Predictors of poor perinatal outcome following maternal perception of reduced fetal movements--a prospective cohort study

Background

Maternal perception of reduced fetal movement (RFM) is associated with increased risk of stillbirth and fetal growth restriction (FGR). RFM is thought to represent fetal compensation to conserve energy due to insufficient oxygen and nutrient transfer resulting from placental insufficiency.

Objective

To identify predictors of poor perinatal outcome after maternal perception of reduced fetal movements (RFM).

Design

Prospective cohort study.

Methods

305 women presenting with RFM after 28 weeks of gestation were recruited. Demographic factors and clinical history were recorded and ultrasound performed to assess fetal biometry, liquor volume and umbilical artery Doppler. A maternal serum sample was obtained for measurement of placentally-derived or modified proteins including: alpha fetoprotein (AFP), human chorionic gonadotrophin (hCG), human placental lactogen (hPL), ischaemia-modified albumin (IMA), pregnancy associated plasma protein A (PAPP-A) and progesterone. Factors related to poor perinatal outcome were determined by logistic regression.

Results

22.1% of pregnancies ended in a poor perinatal outcome after RFM. The most common complication was small-for-gestational age infants. Pregnancy outcome after maternal perception of RFM was related to amount of fetal activity while being monitored, abnormal fetal heart rate trace, diastolic blood pressure, estimated fetal weight, liquor volume, serum hCG and hPL. Following multiple logistic regression abnormal fetal heart rate trace (Odds ratio 7.08, 95% Confidence Interval 1.31–38.18), (OR) diastolic blood pressure (OR 1.04 (95% CI 1.01–1.09), estimated fetal weight centile (OR 0.95, 95% CI 0.94–0.97) and log maternal serum hPL (OR 0.13, 95% CI 0.02–0.99) were independently related to pregnancy outcome. hPL was related to placental mass.

Conclusion

Poor perinatal outcome after maternal perception of RFM is closely related to factors which are connected to placental dysfunction. Novel tests of placental function and associated fetal response may provide improved means to detect fetuses at greatest risk of poor perinatal outcome after RFM.     

Decreased histone deacetylase 2 impairs Nrf2 activation by oxidative stress

Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in cellular defence against oxidative stress by inducing the expression of multiple anti-oxidant genes. However, where high levels of oxidative stress are observed, such as chronic obstructive pulmonary disease (COPD), Nrf2 activity is reduced, although the molecular mechanism for this defect is uncertain. Here, we show that down-regulation of histone deacetylase (HDAC) 2 causes Nrf2 instability, resulting in reduced anti-oxidant gene expression and increase sensitivity to oxidative stress. Although Nrf2 protein was clearly stabilized after hydrogen peroxide (H₂O₂) stimulation in a bronchial epithelial cell line (BEAS2B), Nrf2 stability was decreased and Nrf2 acetylation increased in the presence of an HDAC inhibitor, trichostatin A (TSA). TSA also reduced Nrf2-regulated heme-oxygenase-1 (HO-1) expression in these cells, and this was confirmed in acute cigarette-smoke exposed mice in vivo. HDAC2 knock-down by RNA interference resulted in reduced H₂O₂-induced Nrf2 protein stability and activity in BEAS2B cells, whereas HDAC1 knockdown had no effect. Furthermore, monocyte-derived macrophages obtained from healthy volunteers (non-smokers and smokers) and COPD patients showed a significant correlation between HDAC2 expression and Nrf2 expression (r = 0.92, p < 0.0001). Thus, reduced HDAC2 activity in COPD may account for increased Nrf2 acetylation, reduced Nrf2 stability and impaired anti oxidant defences.     

A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex

The MRN (Mre11-Rad50-Nbs1)-ATM (ataxia-telangiectasia mutated) pathway is essential for sensing and signaling from DNA double-strand breaks. The MRN complex acts as a DNA damage sensor, maintains genome stability during DNA replication, promotes homology-dependent DNA repair and activates ATM. MRN is essential for cell viability, which has limited functional studies of the complex. Small-molecule inhibitors of MRN could circumvent this experimental limitation and could also be used as cellular radio- and chemosensitization compounds. Using cell-free systems that recapitulate faithfully the MRN-ATM signaling pathway, we designed a forward chemical genetic screen to identify inhibitors of the pathway, and we isolated 6-(4-hydroxyphenyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (mirin, 1) as an inhibitor of MRN. Mirin prevents MRN-dependent activation of ATM without affecting ATM protein kinase activity, and it inhibits Mre11-associated exonuclease activity. Consistent with its ability to target the MRN complex, mirin abolishes the G2/M checkpoint and homology-dependent repair in mammalian cells.     

4E10-Resistant HIV-1 Isolated from Four Subjects with Rare Membrane-Proximal External Region Polymorphisms

Human antibody 4E10 targets the highly conserved membrane-proximal external region (MPER) of the HIV-1 transmembrane glycoprotein, gp41, and has extraordinarily broad neutralizing activity. It is considered by many to be a prototype for vaccine development. In this study, we describe four subjects infected with viruses carrying rare MPER polymorphisms associated with resistance to 4E10 neutralization. In one case resistant virus carrying a W680G substitution was transmitted from mother to infant. We used site-directed mutagenesis to demonstrate that the W680G substitution is necessary for conferring the 4E10-resistant phenotype, but that it is not sufficient to transfer the phenotype to a 4E10-sensitive Env. Our third subject carried Envs with a W680R substitution causing variable resistance to 4E10, indicating that residues outside the MPER are required to confer the phenotype. A fourth subject possessed a F673L substitution previously associated with 4E10 resistance. For all three subjects with W680 polymorphisms, we observed additional residues in the MPER that co-varied with position 680 and preserved charged distributions across this region. Our data provide important caveats for vaccine development targeting the MPER. Naturally occurring Env variants described in our study also represent unique tools for probing the structure-function of HIV-1 envelope.     

Why is the South Orkney Island shelf (the world's first high seas marine protected area) a carbon immobilization hotspot?

The Southern Ocean archipelago, the South Orkney Islands (SOI), became the world's first entirely high seas marine protected area (MPA) in 2010. The SOI continental shelf (~44 000 km²), was less than half covered by grounded ice sheet during glaciations, is biologically rich and a key area of both sea surface warming and sea‐ice losses. Little was known of the carbon cycle there, but recent work showed it was a very important site of carbon immobilization (net annual carbon accumulation) by benthos, one of the few demonstrable negative feedbacks to climate change. Carbon immobilization by SOI bryozoans was higher, per species, unit area and ice‐free day, than anywhere‐else polar. Here, we investigate why carbon immobilization has been so high at SOI, and whether this is due to high density, longevity or high annual production in six study species of bryozoans (benthic suspension feeders). We compared benthic carbon immobilization across major regions around West Antarctica with sea‐ice and primary production, from remotely sensed and directly sampled sources. Lowest carbon immobilization was at the northernmost study regions (South Georgia) and southernmost Amundsen Sea. However, data standardized for age and density showed that only SOI was anomalous (high). High immobilization at SOI was due to very high annual production of bryozoans (rather than high densities or longevity), which were 2x, 3x and 5x higher than on the Bellingshausen, South Georgia and Amundsen shelves, respectively. We found that carbon immobilization correlated to the duration (but not peak or integrated biomass) of phytoplankton blooms, both in directly sampled, local scale data and across regions using remote‐sensed data. The long bloom at SOI seems to drive considerable carbon immobilization, but sea‐ice losses across West Antarctica mean that significant carbon sinks and negative feedbacks to climate change could also develop in the Bellingshausen and Amundsen seas.     

Precocious recovery from allotype suppression in transiently chimeric rabbits

Rabbits suppressed for paternal immunoglobulin allotypes specified by the b locus were injected with spleen cells from non-inbred donors at the age of 1 month. This resulted in transient chimerism as shown by the appearance of 10 to >200 μg of donor type Ig per milliliter recipient's serum 1 to 2 weeks after cell transfer. Antibody production by donor cells could not be demonstrated during their survival in the recipients. If, and only if, the donor cells produced Ig of the suppressed allotype, the release from suppression was expedited as judged by the time of appearance and increase of lymphoid cells with membrane-bound Ig of the suppressed type, and also by the onset and rise of secreted Ig of this type in the recipients' sera.     

DIVERSITY AND PHYLOGENETIC PLACEMENT OF BRACTEACOCCUS TEREG (CHLOROPHYCEAE,CHLOROPHYTA) BASED ON 18S RIBOSOMAL RNA GENE SEQUENCE DATA1

Sequence data from the nuclear small-subunit ribosomal RNA gene was obtained for nine strains of Bracteacoccus Tereg, representing at least five morphological species and four distinct geographic locations. These, along with sequence data from two additional chlorophycean taxa, Spongiochloris spongiosa Starr and Ascochloris multinucleata Bold et MacEntee, and 48 published sequences from green algal taxa, were used to determine the phylogenetic placement of Bracteacoccus with respect to other chlorophycean green algae. Results support the monophyly of Bracteacoccus strains, contrasting with patterns observed so far for many other coccoid green algae. The range of variation among Bracteacoccus strains is similar to that of other congeners. Basal body orientation in Bracteacoccus has been interpreted as clockwise; however, the 18S data point to a relationship between Bracteacoccus and taxa with the directly opposed configuration of the flagellar apparatus. No close relationship was found to the multinucleated green coccoids with clockwise orientation of basal bodies, such as Spongiochloris, or to those with parallel basal bodies, such as Spermatozopsis. However, 18S data confirm that the motile and vegetative cells of Bracteacoccus are structurally distinct from the representatives of sphaeroplealean families currently studied. It is premature to reclassify Bracteacoccus until 18S comparisons can be made with additional sphaeroplealean taxa and with algae with similar flagellar structure such as Dictyochloris and Heterochlamydomonas.     

Elevated incubation temperature improves later-life swimming endurance in juvenile Chinook salmon,Oncorhynchus tshawytscha

The effect of incubation and rearing temperature on muscle development and swimming endurance under a high-intensity swimming test was investigated in juvenile Chinook salmon (Oncorhynchus tshawytscha) in a hatchery experiment. After controlling for the effects of fork length (L_F) and parental identity, times to fatigue of fish were higher when fish were incubated or reared at warmer temperatures. Significant differences among combinations of pre- and post-emergence temperatures conformed to 15–15°C > 15–9°C > 9–9°C > 7–9°C > 7–7°C in 2011 when swimming tests were conducted at 300 accumulated temperature units post-emergence and 15–9°C > (7–9°C = 7–7°C) in 2012 when swimming tests were conducted at an L_F of c. 40 mm. The combination of pre- and post-emergence temperatures also affected the number and size of muscle fibres, with differences among temperature treatments in mean fibre cross-sectional area persisting after controlling for L_F and parental effects. Nonetheless, neither fibre number nor fibre size accounted for significant variation in swimming endurance. Thus, thermal carryover effects on swimming endurance were not mediated by thermal imprinting of muscle structure. This is the first study to test how temperature, body size and muscle structure interact to affect swimming endurance during early development in salmon.