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Search Results: 1 - 10 of 194986 matches for " Murray D Mitchell "
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Novel Insights into the Control of Human Pregnancy: Potential Role(s) for Epigenetic Regulation
Roger J. Lins and Murray D. Mitchell
Reproductive Biology Insights , 2012,
Abstract: The appropriate modulation of gene expression in gestational tissues is an essential requirement for a successful pregnancy. Epigenetic control of gene expression through the reversible modification of chromatin has emerged as a fundamental mechanism for the coordination of gene expression in a range of biological systems. Here we summarize recent results in support of our hypothesis that key physiological events and pathological processes occurring throughout human pregnancy are under epigenetic control.
Developmental origins of health and disease: reducing the burden of chronic disease in the next generation
Peter D Gluckman, Mark A Hanson, Murray D Mitchell
Genome Medicine , 2010, DOI: 10.1186/gm135
Abstract: The concept of developmental origins of health and disease is predicated upon the assumption that environmental factors acting early in life (usually in fetal life) have profound effects on vulnerability to disease later in life, often in adulthood. The range of experimental, clinical and epidemiological data linking conditions in early life to later health is now overwhelming [1]. Initially, the focus was on a small fraction of children -those who were born small - but it is now clear that the environment impacts on the development of every child [2]. Observations and experimental approaches have generally considered nutritional changes or, classically, alterations in glucocorticosteroid exposure, reflecting the critical maturational events linked to such events. Indeed, the placenta is in a critical position to cause or modify such challenges by altering nutritional transport functions or the pattern and nature of endocrine signals impacting the fetus. Nor does the story end at birth, because epigenetic development can be influenced by how the infant is fed, and perhaps how its gut is colonized with commensal bacteria.Yet there has been considerable resistance to these ideas. Medicine is replete with reductionist biomedical thinking and this has, in some ways, limited not only our understanding but also our ability to address the challenge of some contemporary health problems. Nowhere is this clearer than in the outcomes of genome-wide association studies where, despite substantial investment, only a relatively small proportion of risk of common non-communicable diseases (NCDs) - such as cardiovascular disease and diabetes - is explained [3]. The economic and humanitarian costs of NCDs are enormous in both the developed and the developing world, and indeed they may destabilize the economies of low-income countries where recent data show that risk markers for these diseases become evident early in the process of socioeconomic improvement, and well below the level o
Epigenetic Regulation of Cytokine Production in Human Amnion and Villous Placenta
Murray D. Mitchell,Anna P. Ponnampalam,Gregory E. Rice
Mediators of Inflammation , 2012, DOI: 10.1155/2012/159709
Abstract: The mechanisms of human preterm labour appear inextricably linked to cytokine biosynthesis by gestational tissues. In turn, cytokine production by gestational tissues has been shown to be regulated by epigenetic mechanisms. In this paper, we demonstrate that cytokine production in gestational tissues is regulated epigenetically in a tissue-specific manner. Furthermore, we show that treatment with a histone deacetylation inhibitor can partially abrogate LPS-stimulated TNFα production in villous placenta but not amnion. LPS treatment significantly (<0.05) increased the production of IL-1β (~10–34-fold), TNFα (~23–>100-fold) and IL10 (~6–10-fold) after 24 h of treatment in villous explants, as expected. There were no significant LPS effects on IL1Ra production. AZA treatment did not have any significant effect on any cytokines' production tested either alone or in combination with LPS. Interestingly, however, the stimulatory effects of LPS on TNFα production were partially mitigated (<0.05) by TSA treatment in villous explants. We suggest caution in the consideration of histone deacetylation inhibitors in pregnancy due to the different responses in gestational tissues.
Gestational Diabetes Mellitus: A Positive Predictor of Type 2 Diabetes?
Gregory E. Rice,Sebastian E. Illanes,Murray D. Mitchell
International Journal of Endocrinology , 2012, DOI: 10.1155/2012/721653
Abstract: The aim of this paper is to consider the relative benefits of screening for type two diabetes mellitus in women with a previous pregnancy complicated by gestational diabetes mellitus. Recent studies suggest that women who experience GDM are at a greater risk of developing type 2 diabetes within 10–20 years of their index pregnancy. If considered as a stand-alone indicator of the risk of developing type 2 diabetes, GDM is a poor diagnostic test. Most women do not develop GDM during pregnancy and of those that do most do not develop type 2 diabetes. There is, however, a clear need for better early detection of predisposition to disease and/or disease onset to significantly impact on this global pandemic. The putative benefits of multivariate approaches and first trimester and preconception screening to increase the sensitivity of risk assignment modalities for type 2 diabetes are proposed. 1. Introduction The keystone to improving disease management and health outcomes remains the early and accurate diagnosis of the predisposition to, or onset of, disease. Early detection of disease risk and onset is the first step in implementing efficacious treatment and improving patient outcomes. In the context of screening for prediabetic and diabetic conditions in asymptomatic individuals, early detection may allow the implementation of dietary, lifestyle, and/or pharmacologic interventions that limit or prevent the development of disease-specific pathophysiologies. The rationale for seeking to develop predictive tests for diabetes and other metabolic disorders, thus, is clearly evident. Recent studies suggest that women who experience gestational diabetes mellitus (GDM) are at a greater risk of developing type 2 diabetes mellitus (type 2 diabetes) within 10–20 years of their index pregnancy [1]. Monitoring glycemic control and intervention strategies to delay or prevent disease onset have been advocated in such women. Type 2 diabetes, however, is a disease of heterogeneous aetiology and GDM is but one risk factor. If considered as a stand-alone indicator of the risk of developing type 2 diabetes, GDM is a poor diagnostic test. Most women do not develop GDM during pregnancy and of those that do most do not develop type 2 diabetes. Postpartum monitoring of women who developed GDM during pregnancy, nevertheless, may be of clinical utility in this higher risk cohort. There is, however, a clear need for better early detection of predisposition to disease and/or disease onset to significantly impact on this global pandemic. For women (and their partners), pregnancy
Modulation of the maternal immune system by the pre-implantation embryo
Caroline G Walker, Susanne Meier, Mathew D Littlejohn, Klaus Lehnert, John R Roche, Murray D Mitchell
BMC Genomics , 2010, DOI: 10.1186/1471-2164-11-474
Abstract: Microarray analyses revealed 1,839 and 1,189 differentially expressed transcripts between pregnant and cyclic animals (with ≥ 1.5 fold change in expression; P-value < 0.05, MTC Benjamini-Hochberg) in caruncular and intercaruncular endometrium respectively. Gene ontology and biological pathway analysis of differentially expressed genes revealed enrichment for genes involved in interferon signalling and modulation of the immune response in pregnant animals.The maternal immune system actively surveys the uterine environment during early pregnancy. The embryo modulates this response inducing the expression of endometrial molecules that suppress the immune response and promote maternal tolerance to the embryo. During this period of local immune suppression, genes of the innate immune response (in particular, antimicrobial genes) may function to protect the uterus against infection.Over the past three decades, there has been a coincidental decline in fertility associated with genetic selection for increased milk production. It is estimated that approximately 50% of the potential profitability from genetic selection for milk production is lost due to a reduction in fertility [1].The fertilisation rate for lactating dairy cattle is around 90% and does not differ between low-moderate and high-producing animals when managed under pastoral conditions[2]. However, the calving rate in lower producing animals is approximately 55%, whereas for high-producing animals, this rate is approximately 35%[2]. Pregnancy losses are thought to occur primarily during the pregnancy recognition/pre-implantation period [2], making studies of endometrial gene expression critical to further understanding of pregnancy establishment, recognition and maintenance within the bovine reproductive cycle.Successful pregnancy in mammals requires both a viable embryo and a receptive endometrium. Synchronous signalling between the endometrium and embryo during the pre-implantation period is critical for norma
Evaluation of real-time PCR endogenous control genes for analysis of gene expression in bovine endometrium
Caroline G Walker, Susanne Meier, Murray D Mitchell, John R Roche, Mathew Littlejohn
BMC Molecular Biology , 2009, DOI: 10.1186/1471-2199-10-100
Abstract: The expression profiles of five commonly used endogenous control genes (GAPDH, PPIA, RPS9, RPS15A, and UXT) and 10 experimentally derived candidate endogenous control genes (SUZ12, C2ORF29, ZNF131, ACTR1A, HDAC1, SLC30A6, CNOT7, DNAJC17, BBS2, and RANBP10) were analysed across 44 samples to determine the most stably expressed gene. Gene stability was assessed using the statistical algorithms GeNorm and Normfinder. All genes presented with low overall variability (0.87 to 1.48% CV of Cq). However, when used to normalise a differentially expressed gene (oxytocin receptor - OXTR) in the samples, the reported relative gene expression levels were significantly affected by the control gene chosen. Based on the results of this analysis, SUZ12 is proposed as the most appropriate control gene for use in bovine endometrium during early pregnancy or the oestrus cycle.This study establishes the suitability of novel endogenous control genes for comparing expression levels in endometrial tissues of pregnant and cycling bovines, and demonstrates the utility of microarray analysis as a method for identifying endogenous control gene candidates.Quantitative real-time reverse transcription PCR (RT-PCR) is an extremely sensitive technique that allows the precise measurement of gene expression across more than seven orders of magnitude[1,2]. RT-PCR is often considered the gold standard for quantifying gene expression, and is commonly used to validate techniques with greater throughput but less overall sensitivity, such as microarray analysis [3-5]. RT-PCR relies on the use of fluorescent dyes to quantify transcript amplification, with the amplification cycle number at which these dyes/transcripts are detected (above background) giving an indication as to the relative abundance of the target molecules. The sensitivity of RT-PCR makes it a powerful tool for gene expression measurement, especially when sample quantities are limited or a transcript is expressed at a low level. However, this
Brief Communication: Sexual dimorphic expression of myostatin and follistatin like-3 in a rat trans-generational under-nutrition model
Hassendrini N Peiris, Anna P Ponnampalam, Murray D Mitchell, Mark P Green
Nutrition & Metabolism , 2010, DOI: 10.1186/1743-7075-7-44
Abstract: Myostatin initially designated as growth differentiation factor 8 (GDF-8), is a distinctive member of the TGF-β super-family, retaining many of the characteristic features found in this family [1]. The functional importance of myostatin is inferred by the high level of sequence homology and conservation seen across a number of species. Synthesized as a precursor protein, myostatin is proteolytically cleaved twice to release the biologically mature form of myostatin, with dimerisation of the mature protein creating the active form of myostatin [1]. The binding of the myostatin dimer to its receptor (ActRIIB) initiates the Smad mediated signaling pathway, which results in the transcription and expression of genes needed to mediate the negative regulation of muscle development. Myostatin function is controlled by a number of inhibitors, the most potent being follistatin like-3 (FSTL-3) [2].Myostatin was initially identified as a negative regulator of muscle development where its inactivation in mice resulted in offspring with a two to three-fold increase in muscle mass [3]. Subsequently, myostatin was identified to affect glucose uptake in the human placenta [4]. Recently, altered placenta myostatin concentrations were identified in developmentally programmed rat model that supports a role as a mediator of this phenomenon [5]. Myostatin has also been shown to be crucial in the modulation of glucose homeostasis and adipogenesis [6,7]. The aim of this study was to utilise a model of trans-generational maternal under-nutrition to investigate potential sexual dimorphic changes in the expression of myostatin and FSTL-3 in rat skeletal muscle.The animal model depicted (Figure 1) was based upon an established model of under-nutrition [8-10]. Briefly, virgin female Wistar rats (F0) reared on an ad libitum (AD) standard chow diet (2018 Teklad Global Rodent Diet; Bicester, UK) were mated at D120 ± 5 of age with males also fed an AD standard chow diet. Following confirmation of m
Update on the Surgical Trial in Lobar Intracerebral Haemorrhage (STICH II): statistical analysis plan
Gregson Barbara A,Murray Gordon D,Mitchell Patrick M,Rowan Elise N
Trials , 2012, DOI: 10.1186/1745-6215-13-222
Abstract: Background Previous studies had suggested that the outcome for patients with spontaneous lobar intracerebral haemorrhage (ICH) and no intraventricular haemorrhage (IVH) might be improved with early evacuation of the haematoma. The Surgical Trial in Lobar Intracerebral Haemorrhage (STICH II) set out to establish whether a policy of earlier surgical evacuation of the haematoma in selected patients with spontaneous lobar ICH would improve outcome compared to a policy of initial conservative treatment. It is an international, multi-centre, prospective randomised parallel group trial of early surgery in patients with spontaneous lobar ICH. Outcome is measured at six months via a postal questionnaire. Results Recruitment to the study began on 27 November 2006 and closed on 15 August 2012 by which time 601 patients had been recruited. The protocol was published in Trials (http://www.trialsjournal.com/content/12/1/124/). This update presents the analysis plan for the study without reference to the unblinded data. The trial data will not be unblinded until after follow-up is completed in early 2013. The main trial results will be presented in spring 2013 with the aim to publish in a peer-reviewed journal at the same time. Conclusion The data from the trial will provide evidence on the benefits and risks of early surgery in patients with lobar ICH. Trial registration ISRCTN: ISRCTN22153967
Hypoxia-Induced Changes in the Bioactivity of Cytotrophoblast-Derived Exosomes
Carlos Salomon, Miharu Kobayashi, Keith Ashman, Luis Sobrevia, Murray D. Mitchell, Gregory E. Rice
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079636
Abstract: Migration of extravillous trophoblasts (EVT) into decidua and myometrium is a critical process in the conversion of maternal spiral arterioles and establishing placenta perfusion. EVT migration is affected by cell-to-cell communication and oxygen tension. While the release of exosomes from placental cells has been identified as a significant pathway in materno-fetal communication, the role of placental-derived exosomes in placentation has yet to be established. The aim of this study was to establish the effect of oxygen tension on the release and bioactivity of cytotrophoblast (CT)-derived exosomes on EVT invasion and proliferation. CT were isolated from first trimester fetal tissue (n = 12) using a trypsin-deoxyribonuclease-dispase/Percol?lmethod. CT were cultured under 8%, 3% or 1% O2 for 48 h. Exosomes from CT-conditioned media were isolated by differential and buoyant density centrifugation. The effect of oxygen tension on exosome release (μg exosomal protein/106cells/48 h) and bioactivity were established. HTR-8/SVneo (EVT) were used as target cells to establish the effect (bioactivity) of exosomes on invasion and proliferation as assessed by real-time, live-cell imaging (Incucyte?). The release and bioactivity of CT-derived exosomes were inversely correlated with oxygen tension (p<0.001). Under low oxygen tensions (i.e. 1% O2), CT-derived exosomes promoted EVT invasion and proliferation. Proteomic analysis of exosomes identified oxygen-dependent changes in protein content. We propose that in response to changes in oxygen tension, CTs modify the bioactivity of exosomes, thereby, regulating EVT phenotype. Exosomal induction of EVT migration may represent a normal process of placentation and/or an adaptive response to placental hypoxia.
Nipple aspiration and ductal lavage in women with a germline BRCA1 or BRCA2 mutation
Gillian Mitchell, Yoland C Antill, William Murray, Judy Kirk, Elizabeth Salisbury, Geoffrey J Lindeman, Juliana Di Iulio, Alvin D Milner, Lisa Devereaux, Kelly-Anne Phillips
Breast Cancer Research , 2005, DOI: 10.1186/bcr1348
Abstract: Between March 2003 and February 2005, 52 women with germline BRCA1 or BRCA2 mutations (median age 43 years, range 27 to 65 years) were scheduled for six-monthly NA, DL and venesection. DL was attempted for all NA fluid-yielding (FY) and any non-FY ducts that could be located at each visit.Twenty-seven (52%) women were postmenopausal, predominantly (19/27) from risk reducing bilateral salpingo-oophorectomy (BSO). FY ducts were identified in 60% of all women, 76% of premenopausal women versus 44% of postmenopausal (P = 0.026). Eighty-five percent of women had successful DL. Success was most likely in women with FY ducts (FY 94% versus non-FY 71% (P = 0.049). DL samples were more likely to be cellular if collected from FY ducts (FY 68% versus non-FY 43%; P = 0.037). Total cell counts were associated with FY status (FY median cell count 30,996, range 0 to >1,000,000 versus non-FY median cell count 0, range 0 to 173,577; P = 0.002). Four women (8%) had ducts with severe atypia with or without additional ducts with mild epithelial atypia; seven others had ducts with mild atypia alone (11/52 (21%) in total). Median total cell count was greater from ducts with atypia (105,870, range 1920 to >1,000,000) than those with no atypia (174, 0 to >1,000,000; P ≤ 0.001).It is feasible to collect serial NA and DL samples from women at high genetic risk of breast cancer, and we are creating a unique, prospective collection of ductal samples that have the potential to be used for discovery of biomarkers of breast cancer risk and evaluate the ongoing effects of risk reducing BSO. DL cellular atypia was not predictive of a current breast cancer and longer follow up is needed to determine whether atypia is an additional marker of future breast cancer risk in this population already at high genetic risk of breast cancer.Germline BRCA1 or BRCA2 mutations are associated with a markedly increased lifetime risk of developing breast cancer [1,2] in female carriers. Not all mutation carriers dev
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