Circulatory Responses to Asphyxia Differ if the Asphyxia Occurs In Utero or Ex Utero in Near-Term Lambs

Background

A cornerstone of neonatal resuscitation teaching suggests that a rapid vagal-mediated bradycardia is one of the first signs of perinatal compromise. As this understanding is based primarily on fetal studies, we investigated whether the heart rate and blood pressure response to total asphyxia is influenced by whether the animal is in utero or ex utero.

Methods

Fetal sheep were instrumented at ∼139 days of gestation and then asphyxiated by umbilical cord occlusion until mean arterial blood pressure decreased to ∼20 mmHg. Lambs were either completely submerged in amniotic fluid (in utero; n = 8) throughout the asphyxia or were delivered and then remained ex utero (ex utero; n = 8) throughout the asphyxia. Heart rate and arterial blood pressure were continuously recorded.

Results

Heart rate was higher in ex utero lambs than in utero lambs. Heart rates in in utero lambs rapidly decreased, while heart rates in ex utero lambs initially increased following cord occlusion (for ∼1.5 min) before they started to decrease. Mean arterial pressure initially increased then decreased in both groups.

Conclusions

Heart rate response to asphyxia was markedly different depending upon whether the lamb was in utero or ex utero. This indicates that the cardiovascular responses to perinatal asphyxia are significantly influenced by the newborn''s local environment. As such, based solely on heart rate, the stage and severity of a perinatal asphyxic event may not be as accurate as previously assumed.     

Cholinergic reactivity of cerebral arteries in the developing fetal and newborn lamb.

Cerebral arteries of newborn pigs and baboons constrict to acetylcholine, suggesting that endothelium-dependent dilator mechanisms may be lacking in immature cerebral arteries. The present study tested this possibility in the immature sheep by examining the response of cerebral arterioles in fetal and newborn sheep to endothelium-dependent dilator, acetylcholine. Pial arteriolar diameter was measured in 9 anaesthetized foetuses in utero (4 preterm, 90-111 days gestation and 5 term, 128-143 days gestation) and in 5 anaesthetized, newborn lambs (14 days) using a closed cranial window with intravital microscopy. Application of acetylcholine to the pial surface induced dose-dependent increase in pial arteriolar diameter in all age groups; EC50 for acetylcholine was 0.10 +/- 0.03, 0.28 +/- 0.08 and 0.26 +/- 0.17 microM for preterm fetal, term fetal, and newborn lambs, respectively. The data demonstrate a sensitive dilator response to acetylcholine in immature fetuses as well as newborn lambs suggesting that cholinergic-mediated release of endothelium-dependent relaxing factor is functional early in gestation. The contractile response to acetylcholine observed in newborn pigs and premature baboons may reflect a species difference rather than maturational lack of endothelium-dependent dilator mechanisms.     

Neurosteroids in the fetus and neonate: potential protective role in compromised pregnancies

Complications during pregnancy and birth asphyxia lead to brain injury, with devastating consequences for the neonate. In this paper we present evidence that the steroid environment during pregnancy and at birth aids in protecting the fetus and neonate from asphyxia-induced injury. Earlier studies show that the placental progesterone production has a role in the synthesis and release of neuroactive steroids or their precursors into the fetal circulation. Placental precursor support leads to remarkably high concentrations of allopregnanolone in the fetal brain and to a dramatic decline with the loss of the placenta at birth. These elevated concentrations influence the distinct behavioral states displayed by the late gestation fetus and exert a suppressive effect that maintains sleep-like behavioral states that are present for much of fetal life. This suppression reduces CNS excitability and suppresses excitotoxicity. With the availability of adequate precursors, mechanisms within the fetal brain ultimately control neurosteroid levels. These mechanisms respond to episodes of acute hypoxia by increasing expression of 5alpha-reductase and P450scc enzymes and allopregnanolone synthesis in the brain. This allopregnanolone response, and potentially that of other neurosteroids including 5alpha-tetrahydrodeoxycorticosterone (TH-DOC), reduces hippocampal cell death following acute asphyxia and suggests that stimulation of neurosteroid production may protect the fetal brain. Importantly, inhibition of neurosteroid synthesis in the fetal brain increases the basal cell death suggesting a role in controlling developmental processes late in gestation. Synthesis of neurosteroid precursors in the fetal adrenal such as deoxycorticosterone (DOC), and their conversion to active neurosteroids in the fetal brain may also have a role in neuroprotection. This suggests that the adrenal glands provide precursor DOC for neurosteroid synthesis after birth and this may lead to a switch from allopregnanolone alone to neuroprotection mediated by allopregnanolone and TH-DOC.     

Biglycan and decorin differentially regulate signaling in the fetal membranes

Preterm birth is the leading cause of newborn mortality in the United States and about one third of cases are caused by preterm premature rupture of fetal membranes, a complication that is frequently observed in patients with Ehlers–Danlos Syndrome. Notably, a subtype of Ehlers–Danlos Syndrome is caused by expression of abnormal biglycan and decorin proteoglycans. As compound deficiency of these two small leucine-rich proteoglycans is a model of preterm birth, we investigated the fetal membranes of Bgn^−/−; Dcn^−/− double-null and single-null mice. Our results showed that biglycan signaling supported fetal membrane remodeling during early gestation in the absence of concomitant changes in TGFβ levels. In late gestation, biglycan signaling acted in a TGFβ-dependent manner to aid in membrane stabilization. In contrast, decorin signaling supported fetal membrane remodeling at early stages of gestation in a TGFβ-dependent manner, and fetal membrane stabilization at later stages of gestation without changes in TGFβ levels. Furthermore, exogenous soluble decorin was capable of rescuing the TGFβ signaling pathway in fetal membrane mesenchymal cells. Collectively, these findings provide novel targets for manipulation of fetal membrane extracellular matrix stability and could represent novel targets for research on preventive strategies for preterm premature rupture of fetal membranes.     

Hypoxia-inducible factors HIF-1alpha and HIF-2alpha are decreased in an experimental model of severe respiratory distress syndrome in preterm lambs

Respiratory distress syndrome (RDS) secondary to preterm birth and surfactant deficiency is characterized by severe hypoxemia, lung injury, and impaired production of nitric oxide (NO) and vascular endothelial growth factor (VEGF). Since hypoxia-inducible factors (HIFs) mediate the effects of both NO and VEGF in part through regulation by prolyl-hydroxylase-containing domains (PHDs) in the presence of oxygen, we hypothesized that HIF-1alpha and -2alpha in the lung are decreased following severe RDS in preterm neonatal lambs. To test this hypothesis, fetal lambs were delivered at preterm gestation (115-day gestation, term = 145 days; n = 4) and mechanically ventilated for 4 h. Lambs developed respiratory failure characterized by severe hypoxemia despite treatment with mechanical ventilation with high inspired oxygen concentrations. Lung samples were compared with nonventilated control animals at preterm (115-day gestation; n = 3) and term gestation (142-day gestation; n = 3). We found that HIF-1alpha protein expression decreased (P < 0.05) and PHD-2 expression increased (P < 0.005) at birth in normal term animals before air breathing. Compared with age-matched controls, HIF-1alpha protein and HIF-2alpha protein expression decreased by 80% and 55%, respectively (P < 0.005 for each) in preterm lambs with RDS. Furthermore, VEGF mRNA was decreased by 40%, and PHD-2 protein expression doubled in RDS lambs. We conclude that pulmonary expression of HIF-1alpha, HIF-2alpha, and the downstream target of their regulation, VEGF mRNA, is impaired following RDS in neonatal lambs. We speculate that early disruption of HIF and VEGF expression after preterm birth and RDS may contribute to long-term abnormalities in lung growth, leading to bronchopulmonary dysplasia.     

Connexin Hemichannel Blockade Is Neuroprotective after Asphyxia in Preterm Fetal Sheep

Asphyxia around the time of preterm birth is associated with neurodevelopmental disability. In this study, we tested the hypothesis that blockade of connexin hemichannels would improve recovery of brain activity and reduce cell loss after asphyxia in preterm fetal sheep. Asphyxia was induced by 25 min of complete umbilical cord occlusion in preterm fetal sheep (103–104 d gestational age). Connexin hemichannels were blocked by intracerebroventricular infusion of mimetic peptide starting 90 min after asphyxia at a concentration of 50 µM/h for one hour followed by 50 µM/24 hour for 24 hours (occlusion-peptide group, n = 6) or vehicle infusion for controls (occlusion-vehicle group, n = 7). Peptide infusion was associated with earlier recovery of electroencephalographic power after asphyxia compared to occlusion-vehicle (p<0.05), with reduced neuronal loss in the caudate and putamen (p<0.05), but not in the hippocampus. In the intragyral and periventricular white matter, peptide administration was associated with an increase in total oligodendrocyte numbers (p<0.05) and immature/mature oligodendrocytes compared to occlusion-vehicle (p<0.05), with a significant increase in proliferation (p<0.05). Connexin hemichannel blockade was neuroprotective and reduced oligodendrocyte death and improved recovery of oligodendrocyte maturation in preterm fetuses after asphyxia.     

Umbilical cord compression produces pulmonary hypertension in newborn lambs: a model to study the pathophysiology of persistent pulmonary hypertension in the newborn

We investigated the effects of chronic intrauterine hypoxaemia produced by prolonged partial umbilical cord compression on the circulation shortly after birth in lambs. Vascular catheters were inserted in 10 fetal sheep at 120 to 130 days gestation to measure descending aortic blood gases, arterial pH, and arterial O2 saturation. An inflatable silicone rubber balloon cuff was also placed around the umbilical cord. After recovery and the return of descending aortic blood gases to the normal range, the balloon was gradually inflated, decreasing the PaO2 from 21.2 +/- 3.6 to 17.5 +/- 1.3 mm Hg and the arterial O2 saturation from 57.1 +/- 9.2% to 37.2% +/- 5.2. After 14.3 +/- 3.7 days of partial umbilical cord compression, the lambs were delivered by Caesarean section, instrumented to measure systemic and pulmonary arterial, right atrial and pulmonary arterial wedge pressures, pulmonary and systemic blood flows, and mechanically ventilated. Five normal lambs were also studied. From 60 to 120 min after delivery, when compared to normal lambs, the umbilical compression lambs had an increased pulmonary arterial pressure (P less than 0.05) pulmonary vascular resistance (P less than 0.05), and right atrial pressure (P less than 0.05) with similar arterial blood gases. In both groups, hypoxic ventilation produced an increase in pulmonary arterial pressure (P less than 0.05) which on return to room air ventilation decreased to baseline in the normal lambs but not in the umbilical cord compression lambs (P less than 0.05). Prolonged partial umbilical cord compression produces chronic fetal hypoxaemia and pulmonary arterial hypertension after birth. This may represent a model to study the pathophysiology of persistent pulmonary hypertension syndrome.     

Pulmonary effects of acute prenatal asphyxia in ventilated premature lambs

The effect of profound repetitive prenatal asphyxial insults on the cardiopulmonary function of premature ventilated lambs was studied. Twenty-nine fetal lambs (approximately 138 days gestational age) were exteriorized. In 16 of these lambs, the umbilical cord was occluded for 4 min then released for 10 min. This asphyxial episode was repeated until the arterial pH was approximately 7.00, and the mean arterial blood pressure was less than 40 mmHg and falling. The 13 control lambs were simply exteriorized with the umbilical circulation intact. The lambs were then ventilated for 3-4 h. There were no differences between the control vs. asphyxiated lambs in pulmonary compliances (0.57 and 0.58 ml.cmH2O-1.kg-1) wet-to-dry weight ratios (8.18 and 7.55), cardiac outputs (177.8 and 141.8 ml.kg-1.min-1), surfactant-saturated phosphatidylcholine pool sizes, or atrial and/or ductal shunts. Asphyxia did not interfere with the redirection of blood away from atelectatic lung segments created by bronchial obstruction with balloon catheters. Also, although the bidirectional flux of protein into and out of the airways of these preterm lambs was large relative to term lambs, there was no effect of asphyxia on this protein leak. In this animal model, prenatal asphyxia did not impact negatively on the severity of the respiratory failure.     

Cerebral Autoregulation Is Minimally Influenced by the Superior Cervical Ganglion in Two- Week-Old Lambs,and Absent in Preterm Lambs Immediately Following Delivery

Cerebral vessels in the premature newborn brain are well supplied with adrenergic nerves, stemming from the superior cervical ganglia (SCG), but their role in regulation of blood flow remains uncertain. To test this function twelve premature or two-week-old lambs were instrumented with laser Doppler flow probes in the parietal cortices to measure changes in blood flow during changes in systemic blood pressure and electrical stimulation of the SCG. In lambs delivered prematurely at ∼129 days gestation cerebral perfusion and driving pressure demonstrated a direct linear relationship throughout the physiologic range, indicating lack of autoregulation. In contrast, in lambs two-weeks of age, surgical removal of one SCG resulted in ipsilateral loss of autoregulation during pronounced hypertension. Electrical stimulation of one SCG elicited unilateral increases in cerebral resistance to blood flow in both pre-term and two-week-old lambs, indicating functioning neural pathways in the instrumented, anesthetized lambs. We conclude cerebral autoregulation is non-functional in preterm lambs following cesarean delivery. Adrenergic control of cerebral vascular resistance becomes effective in newborn lambs within two-weeks after birth but SCG-dependent autoregulation is essential only during pronounced hypertension, well above the normal range of blood pressure.     

Effect of prostaglandins E2 and F2α on umbilical blood flow and fetal hemodynamics

The hemodynamic effects of PGF_2α, PGE₂, and norepinephrine injected into the umbilical arterial circulation were compared in nine fetal lambs in utero. Umbilical blood flow was measured with radioactive microspheres and an electromagnetic flow transducer implanted on the distal aorta of the fetus after ligation of external iliac arteries and other accessible distal aortic branches.PGF_2α and norepinephrine increased fetal arterial pressure and umbilical blood flow while umbilical vascular resistance increased slightly (PGF_2α) or not at all (norepinephrine). PGE₂ increased fetal arterial pressure, decreased umbilical blood flow, and exerted a profound active vasoconstrictor effect on the fetal placental bed. Our data taken together with the observations of others suggest that prostaglandins may play a role in the circulatory adaptations of the fetus at birth and that PGE₂ in high concentrations is likely to have deleterious hemodynamic consequences in the fetus in utero.     

Interleukin-1 Receptor Antagonist Protects against Lipopolysaccharide Induced Diaphragm Weakness in Preterm Lambs

Chorioamnionitis (inflammation of the fetal membranes) is strongly associated with preterm birth and in utero exposure to inflammation significantly impairs contractile function in the preterm lamb diaphragm. The fetal inflammatory response to intra-amniotic (IA) lipopolysaccharide (LPS) is orchestrated via interleukin 1 (IL-1). We aimed to determine if LPS induced contractile dysfunction in the preterm diaphragm is mediated via the IL-1 pathway. Pregnant ewes received IA injections of recombinant human IL-1 receptor antagonist (rhIL-1ra) (Anakinra; 100 mg) or saline (Sal) 3 h prior to second IA injections of LPS (4 mg) or Sal at 119d gestational age (GA). Preterm lambs were killed after delivery at 121d GA (term = 150 d). Muscle fibres dissected from the right hemi-diaphragm were mounted in an in vitro muscle test system for assessment of contractile function. The left hemi-diaphragm was snap frozen for molecular and biochemical analyses. Maximum specific force in lambs exposed to IA LPS (Sal/LPS group) was 25% lower than in control lambs (Sal/Sal group; p=0.025). LPS-induced diaphragm weakness was associated with higher plasma IL-6 protein, diaphragm IL-1β mRNA and oxidised glutathione levels. Pre-treatment with rhIL-1ra (rhIL-1ra/LPS) ameliorated the LPS-induced diaphragm weakness and blocked systemic and local inflammatory responses, but did not prevent the rise in oxidised glutathione. These findings indicate that LPS induced diaphragm dysfunction is mediated via IL-1 and occurs independently of oxidative stress. Therefore, the IL-1 pathway represents a potential therapeutic target in the management of impaired diaphragm function in preterm infants.     

Essential fatty acids in the fetal and newborn lamb

The concentrations of linoleic and linolenic acids and their metabolites in the liver, kidney, brain, erythrocytes and plasma of fetal lambs at various stages of gestation, and of newborn and 2-week-old suckled lambs was determined. Throughout gestation the fetal tissues, erythrocytes and plasma all contained low levels of linoleic and linolenic acids together with consistently high levels of their long-chain polyunsaturated metabolites. The triene: tetraene (eicosa-5,8,11-trienoic acid/arachidonic acid) ratio was always 0.4 or less except at birth when it reached 0.6 in liver and 0.9 in plasma. Milk intake significantly increased the linoleic and linolenic acid levels in the lamb by 2 weeks after birth. These results show that the developing fetal lamb should not be regarded as being deficient in essential fatty acids, as suggested by previous investigators. It is proposed that the total metabolites of linoleic and linolenic acids are the most appropriate measure of the essential fatty acid status of the fetal lamb.     

Renal sympathetic nerve activity during asphyxia in fetal sheep

The sympathetic nervous system (SNS) is an important mediator of fetal adaptation to life-threatening in utero challenges, such as asphyxia. Although the SNS is active well before term, SNS responses mature significantly over the last third of gestation, and its functional contribution to adaptation to asphyxia over this critical period of life remains unclear. Therefore, we examined the hypotheses that increased renal sympathetic nerve activity (RSNA) is the primary mediator of decreased renal vascular conductance (RVC) during complete umbilical cord occlusion in preterm fetal sheep (101 ± 1 days; term 147 days) and that near-term fetuses (119 ± 0 days) would have a more rapid initial vasomotor response, with a greater increase in RSNA. Causality of the relationship of RSNA and RVC was investigated using surgical (preterm) and chemical (near-term) denervation. All fetal sheep showed a significant increase in RSNA with occlusion, which was more sustained but not significantly greater near-term. The initial fall in RVC was more rapid in near-term than preterm fetal sheep and preceded the large increase in RSNA. These data suggest that although RSNA can increase as early as 0.7 gestation, it is not the primary determinant of RVC. This finding was supported by denervation studies. Interestingly, chemical denervation in near-term fetal sheep was associated with an initial fall in blood pressure, suggesting that by 0.8 gestation sympathetic innervation of nonrenal vascular beds is critical to maintain arterial blood pressure during the rapid initial adaptation to asphyxia.     

The effect of prenatal photoperiodic history on the postnatal endocrine status of female lambs

Postnatal photoperiodic experience plays a pivotal role in determining the timing of ovarian activity in female lambs. This study examines whether a photoperiodic history gained while in utero is able to influence this timing.Pregnant Soay ewes were maintained in either long days (n = 7, 18 h light : 6 h dark; group PLD) or short days (n = 12, y h light : 18 h dark; group PSD) from 25 days of gestation. At birth, female lambs (n = 8 per group) were transferred to long days for 10 weeks, and then placed under short days until the end of the experiment at 38 weeks of age. Blood samples were collected from lambs on the day of birth and three times weekly for the duration of the study and the resulting plasma assayed for progesterone and prolactin.Although both gestational photoperiods produced, at best, abbreviated periods of ovarian activity, lambs born to ewes which experienced long days during gestation (group PLD) exhibited elevated plasma progesterone concentrations significantly earlier (P < 0.05) than lambs born to ewes exposed to short days during gestation (group PSD) (mean ± SEM, 193 ± 17 versus 244 ± 14 days for PLD and PSD groups, respectively. Plasma prolactin concentrations in newborn lambs born between late December and early April were not affected by the ambient photoperiod, but reflected the artificial daylength experienced by their mothers during gestation. Lambs born to ewes maintained under long days during gestation (group PLD) had significantly higher prolactin concentrations on the day of birth than lambs born to ewes maintained under short days during gestation (group PSD) (45 ± 5.4 ng/ml versus 7 ± 3.7 ng/ml respectively, P < 0.001). The mean birth weight, rate of live weight gain and live body weight of lambs at the end of the experiment did not vary significantly between treatment groups. These results suggest that the ovine foetus is sensitive to photoperiodic information prior to birth, and develops a photoperiodic history which, under the present experimental conditions, modulates the subsequent endocrine status of the neonatal lamb.     

High Mobility Group-Box 1 (HMGB1) levels are increased in amniotic fluid of women with intra-amniotic inflammation-determined preterm birth,and the source may be the damaged fetal membranes

BackgroundHigh Mobility Group Box-1 (HMGB1) is considered a prototype alarmin molecule. Upon its extracellular release, HMGB1 engages pattern recognition receptors and the Receptor for Advanced Glycation End-products (RAGE) followed by an outpouring of inflammatory cytokines, including interleukin (IL)-6.MethodsWe assayed the amniotic fluid (AF) levels of HMGB1 and IL-6 in 255 women that either had a normal pregnancy outcome or delivered preterm. Immunohistochemistry on fetal membranes was used for cellular localization and validation of immunoassay findings. HMGB1 also was analyzed in amniochorion tissue explants subjected to endotoxin.ResultsAF HMGB1 levels are not gestational age regulated but are increased in women with intra-amniotic inflammation and preterm birth. The likely source is the damaged amniochorion, as demonstrated by immunohistochemistry and explant experiments.ConclusionsOur research supports a role for HMGB1 in the inflammatory response leading to preterm birth. As a delayed phase cytokine, in utero exposure to elevated AF HMGB1 levels may have an impact on the newborn beyond the time of birth.     

妊娠晚期胎羊宫内外科手术的实验研究

目的　以妊娠晚期孕羊为研究对象 ,探讨宫内外科手术的可行性 ,为开展胎儿外科研究建立动物实验模型。方法　通过对妊娠 12 0d左右的 4只双胎孕羊进行宫腔手术 ,切除双胎中 1只胎羊的脚趾或唇部皮肤 ,观察妊娠结果。并取分娩后羔羊脑组织及手术切除部位皮肤作组织形态学观察和评价。结果　妊娠羊经阴道足月分娩后羔羊均成活 ,脚趾及唇部切除处未见疤痕形成 ,皮肤组织形态学观察对照组与实验组未见明显差异 ;脑组织形态学检查仅有 1例实验组羔羊有轻度病理学变化 ,与对照羔羊有差异 ,其余 3例实验羔羊与对照羔羊脑组织结构均正常 ,未见有明显的病理学改变。结论　妊娠羊经宫内胎羊外科手术后能够持续妊娠状态并经阴道自然分娩 ,产出羔羊的精神状态及病理组织学观察结果表明 ,利用妊娠晚期孕羊进行胎儿外科动物实验研究是可行的 ,为进一步开展人类先天性畸形胎儿的早期治疗奠定了动物实验基础     

Cyclic nucleotide phosphodiesterase and protein activator in fetal rabbit tissues.

Cyclic nucleotide phosphodiesterase activity (EC 3.1.4.17) was studied in fetal and newborn rabbit brain, heart, liver, kidney, and lung. Kinetic analysis of phosphodiesterase activity from homogenates of organs from the 25-day embryo suggested the presence of a high K_m and a low K_m activity for both cyclic AMP and cyclic GMP hydrolysis. The addition of 1 μm cyclic GMP to the assay stimulated the hydrolysis of cyclic AMP by whole homogenates of liver, brain, lung, and kidney, but not heart, at all of the ages studied. The addition of micromolar levels of calcium ion stimulated cyclic GMP hydrolysis by homogenates of fetal brain, heart, and kidney, with or without added protein activator. Cyclic GMP phosphodiesterase activity was not stimulated by the addition of calcium ion in homogenates of early fetal rabbit liver and lung, but stimulation was detected in the late embryo and newborn. The presence of the heat-stable protein activator was demonstrated in brain, heart, kidney, liver, and lung tissue at all of the fetal ages studied, and in the newborn rabbit. DEAE-cellulose chromatography demonstrated the presence of three separable enzymes in brain and liver at 15 days, heart at 19 days, and lung and kidney at 25 days of gestation, with no changes in the kinetic properties of the isolated enzymes during development. These experiments suggest that all of the organs studied have the mature array of phosphodiesterases early in development, but an enzyme from liver and lung becomes sensitive to regulatory control by calcium only late in gestation.     

Regulation of brain water during acute hyperosmolality in ovine fetuses, lambs, and adults.

In adult rats, when plasma osmolality increases, water flows across the blood-brain barrier down its concentration gradient from brain to plasma, and brain volume deceases. The brain responds to this stress by gaining osmotically active solutes, which limit water loss. This phenomenon is termed brain volume (water) regulation. We tested the hypothesis that brain volume regulation is more effective in young lambs and adult sheep than in fetuses, premature lambs, and newborn lambs. Brain water responses to acute hyperosmolality were measured in the cerebral cortex, cerebellum, and medulla of fetuses at 60 and 90% of gestation, premature ventilated lambs at 90% of gestation, newborn lambs, young lambs at 20-30 days of age, and adult sheep. After exposure of the sheep to increases in systemic osmolality with mannitol plus NaCl, brain water content and electrolytes were quantified. The ideal osmometer is a system in which impermeable solutes do not enter or leave in response to an osmotic stress. There were significant differences from an ideal osmometer in the cerebral cortex of fetuses at 90% of gestation, cerebral cortex, and cerebellum of newborn lambs, and cerebral cortex, cerebellum, and medulla of young lambs and adult sheep; however, there were no differences in the brain regions of fetuses at 60% of gestation and premature lambs, cerebellum and medulla of fetuses at 90% of gestation, and medulla of newborn lambs. We conclude that 1) brain water loss is maximal and brain volume regulation impaired in most brain regions of fetuses at 60 and 90% of gestation and premature lambs; 2) brain volume regulation develops first in the cerebral cortex of the fetuses at 90% of gestation and in the cerebral cortex and cerebellum of newborn lambs, and then it develops in the medulla of the lambs at 20-30 days of age; 3) brain water loss is limited and volume regulation present in the brain regions of young lambs and adult sheep; and 4) the ability of the brain to exhibit volume regulation develops in a region- and age-related fashion.     

Effects of chronic estrogen-receptor blockade on ovine perinatal pulmonary circulation

Prolonged infusions of 17beta-estradiol reduce fetal pulmonary vascular resistance (PVR), but the effects of endogenous estrogens in the fetal pulmonary circulation are unknown. To test the hypothesis that endogenous estrogen promotes pulmonary vasodilation at birth, we studied the hemodynamic effects of prolonged estrogen-receptor blockade during late gestation and at birth in fetal lambs. We treated chronically prepared fetal lambs with ICI-182,780 (ICI, a specific estrogen-receptor blocker, n = 5) or 1% DMSO (CTRL, n = 5) for 7 days and then measured pulmonary hemodynamic responses to ventilation with low- and high-fraction inspired oxygen (FI(O(2))). Treatment with ICI did not change basal fetal PVR or arterial blood gas tensions. However, treatment with ICI abolished the vasodilator response to ventilation with low FI(O(2)) [change in PVR -30 +/- 6% (CTRL) vs. +10 +/- 13%, (ICI), P < 0.05] without reducing the vasodilator response to ventilation with high FI(O(2)) [change in PVR, -73 +/- 3% (CTRL) vs. -77 +/- 4%, (ICI); P = not significant]. ICI treatment reduced prostacyclin synthase (PGIS) expression by 33% (P < 0.05) without altering expression of endothelial nitric oxide synthase or cyclooxygenase-1 and -2. In situ hybridization and immunohistochemistry revealed that PGIS is predominantly expressed in the airway epithelium of late gestation fetal lambs. We conclude that prolonged estrogen-receptor blockade inhibits the pulmonary vasodilator response at birth and that this effect may be mediated by downregulation of PGIS. We speculate that estrogen exposure during late gestation prepares the pulmonary circulation for postnatal adaptation.     

不同类型妊娠高血压疾病对产妇妊娠结局的影响

目的:探讨不同类型妊娠高血压疾病(PIH)对产妇妊娠结局的影响。方法:选取2011年1月~2013年12月我妇产科院收治的妊娠期出现高血压症状的产妇106例为观察组,并选取同期正常孕产妇100例为对照组,根据诊断标准将观察组患者再分为PIH组(75例)、子痫前期组(21例)以及子痫组(10例),对比4组产妇的胎儿窘迫、胎盘早剥、早产、剖宫产、产后出血以及新生儿窒息的发生率。结果:观察组产妇的胎儿窘迫、胎盘早剥、早产、剖宫产、产后出血以及新生儿窒息的发生率明显高于对照组,差异有统计学意义(P0.05);妊娠期高血压组、子痫前期组、子痫组的胎儿窘迫、胎盘早剥、早产、剖宫产、产后出血以及新生儿窒息的发生率,依次升高,差别有统计学意义(P0.05)。结论:应正确认识到不同类型PIH对妊娠结局的影响以及其并发症的规律,做好预防措施,以减少不良妊娠结局的发生。