuses. Repetitive umbilical cord occlusions in immature sheep fetuses resulted in functional, not structural changes of the fetal brain in surviving fetuses. At this gestational age, amplitude analysis is more sensitive than spectral analysis of the ECoG signal to functional changes of the compromised fetal brain.

The laparoscopic approach of the transabdominal cerclage of the uterine cervix in case of cervical incompetence

Cervical incompetence is characterized by painless cervical dilation in the second or early in the third trimester, with prolapse or ballooning of membranes in the vagina and expulsion of an immature fetus. Unless effectively treated, this sequence tends to recur at each pregnancy. Usually a ‘purse-string’ cerclage as described by McDonald, using a vaginal approach, is effective. If the cervix is too short for this or even absent, a transabdominal cervicoisthmic cerclage (TCC) is indicated. After TCC an eventual pregnancy always culminates in a Caesarean section, as the cerclage cannot be removed vaginally. This is, in fact, the main drawback of this technique. Objective To present the laparoscopic approach to TCC. Case history The patient was a 34-year-old woman with a history of cervical intraepithelial neoplasia and electrosurgical excision of the transformation zone. The pregnancy following this operation ended with an immature delivery, which was attributed to cervical incompetence. Before the next pregnancy, TCC using a laparoscopic approach was carried out. Using one 12-mm port and two 5-mm ports, the cervix was laparoscopically freed from the bladder. The avascular space between the ascending and descending branch of the uterine artery was penetrated and a Mersilene band was guided through, just above the level of the sacrouterine ligaments and tied. The operation lasted 40 minutes and the patient was discharged from the hospital, in a good state of health, the next day. Some months later she had an uneventful pregnancy, and a healthy but growth-retarded son, weighing 1890 g, was delivered by Caesarean section at 37 weeks of gestational age. Conclusion The laparoscopic approach to TCC was successful. The growth retardation in the subsequent pregnancy seemed coincidental. The laparoscopic approach is to be preferred for a planned TCC.

Control of ovine hepatic growth hormone receptor and insulin-like growth factor I by thyroid hormones in utero.

By use of RNase protection assays, hepatic growth hormone receptor (GHR) and insulin-like growth factor I (IGF-I) mRNA abundances were measured in sheep fetuses after experimental manipulation of fetal plasma thyroid hormone concentrations by fetal thyroidectomy (TX) and exogenous infusion of triiodothyronine (T(3)) and cortisol. TX abolished the normal prepartum rise in hepatic GHR abundance but had little effect on hepatic GHR gene expression at 127-130 days (term 145 +/- 2 days). By contrast, it upregulated basal IGF-I expression in immature fetal liver by increasing both Class 1 and Class 2 transcript abundance but had no further effects on IGF-I gene mRNA levels at 142-145 days. Raising plasma T(3) to prepartum values by exogenous infusion of either T(3) or cortisol into immature intact fetuses prematurely raised hepatic GHR and IGF-I mRNA abundances to values similar to those seen in intact fetuses at 142-145 days. In TX fetuses, cortisol infusion increased hepatic GHR mRNA but not total IGF-I mRNA abundance at 127-130 days. These findings show that thyroid hormones have an important role in the regulation of hepatic GHR and IGF-I gene expression in fetal sheep during late gestation and suggest that T(3) mediates the maturational effects of cortisol on the hepatic somatotropic axis close to term.

The PR interval–fetal heart rate relationship during repetitive umbilical cord occlusions in immature fetal sheep

Objective: To evaluate the relationship of the PR interval and fetal heart rate during repetitive umbilical cord occlusions in immature sheep fetuses. Study design: In seven chronically cannulated immature sheep fetuses [gestational age 90.6 days (mean)], we analyzed continuous fetal electrocardiogram recordings during repetitive cord occlusions for 2 out of every 5 min until fetal mean arterial pressure dropped to 50% of baseline value. PR interval–fetal heart rate correlation coefficients (Pearson) was measured on consecutive blocks of 2.5 min. R-values of the baseline and the repetitive occlusion period were compared by Fisher’s exact test. Results: Repetitive cord occlusions resulted in acidosis and hypotension. Two fetuses died at the end of the repetitive occlusion period. Four out of seven fetuses showed a significant change from a negative relationship between the PR interval and fetal heart rate during baseline to a predominantly positive relationship during the repetitive occlusion period. Conclusion: In immature fetal sheep, a change from a negative relationship between the PR interval and fetal heart rate to a predominantly positive relationship between the PR interval and fetal heart rate was observed in four out of seven fetuses following the initiation of repetitive umbilical cord occlusions.

Role of nitric oxide in regulating the ductus arteriosus caliber in fetal rats.

The role of nitric oxide (NO) on the ductus arteriosus (DA) patency was examined in fetal rats at various stages of gestation. N(G)-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg, i.p.), an NO synthase (NOS) inhibitor, or indomethacin (3 mg/kg, p.o.), a cyclooxygenase inhibitor, was administered at 3 hr before cesarean section to pregnant rats ranging from day 17 to day 21 of gestation. Dams were decapitated and the fetuses were obtained by cesarean section. The fetuses were rapidly frozen in an acetone-dry ice mixture. Using rapid-freezing and shaving methods, the calibers of the DA and pulmonary artery were measured. The constrictive effect of L-NAME on the fetal DA caliber was stronger than that of indomethacin in 19-day-old and immature fetuses. In near-term fetuses, the constrictive effects of L-NAME were reduced, while indomethacin caused marked DA constriction. We conclude that endogenous NO may play a major role in regulating the patency of the DA in earlier fetal stages, while dilator prostaglandins may play a greater role in regulating the ductal patency in the near-term fetus.

Clinicopathological analysis of premature infants treated with artificial surfactant.

Our aim was to obtain new information about the relationship between infant responses to surfactant replacement therapy and histopathological changes in vital organs. To accomplish this, the autopsy findings and clinical backgrounds of 41 very low birth weight infants (gestational week 25.6 +/- 2.3; birth weight 806.4 +/- 251.6g) who had died after receiving surfactant replacement therapy were reviewed, and those who responded to therapy were compared with those who did not. Responders were infants in whom the required FiO(2) declined by > 20% or mean airway pressure declined by > 20% within six hours of instilling surfactant (n=18); non-responders were infants who did not meet those criteria (n=23). Gestational age, birth weight and time at treatment were similar in responders and non-responders, but survival was significantly longer in responders. The incidences of hyaline membrane disease, pulmonary interstitial emphysema, hemorrhagic necrosis and parenchymal degeneration of the liver and kidney were all higher in non-responders, whereas the incidences of bronchopulmonary dysplasia and pneumonia were higher in responders. Prior to treatment, acidosis and hypothermia were significantly more severe in non-responders, and perinatal complications, such as fetal distress and intrauterine infection, were observed more often in non-responders. Substantial degradation of vital organs had already occurred during the early post-natal or intrauterine life of the non-responders, which would be expected to interfere with the clinical response to instilled surfactant. It is anticipated that in the future improved monitoring of immature fetuses will be indispensable to improve intrauterine fetal management and to achieve better control over the timing and mode of delivery.

Fetal arterial pressure and heart rate changes in surviving and non-surviving immature fetal sheep following brief repeated total umbilical cord occlusions

Objectives: To describe the changes in fetal heart rate and mean arterial pressure during repetitive total umbilical cord occlusions in immature sheep fetuses, resulting in severe asphyxia or fetal death. To describe the relationship between these changes and concurrent changes in acid–base status. Study design: We performed brief repeated total umbilical cord occlusions, two out of every five min, in 14 immature sheep fetuses (at 90 days of gestation), until fetal mean arterial pressure dropped below 50% of baseline value during two successive occlusions. Fetal blood gas analyses were performed at regular intervals just before cord occlusions. Results: Progressive acidemia and hypotension developed with ongoing occlusions. The degree of hypotension during occlusions increased with ongoing occlusions. The minimum fetal arterial blood pressure during occlusions correlated well with the progressive acidemia. Six fetuses died at the end of the repetitive occlusion period. In the non-survivors, acidemia was more severe and paCO 2 gradually increased during the entire repetitive occlusion period. In the survivors group, a period of transient hypoxia and hypotension was observed with a nadir at +60 min following the final occlusion. Conclusion: Repetitive umbilical cord occlusions in immature sheep fetuses resulted in repetitive periods of hypotension, bradycardia, progressive fetal acidemia and ultimately fetal demise. Minimum fetal arterial blood pressure during occlusions correlated well with the progressive fetal acidemia.

Regulation of in vitro renin secretion by ANG II feedback manipulation in vivo in the ovine fetus.

The renin-angiotensin system is critically important to fetal cardiovascular function and organ development. The feedback regulation of renin secretion by ANG II develops early in gestation yet does not linearly progress from fetal life to adulthood. Renin secretion is elevated in late gestation compared with earlier or postnatal time periods, which suggests that some component of the negative feedback regulation of renin secretion is less sensitive in late gestation. We examined in fetal sheep the age-related consequence of chronic in vivo manipulation of ANG II on renal renin secretion measured in vitro. Immature (101-103 days of gestation) and mature (130-133 days of gestation) fetuses were treated for 72 h with enalaprilat, ANG II or vehicle. Content and basal and isoproterenol-stimulated secretion of prorenin (PR) and active renin (AR) from fetal kidney cortical slices were determined. Enalaprilat pretreatment in vivo increased renal renin content and basal and stimulated secretion of PR and AR in vitro even in immature animals. Immunohistochemical localization showed that enalaprilat treatment caused an age-related recruitment of renin-containing juxtaglomerular cells. Conversely, ANG II pretreatment decreased basal and stimulated PR and AR secretion from immature fetal kidneys, but only inhibited PR secretion from mature kidneys. It also caused an age-related decrease in the percentage of renin-containing juxtaglomerular cells. These results suggest that ANG II feedback modulates not only the synthesis and content of renin, but the sensitivity of the coupling between stimulus and secretion. A critical observation of our study is that the higher renal tissue concentrations of prorenin and active renin in late gestation may be a consequence of reduced sensitivity to ANG II feedback; this is consistent with the increased plasma concentrations of renin found in near-term mammals.

GH-receptor distribution in the ovine foetal adrenal gland: ontogenic and functional studies.

In order to examine the role of GH in the regulation of foetal adrenal development and function, we have localized GH-receptor mRNA and protein in adrenal glands of ovine foetuses at specific stages of gestation. Adrenals from 60-75 day (n=4), 100-110 day (n=4) and 140-145 day (n=3) foetal sheep (term is 145-150 days) and non-pregnant adult animals (n=3) were dissected and fixed. GH-receptor mRNA localization was studied by in situ hybridization using a (35)S-labelled antisense cRNA probe, and protein by immunohistochemistry using a specific monoclonal antibody to the GH-receptor. At all ages studied, GH-receptor mRNA and immunoreactivity could be detected throughout the adrenocortical region. In adult adrenals, GH-receptor mRNA and immunoreactivity were also evident throughout the adrenocortical zone, with the strongest expression confined to a defined region of cells at the interface between the zona glomerulosa and zona fasciculata. Northern blot analysis of 100 day and 140 day foetal adrenals confirmed the presence of a 4.4 kb GH-receptor mRNA transcript, while immunoblotting of foetal adrenals at approximately 110 days of gestation revealed a 55 kDa GH-receptor species. To study the effect of GH on the function and growth of the immature foetal adrenal gland in vivo, chronically catheterized ovine foetuses (n=4), between 100 and 110 days of gestation, were given a pulsatile infusion of recombinant bovine GH (125 microgram/15 min, 24 pulses/24 h) for 72 h. Plasma cortisol and aldosterone levels were compared with age-matched controls receiving saline infusion alone (n=4). It was found that there was no difference in the basal plasma level of cortisol or aldosterone, and that infusion of GH did not alter steroid levels or gross adrenal size and morphology. These studies demonstrate strong expression of the GH-receptor in the developing ovine foetal adrenal cortex. However, in the immature foetus GH infusion is without effect on plasma steroid levels, suggesting that the steroidogenic action of GH in the ovine foetus may be gestationally dependent.

The cardiovascular and cerebrovascular responses of the immature fetal sheep to acute umbilical cord occlusion.

1. In premature fetal sheep (89-93 days gestation) we examined the fetal response to asphyxia induced by 30 min of complete umbilical cord occlusion. Fetuses were also studied during the first 3 days after asphyxia. We measured heart rate, blood pressure, carotid and femoral blood flows, vascular resistance, electroencephalographic activity and cerebral changes in haemoglobin concentration by near infrared spectroscopy (NIRS). 2. Fetuses tolerated 30 min of asphyxia and the cardiovascular response was characterized by three phases: initial redistribution of blood flow away from the periphery to maintain vital organ function, partial failure of this redistribution and near terminal cardiovascular collapse, with profound hypotension and cerebral and peripheral hypoperfusion. 3. Post-asphyxia carotid blood flow and NIRS data demonstrated that between 3-5 h there was a significant secondary reduction in cerebral blood flow, blood volume and oxygenation despite normal perfusion pressure and heart rate. There was also a secondary fall in femoral blood flow which persisted throughout recovery. 4. These data demonstrate that the immature fetus can survive a prolonged period of asphyxia, but paradoxically the capacity to survive exposes the fetus to profound hypotension and hypoperfusion. A secondary period of significant cerebral hypoperfusion and reduced oxygen delivery also occurred post-asphyxia. These cardiovascular and cerebrovascular responses may contribute to the patterns of cerebral injury seen in the human preterm fetus.

Management des HELLP-Syndroms: Erfahrungen und Ergebnisse im Zeitraum von 1980-1996

Fragestellung: Das HELLP-Syndrom (hemolysis, elevated liver enzymes, low platelet) stellt eine seltene und lebensbedrohliche Schwangerschaftskomplikation dar, die mit typischen laborchemischen und klinischen Charakteristika einhergeht. Hinsichtlich des Managements empfehlen viele Autoren eine raservatives Vorgehen verfolgen, um ein höheres Gestationsalter zu erreichen. Ziel unserer Studie war es, das Management und Outcome von Patientinnen mit HELLP-Syndrom im Beobachtungszeitraum (BZR) 1980-1996 zu vergleichen.

Regulation of ductus arteriosus patency by nitric oxide in fetal lambs: the role of gestation, oxygen tension, and vasa vasorum.

We hypothesized that nitric oxide (NO) production by the fetal ductus arteriosus is limited because of low fetal PO2, but that at neonatal PO2, NO might be an important regulator of ductus arteriosus tone. We exposed isolated rings of fetal lamb ductus arteriosus to elevated PO2. L-NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), and methylene blue and 6-anilino-5,8-quinolinedione (LY83583), inhibitors of guanylate cyclase, produced constriction of the ductus arteriosus. When ductus arteriosus rings were exposed to low PO2, L-NAME had no effect, and methylene blue and LY83583 had only a small effect on ductus arteriosus tone. Sodium nitroprusside and calcium ionophore A23187 relaxed ductus arteriosus rings more than aortic rings, and relaxed ductus arteriosus rings from immature fetuses more than those from late gestation fetuses. In contrast, ductus arteriosus rings from both early and late gestation were equally sensitive to 8-bromo-cGMP. By both reverse transcriptase-polymerase chain reaction and immunohistochemistry, endothelial cell NOS and inducible calcium-independent NOS, but not nerve cell NOS, were detected in the ductus arteriosus. Inducible NOS was expressed only by endothelial cells lining the ductus arteriosus lumen; in contrast, endothelial cell NOS was expressed by both luminal and vasa vasorum endothelial cells. The role of inducible NOS in the ductus arteriosus is uncertain because the potency of a specific inducible NOS inhibitor in constricting the ductus arteriosus was negligible compared with that of an endothelial cell NOS inhibitor. We speculate that NO may be an important regulator of ductus arteriosus tone at high but not low PO2. The endothelial cell NOS isoform found in vasa vasorum may be an important source of NO because removal of ductus arteriosus luminal endothelium only partially blocks the effects of L-NAME, methylene blue, and LY83583.

Cerebrovascular Effects of IV Dopamine Infusions in Preterm and Near-Term Fetal Sheep • 1870

Preterm infants often receive IV dopamine infusions after birth to maintain or increase their mean arterial blood pressure (MAP). One rationale for this therapeutic strategy is that reaching a “magic MAP” optimizes cerebral perfusion pressure and prevents brain injury. However, there is little data regarding cerebrovascular responses of the developing brain to IV dopamine. Using chronically-catheterized, unanesthetized fetal sheep, we tested the hypothesis that IV dopamine causes dosedependent cerebral vasoconstriction in immature fetuses. We measured catecholamine levels using an HPLC method, cerebral blood flow (CBF) via radiolabeled microspheres and cerebral arterial and venous (sagittal sinus) O2 content, and we calculated cerebrovascular resistance (CVR = MAP ÷ CBF) and cerebral O2 consumption (CMRO2) and O2 delivery (OD). We studied seven near-term (132 ± 1 days gestation) and eight preterm (93 ± 1 days) fetal sheep two days after vascular catheters were placed in utero. Measurements were made at baseline and at four dopamine infusion rates: 2.5, 7.5, 25 and 75 μg/kg/min. Results: (mean ± SEM) for higher doses: Table In addition, there was a dose-dependent increase in glucose and lactate concentrations, a decrease in arterial pH, but no significant changes in systemic or cerebral oxygenation or CMRO2.

Candida funisitis: A clinicopathologic study of 32 cases.

We report on 32 cases of Candida funisitis and describe the associated clinicopathologic features. The Candida funisitis was characterized grossly by small, circumscribed, yellow-white nodules on the umbilical cord surface and, microscopically, by subamnionic microabscesses in which fungal organisms were demonstrable. Chorioamnionitis was present in all cases. Twenty-four (75%) of the 32 infants were premature. There were 7 perinatal deaths, all in immature fetuses. Five (16%) of the 32 fetuses had congenital candidiasis. Five (16%) of the mothers had a history of intrauterine foreign body, including intrauterine contraceptive device in three and cervical cerclage in two. The diagnosis of Candida funisitis should prompt a careful examination for fetal infection, even though it is associated with congenital candidiasis in only a minority of the cases.