Association between maternal active smoking during pregnancy and placental weight: The Japan environment and Children's study.

INTRODUCTION: Maternal smoking during pregnancy is a well-known risk factor for reduced birthweight. However, research investigating the association between maternal smoking and placental weight is scarce and inconsistent. Our study was conducted to evaluate the association between maternal smoking and placental weight and placental weight/birthweight ratio (PW/BW ratio). METHODS: We used data from a birth cohort study, the Japan Environment and Children's Study (JECS). Main outcome measures were placental weight, PW/BW ratio, and the risk of high PW/BW ratio. High PW/BW ratio was defined as PW/BW ratio above the 90th percentile for gestational age and sex of offspring. The association between maternal smoking and placental weight was estimated as crude and as adjusted beta coefficients by applying linear regression analyses. Logistic regression analyses were also performed to estimate the association between maternal smoking and the risk of high PW/BW ratio. RESULTS: Of the 91,951 pregnant women, the mean placental weight and the mean PW/BW ratio were lowest for the group of women who had never smoked. Smokers had higher odds ratio for high PW/BW ratio compared with non-smokers. Furthermore, among smokers, the mean placental weight and mean PW/BW ratio were lowest in women who smoked less than 5 daily cigarettes, and highest in women who smoked 20 or more daily cigarettes during pregnancy. DISCUSSION: Placental weight was greater and PW/BW ratio was higher among smokers compared with non-smokers. Moreover, the number of daily cigarettes was positively associated with heavy placental weight.

Prediction of time to delivery by transperineal ultrasound in second stage of labor.

OBJECTIVE: To investigate whether the transperineal sonographic (TPS) parameters angle of progression (AoP) and midline angle (MLA) can predict the time remaining in the second stage of labor. METHODS: We evaluated prospectively women with a singleton pregnancy in cephalic presentation at term between October 2013 and September 2014. TPS volumes were obtained immediately after confirmation by digital vaginal examination of a fully dilated cervix. AoP and MLA were measured offline by analyzing the ultrasound volumes. Progression of labor was evaluated every hour during the second stage. The associations of AoP and MLA with the interval between TPS assessment and delivery were evaluated using multivariable Cox proportional hazards analyses in nulliparous and parous women separately. RESULTS: A total of 557 women were evaluated. An AoP ≥ 160° (adjusted hazard ratio (aHR), 2.52 (95% CI, 1.98-3.19)) and MLA ≤ 10° (aHR, 1.79 (95% CI, 1.35-2.34)) in nulliparous women and an AoP ≥ 150° (aHR, 1.86 (95% CI, 1.34-2.57)) and MLA ≤ 20° (aHR, 1.69 (95% CI, 1.21-2.34)) in parous women were significantly associated with the remaining time in labor. The positive/negative likelihood ratios of AoP, MLA, clinical station (fetal head descent as observed by digital examination) and clinical rotation (fetal head rotation as observed by digital examination) at these cut-off points were 3.6/0.6, 2.0/0.6, 1.6/0.6 and 1.6/0.8, respectively, in nulliparous women, and 2.4/0.6, 1.3/0.7, 7.6/0.5 and 5.2/0.7, respectively, in parous women. CONCLUSION: TPS assessment of AoP and MLA in the second stage of labor was useful for predicting the time remaining in labor and had higher predictive value than did digital vaginal examination in nulliparous women. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

A case of fetal hyperthyroidism treated with maternal administration of methimazole.

Prenatal ultrasonography of a pregnant woman with a past history of total thyroidectomy for Graves' disease detected fetal tachycardia, fetal growth restriction and oligohydramnios at 30 weeks gestation. Because a high titer of thyroid-stimulating hormone receptor antibody was noted in maternal serum and the fetal goiter was detected on ultrasonography, fetal hyperthyroidism was strongly suspected and subsequently confirmed with cordocentesis at 31 weeks gestation. After treatment of fetal hyperthyroidism through oral maternal administration of methimazole (MMI) starting at 33 weeks gestation, fetal heart rate and amniotic fluid volume returned to normal ranges. Complete resolution of the fetal goiter was observed at 35 weeks gestation. A male infant was born at 35 weeks 6 days gestation via cesarean section in the absence of thyrotoxic findings; however, cord blood chemical analysis at birth indicated iatrogenic fetal hypothyroidism. In the present report, maternal therapy using MMI to resolve symptoms of fetal thyrotoxicosis, including fetal tachycardia and oligohydramnios, was successfully conducted.

Clinical characteristics of monochorionic twins with large hemoglobin level discordance at birth.

OBJECTIVES: To evaluate neonatal outcomes and clinical characteristics of monochorionic diamniotic (MCDA) twins with a large intertwin hemoglobin (Hb) difference at birth. METHODS: This was a retrospective cohort study of MCDA twin gestations delivered at Osaka Medical Center and Research Institute for Maternal and Child Health between 2003 and 2012. Cases of pregnancy termination, acardiac twins or intrauterine death were excluded. A large intertwin Hb difference at birth was defined as > 8.0 g/dL according to the postnatal criteria for twin anemia-polycythemia sequence (TAPS). The intertwin reticulocyte count ratio (RCR) was calculated by dividing the reticulocyte count of the anemic twin by that of the polycythemic twin. Cases with Hb differences were divided into two groups according to the RCR, TAPS when the RCR was > 1.7 and acute fetofetal hemorrhage (AFFH) when the RCR was ≤ 1.7. Neonatal outcomes were compared between the TAPS and AFFH groups. RESULTS: During the study period, 432 MCDA twin pregnancies of a total of 532 born at our hospital were analyzed. There were 12 (2.8%) cases of a large intertwin Hb difference. The median gestational age at birth of these cases was 34 (range, 23-38) weeks, and all were delivered by Cesarean section. There were seven (1.6%) cases of TAPS and five (1.2%) of AFFH. The neonatal survival rate was 91.7%; in one pair of twins with TAPS neonatal death occurred. All (100%) cases with TAPS and two (40%) with AFFH required blood transfusion or partial-exchange transfusion for at least one infant. CONCLUSIONS: Although the incidence of TAPS and AFFH may be low in MCDA twins, many affected neonates required treatment for hematological abnormalities. Delivery of MCDA twins via Cesarean section does not appear to prevent AFFH, despite the absence of labor.

Protective effect of vitamin E against focal brain ischemia and neuronal death through induction of target genes of hypoxia-inducible factor-1.

Vitamin E has been shown to have protective effects against cerebral ischemia, possibly due to its anti-oxidant effects. However, its non-anti-oxidant, intracellular molecular mechanism remains elusive. For in vivo experiments in rats, orally administered vitamin E significantly reduced not only the brain infarct volume but also space navigation disability after permanent middle cerebral artery (MCA) occlusion. The level of anti-oxidant after MCA occlusion was significantly increased specifically in the ipsilateral brain tissues of vitamin E-treated rats. For in vitro experiments, posttreatment with vitamin E protected primary cultured neurons from nitric oxide-induced insult. Vitamin E induced the expression of the alpha subunit of hypoxia-inducible factor-1 (HIF-1) and its target genes, including vascular endothelial growth factor (VEGF) and heme oxygenase-1. The hypoxia response element on the VEGF promoter was responsible for this vitamin E-induced transcriptional activation of VEGF gene. Taken together, these results suggest that cerebral infarction increased the permeability of vitamin E across the blood-brain barrier, and this increased vitamin E in brain tissue elicited neuroprotective effects not only through scavenging oxidants, as are previously well reported, but also by transactivating HIF-1-dependent genes, which results in protection of brains from ischemic insults.

Pollen-specific regulation of vacuolar H+-PPase expression by multiple cis-acting elements.

We dissected the regulatory region of the AVP1 gene encoding the vacuolar H+-pyrophosphatase (V-PPase) of Arabidopsis thaliana by using a GUS-reporter assay system. The cloned 1.4 kb 5'-regulatory region in the GUS-reporter transgenic plants was sufficient for the light-induced repression. Furthermore, the 1.4 kb regulatory region was active in all tissues examined and its activity was especially enhanced in pollen, whereas the shorter 0.4 kb regulatory region was active only in pollen. Further detailed analyses revealed that the GUS activity in pollen was regulated by at least three cis-acting regions in an additive or synergetic manner. These findings establish a distinct mechanism of the tissue-specific regulation of V-PPase expression in developing pollen. and imply the biological significance of the V-PPase in pollen maturation.

Hand-assisted laparoscopic splenectomy for idiopathic thrombocytopenic purpura during pregnancy.

A successful case of a hand-assisted laparoscopic splenectomy with low-pressure pneumoperitoneum for autoimmune thrombocytopenic purpura in a patient at 23 weeks' gestation is reported. Preoperative splenic arterial embolization was performed on the same day as the operation using painless contour embolic material and super-absorbent polymer microspheres. The abdominal wall retraction method first was applied to avoid the effects of pneumoperitoneum on systemic hemodynamic alterations. However, a sufficient surgical view could not be obtained, as the intra-abdominal organs were elevated because of the enlarged uterus. A surgical view with 4 to 6-mm Hg pneumoperitoneum was available for the hand-assisted splenectomy. The postoperative course was uneventful, and the patient vaginally delivered a healthy infant. A hand-assisted laparoscopic splenectomy with low-pressure pneumoperitoneum after splenic arterial embolization would be feasible for patients with autoimmune thrombocytopenic purpura during a relatively advanced pregnancy.

ORP150 protects against hypoxia/ischemia-induced neuronal death.

Oxygen-regulated protein 150 kD (ORP150) is a novel endoplasmic-reticulum-associated chaperone induced by hypoxia/ischemia. Although ORP150 was sparingly upregulated in neurons from human brain undergoing ischemic stress, there was robust induction in astrocytes. Cultured neurons overexpressing ORP150 were resistant to hypoxemic stress, whereas astrocytes with inhibited ORP150 expression were more vulnerable. Mice with targeted neuronal overexpression of ORP150 had smaller strokes compared with controls. Neurons with increased ORP150 demonstrated suppressed caspase-3-like activity and enhanced brain-derived neurotrophic factor (BDNF) under hypoxia signaling. These data indicate that ORP150 is an integral participant in ischemic cytoprotective pathways.

Novel type Arabidopsis thaliana H(+)-PPase is localized to the Golgi apparatus.

Vacuolar H(+)-PPase, a membrane bound proton-translocating pyrophosphatase found in various species including plants, some protozoan and prokaryotes, has been demonstrated to be localized to the vacuolar membrane in plants. Using a GUS reporter system and a green fluorescent protein (GFP) fusion protein, we investigated the tissue distribution and the subcellular localization, respectively, of a novel type H(+)-PPase encoded by AVP2/AVPL1 identified in the Arabidopsis thaliana genome. We showed that AVP2/AVPL1 is highly expressed at the trichome and the filament of stamen. Furthermore, the fluorescence of GFP-tagged AVP2/AVPL1 showed small dot-like structures that were observed throughout the cytoplasm of various Arabidopsis cells under a fluorescent microscope. The distribution of this dot-like fluorescent pattern was apparently affected by a treatment with brefeldin A. Moreover, we demonstrated that most dot-like fluorescent structures colocalized with a Golgi resident protein. These findings suggest that this novel type H(+)-PPase resides on the Golgi apparatus rather than the vacuolar membrane.

Apolipoprotein E4 stimulates cAMP response element-binding protein transcriptional activity through the extracellular signal-regulated kinase pathway.

Inheritance of the epsilon4 allele of the apolipoprotein E gene (APOE4) is a major risk factor for the development of Alzheimer's disease (AD). Although the association between APOE4 and AD is well documented, the mechanism by which apolipoprotein E exerts an isoform-specific effect on neurons in disease is unknown. In this report, we demonstrate that apoE4 stimulates the transcriptional activity of cAMP-response element-binding protein (CREB) by activating the extracellular signal-regulated kinase (ERK) cascade in rat primary hippocampal neurons. In contrast, apoE3 was unable to stimulate CREB transcriptional activity and unable to activate the ERK pathway. Elevation of intracellular Ca(2+) levels are also involved because treatment with receptor-associated protein, nifedipine, MK801, removal of Ca(2+) from the medium and dantrolene all served to inhibit calcium elevation and attenuate the activation of CREB. Treatment with an apoE peptide was also found to facilitate transcription of the CREB-dependent genes, c-fos and Bcl-2. In contrast to treatment with apoE3, our findings suggest apoE4 and apoE-peptide induce a novel signaling pathway.

Activated cAMP-response element-binding protein regulates neuronal expression of presenilin-1.

Upon binding to the cAMP-response element of a gene's promoter, the transcription factor known as cAMP-response element-binding protein (CREB) facilitates transcription of many different neuronal genes including those involved with synaptic function. Based on our previous reports of gene structure (GenBank accession number AF029701 ), we now demonstrate that activated CREB binds to the proximal promoter of the human presenilin-1 (PS-1) gene to activate PS-1 transcription in rat and in human neuronal cells. Specific stimulation of the N-methyl-d-aspartate subtype of neuronal glutamate receptors activates CREB and results in increased PS-1 expression. Similarly, treatment with brain-derived neurotrophic factor activates CREB and increases PS-1 expression in a dose-dependent fashion. By using adenovirus vectors expressing dominant negative forms of CREB, we were able to show that induction of PS-1 expression requires the activation of CREB. Conversely, constitutive expression of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) results in activation of CREB and increased PS-1 expression that can be blocked by the addition of selective MEK inhibitors. Our findings suggest a hypothesis where stimulation of N-methyl-d-aspartate receptors signals CREB activation to enhance PS-1 gene product expression that contributes to normal neuronal functions.

Akt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of p53.

Survival factors suppress apoptosis by activating the serine/threonine kinase Akt. To investigate the molecular mechanism underlying activated Akt's ability to protect neurons from hypoxia or nitric oxide (NO) toxicity, we focused on the apoptosis-related functions of p53 and caspases. We eliminated p53 by employing p53-deficient neurons and increased p53 by infection with recombinant adenovirus capable of transducing p53 expression, and we now show that p53 is implicated in the apoptosis induced by hypoxia or NO treatments of primary cultured hippocampal neurons. Although hypoxia and NO induced p53, treatment with insulin-like growth factor-1 significantly inhibited caspase-3-like activation, neuronal death and transcriptional activity of p53. These insulin-like growth factor-1 effects are prevented by wortmannin, a phosphatidylinositol 3-kinase inhibitor. Adenovirus-mediated expression of activated-Akt kinase suppressed p53-dependent transcriptional activation of responsive genes such as Bax, suppressed caspase-3-like protease activity and suppressed neuronal cell death with no effect on the cellular accumulation and nuclear translocation of p53. In contrast, overexpression of kinase-defective Akt failed to suppress these same activities. These results suggest a mechanism where Akt kinase activation reduces p53's transcriptional activity that ultimately rescues neurons from hypoxia- or NO-mediated cell death.

Low density lipoprotein receptor-related protein gene polymorphisms and risk for late-onset Alzheimer's disease in a Japanese population.

Low density lipoprotein (LDL) receptor-related protein (LRP) gene polymorphisms located in the 5' region and in exon 3, and the apolipoprotein E (APOE) genotype were determined in 100 Japanese patients affected by late-onset Alzheimer's disease (AD). We matched 246 controls for age and found no association between the polymorphism located in the 5' region of the LRP gene. The distribution of LRP exon 3 genotypes and alleles did not differ between AD and the control groups. However, the frequency of T allele in the Alzheimer's group having APOE-epsilon4 was lower than that in the control group having APOE-epsilon4, but it was only marginally significant (p = 0.022). Age of onset was significantly younger in the patients with CC genotype than those carrying the T allele (p = 0.03), and this trend was more evident among non-APOE-epsilon4 carriers (p = 0.008). These results support the possibility that ApoE and LRP may contribute to the development of AD.

Changes in cytokine production during and after normal pregnancy.

PROBLEM: The systemic T helper 1/T helper 2 (Th1/Th2) cytokine balance during normal human pregnancy is controversial, and observations about the balance in the postpartum period have only been reported for up to 3 months. METHOD: Whole-blood, from 83 healthy pregnant women, 80 healthy postpartum women, and 31 healthy non-pregnant women was stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin, and the levels of cytokines in the supernatant were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The production of all measured cytokines decreased during pregnancy, especially in the second trimester. After delivery, interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) increased from 2 to 11 months postpartum, and IL-4 increased from 6 to 11 months postpartum. CONCLUSIONS: These data indicate that 1) decreases in production of both Th1-and Th2-type cytokines during pregnancy may be related to the pregnancy-induced amelioration of autoimmune diseases: 2) increases in production of both Th1- and Th2-type cytokines in the postpartum period may be related to the postpartum aggravation of autoimmune diseases.

A pathway of neuronal apoptosis induced by hypoxia/reoxygenation: roles of nuclear factor-kappaB and Bcl-2.

As a model of the reperfusion injury found in stroke, we have exposed neurons to hypoxia followed by reoxygenation. Neurons treated with hypoxia/reoxygenation (H/R) respond by activating nuclear factor-kappaB (NFkappaB), releasing cytochrome c from their mitochondria, and ultimately dying. Further supporting an apoptotic mechanism, expression of the antiapoptotic Bcl-2 and Bcl-x proteins was increased following H/R. In this model, adenoviral-mediated transduction of lkappaB expression inhibited NFkappaB activation and significantly accelerated cytochrome c release and caspase-dependent neuronal death. At the same time, expression of mutated lkappaB prevented the increased expression of endogenous Bcl-2 and Bcl-x. In the presence of mutated lkappaB, singular overexpression of only Bcl-2 by adenoviral-mediated transduction significantly inhibited cytochrome c release, caspase-3-like activation, and cell death in response to H/R. These findings suggest a pathway where NFkappaB activation induces overexpression of Bcl-2 and Bcl-x, which function to prevent apoptotic cell death following H/R treatments.

High incidence of respiratory distress syndrome (RDS) in infants born to mothers with placenta previa.

OBJECTIVE: To evaluate the incidence of respiratory distress syndrome (RDS) in infants born to mothers with placenta previa and to assess the risk factors for RDS. METHODS: Ninety-nine pregnant women with placenta previa who delivered by cesarean section at 30-35 weeks of gestation were compared retrospectively with 102 pregnant women matched for week of gestation and birth year, who underwent elective cesarean section. Maternal characteristics, neonatal outcome, and incidence of RDS were analyzed. Umbilical cord blood samples were collected at delivery and were used to determine cortisol, epinephrine, and norepinephrine levels. Student's t-test, the chi-square test, and Fisher's exact test were used for statistical comparisons. P < 0.05 was considered significant. The Mann-Whitney U test was used for comparison of continuous variables. RESULTS: Preeclampsia, histological chorioamnionitis, and premature rupture of membranes were significantly lower in the placenta previa group (placenta previa: 2.0% vs. control: 14.7%, P < 0.01; 14.1% vs. 30.1%, P < 0.01; 7.1% vs. 17.6%, P < 0.05, respectively). The incidence of RDS was significantly higher in the placenta previa group than in the control group (29.3% vs. 6.9%, P < 0.0001). The cortisol level in umbilical cord blood in the placenta previa group was lower than in the control group (median 7.3, range 4.4-14.9 microg/dl vs. median 10.6, range 4.9-30.3 microg/dl, P < 0.05). There were no significant differences in epinephrine or norepinephrine levels between the two groups. CONCLUSIONS: The incidence of RDS in infants delivered at 30-35 weeks' gestation by cesarean section was significantly higher in mothers with placenta previa than in women without placenta previa. This may reflect decreased fetal stress since the cord blood cortisol levels were found to be lower in women with placenta previa.

Activation of Akt kinase inhibits apoptosis and changes in Bcl-2 and Bax expression induced by nitric oxide in primary hippocampal neurons.

Emerging data indicate that growth factors such as insulin-like growth factor-1 (IGF-1) prevent neuronal death due to nitric oxide (NO) toxicity. On the other hand, growth factors can promote cell survival by acting on phosphatidylinositol 3-kinase (PI3-kinase) and its downstream target, serine-threonine kinase Akt, in various types of cells. Here, we examined the mechanism by which IGF-1 inhibits neuronal apoptosis induced by NO in primary hippocampal neurons. IGF-1 was capable of preventing apoptosis and caspase-3-like activation induced by a NO donor, sodium nitroprusside or 3-morpholin-osydnonimine. Incubation of neurons with a P13-kinase inhibitor, wortmannin or LY294002, blocked the effects of IGF-1 on NO-induced neurotoxicity and caspase-3-like activation. In addition, the P13-kinase inhibitors blocked the effect of IGF-1 on down-regulation in Bcl-2 and upregulation in Bax expression induced by NO. Adenovirus-mediated overexpression of the activated form of Akt significantly inhibited NO-induced cell death, caspase-3-like activation, and changes in Bcl-2 and Bax expression. Moreover, expression of the kinase-defective form of Akt almost completely blocked the effects of IGF-1. These findings suggest that activation of Akt is necessary and sufficient for the effect of IGF-1 and is capable of preventing NO-induced apoptosis by modulating the NO-induced changes in Bcl-2 and Bax expression.

Prediction of postpartum onset of rheumatoid arthritis.

OBJECTIVE: To investigate the prediction of the postpartum onset of rheumatoid arthritis (RA). METHODS: Two thousand five hundred and forty seven healthy pregnant subjects were examined prospectively and the relation between serum rheumatoid factors (RF) and postpartum onset of RA was observed. Rheumatoid factors were measured in early pregnancy by the antihuman IgG latex agglutination test (Latex test) and antirabbit IgG haemagglutination test (RAHA test). RESULTS: Latex test and RAHA test were positive in 26 (1.0%) and 64 (2.5%) pregnant subjects, respectively. Four hundred and ten subjects of 2547 pregnant women could be followed up for one year after delivery. None of 401 subjects without RF, or with only one RF on either Latex test or RAHA test, developed RA after delivery. Two (22.2%) of nine subjects with both RFs developed RA at one and three months postpartum, respectively. Transient arthralgia was found within 12 months postpartum in three of nine (33.3%) subjects with both RFs and this prevalence was significantly higher than that in RF negative subjects (8.1%). CONCLUSION: Postpartum onset of RA was found in at least 2 of 2547 healthy subjects (0.08%) and onset was predicted by positive test for rheumatoid factors.