Ektoras X Georgiou

Inflammation drives atherosclerosis. Both immune and resident vascular cell types are involved in the development of atherosclerotic lesions. The phenotype and function of these cells are key in determining the development of lesions. Toll-like receptors are the most characterised innate immune receptors and are responsible for the recognition of exogenous conserved motifs on pathogens, and, potentially, some endogenous molecules. Both endogenous and exogenous TLR agonists may be present in atherosclerotic plaques. Engagement of toll-like receptors on immune and resident vascular cells can affect atherogenesis as signalling downstream of these receptors can elicit proinflammatory cytokine release, lipid uptake, and foam cell formation and activate cells of the adaptive immune system. In this paper, we will describe the expression of TLRs on immune and resident vascular cells, highlight the TLR ligands that may act through TLRs on these cells, and discuss the consequences of TLR activation in atherosclerosis.

BACKGROUND: Endometriosis is known to have an impact on fertility and it is common for women affected by endometriosis to require fertility treatments, including in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI), to improve the chance of pregnancy. It has been postulated that long-term gonadotrophin-releasing hormone (GnRH) agonist therapy prior to IVF or ICSI can improve pregnancy outcomes. This systematic review supersedes the previous Cochrane Review on this topic (Sallam 2006). OBJECTIVES: To determine the effectiveness and safety of long-term gonadotrophin-releasing hormone (GnRH) agonist therapy (minimum 3 months) versus no pretreatment or other pretreatment modalities, such as long-term continuous combined oral contraception (COC) or surgical therapy of endometrioma, before standard in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) in women with endometriosis. SEARCH METHODS: We searched the following electronic databases from their inception to 8 January 2019: Cochrane Gynaecology and Fertility Specialised Register of Controlled Trials, CENTRAL via the Cochrane CENTRAL Register of Studies ONLINE (CRSO), MEDLINE, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL). We searched trial registries to identify unpublished and ongoing trials. We also searched DARE (Database of Abstracts of Reviews of Effects), Web of Knowledge, OpenGrey, Latin American and Caribbean Health Science Information Database (LILACS), PubMed, Google and reference lists from relevant papers for any other relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) involving women with surgically diagnosed endometriosis that compared use of any type of GnRH agonist for at least three months before an IVF/ICSI protocol to no pretreatment or other pretreatment modalities, specifically use of long-term continuous COC (minimum of 6 weeks) or surgical excision of endometrioma within six months prior to standard IVF/ICSI. The primary outcomes were live birth rate and complication rate per woman randomised. DATA COLLECTION AND ANALYSIS: statistic. We assessed the quality of evidence using GRADE criteria. MAIN RESULTS: = 0%; very low-quality evidence). Long-term GnRH agonist therapy versus long-term continuous COC No studies reported on this comparison. Long-term GnRH agonist therapy versus surgical therapy of endometrioma No studies reported on this comparison. AUTHORS' CONCLUSIONS: This review raises important questions regarding the merit of long-term GnRH agonist therapy compared to no pretreatment prior to standard IVF/ICSI in women with endometriosis. Contrary to previous findings, we are uncertain as to whether long-term GnRH agonist therapy impacts on the live birth rate or indeed the complication rate compared to standard IVF/ICSI. Further, we are uncertain whether this intervention impacts on the clinical pregnancy rate, multiple pregnancy rate, miscarriage rate, mean number of oocytes and mean number of embryos. In light of the paucity and very low quality of existing data, particularly for the primary outcomes examined, further high-quality trials are required to definitively determine the impact of long-term GnRH agonist therapy on IVF/ICSI outcomes, not only compared to no pretreatment, but also compared to other proposed alternatives to endometriosis management.

OBJECTIVE: To analyse the outcome of referrals for external cephalic version (ECV). DESIGN: Retrospective cohort study of prospectively collected data. SETTING: Major university hospital, UK. SAMPLE: Women with non-cephalic presentation at term and no prior caesarean, referred to a specialist clinic. METHODS: Details of referrals, ECV attempts, and perinatal outcomes were prospectively collected and analysed. Multivariate binary logistic regression models were created to determine independent predictors of ECV success, reversion, and spontaneous version. MAIN OUTCOME MEASURES: External cephalic version success rates, predictors of success and cephalic presentation at birth, and perinatal outcomes. RESULTS: Three thousand eight had confirmed breech presentation; 2614 women underwent ECV. Ineligibility for ECV occurred in 117 breech presentations (3.9%), and 297 eligible women (10.2%) declined it. ECV was successful in 1280 (49.0%, 95% CI 47.0-50.9%) (40% in nulliparous women; 64% in others); 1234 (97.3%) were cephalic at birth. Spontaneous version after failure occurred in 4.3% and was more common in multiparas (aOR 2.47, 95% CI 1.43-4.26) and those with a posterior fetal back (aOR 6.09, 95% CI 1.90-19.53). Reversion after successful ECV occurred in 2.2%. In women with a successful ECV whose fetus remained cephalic at birth, 85.7% delivered vaginally. The corrected perinatal mortality of the ECV cohort was 0.12%. CONCLUSION: External cephalic version has a low complication rate and is effective for most breech presentations, enabling vaginal birth and avoiding caesarean section. TWEETABLE ABSTRACT: External cephalic version can safely be performed with most breech presentations.

Progesterone is widely used to prolong gestation in women at risk of preterm labour (PTL), and acts at least in part via the inhibition of inflammatory cytokine-induced prostaglandin synthesis. This study investigates the mechanisms responsible for this inhibition in human myometrial cells. We used reporter constructs to demonstrate that interleukin 1beta (IL-1b) inhibits progesterone driven PRE activation via p65 activation and that IL-1b reduced progesterone driven gene expression (FKBP5). Conversely, we found that the activity of a p65-driven NFkB reporter construct was reduced by overexpression of progesterone receptor B (PRB) alone and that this was enhanced by the addition of MPA and that both MPA and progesterone suppressed IL-1b-driven cyclo-oxygenase-2 (COX-2) expression. We found that over-expressed Halo-tagged PRB, but not PRA, bound to p65 and that in IL-1b-treated cells, with no overexpression of either PR or p65, activated p65 bound to PR. However, we found that the ability of MPA to repress IL-1b-driven COX-2 expression was not enhanced by overexpression of either PRB or PRA and that although the combined PR and GR antagonist Ru486 blocked the effects of progesterone and MPA, the specific PR antagonist, Org31710, did not, suggesting that progesterone and MPA act via GR and not PR. Knockdown using siRNA confirmed that both MPA and progesterone acted via GR and not PR or AR to repress IL-1b-driven COX-2 expression. We conclude that progesterone acts via GR to repress IL-1b-driven COX-2 activation and that although the interaction between p65 and PRB may be involved in the repression of progesterone driven gene expression it does not seem to be responsible for progesterone repression of IL-1b-induced COX-2 expression.