Abnormal uterine activity in pregnancy causes a range of important clinical disorders, including preterm birth, dysfunctional labour and post-partum haemorrhage. Uterine contractile patterns are controlled by the generation of complex electrical signals at the myometrial smooth muscle plasma membrane. To identify novel targets to treat conditions associated with uterine dysfunction, we undertook a genome-wide screen of potassium channels that are enriched in myometrial smooth muscle. Computational modelling identified Kir7.1 as potentially important in regulating uterine excitability during pregnancy. We demonstrate Kir7.1 current hyper-polarizes uterine myocytes and promotes quiescence during gestation. Labour is associated with a decline, but not loss, of Kir7.1 expression. Knockdown of Kir7.1 by lentiviral expression of miRNA was sufficient to increase uterine contractile force and duration significantly. Conversely, overexpression of Kir7.1 inhibited uterine contractility. Finally, we demonstrate that the Kir7.1 inhibitor VU590 as well as novel derivative compounds induces profound, long-lasting contractions in mouse and human myometrium; the activity of these inhibitors exceeds that of other uterotonic drugs. We conclude Kir7.1 regulates the transition from quiescence to contractions in the pregnant uterus and may be a target for therapies to control uterine contractility.

Oxytocin receptor (OTR) expression is increased before the onset of labor in all models of parturition. However, the mechanisms responsible for the increase in OTR expression are uncertain. Animal data suggest that uterine stretch increases OTR mRNA expression. In primary cultures of human uterine smooth muscle cells obtained from nonpregnant (NP) women and pregnant women before (NL) and after (L) the onset of labor, we investigated the effect of stretch on the expression of OTR mRNA and DNA binding of activator protein-1 (AP-1), CCAAT/enhancer binding protein (C/EBP)beta, and nuclear factor-kappaB transcription factors. OTR expression was least in NL, intermediate in NP, and greatest in L cells. Stretch of NL cells resulted in up-regulation of OTR mRNA expression associated with increased OTR gene promoter activity. Stretch of NP and L cells did not affect OTR mRNA expression. The increased promoter activity was associated with increased DNA binding of C/EBP and AP-1 but not nuclear factor-kappaB transcription factors. Overexpression of C/EBP, but not AP-1, increased OTR promoter activity. We conclude that stretch of NL cells results in increased OTR mRNA expression probably through increased C/EBPbeta DNA binding. These data suggest that stretch contributes to the massive increase in OTR expression before the onset of human labor.

BackgroundEducating doctors is expensive and poor performance by future graduates can literally cost lives. Whilst the practice of medicine is highly evidence based, medical education is much less so. Research on medical school selection, undergraduate progression, Fitness to Practise (FtP) and postgraduate careers has been hampered across the globe by the challenges of uniting the data required. This paper describes the creation, structure and access arrangements for the first UK-wide attempt to do so.OverviewA collaborative approach has created a research database commencing with all entrants to UK medical schools in 2007 and 2008 (UKMED Phase 1). Here the content is outlined, governance arrangements considered, system access explained, and the potential implications of this new resource discussed. The data currently include achievements prior to medical school entry, admissions tests, graduation point information and also all subsequent data collected by the General Medical Council, including FtP, career progression, annual National Training Survey (NTS) responses, career choice and postgraduate exam performance data. UKMED has grown since the pilot phase with additional datasets; all subsequent years of students/trainees and stronger governance processes. The inclusion of future cohorts and additional information such as admissions scores or bespoke surveys or assessments is now being piloted. Thus, for instance, new scrutiny can be applied to selection techniques and the effectiveness of educational interventions. Data are available free of charge for approved studies from suitable research groups worldwide.ConclusionIt is anticipated that UKMED will continue on a rolling basis. This has the potential to radically change the volume and types of research that can be envisaged and, therefore, to improve standards, facilitate workforce planning and support the regulation of medical education and training. This paper aspires to encourage proposals to utilise this exciting resource.

Oxytocin receptor (OTR) mRNA expression has previously been demonstrated in human myometrium, decidua, chorion and amnion but the effect of gestational age and the onset of labour has not been determined in these individual tissues. Spatial OTR mRNA expression was examined by in situ hybridization and ligand binding was confirmed using autoradiography with the iodinated oxytocin antagonist d(CH 2 ) 5