Fetal sex dependency in pregnancy; fetal and maternal outcomes : The Generation R Study

The aim of this thesis was to evaluate fetal sex specific differences on placental, fetal and maternal level and to assess different definitions on fetal growth restriction and their associations with childhood outcomes. All studies described in this thesis were embedded in The Generation R Study, a prospective cohort study from early pregnancy onwards in Rotterdam, The Netherlands. The first and second aim of this thesis concerned fetal growth restriction (FGR) and its association with childhood outcomes and the search for a biomarker to retrospectively assess FGR. We showed that FGR, just as neonates born small for gestational age (SGA), is associated with accelerated growth at the age of two years and altered cardiovascular outcomes at six years. This study emphasizes that despite birth weight, a deviating growth curve is associated with adverse health in childhood and therefore possibly adulthood. Moreover we showed that lower umbilical cord levels of placental growth factor (PlGF) are associated with lower birth weight, different fetal growth patterns and a deviating growth curve. Therefore, PlGF might be a promising biomarker to determine deviations in fetal growth and FGR retrospectively enabling follow-up of these neonates in the postnatal period. The third aim of this thesis was to evaluate fetal sex specific differences on a placental, fetal and maternal level. Fetal sex specific differences were found on all these three levels. Within the placental biomarker production fetal sex specific differences exist, in which women carrying a female fetus have higher serum levels of PlGF, s-Flt1 and PAI-2 in the first trimester of pregnancy. However, in pregnancies complicated with pre-eclampsia, spontaneous preterm birth or SGA these fetal sex specific differences are not observed. This suggests that other mechanisms causing these complications may dominate the effect of fetal sex. Moreover sex specific difference were observed in fetal growth. Already in the first trimester of pregnancy male crown-rump-length (CRL) is larger as compared with female CRL. In the second and third trimester of pregnancy head and abdominal circumference are larger in male fetuses, while femur length is larger in female fetuses. Also different growth patterns were observed. Interestingly, these different growth patterns persist postnatally. On the level of maternal vascular adaptation to pregnancy, differential blood pressure patterns are observed between pregnancies with a male or female fetus. In pregnancies with a male fetus, the uterine artery pulsatility index and the occurrence of notching was higher as compared with pregnancies with a female fetus. Eventually, the results will contribute to the development of strategies for optimizing health and healthcare for both pregnant women and their children. Since currently fetal sex is not taken into account in research, we recommend that all studies regarding maternal adaptation to pregnancy, placental biology, fetal growth, pregnancy complications and pharmacological therapies should stratify for fetal sex

Altered functional brain network connectivity and glutamate system function in transgenic mice expressing truncated Disrupted-in-Schizophrenia 1

Considerable evidence implicates DISC1 as a susceptibility gene for multiple psychiatric diseases. DISC1 has been intensively studied at the molecular, cellular and behavioral level, but its role in regulating brain connectivity and brain network function remains unknown. Here, we utilize a set of complementary approaches to assess the functional brain network abnormalities present in mice expressing a truncated Disc1 gene (Disc1tr Hemi mice). Disc1tr Hemi mice exhibited hypometabolism in the prefrontal cortex (PFC) and reticular thalamus along with a reorganization of functional brain network connectivity that included compromised hippocampal–PFC connectivity. Altered hippocampal–PFC connectivity in Disc1tr Hemi mice was confirmed by electrophysiological analysis, with Disc1tr Hemi mice showing a reduced probability of presynaptic neurotransmitter release in the monosynaptic glutamatergic hippocampal CA1–PFC projection. Glutamate system dysfunction in Disc1tr Hemi mice was further supported by the attenuated cerebral metabolic response to the NMDA receptor (NMDAR) antagonist ketamine and decreased hippocampal expression of NMDAR subunits 2A and 2B in these animals. These data show that the Disc1 truncation in Disc1tr Hemi mice induces a range of translationally relevant endophenotypes underpinned by glutamate system dysfunction and altered brain connectivity

Maternal cardiovascular adaptation to twin pregnancy: A population-based prospective cohort study

Background: In women with singleton pregnancies, maternal adaptation is considered a stress test for later life cardiovascular disease. The aim of this study was to assess maternal adaptation in women with twin pregnancies compared to women carrying singletons during and after pregnancy. Methods: This was a population based prospective cohort study of 91 women with twin pregnancies and 8107 women carrying singletons. The association of twin pregnancy and maternal adaptation was examined using regression analyses. In pregnancy, we measured soluble fms-like tyrosine kinase-1 (sFLT-1), placental growth (PGF) factor, systolic (SBP) and diastolic blood pressure (DBP), and the occurrence of pre-eclampsia (PE). After pregnancy, measurements were obtained on SBP and DBP, cardiac function, retinal calibres, intima media thickness and distensibility of the common carotid artery. Results: sFLT-1 and PGF concentrations were higher in early (13.4 weeks) and mid-pregnancy (20.4 weeks) in women with twin pregnancies compared to women with singleton pregnancies. Women with twin pregnancies had a different DBP pattern in pregnancy. Women with twin pregnancies were more likely to have PE (odds ratio 3.63; 95% CI [1.76 to 7.48]). Six and ten years after pregnancy, no differences in maternal adaptation were observed. Conclusions: Women with twin pregnancies show an altered adaptation during pregnancy compared to women with singleton pregnancies. This is associated with a substantially increased incidence of PE, but does not lead to persistent altered maternal adaptation years after pregnancy

Predictions of alpha-decay half-lives based on potentials from self-consistent mean-field models

We present a microscopic model for the calculation of alpha-decay half lives employing potentials obtained from relativistic and non-relativistic self-consistent mean-field models. The nuclear and Coulomb potentials are used to obtain the tunneling probability and, in one model variant, also the knocking frequency. The model contains only one parameter. We compare this approach employing several modern mean-field parametrizations to experimental data and to the semi-empirical Viola-Seaborg systematics. We extrapolate our model to superheavy nuclei where assumptions entering semi-empirical approaches might lose validity.Comment: latex, 15 pages, 4 eps figures, accepted for publication in Nucl. Phys.

Fetal sex and maternal pregnancy outcomes: a systematic review and meta-analysis

BACKGROUND: Since the placenta also has a sex, fetal sex-specific differences in the occurrence of placenta-mediated complications could exist. OBJECTIVE: To determine the association of fetal sex with multiple maternal pregnancy complications. SEARCH STRATEGY: Six electronic databases Ovid MEDLINE, EMBASE, Cochrane Central, Web-of-Science, PubMed, and Google Scholar were systematically searched to identify eligible studies. Reference lists of the included studies and contact with experts were also used for identification of studies. SELECTION CRITERIA: Observational studies that assessed fetal sex and the presence of maternal pregnancy complications within singleton pregnancies. DATA COLLECTION AND ANALYSES: Data were extracted by 2 independent reviewers using a predesigned data collection form. MAIN RESULTS: From 6522 original references, 74 studies were selected, including over 12,5 million women. Male fetal sex was associated with term pre-eclampsia (pooled OR 1.07 [95%CI 1.06 to 1.09]) and gestational diabetes (pooled OR 1.04 [1.02 to 1.07]). All other pregnancy complications (i.e., gestational hypertension, total pre-eclampsia, eclampsia, placental abruption, and post-partum hemorrhage) tended to be associated with male fetal sex, except for preterm pre-eclampsia, which was more associated with female fetal sex. Overall quality of the included studies was good. Between-study heterogeneity was high due to differences in study population and outcome definition. CONCLUSION: This meta-analysis suggests that the occurrence of pregnancy complications differ according to fetal sex with a higher cardiovascular an

Birthing practices of traditional birth attendants in South Asia in the context of training programmes

Traditional Birth Attendants (TBA) training has been an important component of public health policy interventions to improve maternal and child health in developing countries since the 1970s. More recently, since the 1990s, the TBA training strategy has been increasingly seen as irrelevant, ineffective or, on the whole, a failure due to evidence that the maternal mortality rate (MMR) in developing countries had not reduced. Although, worldwide data show that, by choice or out of necessity, 47 percent of births in the developing world are assisted by TBAs and/or family members, funding for TBA training has been reduced and moved to providing skilled birth attendants for all births. Any shift in policy needs to be supported by appropriate evidence on TBA roles in providing maternal and infant health care service and effectiveness of the training programmes. This article reviews literature on the characteristics and role of TBAs in South Asia with an emphasis on India. The aim was to assess the contribution of TBAs in providing maternal and infant health care service at different stages of pregnancy and after-delivery and birthing practices adopted in home births. The review of role revealed that apart from TBAs, there are various other people in the community also involved in making decisions about the welfare and health of the birthing mother and new born baby. However, TBAs have changing, localised but nonetheless significant roles in delivery, postnatal and infant care in India. Certain traditional birthing practices such as bathing babies immediately after birth, not weighing babies after birth and not feeding with colostrum are adopted in home births as well as health institutions in India. There is therefore a thin precarious balance between the application of biomedical and traditional knowledge. Customary rituals and perceptions essentially affect practices in home and institutional births and hence training of TBAs need to be implemented in conjunction with community awareness programmes

Mutations in MAP3K7 that Alter the Activity of the TAK1 Signaling Complex Cause Frontometaphyseal Dysplasia.

Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia affecting the long bones and skull. The cause of FMD in some individuals is gain-of-function mutations in FLNA, although how these mutations result in a hyperostotic phenotype remains unknown. Approximately one half of individuals with FMD have no identified mutation in FLNA and are phenotypically very similar to individuals with FLNA mutations, except for an increased tendency to form keloid scars. Using whole-exome sequencing and targeted Sanger sequencing in 19 FMD-affected individuals with no identifiable FLNA mutation, we identified mutations in two genes-MAP3K7, encoding transforming growth factor β (TGF-β)-activated kinase (TAK1), and TAB2, encoding TAK1-associated binding protein 2 (TAB2). Four mutations were found in MAP3K7, including one highly recurrent (n = 15) de novo mutation (c.1454C>T [ p.Pro485Leu]) proximal to the coiled-coil domain of TAK1 and three missense mutations affecting the kinase domain (c.208G>C [p.Glu70Gln], c.299T>A [p.Val100Glu], and c.502G>C [p.Gly168Arg]). Notably, the subjects with the latter three mutations had a milder FMD phenotype. An additional de novo mutation was found in TAB2 (c.1705G>A, p.Glu569Lys). The recurrent mutation does not destabilize TAK1, or impair its ability to homodimerize or bind TAB2, but it does increase TAK1 autophosphorylation and alter the activity of more than one signaling pathway regulated by the TAK1 kinase complex. These findings show that dysregulation of the TAK1 complex produces a close phenocopy of FMD caused by FLNA mutations. Furthermore, they suggest that the pathogenesis of some of the filaminopathies caused by FLNA mutations might be mediated by misregulation of signaling coordinated through the TAK1 signaling complex

Search for Colour Singlet and Colour Reconnection Effects in Hadronic Z Decays at LEP

A search is performed in symmetric 3-jet hadronic Z decay events for evidence of colour singlet production or colour reconnection effects. Asymmetries in the angular separation of particles are found to be sensitive indicators of such effects. Upper limits on the level of colour singlet production and colour reconnection effects are established for a variety of models

Search for Colour Reconnection Effects in e+e- -> W+W- -> hadrons through Particle-Flow Studies at LEP

A search for colour reconnection effects in hadronic decays of W pairs is performed with the L3 detector at centre-of-mass energies between 189 and 209 GeV. The analysis is based on the study of the particle flow between jets associated to the same W boson and between two different W bosons in qqqq events. The ratio of particle yields in the different interjet regions is found to be sensitive to colour reconnection effects implemented in some hadronisation models. The data are compared to different models with and without such effects. An extreme scenario of colour reconnection is ruled out