123 results found
Kindinger L, MacIntyre D, Lee Y, et al., 2016, Cervical cerclage using braided suture induces vaginal dysbiosis, inflammation and is associated with increased rates of preterm birth, Publisher: WILEY-BLACKWELL, Pages: E4-E4, ISSN: 1470-0328
Kindinger LM, Kyrgiou M, MacIntyre DA, et al., 2016, Preterm Birth Prevention Post-Conization: A Model of Cervical Length Screening with Targeted Cerclage, PLOS One, Vol: 11, ISSN: 1932-6203
Women with a history of excisional treatment (conization) for cervical intra-epithelial neoplasia (CIN) are at increased risk of preterm birth, perinatal morbidity and mortality in subsequent pregnancy. We aimed to develop a screening model to effectively differentiate pregnancies post-conization into low- and high-risk for preterm birth, and to evaluate the impact of suture material on the efficacy of ultrasound indicated cervical cerclage. We analysed longitudinal cervical length (CL) data from 725 pregnant women post-conization attending preterm surveillance clinics at three London university Hospitals over a ten year period (2004–2014). Rates of preterm birth <37 weeks after targeted cerclage for CL<25mm were compared with local and national background rates and expected rates for this cohort. Rates for cerclage using monofilament or braided suture material were also compared. Of 725 women post-conization 13.5% (98/725) received an ultrasound indicated cerclage and 9.7% (70/725) delivered prematurely, <37weeks; 24.5% (24/98) of these despite insertion of cerclage. The preterm birth rate was lower for those that had monofilament (9/60, 15%) versus braided (15/38, 40%) cerclage (RR 0.7, 95% CI 0.54 to 0.94, P = 0.008). Accuracy parameters of interval reduction in CL between longitudinal second trimester screenings were calculated to identify women at low risk of preterm birth, who could safely discontinue surveillance. A reduction of CL <10% between screening timepoints predicts term birth, >37weeks. Our triage model enables timely discharge of low risk women, eliminating 36% of unnecessary follow-up CL scans. We demonstrate that preterm birth in women post-conization may be reduced by targeted cervical cerclage. Cerclage efficacy is however suture material-dependant: monofilament is preferable to braided suture. The introduction of triage prediction models has the potential to reduce the number of unnecessary CL scan for women at low risk of
Kindinger LM, MacIntyre DA, Lee YS, et al., 2016, Relationship between vaginal microbial dysbiosis, inflammation and pregnancy outcomes in cervical cerclage, Science Translational Medicine, Vol: 8, ISSN: 1946-6242
Preterm birth, the leading cause of death in children under five, may be caused by inflammation triggered by ascending vaginal infection. About two million cervical cerclages are performed annually to prevent preterm birth. The procedure is thought to provide structural support and maintain the endocervical mucus plug as a barrier to ascending infection. Two types of suture material are used for cerclage: monofilament or multifilament braided. Braided sutures are most frequently used, though no evidence exists to favor them over monofilament sutures. In this study we assessed birth outcomes in a retrospective cohort of 678 women receiving cervical cerclage in 5 UK university hospitals and showed that braided cerclage was associated with increased intrauterine death (15% v 5%, P = 0.0001) and preterm birth (28% v 17%, P = 0.0006) compared to monofilament suture. To understand the potential underlying mechanism, we performed a prospective, longitudinal study of the vaginal microbiome in women at risk of preterm birth because of short cervical length (≤25 mm) who received braided (n=25) or monofilament (n=24) cerclage under otherwise comparable circumstances. Braided suture induced a persistent shift towards vaginal microbiome dysbiosis characterized by reduced Lactobacillus spp. and enrichment of pathobionts. Vaginal dysbiosis was associated with inflammatory cytokine and interstitial collagenase excretion into cervicovaginal fluid and premature cervical remodeling. Monofilament suture had comparatively minimal impact upon the vaginal microbiome and its interactions with the host. These data provide in vivo evidence that a dynamic shift of the human vaginal microbiome toward dysbiosis correlates with preterm birth.
Cook J, MacIntyre D, Sykes L, et al., 2016, Prediction of cervical shortening and preterm delivery using specific cell free plasma microRNAs, Publisher: Wiley, Pages: 59-60, ISSN: 1470-0328
Kindinger L, MacIntyre D, Lee Y, et al., 2016, Cervical cerclage using braided suture induces vaginal dysbiosis, inflammation, and is associated with increased preterm birth, British Maternal & Fetal Medicine Society (BMFMS) 18th Annual Conference 2016, Publisher: Wiley, Pages: 8-8, ISSN: 1470-0328
Cook J, MacIntyre D, Kim SH, et al., 2016, Hsa-miR-146b-3p is functionally modulated by nuclear factor-kappa B in human myometrial cells, British Maternal & Fetal Medicine Society (BMFMS) 18th Annual Conference 2016, Publisher: WILEY-BLACKWELL, Pages: 102-102, ISSN: 1470-0328
Kim SH, Pohl O, Chollet A, et al., 2016, The inhibition of oxytocin-driven pro-inflammatory effects in both human myometrium and amnion by the oxytocin receptor antagonist, OBE001, British Maternal & Fetal Medicine Society (BMFMS) 18th Annual Conference 2016, Publisher: Wiley, Pages: 11-12, ISSN: 1471-0528
Cook J, MacIntyre D, Sykes L, et al., 2016, Expression of specific cell-free plasma microRNAs is associated with cervical shortening in women at risk of preterm birth, British Maternal & Fetal Medicine Society (BMFMS) 18th Annual Conference 2016, Publisher: WILEY-BLACKWELL, Pages: 103-103, ISSN: 1470-0328
Arulkumaran S, Kim SH, Pohl O, et al., 2016, The inhibition of both spontaneous and oxytocin-induced contractions of human pregnant myometrium by the oxytocin receptor antagonist, OBE001, British Maternal & Fetal Medicine Society (BMFMS) 18th Annual Conference 2016, Publisher: Wiley, Pages: 103-104, ISSN: 1471-0528
Kim SH, Pohl O, Chollet A, et al., 2016, The OTR Antagonist, OBE001, Inhibits OT-Driven Proinflammatory Effects in Both Human Myometrium and Amnion, 63rd Annual Scientific Meeting of the Society-for-Reproductive-Investigation, Publisher: SAGE PUBLICATIONS INC, Pages: 123A-123A, ISSN: 1933-7191
Cook JR, MacIntyre DA, Sykes L, et al., 2016, Prediction of Cervical Shortening and Preterm Delivery Using Specific Cell Free Plasma MicroRNAs, 63rd Annual Scientific Meeting of the Society for Reproductive Investigation, Publisher: SAGE Publications, Pages: 191A-192A, ISSN: 1933-7205
Arulkumaran S, Kim SH, Pohl O, et al., 2016, The OTR Antagonist, OBE001, Inhibits Both Spontaneous and OT-Induced Contractions of Human Pregnant Myometrium In Vitro., 63rd Annual Scientific Meeting of the Society-for-Reproductive-Investigation, Publisher: SAGE PUBLICATIONS INC, Pages: 299A-299A, ISSN: 1933-7191
Kim SH, Robinson S, Cook J, et al., 2016, The OTR Antagonist, OBE001, Suppresses the Effects of OT on miRNA Expression in Human Myometrium., 63rd Annual Scientific Meeting of the Society-for-Reproductive-Investigation, Publisher: SAGE PUBLICATIONS INC, Pages: 205A-205A, ISSN: 1933-7191
Nawathe AR, Christian M, Kim SH, et al., 2016, Insulin-like growth factor axis in pregnancies affected by fetal growth disorders, Clinical Epigenetics, Vol: 8, ISSN: 1868-7083
Kim SH, MacIntyre DA, Hanyaloglu AC, et al., 2015, The oxytocin receptor antagonist, Atosiban, activates pro-inflammatory pathways in human amnion via G(alpha i) signalling, Molecular and Cellular Endocrinology, Vol: 420, Pages: 11-23, ISSN: 1872-8057
Pirianov G, MacIntyre DA, Lee Y, et al., 2015, Specific inhibition of c-Jun N-terminal kinase delays preterm labour and reduces mortality, Reproduction, Vol: 150, Pages: 269-277, ISSN: 1741-7899
Preterm labour (PTL) is commonly associated with infection and/or inflammation. Lipopolysaccharide (LPS) from different bacteria can be used to independently or mutually activate Jun N-terminal kinase (JNK)/AP1- or NF-κB-driven inflammatory pathways that lead to PTL. Previous studies using Salmonella abortus LPS, which activates both JNK/AP-1 and NF-κB, showed that selective inhibition of NF-κB delays labour and improves pup outcome. Where labour is induced using Escherichia coli LPS (O111), which upregulates JNK/AP-1 but not NF-κB, inhibition of JNK/AP-1 activation also delays labour. In this study, to determine the potential role of JNK as a therapeutic target in PTL, we investigated the specific contribution of JNK signalling to S. Abortus LPS-induced PTL in mice. Intrauterine administration of S. Abortus LPS to pregnant mice resulted in the activation of JNK in the maternal uterus and fetal brain, upregulation of pro-inflammatory proteins COX-2, CXCL1, and CCL2, phosphorylation of cPLA2 in myometrium, and induction of PTL. Specific inhibition of JNK by co-administration of specific D-JNK inhibitory peptide (D-JNKI) delayed LPS-induced preterm delivery and reduced fetal mortality. This is associated with inhibition of myometrial cPLA2 phosphorylation and proinflammatory proteins synthesis. In addition, we report that D-JNKI inhibits the activation of JNK/JNK3 and caspase-3, which are important mediators of neural cell death in the neonatal brain. Our data demonstrate that specific inhibition of TLR4-activated JNK signalling pathways has potential as a therapeutic approach in the management of infection/inflammation-associated PTL and prevention of the associated detrimental effects to the neonatal brain.
Yulia A, Thomas S, Singh N, et al., 2015, Pregnancy outcome following the indication of cerclage, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 122, Pages: 226-227, ISSN: 1470-0328
Kim SH, Tulsyan S, Da Silva FMA, et al., 2015, The proinflammatory effects of oxytocin in human myometrium require both Gaq and Gai proteins and are not inhibited by the oxytocin receptor antagonist- atosiban, Publisher: WILEY-BLACKWELL, Pages: 356-356, ISSN: 1470-0328
Cook JR, Macintyre DA, Samara E, et al., 2015, Exogenous oxytocin modulates human myometrial microRNAs, Publisher: WILEY-BLACKWELL, Pages: 226-226, ISSN: 1470-0328
Nawathe A, Savvidou M, Christian M, et al., 2015, Differences in placental epigenetic regulation in pregnancies affected by fetal growth disorders, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 122, Pages: 62-62, ISSN: 1470-0328
Nawathe A, Savvidou M, Christian M, et al., 2015, Role of metformin and insulin in epigenetic regulation of IGF axis in women with gestational diabetes, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 122, Pages: 308-308, ISSN: 1470-0328
Cook JR, MacIntyre DA, Samara E, et al., 2015, Exogenous oxytocin modulates human myometrial microRNAs, American Journal of Obstetrics and Gynecology, Vol: 213, Pages: 65.e1-65.e9, ISSN: 0002-9378
Objective: MicroRNAs (miRNAs) play a modulatory role in pathways that lead to labor onset, although oxytocin is known to modulate gene expression within the myometrium. We aimed to identify miRNAs whose expression is regulated by oxytocin in pregnant human myometrium. Study Design: Myometrial miRNA expression profiles were compared between samples collected from women at term before the onset of labor (no labor; n= 8) and after labor onset after early exogenous oxytocin treatment (n= 8). Multivariate modelling was used to assess differences in miRNA profiles. Biologic validation was undertaken on 3 independent patient cohorts (no labor, n= 10; labor induced with oxytocin, n= 8; and spontaneous labor with no oxytocin treatment, n= 10). Invitro studies that used primary myocytes were undertaken to assess target miRNA expression after oxytocin treatment. Target genes of candidate miRNAs were identified in silico and cross-referenced with genes that are known to be associated with labor or expressed in myometrium. Results: In total, 1309 miRNAs were analyzed by microarray, of which 494 were detected in human myometrium. Multivariate modeling identified 12 target miRNAs the differential expression of which was most responsible for the observed separation of the 2 patient populations in the primary discovery cohorts. Biologic validation in the independent secondary sample cohorts showed that oxytocin independently regulated 5 miRNAs (hsa-miR-146b-3p, hsa-miR-196b-3p, hsa-miR-223-3p, hsa-miR-873-5p, and hsa-miR-876-5p). Additionally, hsa-miR-146b-3p was increased both in labor that was induced with oxytocin and in myometrium from spontaneous labor with no oxytocin treatment compared with no labor samples. Four of the validated miRNAs (hsa-miR-146a-5p, hsa-miR-146b-3p, hsa-miR-196b-3p, and hsa-miR-876-5p) were expressed in primary human myocytes; oxytocin treatment of these cells replicated the directional changes that were observed invivo. Conclusion: Oxytocin alters the e
Cook J, MacIntyre D, Samara E, et al., 2015, Exogenous oxytocin modulates human myometrial microRNAs, Publisher: Elsevier, Pages: E1-E9, ISSN: 1097-6868
Kim SH, MacIntyre DA, Da Silva MF, et al., 2015, Oxytocin activates NF-kappa B-mediated inflammatory pathways in human gestational tissues, MOLECULAR AND CELLULAR ENDOCRINOLOGY, Vol: 403, Pages: 64-77, ISSN: 0303-7207
Nawathe A, Hye KS, Savvidou M, et al., 2015, Gestational Diabetes and Epigenetic Dysfunction of the IGF Axis and Its Binding Proteins., REPRODUCTIVE SCIENCES, Vol: 22, Pages: 254A-254A, ISSN: 1933-7191
Cook JR, MacIntyre DA, Samara E, et al., 2015, Oxytocin Modulates a Unique Set of Human Myometrial MicroRNAs, Publisher: SAGE PUBLICATIONS INC, Pages: 67A-67A, ISSN: 1933-7191
Cook JR, MacIntyre DA, Samara E, et al., 2014, hsa-miR-223 is differentially expressed in labouring and non-labouring human myometrium at term, Publisher: WILEY-BLACKWELL, Pages: E4-E4, ISSN: 1470-0328
Nawathe A, Hye KS, Savvidou M, et al., 2014, Insulin-like growth factors and binding protein expressions in fetal growth disorders and maternal diabetes, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 121, Pages: E2-E3, ISSN: 1470-0328
Singh N, Yuiia A, Terzidou V, et al., 2014, 6.3 The Commonalities and Differences in the Molecular Expression of Different Phenotype-specific Causes of Preterm Labour in Comparison to Term Labour., Arch Dis Child Fetal Neonatal Ed, Vol: 99
: Preterm birth comprises of several distinct clinical phenotypes. The commonalities and differences of the genes altered in the different phenotypes of preterm labour (PTL) have yet to be elucidated. Myometrial biopsies were collected during caesarean section from women in preterm no labour (PNL; n = 26), preterm labour (chorioamnionitis, placental abruption, polyhydramnios and idiopathic; n = 11, 6, 16 and 4 respectively), preterm twins (NL and L; n = 12), term no labour (n = 18), term early labour (EAL, <3 cm dilatation; n = 10) and established labour (ESL, ≥3 cm dilatation; n = 12). Samples were rapidly frozen at -80(0)C. Total RNA was extracted using RNeasy kit from Qiagen and converted to cDNA. Copy numbers of PGHS-2, CXCL-8, oxytocin receptor, IL-6, connexin 43 and GAPDH were measured by qPCR using Rotor-Gene(TM) (Corbett Research, Australia). In PTL compared to PNL, PGHS-2 was significantly overall increased in all the phenotype specific groups except placental abruption (p < 0.05). PGHS-2 levels were also significantly increased in twin no labour versus PNL (p < 0.05), but there was no difference in PGHS-2 expression between twin no labour and twin labour. There was no statistical difference in the expression of PGHS-2 when the different phenotypes of PTL were compared to both EAL and ESL. There was no significant change in the expression of CXCL-8 or OTR among both the labouring and non-labouring preterm phenotypes. Connexin-43 expression did not change among the preterm groups. These data show that PGHS-2 appears to play a significant role in driving the process of preterm labour in all distinct phenotypes (except placental abruption).
Kim SH, Blanks A, Thornton S, et al., 2014, 6.2 Atosiban activates NF-κB and pro-inflammatory pathways in human amnion via Gαi signalling., Pages: A7-A8
: Inflammation is recognized as one of the key characteristics of both preterm and term labour. There is accumulating evidence suggesting that NF-κB plays a significant role in the physiology of human labour. NF-κB has been shown to increase in human amnion in association with labour. In term pre-labour amniocytes, OT couples with Gαi, but not Gαq, to induce sequential activation of MAPKs and NF-κB to increase expression of downstream pro-labour genes including PG synthetic enzymes and inflammatory cytokines/chemokines. We have previously reported that the OTR antagonist, atosiban, does not inhibit, but stimulates both MAPKs and NF-κB in amnion. Here, we investigate the downstream effects of NF-κB activation by atosiban and the relevant G protein coupling involved. Following activation of MAPKs and NF-κB with atosiban stimulation, there were significant increases in mRNA expressions of NF-κB-regulated genes; IL-6, CCL5, and COX-2, and increases in the release of IL-6 and CCL5 after 2 h and 6 h, respectively (p < 0.05, ANOVA). In addition, upregulation of COX-2 and activation of cPLA2 were observed at protein level, as well as the subsequent PGE2 production (p < 0.05, ANOVA). Pretreatment with PTX reduced the effect of atosiban on NF-κB, ERK and p38 activation, and inhibited COX-2 and p-cPLA2 expression, indicating that these effects are mediated through Gαi (p < 0.05, ANOVA). We conclude that atosiban induces activation of NF-κB and increase expression of downstream pro-labour genes via OTR- Gαi coupling. Therefore, therapeutic modulation of the OT/OTR system for clinical management of term/preterm labour should consider potential inflammatory activation by ligand-directed signalling.
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