Obstetrician-assessed maternal health at pregnancy predicts offspring future health

Background: We aimed to examine the association between obstetrician assessment of maternal physical health at the time of pregnancy and offspring cardiovascular disease risk.<p></p> Methods and Principal Findings: We examined this association in a birth cohort of 11,106 individuals, with 245,000 person years of follow-up. We were concerned that any associations might be explained by residual confounding, particularly by family socioeconomic position. In order to explore this we used multivariable regression models in which we adjusted for a range of indicators of socioeconomic position and we explored the specificity of the association. Specificity of association was explored by examining associations with other health related outcomes. Maternal physical health was associated with cardiovascular disease: adjusted (socioeconomic position, complications of pregnancy, birthweight and childhood growth at mean age 5) hazard ratio comparing those described as having poor or very poor health at the time of pregnancy to those with good or very good health was 1.55 (95%CI: 1.05, 2.28) for coronary heart disease, 1.91 (95%CI: 0.99, 3.67) for stroke and 1.57 (95%CI: 1.13, 2.18) for either coronary heart disease or stroke. However, this association was not specific. There were strong associations for other outcomes that are known to be related to socioeconomic position (3.61 (95%CI: 1.04, 12.55) for lung cancer and 1.28 (95%CI:1.03, 1.58) for unintentional injury), but not for breast cancer (1.10 (95%CI:0.48, 2.53)).<p></p> Conclusions and Significance: These findings demonstrate that a simple assessment of physical health (based on the appearance of eyes, skin, hair and teeth) of mothers at the time of pregnancy is a strong indicator of the future health risk of their offspring for common conditions that are associated with poor socioeconomic position and unhealthy behaviours. They do not support a specific biological link between maternal health across her life course and future risk of cardiovascular disease in her offspring.<p></p&gt

Relationship between diffusion capacity and small airway abnormality in COPDGene.

Impaired single breath carbon monoxide diffusing capacity (DLCO) is associated with emphysema. Small airways disease (SAD) may be a precursor lesion to emphysema, but the relationship between SAD and DLCO is undescribed. We hypothesized that in mild COPD, functional SAD (fSAD) defined by computed tomography (CT) and Parametric Response Mapping methodology would correlate with impaired DLCO. Using data from ever-smokers in the COPDGene cohort, we established that fSAD correlated significantly with lower DLCO among both non-obstructed and GOLD 1-2 subjects. The relationship between DLCO with CT-defined emphysema was present in all GOLD stages, but most prominent in severe disease. TRIAL REGISTRATION: NCT00608764. Registry: COPDGene. Registered 06 February 2008, retrospectively registered

Exploring metabolic pathway disruption in the subchronic phencyclidine model of schizophrenia with the generalized singular value decomposition

The quantification of experimentally-induced alterations in biological pathways remains a major challenge in systems biology. One example of this is the quantitative characterization of alterations in defined, established metabolic pathways from complex metabolomic data. At present, the disruption of a given metabolic pathway is inferred from metabolomic data by observing an alteration in the level of one or more individual metabolites present within that pathway. Not only is this approach open to subjectivity, as metabolites participate in multiple pathways, but it also ignores useful information available through the pairwise correlations between metabolites. This extra information may be incorporated using a higher-level approach that looks for alterations between a pair of correlation networks. In this way experimentally-induced alterations in metabolic pathways can be quantitatively defined by characterizing group differences in metabolite clustering. Taking this approach increases the objectivity of interpreting alterations in metabolic pathways from metabolomic data. We present and justify a new technique for comparing pairs of networks - in our case these networks are based on the same set of nodes and there are two distinct types of weighted edges. The algorithm is based on the Generalized Singular Value Decomposition (GSVD), which may be regarded as an extension of Principle Components Analysis to the case of two data sets. We show how the GSVD can be interpreted as a technique for reordering the two networks in order to reveal clusters that are exclusive to only one. Here we apply this algorithm to a new set of metabolomic data from the prefrontal cortex (PFC) of a translational model relevant to schizophrenia, rats treated subchronically with the N-methyl-D-Aspartic acid (NMDA) receptor antagonist phencyclidine (PCP). This provides us with a means to quantify which predefined metabolic pathways (Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolite pathway database) were altered in the PFC of PCP-treated rats. Several significant changes were discovered, notably: 1) neuroactive ligands active at glutamate and GABA receptors are disrupted in the PFC of PCP-treated animals, 2) glutamate dysfunction in these animals was not limited to compromised glutamatergic neurotransmission but also involves the disruption of metabolic pathways linked to glutamate; and 3) a specific series of purine reactions Xanthine Inosine adenylosuccinate is also disrupted in the PFC of PCP-treated animals. Network reordering via the GSVD provides a means to discover statistically validated differences in clustering between a pair of networks. In practice this analytical approach, when applied to metabolomic data, allows us to quantify the alterations in metabolic pathways between two experimental groups. With this new computational technique we identified metabolic pathway alterations that are consistent with known results. Furthermore, we discovered disruption in a novel series of purine reactions that may contribute to the PFC dysfunction and cognitive deficits seen in schizophrenia

Practising the Space Between: Embodying Belief as an Evangelical Anglican Student

This article explores the formation of British evangelical university students as believers. Drawing on ethnographic fieldwork conducted with a conservative evangelical Anglican congregation in London, I describe how students in this church come to embody a highly cognitive, word-based mode of belief through particular material practices. As they learn to identify themselves as believers, practices of reflexivity and accountability enable them to develop a sense of narrative coherence in their lives that allows them to negotiate tensions that arise from their participation in church and broader social structures. I demonstrate that propositional belief – in contexts where it becomes an identity marker – is bound up with relational practices of belief, such that distinctions between “belief in” and “belief that” are necessarily blurred in the lives of young evangelicals

Lake-size dependency of wind shear and convection as controls on gas exchange

High-frequency physical observations from 40 temperate lakes were used to examine the relative contributions of wind shear (u*) and convection (w*) to turbulence in the surface mixed layer. Seasonal patterns of u* and w* were dissimilar; u* was often highest in the spring, while w * increased throughout the summer to a maximum in early fall. Convection was a larger mixed-layer turbulence source than wind shear (u */w*-1 for lakes* and w* differ in temporal pattern and magnitude across lakes, both convection and wind shear should be considered in future formulations of lake-air gas exchange, especially for small lakes. © 2012 by the American Geophysical Union.Jordan S. Read, David P. Hamilton, Ankur R. Desai, Kevin C. Rose, Sally MacIntyre, John D. Lenters, Robyn L. Smyth, Paul C. Hanson, Jonathan J. Cole, Peter A. Staehr, James A. Rusak, Donald C. Pierson, Justin D. Brookes, Alo Laas, and Chin H. W

Specific inhibition of c-Jun N-terminal kinase delays preterm labour and reduces mortality

Preterm labour (PTL) is commonly associated with infection and/or inflammation. Lipopolysaccharide (LPS) from different bacteria can be used to independently or mutually activate Jun N-terminal kinase (JNK)/AP1- or NF-kB-driven inflammatory pathways that lead to PTL. Previous studies using Salmonella abortus LPS, which activates both JNK/AP-1 and NF-kB, showed that selective inhibition of NF-kB delays labour and improves pup outcome. Where labour is induced using Escherichia coli LPS (O111), which upregulates JNK/AP-1 but not NF-kB, inhibition of JNK/AP-1 activation also delays labour. In this study, to determine the potential role of JNK as a therapeutic target in PTL, we investigated the specific contribution of JNK signalling to S. Abortus LPS-induced PTL in mice. Intrauterine administration of S. Abortus LPS to pregnant mice resulted in the activation of JNK in the maternal uterus and fetal brain, upregulation of pro-inflammatory proteins COX-2, CXCL1, and CCL2, phosphorylation of cPLA2 in myometrium, and induction of PTL. Specific inhibition of JNK by co-administration of specific D-JNK inhibitory peptide (D-JNKI) delayed LPS-induced preterm delivery and reduced fetal mortality. This is associated with inhibition of myometrial cPLA2 phosphorylation and proinflammatory proteins synthesis. In addition, we report that D-JNKI inhibits the activation of JNK/JNK3 and caspase-3, which are important mediators of neural cell death in the neonatal brain. Our data demonstrate that specific inhibition of TLR4-activated JNK signalling pathways has potential as a therapeutic approach in the management of infection/inflammation-associated PTL and prevention of the associated detrimental effects to the neonatal brain

The oxytocin receptor antagonist, Atosiban, activates pro-inflammatory pathways in human amnion via Gαi signalling

Oxytocin (OT) plays an important role in the onset of human labour by stimulating uterine contractions and promoting prostaglandin/inflammatory cytokine synthesis in amnion via oxytocin receptor (OTR) coupling. The OTR-antagonist, Atosiban, is widely used as a tocolytic for the management of acute preterm labour. We found that in primary human amniocytes, Atosiban (10 μM) signals via PTX-sensitive Gαi to activate transcription factor NF-κB p65, ERK1/2, and p38 which subsequently drives upregulation of the prostaglandin synthesis enzymes, COX-2 and phospho-cPLA2 and excretion of prostaglandins (PGE2) (n = 6; p < 0.05, ANOVA). Moreover, Atosiban treatment increased expression and excretion of the inflammatory cytokines, IL-6 and CCL5. We also showed that OT-simulated activation of NF-κB, ERK1/2, and p38 and subsequent prostaglandin and inflammatory cytokine synthesis is via Gαi−2 and Gαi−3 but not Gαq, and is not inhibited by Atosiban. Activation or exacerbation of inflammation is not a desirable effect of tocolytics. Therefore therapeutic modulation of the OT/OTR system for clinical management of term/preterm labour should consider the effects of differential G-protein coupling of the OTR and the role of OT or selective OTR agonists/antagonists in activating proinflammatory pathways

Reflecting on loss in Papua New Guinea

This article takes up the conundrum of conducting anthropological fieldwork with people who claim that they have 'lost their culture,' as is the case with Suau people in the Massim region of Papua New Guinea. But rather than claiming culture loss as a process of dispossession, Suau claim it as a consequence of their own attempts to engage with colonial interests. Suau appear to have responded to missionization and their close proximity to the colonial-era capital by jettisoning many of the practices characteristic of Massim societies, now identified as 'kastom.' The rejection of kastom in order to facilitate their relations with Europeans during colonialism, followed by the mourning for kastom after independence, both invite consideration of a kind of reflexivity that requires action based on the presumed perspective of another

Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics

Background Preterm birth is now recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; however, the relative contribution of each remains unclear. In this study we aimed to characterize temporal transcriptome changes in the uterus preceding term labor and preterm labor (PTL) induced by progesterone withdrawal or inflammation in the mouse and compare these findings with human data.Methods Myometrium was collected at multiple time points during gestation and labor from three murine models of parturition: (1) term gestation; (2) PTL induced by RU486; and (3) PTL induced by lipopolysaccharide (LPS). RNA was extracted and cDNA libraries were prepared and sequenced using the Illumina HiSeq 2000 system. Resulting RNA-Seq data were analyzed using multivariate modeling approaches as well as pathway and causal network analyses and compared against human myometrial transcriptome data.Results We identified a core set of temporal myometrial gene changes associated with term labor and PTL in the mouse induced by either inflammation or progesterone withdrawal. Progesterone withdrawal initiated labor without inflammatory gene activation, yet LPS activation of uterine inflammation was sufficient to override the repressive effects of progesterone and induce a laboring phenotype. Comparison of human and mouse uterine transcriptomic datasets revealed that human labor more closely resembles inflammation-induced PTL in the mouse.Conclusions Labor in the mouse can be achieved through inflammatory gene activation yet these changes are not a requisite for labor itself. Human labor more closely resembles LPS-induced PTL in the mouse, supporting an essential role for inflammatory mediators in human “functional progesterone withdrawal.” This improved understanding of inflammatory and progesterone influence on the uterine transcriptome has important implications for the development of PTL prevention strategies

Adenosine-mono-phosphate-activated protein kinase-independent effects of metformin in T cells

The anti-diabetic drug metformin regulates T-cell responses to immune activation and is proposed to function by regulating the energy-stress-sensing adenosine-monophosphate-activated protein kinase (AMPK). However, the molecular details of how metformin controls T cell immune responses have not been studied nor is there any direct evidence that metformin acts on T cells via AMPK. Here, we report that metformin regulates cell growth and proliferation of antigen-activated T cells by modulating the metabolic reprogramming that is required for effector T cell differentiation. Metformin thus inhibits the mammalian target of rapamycin complex I signalling pathway and prevents the expression of the transcription factors c-Myc and hypoxia-inducible factor 1 alpha. However, the inhibitory effects of metformin on T cells did not depend on the expression of AMPK in T cells. Accordingly, experiments with metformin inform about the importance of metabolic reprogramming for T cell immune responses but do not inform about the importance of AMPK