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In this study, the drug kinetics of tadalafil were compared between pregnant and non-pregnant women to determine the ideal dosage to promote uterine blood flow.We recruited five pregnant and five non-pregnant women, all of which were administered tadalafil (20 mg/day). The blood concentration of tadalafil was measured 1, 2, 4, 6, 8, and 24 h after administration. We investigated the side effects within 4 days of tadalafil administration and compared the cumulative frequency between the two groups.The mean area under the concentration-time curve and maximum blood concentration of tadalafil were not different between the pregnant and non-pregnant groups. Time to maximum blood concentration was delayed by 1 min on average in the pregnant group compared with the non-pregnant group. The cumulative frequency of side effects was significantly lower in the pregnant group than in the non-pregnant group (P = 0.026). No side effects were observed in either group after the fifth day of the tadalafil administration.Although there was no difference in maximum blood concentration between non-pregnant and pregnant women, the rate of side effects was lower in pregnant women than in non-pregnant women. Therefore, pregnant women may tolerate tadalafil better.

Cerebral palsy is more common among preterm infants than among full-term infants. Although there is still no clear evidence that fetal heart rate monitoring effectively reduces cerebral palsy incidence, it is helpful to estimate the timing of brain injury leading to cerebral palsy and the causal relationship with delivery based on the fetal heart rate evolution patterns. Understanding the relationship between the timing and the type of brain injury can help to identify preventive measures in obstetrical care.This study aimed to examine the relationship between the timing of insults and the type of brain injury in preterm infants with severe cerebral palsy.This longitudinal study was based on a nationwide database for cerebral palsy. The data of infants with severe cerebral palsy (equivalent to levels 3-5 of the Gross Motor Function Classification System-Expanded and Revised), born between 2009 and 2014 at 28 to 33 weeks of gestation, were included. The intrapartum fetal heart rate evolution patterns were evaluated by 3 obstetricians blinded to clinical information other than gestational age at birth, and these were categorized after agreement by at least 2 of the 3 reviewers into (1) continuous bradycardia, (2) persistently nonreassuring (prenatal onset), (3) reassuring-prolonged deceleration, (4) Hon's pattern (intrapartum onset), (5) persistently reassuring (pre- or postnatal onset), and (6) unclassified. Infant brain magnetic resonance imaging findings at term-equivalent age were assessed by a pediatric neurologist blinded to the background details, except for gestational age at birth and corrected age at image acquisition, and these were categorized as (1) basal ganglia-thalamus, (2) white matter, (3) watershed cortex or subcortex, (4) stroke, (5) normal, and (6) unclassified based on the predominant site involved. The risk factors for the basal ganglia-thalamus group were compared with those of the combined white matter and watershed injuries group.Among 1593 infants with severe cerebral palsy, 231 were born at 28 to 33 weeks of gestation, and 140 met the eligibility criteria. Fetal heart rate evolution patterns were categorized as bradycardia (17% [24]); persistently nonreassuring (40% [56]); reassuring-prolonged deceleration (7% [10]); reassuring-Hon (6% [8]); persistently reassuring (7% [10]); and unclassified (23% [32]). Cerebral palsy was presumed to have an antenatal onset in 57% of infants and to have been caused by intrapartum insult in 13% of infants. Magnetic resonance imaging showed that 34% (n=48) of infants developed basal ganglia-thalamus-dominant brain injury. Of the remaining 92 infants, 43% (60) showed white matter injuries, 1% (1) showed watershed injuries, 4% (5) showed stroke, 1% (1) had normal findings, and 18% (25) had unclassified findings. Infants with continuous bradycardia (adjusted odds ratio, 1033.06; 95% confidence interval, 15.49-68,879.92) and persistently nonreassuring fetal heart rate patterns (61.20; 2.09-1793.12) had a significantly increased risk for basal ganglia-thalamus injury.Severe cerebral palsy was presumed to have an antenatal onset in 57% of infants and to have been caused by intrapartum insult in only 13% of infants born at 28 to 33 weeks of gestation. Although the white matter-watershed injury was predominant in the study populations, severe acute hypoxia-ischemia may be an important prenatal etiology of severe cerebral palsy in preterm infants.

This study aimed to evaluate whether the Edinburgh Postnatal Depression Scale (EPDS) score predicts the occurrence of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) after delivery.The women in this study were registered at 35-36 weeks of pregnancy at Mie University Hospital from 2013 to 2015. We prospectively divided the puerperants into those with an EPDS score ≥9 (the high-EPDS group) and those with an EPDS score9 (the low-EPDS group) at 1 month postpartum. We compared the incidence rate of severe PMS and PMDD between both groups at 1 year after delivery.Of 200 registered cases, 178 (89.0%) did not experience severe PMS or PMDD before pregnancy. Among them, 21 were in the high-EPDS group, and 89 in the low-EPDS group. Four of the 21 women (19.0%) in the high-EPDS group and five of the 89 (5.6%) in the low-EPDS group had severe PMS or PMDD at 1 year after delivery. The incidence rate of severe PMS or PMDD in the high-EPDS group was higher than that in the low-EPDS group (p = 0.07).The novel finding of this study is that the EPDS may predict the occurrence of severe PMS/PMDD after delivery. The EPDS will contribute to the early detection of these diseases and to improving the quality of life of the patients by allowing treatment initiation at an early stage.

OBJECTIVE. To propose an ideal patient candidate with early-stage cervical cancer for undergoing fertility-sparing trachelectomy. METHODS. This nationwide, multicenter, retrospective study was conducted by the Japan Society of Obstetrics and Gynecology involving women aged

Background Standardized treatment of fetal tachyarrhythmia has not been established. Objectives This study sought to evaluate the safety and efficacy of protocol-defined transplacental treatment for fetal supraventricular tachycardia (SVT) and atrial flutter (AFL). Methods In this multicenter, single-arm trial, protocol-defined transplacental treatment using digoxin, sotalol, and flecainide was performed for singleton pregnancies from 22 to Results A total of 50 patients were enrolled at 15 institutions in Japan from 2010 to 2017; short ventriculoatrial (VA) SVT (n = 17), long VA SVT (n = 4), and AFL (n = 29). One patient with AFL was excluded because of withdrawal of consent. Fetal tachyarrhythmia resolved in 89.8% (44 of 49) of cases overall and in 75.0% (3 of 4) of cases of fetal hydrops. Pre-term births occurred in 20.4% (10 of 49) of patients. Maternal AEs were observed in 78.0% (39 of 50) of patients. Serious AEs occurred in 1 mother and 4 fetuses, thus resulting in discontinuation of protocol treatment in 4 patients. Two fetal deaths occurred, mainly caused by heart failure. Neonatal tachyarrhythmia was observed in 31.9% (15 of 47) of neonates within 2 weeks after birth. Conclusions Protocol-defined transplacental treatment for fetal SVT and AFL was effective and tolerable in 90% of patients. However, it should be kept in mind that serious AEs may take place in fetuses and that tachyarrhythmias may recur within the first 2 weeks after birth.

The severity of the hemolytic disease of the fetus and newborn (HDFN) due to Jra mismatch ranges from no symptoms to severe anemia that requires intrauterine and exchange transfusions. We encountered a newborn, born to a healthy mother having anti-Jra at 38 weeks of pregnancy, who had moderate anemia, a positive direct antiglobulin test (DAT) result, no increased erythropoiesis, and no jaundice at birth. Flow cytometry revealed that the Jra antigen of red cells in the infant was nearly negative at birth, biphasic at 5 weeks, and lowly expressed at 7 months of life. We searched online for previous case reports on HDFN due to Jra incompatibility. Among 63 reported cases, excluding 25 cases, 38 were included with the present case for analysis. Of 39 newborns, 10 developed clear anemia (hemoglobin

Arterial switch operation (ASO) for dextro-transposition of the great arteries (d-TGA) has gradually replaced the atrial switch operation and has become the standard operation. To date, the outcomes of pregnant women with d-TGA after this new operation have not been investigated. In this study, we investigated the impact of ASO on pregnant outcomes and mid-term prognosis in women with d-TGA and compared with the atrial switch operation through the literature review.There were 20 pregnancies in 10 women with d-TGA after ASO and 6 resulted in abortion. Among 14 successful pregnancies in 10 women, 11 pregnancies achieved the term delivery and 3 pregnancies, including 1 twin pregnancy, resulted in preterm labor. Maternal cardiovascular events occurred in 4 (heart failure and arrhythmias in 3 and arrhythmia in 1), and all were controllable with medications. Risk factors for the peripartum cardiac events were older age at ASO and delivery, and higher concentration of brain natriuretic peptide (BNP) at first trimester (p0.05). In 7-60 month-follow-up after delivery, no case showed deterioration of functional class and systemic ventricular function. According to the literature review, women after ASO demonstrated a better prognosis than those after the atrial switch operation.The majority of women with d-TGA after ASO tolerated pregnancy and delivery well. The older age at ASO, an elderly pregnancy, and higher BNP levels at the first trimester were possibly risk factors of peripartum cardiovascular events among the group. The literature reviews and this study may indicate the advantage of systemic left ventricle compared with systemic right ventricle in long-term outcomes after delivery.

The present retrospective study provides an in-depth analysis of the maternal sepsis-related deaths reported in Japan, and aims to guide future care regarding maternal sepsis. This is a nationwide, retrospective, descriptive cohort study. Data were retrospectively analyzed on all maternal death cases related to sepsis reported in Japan from 2010 through 2016. A total of 7,347,727 births and 317 maternal deaths were reported during the study period. The cause of maternal death was sepsis in 24 women (7.5%). Causative bacteria were Streptococcus pyogenes (54.2%), Chlamydia psittaci (8.3%), Mycobacterium tuberculosis (8.3%), Escherichia coli (4.2%), Neisseria meningitidis (4.2%), Epstein-Barr virus (4.2%), and unknown (16.6%). In maternal death due to S. pyogenes (13 women), onset periods ware antepartum in 10 women (76.9%) and postpartum in 3 (23.1%); death within 24 h after hospital admission occurred in 7 women (53.8%); and the median time from hospital admission to death was 12 h (6–744 h). The most common causative bacteria in to maternal sepsis-related death were GAS. When encountering severe sepsis during the peripartum period, we recommend considering severe GAS infection and early intervention.

Objective: We studied the effect and safety of epidural anesthesia during labor in pregnant women with cardiovascular disease. Materials and methods: In the pregnant women with cardiovascular disease, we compared maternal outcome and suppressive effect on blood pressure retrospectively between the epidural group (anesthetized epidurally during labor) and the no-epidural group (not anesthetized epidurally during labor). Results: A total of 277 patients were included in the analyses. Cardiovascular events decreased significantly in epidural group (P

Post-partum obstetric haemorrhage is a leading cause of mortality among Japanese women, generally treated with haemostatic measures followed by supplementary transfusion. Commonly used in the setting of severe trauma, massive transfusion protocols (MTPs), preparations of red blood cell concentrate (RBC) and fresh frozen plasma (FFP) with additional supplements, have proved effective in decreasing patient mortality following major obstetric bleeding events. Although promising, the optimal configuration of RBC and FFP utilized for obstetric bleeding needs to be verified. Here, we conducted a systematic literature review to define the optimal ratio of RBC to FFP for transfusion therapy during instances of obstetric bleeding. Our analysis extracted four retrospective, observational studies, all demonstrating that an FFP/RBC ratio of ≥1 was associated with improved patient outcomes following obstetric haemorrhage. We therefore conclude that, from the standpoint of haemostatic resuscitation, an FFP/RBC ratio of ≥1 is a necessary condition for optimal clinical management during MTP administration in the field of obstetrics. Hence, we further propose an optimized MTP strategy to be utilized in the setting of severe obstetric bleeding.

Background: In Japan, there are more than 2000 maternity facilities that provide delivery services for approximately 860 thousand deliveries per year. More than half of all deliveries are managed in private clinics which medical resources are limited and maternal transport is often required. In such condition, we aimed to identify the characteristics of and measures taken by Japanese medical facilities providing maternity services that have recorded cases of nosocomial infection with SARS-CoV-2, which causes (COVID-19). Methods: A nationwide questionnaire survey about nosocomial COVID-19 was conducted in July 2020. A case-control study was conducted by including medical facilities with (Cases) and without (Control) nosocomial COVID-19. Findings: Responses from 1,418 medical facilities were assessed (65% of all delivery facilities in Japan). Seventy-five COVID-19-positive pregnant women were treated in 48 facilities. Nosocomial infection was reported in 4.1% of the facilities. Nine patients developed a nosocomial infection in the maternity ward or obstetric department. Variables that contributed to nosocomial COVID-19 were chest CT on admission (adjusted odds ratio [95% confidence interval], 4.76 [2.44–9.27]), PCR test for SARS-CoV-2 before delivery (2.27 [1.21–4.25]), transfer of pregnant women with fever to another hospital (0.21 [0.06–0.71]), and private clinics (0.17 [0.05–0.60]). Interpretation: Nosocomial infection is likely to occur in large hospitals that treat a higher number of patients than private clinics do. Nosocomial infection can occur even in medical facilities performing COVID-19 screening tests, such as chest CT and PCR test. Funding Statement: Nationwide survey associated with COVID-19 infection, The Japan Association of Obstetricians and Gynecologists (JAOG). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This study was approved by the JAOG (No. 80, July 1st, 2020). This investigation was conducted according to the principles of the Declaration of Helsinki. Informed consent was not obtained from patients or their families because this study was based on the analysis of facility forms, and the patient records/information was anonymized prior to the analysis.

Background: The clinical features of coronavirus disease (COVID-19) in pregnant women remain unknown. We describe the clinical characteristics and outcomes of pregnant women with COVID-19 in Japan. Methods: A nationwide survey of pregnant women with COVID-19 was conducted in July 2020. A questionnaire was sent to all institutions offering maternity services in Japan. Information regarding maternal characteristics, epidemiological, clinical, treatment, and perinatal outcomes were extracted. Findings: Responses from 1418 institutions were assessed (65% of all delivery institutions in Japan). Seventy-two pregnant women were reported to be diagnosed with COVID-19 between January and June 2020. The positive rate of the universal screening test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for asymptomatic pregnant women was 0·03% (2/7428). The most common route of infection was familial (57%). Fifty-eight pregnant women with COVID-19 were symptomatic, of which 5 (8·6%) had a severe infection. There was one death, a tourist. Severe respiratory symptoms, oxygen administration, and pneumonia were frequently reported in the 3rd trimester and postpartum period compared to early pregnancy (22·2% vs. 2·5% (p=0·03), 38·9% vs. 7·5% (p=0·01), and 50·0% vs. 7·5% (p

The impact of rapid weight gain on glucose metabolism during the early postnatal period remains unclear. We investigated the influence of rapid weight gain under different nutritional conditions on glucose metabolism, focusing on the production of pancreatic and gastric peptides. On postnatal day (PND) 2, C57BL/6N pups were divided into three groups: control (C) pups whose dams were fed a control diet (10%kcal fat) and nursed 10 pups each; maternal high-fat diet (HFD) pups whose dams were fed an HFD (45%kcal fat) and nursed 10 pups each; and overfeeding (OF) pups whose dams were fed the control diet and nursed 4 pups each. Data were collected on PND 7, 14 and 21. The body weight gains of the HFD and OF pups were 1.2 times higher than that of the C pups. On PND 14, the HFD pups had higher blood glucose levels, but there were no significant differences in serum insulin levels between the HFD and C pups. The OF pups had higher blood glucose and serum insulin levels than that of the C pups. Insulin resistance was found in the HFD and OF pups. On PND 14, the content of incretins in the jejunum was increased in the OF pups, and acyl ghrelin in the stomach was upregulated in the HFD and OF pups. These results suggest that neonatal weight gain induced by overfeeding pups and maternal high-fat diet during the early postnatal period modulates the insulin sensitivity and the production of pancreatic and gastrointestinal peptides.

The impact of an increase in maternal fat consumption on fetal metabolic programming separately from maternal obesity remains unclear. The purpose of this study was to document the effect of in utero high-fat diet exposure on the development of metabolic syndrome characteristics in offspring. C57BL/6 female mice were fed either a control diet (10% fat) or a moderately high-fat (MHF) diet (45% fat) until delivery. All pups were fostered to mothers fed with the control diet. Pups were raised on the control diet and assessed until 35 weeks of age. The caloric intake from fat was significantly increased in the MHF dams compared with the control dams. There were no significant differences in the maternal weight at mating or at gestational Day 18 between the two groups. The MHF offspring did not become obese, but they developed hypertension and glucose intolerance. Moreover, the MHF offspring had significantly higher serum non-esterified fatty acid and triglyceride levels during the refeeding state following fasting as compared with the control offspring. Serum adiponectin levels were significantly lower, and the cell size of the mesenteric adipose tissue was significantly larger in the MHF offspring than in the control offspring. The mRNA levels of the proinflammatory macrophage markers in the mesenteric adipose tissue were significantly higher in the MHF offspring than those of the control offspring. These results suggest that in utero high-fat diet exposure causes hypertension and glucose intolerance resulting from mesenteric adipose tissue dysfunction in offspring, independently of maternal obesity.

Background: Standardized treatment of fetal supraventricular tachycardia (SVT) and atrial flutter (AFL) has not been established. The aim of this study was to evaluate the safety and efficacy of protocol-defined transplacental treatment for fetal SVT and AFL. Methods: In this multicentre single-arm trial (UMIN Clinical Trials Registry number 000004270), protocol-defined transplacental treatment using digoxin, sotalol, and flecainide was performed for singletons from 22 to

Intrauterine growth retardation (IUGR) occurs in 3% to 7% of all pregnancies. Recent human studies have indicated that neurodevelopmental disabilities, learning disorders, memory impairment, and mood disturbance are common in IUGR offspring. However, the interactions between IUGR and neurodevelopmental disorders are unclear because of the wide range of causes of IUGR, such as maternal malnutrition, placental insufficiency, pregnancy toxemia, and fetal malformations. Meanwhile, many studies have shown that moderate food restriction enhances spatial learning and improves mood disturbance in adult humans and animals. To date, the effects of maternal moderate food restriction on fetal brain remain largely unknown. In this study, we hypothesized that IUGR would be caused by even moderate food restriction in pregnant females and that the offspring would have neurodevelopmental disabilities. Mid-pregnant mice received moderate food restriction through the early lactation period. The offspring were tested for aspects of physical development, behavior, and neurodevelopment. The results showed that moderate maternal food restriction induced IUGR. Offspring had low birth weight and delayed development of physical and coordinated movement. Moreover, IUGR offspring exhibited mental disabilities such as anxiety and poor cognitive function. In particular, male offspring exhibited significantly impaired cognitive function at 3 weeks of age. These results suggested that a restricted maternal diet could be a risk factor for developmental disability in IUGR offspring and that male offspring might be especially susceptible.

Neonatal stroke occurs in approximately 1/4000 live births and results in life-long neurological impairments: e.g., cerebral palsy. Currently, there is no evidence-based specific treatment for neonates with stroke. Several studies have reported the benefits of umbilical cord blood (UCB) cell treatment in rodent models of neonatal brain injury. However, all of the studies examined the effects of administering either the UCB mononuclear cell fraction or UCB-derived mesenchymal stem cells in neonatal rat models. The objective of this study was to examine the effects of human UCB CD34(+) cells (hematopoietic stem cell/endothelial progenitor cells) in a mouse model of neonatal stroke, which we recently developed. On postnatal day 12, immunocompromized (SCID) mice underwent permanent occlusion of the left middle cerebral artery (MCAO). Forty-eight hours after MCAO, human UCB CD34(+) cells (1×10(5)cells) were injected intravenously into the mice. The area in which cerebral blood flow (CBF) was maintained was temporarily larger in the cell-treated group than in the phosphate-buffered saline (PBS)-treated group at 24h after treatment. With cell treatment, the percent loss of ipsilateral hemispheric volume was significantly ameliorated (21.5±1.9%) compared with the PBS group (25.6±5.1%) when assessed at 7weeks after MCAO. The cell-treated group did not exhibit significant differences from the PBS group in either rotarod (238±46s in the sham-surgery group, 175±49s in the PBS group, 203±54s in the cell-treated group) or open-field tests. The intravenous administration of human UCB CD34(+) cells modestly reduced histological ischemic brain damage after neonatal stroke in mice, with a transient augmentation of CBF in the peri-infarct area.

Background Pregnancy-associated hemorrhagic stroke is considered a serious complication. Although coagulopathy, pregnancy-induced hypertension, eclampsia, and other systemic complications have been emphasized, pre-existing cerebrovascular diseases (CVDs) have not been fully analyzed. To clarify the role of these vascular lesions more in detail, the Japan Neurosurgical Society conducted a nationwide survey on all the neurosurgical institutes across Japan. Methods This 2-year survey focused on hemorrhagic stroke occurring in pregnancy, delivery, and puerperium. Clinical data based on retrospective chart review were obtained through a questionnaire and analyzed according to the time of onset, underlying CVDs, obstetric systemic complications, therapeutic approaches, and maternal and neonatal prognoses. Results The survey identified 97 hemorrhagic strokes that were associated with pregnancy. Baseline CVDs responsible for hemorrhage were detected in 54 cases (55.7%), among which 47 lesions (87.0%) had been undiagnosed before stroke onset. The detection rate of baseline CVDs before the 32nd week of gestation was significantly higher than that after the 32nd week (90.0% versus 53.3%, P = .0017). Arteriovenous malformations (AVMs) were the most frequent CVDs causing intracranial hemorrhage, occurring at 1.8 times the frequency of ruptured aneurysms during pregnancy. Poor outcomes, including 10 deaths, were seen in 36.1% of the cases despite aggressive treatment. Conclusion Pregnancy-associated hemorrhagic strokes frequently concealed baseline CVDs, especially when they occurred before the 32nd week of gestation. AVMs were the predominant bleeding source. For appropriate treatment, therefore, close examination for cerebral vascular lesions is essential when a pregnancy-associated hemorrhagic stroke is encountered.

Neonatal stroke occurs in 1/4000 live births and leaves life-long neurological impairments, such as cerebral palsy and epilepsy. Currently, the rodent models of neonatal stroke that are available exhibit significant inter-animal variability, which makes it difficult to accurately assess the mechanisms of brain injury and the efficacy of candidate treatments. We aimed to introduce a novel, highly reproducible model of stroke, middle cerebral artery occlusion (MCAO), in immature mice, and to evaluate the reproducibility of this model compared with a conventional hypoxia-ischemia (HI) model. Postnatal day 12 CB-17 mice underwent left MCAO by direct electrocoagulation. The MCAO model exhibited excellent long-term survival; 85% up to 8 weeks after the insult. Infarct was evident in every animal with MCAO (n=27) and was confined to the cortex, with the exception of some mild thalamic injury. While the % stroke volume 48 h after the insult was consistent in the MCAO group, range: 17.8-30.4% (minimum-maximum), it was substantially less consistent in the HI group, range: 3.0-70.1%. This contrasting variability between the two models was also evident in the cerebral blood flow, 24h after the insult, and in the ipsilateral hemispheric volume, as assessed at 8 weeks after the insult. Mice with MCAO exhibited significant neurofunctional deficits in the rotarod and open-field tests. Preclinical studies for neonatal stroke could become more reliable using this model, with even a potential reduction in the number of pups required for statistical significance. The contrasting variability between the two models may provide insights into the factors that contribute to inter-animal variability in brain injury.

The aeroacoustic sound generated from the flow around two NACA four-digit airfoils is investigated numerically, at relatively low Reynolds numbers that do not prompt boundary-layer transition. By using high-order finite-difference schemes to discretize compressible Navier–Stokes equations, the sound scattered on airfoil surface is directly resolved as an unsteady pressure fluctuation. As the wavelength of an emitted noise is shortened compared to the airfoil chord, the diffraction effect on non-compact chord length appears more noticeable, developing multiple lobes in directivity. The instability mechanism that produces sound sources, or unsteady vortical motions, is quantitatively examined, also by using a linear stability theory. While the evidence of boundary-layer instability waves is captured in the present result, the most amplified frequency in the boundary shear layer does not necessarily agree with the primary frequency of a trailing-edge noise, when wake instability is dominant in laminar flow. This contradicts the observation of other trailing-edge noise studies at higher Reynolds numbers. However, via acoustic disturbances, the boundary-layer instability may become more significant, through the resonance with the wake instability, excited by increasing a base-flow Mach number. Evidence suggests that this would correspond to the onset of an acoustic feedback loop. The wake-flow frequencies derived by an absolute-instability analysis are compared with the frequencies realized in flow simulations, to clarify the effect of an acoustic feedback mechanism, at a low Reynolds number.

Progesterone and its metabolite, allopregnanolone, are neurosteroids that are present at high concentrations in fetal brains that decrease right after birth. Allopregnanolone is a potent positive modulator of γ-aminobutyric acid A (GABA(A)) receptor function. We examined the effect of exogenous administration of these steroids on hypoxic-ischemic encephalopathy in immature rats. Progesterone (10mg/kg), allopregnanolone (10mg/kg), or vehicle alone was intraperitoneally administered immediately before and then subcutaneously 6h and 24h after hypoxia-ischemia to postnatal day 7 (P7), day 14 (P14), and day 21 (P21) rats. The effects of the treatments were evaluated using histological analyses (hemispheric volumes and semi-quantitative scoring for neuropathologic injury). Both progesterone and allopregnanolone significantly exacerbated brain injury in P7 and P14 rats, but not in P21 rats. This detrimental effect was similar across the examined brain regions (the cortex, striatum, hippocampus, and thalamus) and showed no sex differences. Co-administration of the GABA(A) receptor antagonist, bicuculline, partially mitigated the exacerbating effect of allopregnanolone. Based on the similarity of the effects of these neurosteroids, we speculate that progesterone accentuates neuronal injury mainly via the activity of allopregnanolone. The present study indicates that the detrimental effects of allopregnanolone were, at least in part, mediated via GABAergic neuroexcitability. This is in line with the notion that GABA is excitatory for immature neurons, while it is inhibitory for mature neurons.

Adrenomedullin (AM) is a novel vasoactive peptide which regulates vascular tone and vascular endothelial cell growth. We recently reported that lymphatic endothelial cells (LECs) are also an attractive target of AM and concluded that AM is a potent mediator of lympangiogenesis. In the present study, we conducted a genome-wide analysis of genes that are regulated by AM in LECs. AM profoundly suppressed gene expression of cell adhesion receptors and inflammatory factors in LECs, such as intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), endothelial adhesion molecule-1 (E-selectin), interleukin-8, and chemokines, QRT-PCR and flow cytometry analysis showed that AM dose-dependently suppressed the TNF-a-induced mRNA and protein expression of ICAM-1 and VCAM-l. Treatment of LECs with a cell permeable cyclic adenosine monophosphate (cAMP) analog, 8-Br-cAMP, mimicked the suppressive effect of AM on the expression of adhesion molecules. Moreover, both AM and 8-Br-cAMP suppressed TNF-α-induced NF-κB activation in LECs, indicating that AM reduces expression of adhesion molecules in LECs via a cAMP/NF-kB dependent pathway. These results suggest that AM may have an important role in the regulation of the expression of adhesion molecules in lymphatic endothelium, which is critical in the control of immune and inflammatory responses.

We reported previously that the autologous administration of bone marrow-derived mesenchymal stem cells (BM-MSC) significantly attenuated myocardial dysfunction and injury in a rat model of acute myocarditis by stimulating angiogenesis and reducing inflammation. Because BM aspiration procedures are invasive and can yield low numbers of MSC after processing, we focused on fetal membranes (FMs) as an alternative source of MSC to provide a large number of cells. We investigated whether the allogeneic administration of FM-derived MSC (FM-MSC) attenuates myocardial injury and dysfunction in a rat myocarditis model. Experimental autoimmune myocarditis (EAM) was induced in male Lewis rats by injecting porcine cardiac myosin. Allogeneic FM-MSC obtained from major histocompatibility complex-mismatched ACI rats (5 × 10(5) cells/animal) were injected intravenously into Lewis rats one week after myosin administration. At day 21, severe cardiac inflammation and deterioration of cardiac function were observed. The allogeneic administration of FM-MSC significantly attenuated inflammatory cell infiltration and monocyte chemoattractant protein 1 expression in the myocardium and improved cardiac function. In a T-lymphocyte proliferation assay, the proliferative response of splenic T lymphocytes was significantly lower in cells obtained from FM-MSC-treated EAM rats that reacted to myosin than in cells obtained from vehicle-treated rats with EAM. T-lymphocyte activation was significantly reduced by coculture with FM-MSC. The allogeneic administration of FM-MSC attenuated myocardial dysfunction and inflammation, and the host cell-mediated immune response was attenuated in a rat model of acute myocarditis. These results suggest that allogeneic administration of FM-MSC might provide a new therapeutic strategy for the treatment of acute myocarditis.

Fetal magnetocardiography (FMCG) was recorded for 20 min to investigate its clinical efficacy. The multichannel SQUID system (MC-6400, Hitachi-Hightechnologies, Japan), which covers a wide area of the torso of pregnant women was used for recording FMCG. We also used simple methods to relieve adverse problems in long-duration measurement for pregnant women in the supine position: (1) light 10-min walking before FMCG measurement to reduce fetal movement, (2) placing a soft cushion under the patient's back to relieve back pains and (3) bending the knees to avoid supine hypotensive syndrome. All these methods were useful in relieving adverse problems.

The occurrence of hypoxia-ischemia (HI) during early fetal or neonatal stages of an individual leads to the damaging of immature neurons resulting in behavioral and psychological dysfunctions. Free radical-mediated lipid peroxidation is the main cause of neurotoxicity including neonatal brain damage. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a novel anti-oxidant agent and the drug of choice in the treatment of acute ischemic brain disorders in adult patient. The purpose of this study is to determine the direct effects of edaravone in inhibiting the lipid peroxidation production in the neonatal rat brains during hypoxic-ischemic insult by electron paramagnetic resonance (EPR) spectoroscopy and in vivo brain microdialysis. Seven-day-old Wistar rats were subjected to left common carotid artery ligation and a probe was inserted in the rat hippocampus. Edaravone (5, 50, or 100 microM) or saline was perfused with a spin trap agent (alpha-(4-pyridyl-N-oxide)-N-tert-butylnitrone; POBN) before, during and after hypoxia (1h of 8% O2 exposure) and then analyzed by EPR. Edaravone (100 microM) did not show any EPR evidence of POBN adduct formation during and after hypoxic-ischemic insult. However, the EPR signal increased, but not significantly during the hypoxic period in the hypoxic and edaravone 50 microM-treated groups compared to control. Edaravone at 5 microM significantly increased the EPR signals compared to control. This study shows that edaravone directly and dose-dependently inhibited the formation of lipid free radicals produced during hypoxic-ischemic insult in the neonatal rat brain. These results suggest that edaravone is able to attenuate neuronal damage in the rat neonatal brain by inhibiting the formation of lipid radicals.

The purpose of this study was to elucidate a role for edaravone, a free radical scavenger 3-methyl-1-phenyl-2-pyrazolin-5-one, in neonatal hypoxic-ischemic brain damage. We determined the level of thiobarbituric acid reactive substances as an index of lipid peroxidation and nitric oxide metabolites as nitric oxide production.Seven-day-old Wistar rats were subjected to left common carotid artery ligation followed by 2 hours of 8% oxygen exposure. Then, the rats were administered edaravone (9 mg/kg) or saline solution intraperitoneally. Cerebrospinal fluid was withdrawn just before the rats were killed at 2, 5, 24, and 48 hours after hypoxia, and brains were removed. The thiobarbituric acid reactive substances and nitric oxide metabolites levels were measured in the brain tissue and cerebrospinal fluid, respectively.On the ligated side, edaravone significantly decreased thiobarbituric acid reactive substances levels at 5 and 24 hours after hypoxia, compared with saline group (P.01). Edaravone significantly decreased the nitric oxide metabolites level in the cerebrospinal fluid only at 5 hours, compared with saline group (P.01).Edaravone potently and transiently inhibited lipid peroxidation and the production of nitric oxide in the neonatal rat brain after hypoxic-ischemic insult.

Objective We examined whether progenitor neural stem cells can differentiate successfully into mature neurons and astrocytes in a rat model of neonatal hypoxic-ischemic encephalopathy. Study design Seven-day-old Wistar rats were subjected to hypoxic-ischemic stress. At days 5 to 7 after hypoxic-ischemic stress, 5-bromodeoxyuridine (an early marker of cell proliferation) was injected, and the brains were retrieved at 14, 28, and 42 days after hypoxic-ischemic stress. Immunohistochemical and immunofluorescent studies were carried out for 5-bromodeoxyuridine, neuronal nuclear antigen (a marker protein of matured neuron), and glial fibrillary acidic protein (a protein marker of mature astrocytes). Results Only 1% of neuronal nuclear antigen–positive and 4.6% of glial fibrillary acidic protein–positive cells could be detected among the 5-bromodeoxyuridine-immunopositive cells in the peri-infarcted area of the cortex and the striatum, respectively, at 14 days after hypoxic-ischemic stress. There were no such double-staining cells at 28 and 42 days after hypoxic-ischemic stress. Conclusion The intrinsic ability for neurologic self-repair was limited at the maturation step after hypoxic-ischemic stress in the neonatal rat brain.

Objective There are no established therapies for preventing or rescuing perinatal infection or inflammation-induced perinatal brain damage. We administered dexamethasone (DEX), a synthetic corticosteroid anti-inflammatory drug, to neonatal rats in a model of such damage induced by a combination of lipopolysaccharide (LPS) and hypoxia-ischemia (HI), which produces characteristic histologic and behavioral abnormalities. Study design Four hours after the injection of LPS (1 mg/kg, i.p.), 7-day-old Wistar rat pups were subjected to unilateral HI for 1 hour according to Levine's procedure. Injections of 0.5 mg/kg of dexamethasone (DEX-treated group, n = 15) or saline (saline-treated group, n = 15) were given 4 hours before HI. A sham-operated control group received neither LPS nor HI (n = 15). We chose rats of this age because their stage of brain maturation is similar to the human neonate. Over the 7 to 16 weeks after treatment, a choice reaction time (CRT) task was used for assessment of attention processes in each group, an 8-arm radial maze task was used to test short-term memory, and a water maze task was used to test long-term memory. In the CRT task, the reward food was released when the tested animal correctly pressed a lever on the side of an illuminating lamp. The correct and incorrect lever pressings were counted. In the 8-arm radial maze task, rats were allowed to move freely, seeking a reward of food placed at the end of 1 arm. An error was defined as the choice of an arm that had already been visited. In the water maze, rats had to swim to seek a concealed platform as aversive escape motivation. At 19 weeks, the rats were euthanized, the brain was removed, sectioned coronally, and the volume of each part was measured. Results The striatum, cortex, and hippocampus showed reductions in volume in the saline-treated group (42.7%, 49.2%, and 34.9% decreases compared with the sham-operated controls, respectively), but this was not observed in the DEX-treated group. All learning and memory processes were impaired with the combination of LPS and HI treatment, but these deficits were almost completely prevented by DEX treatment. Conclusion Dexamethasone is a promising candidate for prevention of infection and inflammation-induced perinatal brain damage. The impact of dexamethasone identifies potential therapeutic pathways once the mechanism of dexamethasone's protection is determined.

Ischemia/hypoxia (I/H) causes severe perinatal brain disorders such as cerebral palsy. The neonatal brain possesses much plasticity, and to enhance new cell production would be an innovative means of therapy for such disorders. In order to elucidate the dynamic changes of neural progenitor cells in the neonatal brain after ischemia, we investigated new cells production in the subventricular zone and subsequent migration of these cells to the injured area. Newly produced cells were confirmed by incorporation of bromodeoxyuridine (BrdU), and attempt for differentiation was investigated by immunohistochemistry for molecular markers of each cellular lineage. In the sham-control brain, there were many BrdU-labeled cells which gradually decreased as the animal becomes older. Many of these cells were oligodendroglial progenitor or microglial cells. Although there were only few neuronal cells labeled for BrdU in the sham-control, they dramatically increased after I/H. They were located at just beneath the subventricular zone where the progenitor cells reside and to the injured area, indicating that newly produced cells migrated to the infarct region and differentiated into neuronal precursor cells in order to compensate the lost neural cells. We found that BrdU-labeled astroglial, oligodendroglial progenitor, and microglial cells were also increased after I/H, suggesting that they also play active roles in recovery. Progenitor cells may have potential for treating perinatal brain disorders.

Objective We assessed the long-term effects of perinatal hypoxia-ischemia and endotoxin on attention and short- and long-term memory in neonatal rats with the use of behavioral tasks and brain histologic results. Study design Four hours after injections of lipopolysaccharide (1 mg/kg, intraperitoneally) or saline solution, 7-day-old Wistar rat pups were subjected to unilateral hypoxia-ischemia for 1 hour. We studied 4 groups: controls (n = 43 rats), lipopolysaccharide alone (n = 12 rats), hypoxia-ischemia alone (n = 29 rats), and combined lipopolysaccharide + hypoxia-ischemia treatment (n = 34 rats). Seven to 16 weeks after the treatment, we measured attention with a choice reaction time task, short-term memory with an 8-arm radial maze task, and long-term memory with a water maze task. At 19 weeks of age, the brain was removed, fixed, and sectioned coronally; and the volume of each part was measured. Results A loss of volume in the hippocampus was observed in the lipopolysaccharide, hypoxia-ischemia, and lipopolysaccharide + hypoxia-ischemia groups; a loss of striatum was observed in the hypoxia-ischemia and lipopolysaccharide + hypoxia-ischemia groups, but loss of cortex was observed only in the lipopolysaccharide + hypoxia-ischemia group. The lipopolysaccharide, hypoxia-ischemia, and lipopolysaccharide + hypoxia-ischemia groups showed significantly poorer performance (attention deficit) than controls in the choice reaction time task. Correct choices decreased, and error increased in the lipopolysaccharide + hypoxia-ischemia group compared with the other groups in the radial maze task, which shows short-term memory impairment. Swimming distance was significantly greater in the hypoxia-ischemia and lipopolysaccharide + hypoxia-ischemia groups than in the other 2 groups in the water maze test, which shows long-term memory impairment. Conclusion Combined lipopolysaccharide and hypoxia-ischemia treatment synergistically induced short-term memory impairment that is associated with loss of cortical volume.

A rat model of neonatal hypoxic-ischemic encephalopathy (Rice's model) was obtained by unilateral ligation of the common carotid artery of 7-day-old rats with hypoxia (exposure to 8% oxygen). To estimate the in vivo intracerebral reducing ability of the mature rats (8 weeks old) of Rice's model, temporal electron paramagnetic resonance (EPR) imaging of the brain of a rat receiving a blood-brain barrier-permeable nitroxide radical, 3-hydroxymethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl, was performed. In this imaging technique, the decay rate of the EPR signal intensity in a selected region of the brain is indicative of region-specific reducing ability. The effect of neonatal treatment of an antioxidant agent, 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186), after a hypoxic-ischemic insult was also tested. It was found that the reducing ability had been depleted in the contralateral hemisphere of Rice's model rats; this depletion was suppressed by administering MCI-186.

Several studies have shown that abnormal intrapartum fetal heart rate patterns are the results from pre-existing fetal brain damage. We evaluated intrapartum fetal heart rate pattern of cytomegalovirus-infected fetuses and correlated the patterns with neurologic outcomes.Between 1991 and 2001, there were 20 cytomegalovirus-infected fetuses. We selected 40 fetuses as control subjects that were matched for gestational age and birth weight. Fetal heart rate was interpreted according to the guidelines of the National Institute for Child and Human Development. The incidence of abnormal fetal heart rate pattern and umbilical blood gases were compared between both groups. We also investigated the factors that contributed to abnormal fetal heart rate pattern in the cytomegalovirus group.Nonreassuring fetal heart rate patterns (prolonged deceleration and recurrent late deceleration) were observed in 8 of 20 fetuses (prolonged deceleration, 7 fetuses; recurrent late deceleration, 1 fetus) in the cytomegalovirus group and in 3 of 41 fetuses (prolonged deceleration, 1 fetus; recurrent late deceleration, 2 fetuses) in the control group (P.05, Fisher test). Baseline fetal heart rate variability was minimal in 4 of the 7 prolonged deceleration cases in the cytomegalovirus group. Umbilical pH7.1 was found for 1 fetus in the cytomegalovirus group. The average umbilical arterial pH values were similar in both the groups. In the cytomegalovirus group, there were no differences in the incidence of contributing factors between 8 fetuses with abnormal fetal heart rate pattern (prolonged deceleration and recurrent late deceleration) and 8 fetuses with no change. There were 3 fetuses with cerebral palsy: 2 fetuses in the no change group and 1 fetus in the prolonged deceleration group. Antigenemia was positive exclusively in 4 cases with abnormal fetal heart rate pattern (P.05).Cytomegalovirus-infected fetuses are more likely to show abnormal intrapartum fetal heart rate patterns than low-risk control fetuses, which suggests that the perinatal detection of cytomegalovirus is necessary to distinguish hypoxic-ischemic encephalopathy.

Staggered grids have been widely used with finite difference approaches for incompressible flow simulation. They retain conservation properties that stabilize the flow field, and avoid odd-even decoupling in the pressure field. On a non-uniform mesh, however, the accuracy of finite difference schemes is degraded to the order of the mesh stretch, if all the conservation properties are to be upheld. This study shows how a non-uniform numerical mesh creates short wavelength errors in convective terms, especially when the grid spacing varies in the streamwise direction. The conservation properties of convective schemes on a non-uniform mesh can conflict with aspects of numerical accuracy. It is crucial to employ an area-weighted average for the convection velocity in order to impose mass conservation in the presence of mesh stretching. Truncation error analysis indicates that energy conserving schemes produce anti-diffusion error if the mesh is stretched, or positive diffusion if it is narrowed. An alternative convection scheme that minimizes the mesh-stretch error is proposed and evaluated through numerical simulations. The nature of mesh stretch error is illustrated by a direct numerical simulation of turbulent channel flow.

We previously reported that rats exposed to neonatal hypoxic-ischemic (HI) insult showed selective and long-lasting learning and memory impairments in the plus maze, 8-arm radial maze, choice reaction time (CRT) task, and water maze, and that they showed severe brain injury to areas such as parietal cortex, hippocampus, striatum and thalamus. In this study, we examined the effects of hypothermia and hyperthermia on learning and memory deficits following neonatal HI insult. Seven-day-old Wistar rats were subjected to left carotid artery ligation followed by 2 h of hypoxia (8% O2/92% N2) under three different temperature conditions: 27 degrees C (hypothermia), 33 degrees C (normothermia) and 37 degrees C (hyperthermia) in temperature-controlled chambers. Hypothermia significantly reduced attentional deficits in the CRT task and spatial learning deficits in the water maze, and protected against severe brain injury in comparison with the control temperature. On the other hand, hyperthermia aggravated the behavioral deficits and brain injury. These outcomes clearly show that temperature regulation during HI insult plays an important role in the induction of behavioral and histological changes following neonatal HI insult in rats.

Our purpose was to evaluate the clinical validity of electronic fetal heart rate monitoring to detect fetal acidemia and to evaluate the prevalence of cerebral palsy in unselected low-risk pregnancies.We selected two secondary and two tertiary level institutions in which 10,030 infants were born. Among them, 5546 of the pregnancies were low-risk pregnancies by antepartum evaluation. The fetal heart rate patterns were interpreted according to the guidelines of the National Institute of Child Health and Human Development. The correlations between the fetal heart rate pattern and umbilical blood gases and the fetal heart rate pattern and cerebral palsy were studied. Spastic cerebral palsy was diagnosed ator =1 year by pediatric neurologists. Statistics included unpaired t test, contingency table with chi(2) and Fisher tests, and one-way analysis of variance with Bonferroni/Dunn test.On the basis of the severity of decelerations, frequency of decelerations, and decreased variability, umbilical pH, and Po(2) level were decreased accordingly, and incidence of pH7.1 was increased. Sensitivity and false-positive rate of nonreassuring fetal heart rate patterns for fetal acidemia were 63% and 89%. There were nine cerebral palsy cases: six of the cases were preexisting asphyxia before monitoring was initiated, two of the cases were cytomegaloviral infections, and one of the cases was a maternal amniotic fluid embolism.In low-risk pregnancies, intrapartum fetal heart rate monitoring was useful to detect fetal acidemia. Cerebral palsy caused by intrapartum asphyxia was restricted to unavoidable accidents under continuous fetal heart rate monitoring.

We examined for 18 weeks the effect of dexamethasone treatment on learning and memory impairment produced by hypoxic-ischemic stress at postnatal day 7 in rat in addition to brain histological study. Dexamethasone of 0.5 mg/kg was injected i.p. 4 h before hypoxic-ischemic stress, in which the left carotid artery was ligated followed by 2 h hypoxia (8% oxygen). Dexamethasone treatment improved behavior in each learning task: in choice reaction time tasks relating to the attention process, in 8-arm radial maze task examining working and reference memory, and in water maze task relating to reference memory. Improvement to the extent of the sham-control level was observed. Dexamethasone treatment also completely prevented histological brain damage. No adverse effect in learning and memory tests was observed in the animals treated with dexamethasone without hypoxic-ischemic stress. It is concluded that dexamethasone treatment is significantly effective in prevention not only of histological brain damage but also of learning and memory impairment occasioned by subsequent hypoxic-ischemic insult, warranting further clinical investigation.

The free radical scavenger 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186), which has been approved in Japan for use in patients with cerebral infarction, was used to treat ischemic-hypoxic brain damage in neonatal rats. Seven-day-old rat pups were subjected to a modified Levine procedure, then given either vehicle or MCI-186 (at one of three dosage levels: 3, 6, or 9 mg/kg), and the extent of brain damage was evaluated either 24 h or 7 days later. The administration of MCI-186 significantly attenuated damage, in a dose-dependent manner. These results indicate that MCI-186 is a promising candidate for the treatment of neonatal hypoxic-ischemic encephalopathy.

Objective: This study was intended to investigate the temporal changes in heat shock protein 72 expression and microtubule-associated protein 2 disappearance in rat brain at 2 different ages after hypoxic-ischemic insult. Study Design: Both 5-day-old and 14-day-old Wistar rats were subjected to unilateral common carotid artery ligation and hypoxia in 8% oxygen for 2 hours at 33°C. Brain sections were examined sequentially for heat shock protein 72 expression at 0.5, 3, 6, 12, 24, 48, and 72 hours of recovery after hypoxia-ischemia and for microtubule-associated protein 2 disappearance at 0, 24, 48, and 72 hours of recovery and at 7 days of recovery after hypoxia-ischemia. Results of immunohistochemical staining for heat shock protein 72 and microtubule-associated protein 2 were used as markers for detection of early hypoxic-ischemic brain damage. Permanent neuronal damage was assessed with hematoxylin and eosin staining at 7 days after hypoxia. Results: In 5-day-old rats microtubule-associated protein 2 expression was lost as early as 0 hours after hypoxia-ischemia in the cerebral cortex and hippocampus, with a peak at 48 hours after which expression recovered. Expression of heat shock protein 72 was detected in the ligated hemisphere at 0.5 hours after hypoxia-ischemia and peaked at 6 to 24 hours of recovery. In 14-day-old rats microtubule-associated protein 2 was stained in the cortex at 0 hours after hypoxia-ischemia but gradually disappeared in the cerebral cortex and hippocampus after 24 hours of recovery. The expression of heat shock protein 72 was not detected by 6 hours of recovery in the cerebral cortex and by 3 to 12 hours of recovery in the hippocampus, but heat shock protein 72 was persistently expressed in the cortex and hippocampus after 48 hours of recovery. Neuronal damage was significantly less in 5-day-old rats than in 14-day-old rats. Conclusion: In 5-day-old rats hypoxia-ischemia causes earlier changes in heat shock protein 72 and microtubule-associated protein 2 immunostaining results and causes less severe brain damage than in 14-day-old rats. (Am J Obstet Gynecol 1999;180:1254-62.)