Maternal ethnic group and pregnancy anthropometrics in the development of maternal and infant health outcomes

Ph. D. ThesisAim: To investigate associations between pregnancy outcomes, South Asian ethnicity and pre-/early-pregnancy maternal anthropometrics (MA) and gestational anthropometric change (GAC). Methods: A mixed methods approach was used to develop an evidence-based conceptual model of associations between outcomes and MA/GAC, involving: a systematic review, a framework-based synthesis and expert opinion. The conceptual model was tested using the Born in Bradford cohort data for Pakistani and White women. Regression models were used to investigate associations, adjusting for socio-demographic, behavioural and clinical factors. Results: The evidence-based conceptual model hypothesised that gestational diabetes (GDM), hypertensive disorders of pregnancy (HDP), mode of delivery, maternal mortality, birth weight, gestational age at delivery, stillbirth, perinatal mortality, post-partum IGT, PPWR, breastfeeding, infant anthropometrics and maternal and child blood pressure in the longer term were associated with MA and GAC. Pakistani women had significantly increased odds of GDM (Adjusted odds ratio (AOR) 1.08 (95%CI 1.06-1.11), HDP (AOR 1.11 (95%CI 1.08-1.15), Cesarean-section (AOR 1.05 (95%CI 1.01-1.08)), and induction (AOR 1.07 (95%CI 1.05-1.09)), and increased birth weight (adjusted coefficients; 13.77g (95%CI 9.24-18.30) associated with increasing BMI. With increasing GWG, birth weight increased for Pakistani women (adjusted coefficients; 22.92g (95%CI 18.07-27.78)). Significant interactions were identified for BMI and ethnicity on GDM (p=0.045), pre-term birth (p=0.049) following adjustment. There were no significant interactions between GWG and ethnicity on other pregnancy outcomes following adjustment. This was also true when using Asian-specific BMI criteria to calculate GWG. Conclusion: There were ethnic differences in the shape of the association between BMI and GDM, and pre-term birth, following adjustment. In this cohort, there was no evidence of an ethnic difference in the association between any pregnancy outcome investigated and GWG following adjustment. More research is needed to investigate additional measures of GAC, and using other datasets looking at all South Asian subgroups.MRC, Faculty of Medical Sciences Newcastle Universit

The mucosal firewalls against commensal intestinal microbes

Mammals coexist with an extremely dense microbiota in the lower intestine. Despite the constant challenge of small numbers of microbes penetrating the intestinal surface epithelium, it is very unusual for these organisms to cause disease. In this review article, we present the different mucosal firewalls that contain and allow mutualism with the intestinal microbiot

Functional Flexibility of Intestinal IgA – Broadening the Fine Line

Intestinal bacteria outnumber our own human cells in conditions of both health and disease. It has long been recognized that secretory antibody, particularly IgA, is produced in response to these microbes and hypothesized that this must play an important role in defining the relationship between a host and its intestinal microbes. However, the exact role of IgA and the mechanisms by which IgA can act are only beginning to be understood. In this review we attempt to unravel the complex interaction between so-called “natural,” “primitive” (T-cell-independent), and “classical” IgA responses, the nature of the intestinal microbiota/intestinal pathogens and the highly flexible dynamic homeostasis of the mucosal immune system. Such an analysis reveals that low-affinity IgA is sufficient to protect the host from excess mucosal immune activation induced by harmless commensal microbes. However, affinity-maturation of “classical” IgA is essential to provide protection from more invasive commensal species such as segmented filamentous bacteria and from true pathogens such as Salmonella typhimurium. Thus a correlation is revealed between “sophistication” of the IgA response and aggressiveness of the challenge. A second emerging theme is that more-invasive species take advantage of host inflammatory mechanisms to more successfully compete with the resident microbiota. In many cases, the function of IgA may be to limit such inflammatory responses, either directly by coagulating or inhibiting virulence of bacteria before they can interact with the host or by modulating immune signaling induced by host recognition. Therefore IgA appears to provide an added layer of robustness in the intestinal ecosystem, promoting “commensal-like” behavior of its residents

The association between maternal body mass index and child obesity : a systematic review and meta-analysis

Funding: ES is a PhD student funded by the Medical Research Council (reference MR/K501396/1, https://mrc.ukri.org/). AP is a PhD student funded by the Economic and Social Research Council (reference 160149300, https://www.ninedtp.ac.uk/). ZA is a PhD student funded by Newcastle University Research Excellence Academy (https://www.ncl.ac.uk). NH is funded by a National Institute of Health Research Career Development Fellowship (reference CDF-2018-11-ST2-011, https://www.nihr.ac.uk/our-research-community/NIHR-academy). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments The authors would like to acknowledge Shannon Robalino (information scientist) for support in developing search strategies for database searches, and the authors who responded to our correspondence about additional data required for the meta-analysis. Authors who responded to our correspondence and provided the data requested were Dr Aline Andres, Professor Patrick Catalano, Dr Romy Gaillard, Professor Dana Dabelea, Dr Ai Kubo, Professor David Taylor-Robinson, Dr Sophie Wickham, Professor Christine Olson, and Dr Stephen Weng. Authors who responded to our correspondence but were unable to provide data were Zoe Bider-Canfield, Dr Claire Margerison-Zilko, Professor Juliana Kain, Dr Marieke de Hoog, and Professor Aaron Caughey.Peer reviewedPublisher PD

Microbiota colonization tunes the antigen threshold of microbiota-specific T cell activation in the gut

Harnessing the potential of commensal bacteria for immunomodulatory therapy in the gut requires the identification of conditions that modulate immune activation towards incoming colonizing bacteria. In this study, we used the commensal Bacteroides thetaiotaomicron (B.theta) and combined it with B.theta-specific transgenic T cells, in the context of defined colonization of gnotobiotic and immunodeficiency mouse models, to probe the factors modulating bacteria-specific T cell activation against newly colonizing bacteria. After colonizing germ-free (GF) and conventionally raised (SPF) mice with B.theta, we only observed proliferation of B.theta-specific T cells in GF mice. Using simple gnotobiotic communities we could further demonstrate that T-cell activation against newly colonizing gut bacteria is restricted by previous bacteria colonization in GF mice. However, this restriction requires a functional adaptive immune system as Rag1$^{-/-}$ allowed B.theta-specific T cell proliferation even after previous colonization. Interestingly, this phenomenon seems to be dependent on the type of TCR-transgenic model used. B.theta-specific transgenic T cells also proliferated after gut colonization with an E.coli strain carrying the B.theta-specific epitope. However, this was not the case for the SM-1 transgenic T cells as they did not proliferate after similar gut colonization with an E.coli strain expressing the cognate epitope. In summary, we found that activation of T cells towards incoming bacteria in the gut is modulated by the influence of colonizing bacteria on the adaptive immune system of the host

User-centered development of a Virtual Research Environment to support collaborative research events

This paper discusses the user-centred development process within the Collaborative Research Events on the Web (CREW) project, funded under the JISC Virtual Research Environments (VRE) programme. After presenting the project, its aims and the functionality of the CREW VRE, we focus on the user engagement approach, grounded in the method of co-realisation. We describe the different research settings and requirements of our three embedded user groups and the respective activities conducted so far. Finally we elaborate on the main challenges of our user engagement approach and end with the project’s next steps

A computational framework for generating patient-specific vascular models and assessing uncertainty from medical images

Patient-specific computational modeling is a popular, non-invasive method to answer medical questions. Medical images are used to extract geometric domains necessary to create these models, providing a predictive tool for clinicians. However, in vivo imaging is subject to uncertainty, impacting vessel dimensions essential to the mathematical modeling process. While there are numerous programs available to provide information about vessel length, radii, and position, there is currently no exact way to determine and calibrate these features. This raises the question, if we are building patient-specific models based on uncertain measurements, how accurate are the geometries we extract and how can we best represent a patient's vasculature? In this study, we develop a novel framework to determine vessel dimensions using change points. We explore the impact of uncertainty in the network extraction process on hemodynamics by varying vessel dimensions and segmenting the same images multiple times. Our analyses reveal that image segmentation, network size, and minor changes in radius and length have significant impacts on pressure and flow dynamics in rapidly branching structures and tapering vessels. Accordingly, we conclude that it is critical to understand how uncertainty in network geometry propagates to fluid dynamics, especially in clinical applications.Comment: 21 pages, 9 figure

ATP released by intestinal bacteria limits the generation of protective IgA against enteropathogens

T cell dependent secretory IgA (SIgA) generated in the Peyer’s patches (PPs) of the small intestine shapes a broadly diverse microbiota that is crucial for host physiology. The mutualistic co-evolution of host and microbes led to the relative tolerance of host’s immune system towards commensal microorganisms. The ATP-gated ionotropic P2X7 receptor limits T follicular helper (Tfh) cells expansion and germinal center (GC) reaction in the PPs. Here we show that transient depletion of intestinal ATP can dramatically improve high-affinity IgA response against both live and inactivated oral vaccines. Ectopic expression of Shigella flexneri periplasmic ATP-diphosphohydrolase (apyrase) abolishes ATP release by bacteria and improves the specific IgA response against live oral vaccines. Antibody responses primed in the absence of intestinal extracellular ATP (eATP) also provide superior protection from enteropathogenic infection. Thus, modulation of eATP in the small intestine can affect highaffinity IgA response against gut colonizing bacteria

APAF1 is a key transcriptional target for p53 in the regulation of neuronal cell death

p53 is a transcriptional activator which has been implicated as a key regulator of neuronal cell death after acute injury. We have shown previously that p53-mediated neuronal cell death involves a Bax-dependent activation of caspase 3; however, the transcriptional targets involved in the regulation of this process have not been identified. In the present study, we demonstrate that p53 directly upregulates Apaf1 transcription as a critical step in the induction of neuronal cell death. Using DNA microarray analysis of total RNA isolated from neurons undergoing p53-induced apoptosis a 5–6-fold upregulation of Apaf1 mRNA was detected. Induction of neuronal cell death by camptothecin, a DNA-damaging agent that functions through a p53-dependent mechanism, resulted in increased Apaf1 mRNA in p53-positive, but not p53-deficient neurons. In both in vitro and in vivo neuronal cell death processes of p53-induced cell death, Apaf1 protein levels were increased. We addressed whether p53 directly regulates Apaf1 transcription via the two p53 consensus binding sites in the Apaf1 promoter. Electrophoretic mobility shift assays demonstrated p53–DNA binding activity at both p53 consensus binding sequences in extracts obtained from neurons undergoing p53-induced cell death, but not in healthy control cultures or when p53 or the p53 binding sites were inactivated by mutation. In transient transfections in a neuronal cell line with p53 and Apaf1 promoter–luciferase constructs, p53 directly activated the Apaf1 promoter via both p53 sites. The importance of Apaf1 as a p53 target gene in neuronal cell death was evaluated by examining p53-induced apoptotic pathways in primary cultures of Apaf1-deficient neurons. Neurons treated with camptothecin were significantly protected in the absence of Apaf1 relative to those derived from wild-type littermates. Together, these results demonstrate that Apaf1 is a key transcriptional target for p53 that plays a pivotal role in the regulation of apoptosis after neuronal injury