TGF beta 1 attenuates expression of prolactin and IGFBP-1 in decidualized endometrial stromal cells by both SMAD-dependent and SMAD-independent pathways

Background: Decidualization (differentiation) of the endometrial stromal cells during the secretory phase of the menstrual cycle is essential for successful implantation. Transforming Growth Factor beta 1 (TGF beta 1) canonically propagates its actions via SMAD signalling. A role for TGF beta 1 in decidualization remains to be established and published data concerning effects of TGF beta 1 on markers of endometrial decidualization are inconsistent. Methodology/Principal Findings: Non-pregnant endometrial stromal cells (ESC) and first trimester decidual stromal cells (DSC) were cultured in the presence or absence of a decidualizing stimulus. Incubation of ESCs with TGF beta 1 (10 ng/ml) down-regulated the expression of transcripts encoding the decidual marker proteins prolactin (PRL), insulin-like growth factor binding protein-1 (IGFBP-1) and tissue factor (TF). TGF beta 1 also inhibited secretion of PRL and IGFBP-1 proteins by ESCs and surprisingly this response preceded down-regulation of their mRNAs. In contrast, DSCs were more refractory to the actions of TGF beta 1, characterized by blunted and delayed down-regulation of PRL, IGFBP-1, and TF transcripts, which was not associated with a significant reduction in secretion of PRL or IGFBP-1 proteins. Addition of an antibody directed against TGF beta 1 increased expression of IGFBP-1 mRNA in decidualised cells. Knockdown of SMAD 4 using siRNAs abrogated the effect of TGF beta 1 on expression of PRL in ESCs but did not fully restore expression of IGFBP-1 mRNA and protein. Conclusions/Significance: TGF beta 1 inhibits the expression and secretion of decidual marker proteins. The impact of TGF beta 1 on PRL is SMAD-dependent but the impact on IGFBP1 is via an alternative mechanism. In early pregnancy, resistance of DSC to the impact of TGF beta 1 may be important to ensure tissue homeostasis

Development of Soft-Hardware Platform for Training System Design of Electrotechnical Complexes and Electric Drives

The article presents the results of the development of software and hardware platform as the equipment for the training of children and youth work skills with robotics, allowing in the future to apply this knowledge in practice, implementing automation system for home use. We consider the problems of existing solutions. The main difference is the integration of the proposed fees and extensions into a single set by connecting the connectors and the ability to connect third-party components from different manufacturers, without limiting users. As well as a simplified method using a visual object-oriented programming allows you to immediately engage in the work. Prepared lessons and tasks in the game style simplifies the information and allows you to understand how you can apply one or another technical solution

GaPP: a pilot randomised controlled trial of the efficacy of action of gabapentin for the management of chronic pelvic pain in women: study protocol

<p><b>Introduction:</b> Chronic pelvic pain (CPP) affects >1 million UK women. Annual healthcare costs are estimated at >£150 million. Proven interventions for CPP are limited, and treatment is often unsatisfactory. Gabapentin is increasingly prescribed due to reports of effectiveness in other chronic pain conditions, but there are insufficient data supporting value in CPP specifically. The mechanism by which gabapentin exerts its analgesic action is unknown. Given the prevalence and costs of CPP, the authors believe that a large, multicentre, placebo-controlled, double-blind randomised controlled trial to evaluate the efficacy of gabapentin in management of CPP is required. The focus of this study is a pilot to inform planning of a future randomised controlled trial.</p> <p><b>Methods and analysis:</b> The authors plan to perform a two-arm, parallel, randomised controlled pilot trial. The authors aim to recruit 60 women with CPP in NHS Lothian and NHS Grampian (UK) and randomise them to gabapentin or placebo. Response to treatment will be monitored by questionnaire compared at 0, 3 and 6 months. The primary objective is to assess recruitment and retention rates. The secondary objectives are to determine the effectiveness and acceptability to participants of the proposed methods of recruitment, randomisation, drug treatments and assessment tools and to perform a pretrial cost-effectiveness assessment of treatment with gabapentin.</p> <p><b>Ethics and dissemination:</b> Ethical approval has been obtained from the Scotland A Research Ethics Committee (LREC 12/SS/0005). Data will be presented at international conferences and published in peer-reviewed journals.</p&gt

Chronic pelvic pain in women: an embedded qualitative study to evaluate the perceived benefits of the meridian balance method electro-acupuncture treatment, health consultation and National Health Service standard care

Ethical approval was granted by the Scotland Research Ethics Committee (REC 14/SS/1022).Trial registration: ClinicalTrials.gov (NCT02295111)Erna Haraldsdottir - orcid: 0000-0002-6451-1374 https://orcid.org/0000-0002-6451-1374Introduction: Chronic pelvic pain (CPP) – defined as intermittent or constant pain in the lower abdomen or pelvis of at least 6 months’ duration, not occurring exclusively with menstruation or intercourse and not associated with pregnancy – is estimated to affect 6–27% of women worldwide. In the United Kingdom, over 1 million women suffer from CPP, which has been highlighted as a key area of unmet need. Current medical treatments for CPP are often associated with unacceptable side effects. A specific style of acupuncture, the meridian balance method electro-acupuncture (BMEA) and traditional Chinese medicine health consultation (TCM HC (BMEA + TCM HC = BMEA treatment)), may be effective for CPP in women. Aim: Three focus group discussions and semi-structured telephone interviews were embedded in a randomised controlled feasibility trial to gain in-depth description of the perceived benefits of the participants’ respective interventions. Methods: Women with CPP were randomised into the BMEA treatment, TCM HC or National Health Service standard care (NHS SC). Focus group discussions were recorded, transcribed and analysed thematically. Semi-structured telephone interviews were conducted post focus group discussions. Findings: A total of 30 women were randomised into BMEA treatment, TCM HC or NHS SC. A total of 11 participants attended the three focus group discussions. Thematic analysis of focus group discussions showed: a perceived pain reduction, enhanced sleep, energy level and sense of well-being in the BMEA treatment and TCM HC groups; a dislike for the adverse effects of medications, frustration at the lack of effective treatment, heavy reliance on medications and services that are helpful, in the NHS SC group. Semi-structured telephone interviews showed that the methodology was acceptable to the participants. Conclusion: The embedded focus group discussions captured the rich and complex narratives of the participants and provided insights into the perceived benefits of the BMEA treatment, TCM HC and NHS SC interventions.The research was partly supported by the Morag Robinson Legacy, the Alexander Dykes Fund and Barbour Watson Trust.13pubpub

Development of a Bayesian response-adaptive trial design for the Dexamethasone for Excessive Menstruation study

It is often unclear what specific adaptive trial design features lead to an efficient design which is also feasible to implement. This article describes the preparatory simulation study for a Bayesian response-adaptive dose-finding trial design. Dexamethasone for Excessive Menstruation aims to assess the efficacy of Dexamethasone in reducing excessive menstrual bleeding and to determine the best dose for further study. To maximise learning about the dose response, patients receive placebo or an active dose with randomisation probabilities adapting based on evidence from patients already recruited. The dose-response relationship is estimated using a flexible Bayesian Normal Dynamic Linear Model. Several competing design options were considered including: number of doses, proportion assigned to placebo, adaptation criterion, and number and timing of adaptations. We performed a fractional factorial study using SAS software to simulate virtual trial data for candidate adaptive designs under a variety of scenarios and to invoke WinBUGS for Bayesian model estimation. We analysed the simulated trial results using Normal linear models to estimate the effects of each design feature on empirical type I error and statistical power. Our readily-implemented approach using widely available statistical software identified a final design which performed robustly across a range of potential trial scenarios

In silico analysis identifies a novel role for androgens in the regulation of human endometrial apoptosis

CONTEXT: The endometrium is a multicellular, steroid-responsive tissue that undergoes dynamic remodeling every menstrual cycle in preparation for implantation and, in absence of pregnancy, menstruation. Androgen receptors are present in the endometrium. OBJECTIVE: The objective of the study was to investigate the impact of androgens on human endometrial stromal cells (hESC). DESIGN: Bioinformatics was used to identify an androgen-regulated gene set and processes associated with their function. Regulation of target genes and impact of androgens on cell function were validated using primary hESC. SETTING: The study was conducted at the University Research Institute. PATIENTS: Endometrium was collected from women with regular menses; tissues were used for recovery of cells, total mRNA, or protein and for immunohistochemistry. RESULTS: A new endometrial androgen target gene set (n = 15) was identified. Bioinformatics revealed 12 of these genes interacted in one pathway and identified an association with control of cell survival. Dynamic androgen-dependent changes in expression of the gene set were detected in hESC with nine significantly down-regulated at 2 and/or 8 h. Treatment of hESC with dihydrotestosterone reduced staurosporine-induced apoptosis and cell migration/proliferation. CONCLUSIONS: Rigorous in silico analysis resulted in identification of a group of androgen-regulated genes expressed in human endometrium. Pathway analysis and functional assays suggest androgen-dependent changes in gene expression may have a significant impact on stromal cell proliferation, migration, and survival. These data provide the platform for further studies on the role of circulatory or local androgens in the regulation of endometrial function and identify androgens as candidates in the pathogenesis of common endometrial disorders including polycystic ovarian syndrome, cancer, and endometriosis

SULFATION PATHWAYS:A role for steroid sulphatase in intracrine regulation of endometrial decidualisation

In women, establishment of pregnancy is dependent upon ‘fine-tuning’ of the endometrial microenvironment, which is mediated by terminal differentiation (decidualisation) of endometrial stromal fibroblasts (ESFs). We have demonstrated that intracrine steroid metabolism plays a key role in regulating decidualisation and is essential for time-dependent expression of key factors required for endometrial receptivity. The primary aim of the current study was to determine whether sulphated steroids can act as precursors to bioactive sex steroids during decidualisation. We used primary human ESF and a robust in vitro model of decidualisation to assess the expression of genes associated with sulphation, desulphation and transport of sulphated steroids in human ESF as well as the impact of the steroid sulphatase (STS) inhibitor STX64 (Irosustat). We found evidence for an increase in both expression and activity of STS in response to a decidualisation stimulus with abrogation of oestrone biosynthesis and decreased secretion of the decidualisation marker IGFBP1 in the presence of STX64. These results provide novel insight into the contribution of STS to the intracrine regulation of decidualisation.</jats:p