Publications
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Nasri NM, Zollner J, Leiper J, et al., 2017, Effect of Gender on the Innate Immune Response in Septic Mice, 64th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: SAGE PUBLICATIONS INC, Pages: 144A-144A, ISSN: 1933-7191
Lai PF, Tribe RM, Johnson MR, 2017, Effects of Tension on cAMP-Driven Control of Contractility in Human Myometrial Tissue., 64th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: SAGE PUBLICATIONS INC, Pages: 244A-244A, ISSN: 1933-7191
Georgopoulou A, Leiper J, Johnson MR, 2017, Fetal Asymmetric Dimethylarginine Regulates Maternal Haemodynamics., 64th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: SAGE PUBLICATIONS INC, Pages: 67A-67A, ISSN: 1933-7191
Yulia A, Singh N, Sooranna SR, et al., 2017, The role of cyclic AMP as an anti-inflammatory in human myometrium, Publisher: WILEY, Pages: 102-103, ISSN: 1470-0328
Cauldwell M, Cox M, Gatzoulis M, et al., 2017, The management of labour in women with cardiac disease: need for more evidence?, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 124, Pages: 1307-1309, ISSN: 1470-0328
Cauldwell M, Patel RR, Steer PJ, et al., 2017, Managing subfertility in patients with heart disease: What are the choices?, AMERICAN HEART JOURNAL, Vol: 187, Pages: 29-36, ISSN: 0002-8703
Edey LF, O'Dea KP, Herbert BR, et al., 2016, The local and systemic immune response to intrauterine LPS in the prepartum mouse, Biology of Reproduction, Vol: 95, Pages: 1-10, ISSN: 1529-7268
Inflammation plays a key role in human term and preterm labor (PTL). Intrauterine LPS has been widely used to model inflammation-induced complications of pregnancy, including PTL. It has been shown to induce an intense myometrial inflammatory cell infiltration, but the role of LPS-induced inflammatory cell activation in labor onset and fetal demise is unclear. We investigated this using a mouse model of PTL, where an intrauterine injection of 10 μg of LPS (serotype 0111:B4) was given at E16 of CD1 mouse pregnancy. This dose induced PTL at an average of 12.7 h postinjection in association with 85% fetal demise. Flow cytometry showed that LPS induced a dramatic systemic inflammatory response provoking a rapid and marked leucocyte infiltration into the maternal lung and liver in association with increased cytokine levels. Although there was acute placental inflammatory gene expression, there was no corresponding increase in fetal brain inflammatory gene expression until after fetal demise. There was marked myometrial activation of NFκB and MAPK/AP-1 systems in association with increased chemokine and cytokine levels, both of which peaked with the onset of parturition. Myometrial macrophage and neutrophil numbers were greater in the LPS-injected mice with labor onset only; prior to labor, myometrial neutrophils and monocytes numbers were greater in PBS-injected mice, but this was not associated with an earlier onset of labor. These data suggest that intrauterine LPS induces parturition directly, independent of myometrial inflammatory cell infiltration, and that fetal demise occurs without fetal inflammation. Intrauterine LPS provokes a marked local and systemic inflammatory response but with limited inflammatory cell infiltration into the myometrium or placenta.
Georgiou E, Lei K, Lai P, et al., 2016, Progesterone repression of IL-1β action is maintained in human myometrium after the onset of labour, Publisher: WILEY-BLACKWELL, Pages: E12-E13, ISSN: 1470-0328
Georgiou E, Lei K, Singh N, et al., 2016, Chorioamnionitis-induced preterm labour is associated with progesterone receptor cofactor protein changes, Publisher: WILEY-BLACKWELL, Pages: E10-E10, ISSN: 1470-0328
Zollner J, Leiper J, Johnson M, 2016, A novel therapeutic avenue: pharmacological inhibition of the dimethylarginine-dimethylaminohydrolase 1 (DDAH1) enzyme system improves survival and haemodynamic function in a rodent model of severe sepsis in pregnancy, Publisher: WILEY-BLACKWELL, Pages: E7-E7, ISSN: 1470-0328
Cauldwell M, Swan L, Uebing A, et al., 2016, The management of third stage of labour in women with heart disease needs more attention, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 223, Pages: 23-24, ISSN: 0167-5273
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Orwat S, Diller G-P, van Hagen IM, et al., 2016, Risk of pregnancy in moderate and severe aortic stenosis from the multinational ROPAC registry, Journal of the American College of Cardiology, Vol: 68, Pages: 1727-1737, ISSN: 0735-1097
BACKGROUND Controversial results on maternal risk and fetal outcome have been reported in women with aorticstenosis (AS).OBJECTIVES The authors sought to investigate maternal and fetal outcomes in patients with AS in a large cohort.METHODS The Registry on Pregnancy and Cardiac Disease (ROPAC) is a global, prospective observational registry ofwomen with structural heart disease, providing a uniquely large study population. Data of women with moderate(peak gradient 36 to 63 mm Hg) and severe AS (peak gradient $64 mm Hg) were analyzed.RESULTS Of 2,966 pregnancies in ROPAC, the authors identified 96 women who had at least moderate AS (34 withsevere AS). No deaths were observed during pregnancy and in the first week after delivery. However, 20.8% of womenwere hospitalized for cardiac reasons during pregnancy. This was significantly more common in severe AS compared withmoderate AS (35.3% vs. 12.9%; p ¼ 0.02), and reached the highest rate (42.1%) in severe, symptomatic AS. Pregnancywas complicated by heart failure in 6.7% of asymptomatic and 26.3% of symptomatic patients, but could be managedmedically, except for 1 patient who was symptomatic before pregnancy and underwent balloon valvotomy. Childrenof patients with severe AS had a significantly higher percentage of low birth weight (35.0% vs. 6.0%; p ¼ 0.006).CONCLUSIONS Mortality in pregnant women with AS, including those with severe AS, appears to be close to zero inthe current era. Symptomatic and severe AS does, however, carry a substantial risk of heart failure and is associated withhigh rates of hospitalization for cardiac reasons, although heart failure can nearly always be managed medically.The results highlight the importance of appropriate pre-conceptional patient evaluation and counseling.(J Am Coll Cardiol 2016;68:1727–37) © 2016 by the American College of Cardiology Foundation.
Yulia A, Singh N, Lei K, et al., 2016, Cyclic AMP effectors regulate myometrial oxytocin receptor expression, Endocrinology, Vol: 157, Pages: 4411-4422, ISSN: 1945-7170
The factors that initiate human labor are poorly understood. We have tested the hypothesis that a decline in cAMP/protein kinase A (PKA) function leads to the onset of labor. Initially, we identified myometrial cAMP/PKA-responsive genes (six up-regulated and five down-regulated genes) and assessed their expression in myometrial samples taken from different stages of pregnancy and labor. We found that the oxytocin receptor (OTR) was one of the cAMP-repressed genes, and, given the importance of OTR in the labor process, we studied the mechanisms involved in greater detail using small interfering RNA, chemical agonists, and antagonists of the cAMP effectors. We found that cAMP-repressed genes, including OTR, increased with the onset of labor. Our in vitro studies showed that cAMP acting via PKA reduced OTR expression but that in the absence of PKA, cAMP acts via exchange protein activated by cAMP (EPAC) to increase OTR expression. In early labor myometrial samples, PKA levels and activity declined and Epac1 levels increased, perhaps accounting for the increase in myometrial OTR mRNA and protein levels at this time. In vitro exposure of myometrial cells to stretch and IL-1β increased OTR levels and reduced basal and forskolin-stimulated cAMP and PKA activity, as judged by phospho-cAMP response element-binding protein levels, but neither stretch nor IL-1β had any effect on PKA or EPAC1 levels. In summary, there is a reduction in the activity of the cAMP/PKA pathway with the onset of human labor potentially playing a critical role in regulating OTR expression and the transition from myometrial quiescence to activation.
Sivarajasingam SP, Imami N, Johnson M, 2016, Cytokines and myometrial signalling in human labour, Journal of Endocrinology, Vol: 231, Pages: R101-R119, ISSN: 1479-6805
Human labour is an inflammatory event, physiologically driven by an interaction between hormonal and mechanical factors and pathologically associated with infection, bleeding and excessive uterine stretch. The initiation and communicators of inflammation is still not completely understood, however the role of cytokines and chemokine have been implicated. We summarise the current understanding of the nature and role of cytokines, chemokines and hormones and their involvement in signalling within the myometrium particularly during labour.
van Hagen IM, Cornette J, Johnson MR, et al., 2016, Managing cardiac emergencies in pregnancy, Heart, Vol: 103, Pages: 159-173, ISSN: 1468-201X
Ogundipe E, Johnson MR, Wang Y, et al., 2016, Peri-conception maternal lipid profiles predict pregnancy outcomes, Prostaglandins, Leukotrienes and Essential Fatty Acids, Vol: 114, Pages: 35-43, ISSN: 0952-3278
In this study, healthy women and those at high-risk of adverse pregnancy outcomes (pre-eclampsia, fetal growth restriction, gestational diabetes) were selected to assess the effect of fatty acid supplementation. The purpose of this paper is to report two novel findings (i) at recruitment the receiver operating characteristic (ROC) for erythrocyte oleic acid predicted spontaneous delivery at 34 weeks gestation (ROC=0.926 n=296) for all women entering the study. Further analysis revealed oleic and all monounsaturated fatty acids were similarly predictive with or without a supplement during the pregnancy. (ii) At delivery, we observed a biomagnification of saturated fatty acids from mother to fetus with the reverse for monounsaturates. The major conclusions are (i) the status of the mother in the months prior to conception is a stronger predictor of preterm delivery than the events during the pregnancy. (ii) Saturated fats may be playing an important function in supporting fetal membrane growth.
Sliwa-Hahnle K, Van Hagen I, Budts W, et al., 2016, Pulmonary hypertension and pregnancy outcomes: data from the ROPAC study of the European Society of Cardiology, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 1185-1185, ISSN: 0195-668X
Van Hagen IM, Thorne S, Taha N, et al., 2016, Risks of pregnancy in women with rheumatic mitral valve disease: data from ROPAC, an ESC registry, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 1240-1241, ISSN: 0195-668X
Kim CH, Hvoslef-Eide M, Nilsson SR, et al., 2016, Erratum to: The continuous performance test (rCPT) for mice: a novel operant touchscreen test of attentional function., Psychopharmacology, Vol: 233, Pages: 3471-3471, ISSN: 1432-2072
Lai PF, Tribe RM, Johnson MR, 2016, Differential impact of acute and prolonged cAMP agonist exposure on protein kinase A activation and human myometrium contractile activity, Journal of Physiology-London, Vol: 594, Pages: 6369-6393, ISSN: 1469-7793
Acute cAMP elevation inhibits myometrial contractility, but the mechanisms responsible are not fully defined and the long-term effects uncertain. These need to be defined in pregnant human myometrium before the therapeutic potential of cAMP-elevating agents in the prevention of preterm labour can be realised. In the present study, we tested the hypotheses that PKA activity is necessary for cAMP-induced myometrial relaxation and prolonged cAMP elevation can prevent myometrial contractions. Myometrial tissues obtained from term, pre-labour elective Caesarean sections were exposed to receptor-independent cAMP agonists to determine the relationship between myometrial contractility (spontaneous and oxytocin-induced), PKA activity, HSP20 phosphorylation and expression of contraction-associated and cAMP signalling proteins. Acute (1 h) application of cAMP agonists promoted myometrial relaxation but this was weakly related to PKA activation. PKA-specific activator, 6-Bnz-cAMP, increased PKA activity (6.8 ± 2.0 mean fold versus vehicle; P = 0.0313) without inducing myometrial relaxation. Spontaneous myometrial contractility declined after 24 h but was less marked when tissues were constantly exposed to cAMP agonists, especially for 8-bromo-cAMP (4.3 ± 1.2 mean fold versus vehicle; P = 0.0043); this was associated with changes to calponin, cofilin and HSP20 phosphorylated/total protein levels. Oxytocin-induced contractions were unaffected by pre-incubation with cAMP agonists despite treatments being able to enhance PKA activity and HSP20 phosphorylation. These data suggest that cAMP-induced myometrial relaxation is not solely dependent on PKA activity and the ability of cAMP agonists to repress myometrial contractility is lost with prolonged exposure. We conclude that cAMP agonist treatment alone may not prevent preterm labour.
Cauldwell M, Von Klemperer K, Uebing A, et al., 2016, The management of the second stage of labour in women with cardiac: a mixed methods study, International Journal of Cardiology, Vol: 222, Pages: 732-736, ISSN: 1874-1754
ObjectiveTo examine the duration of the passive and active parts of the second stage (SS) of labour in women with cardiac disease (CD) and to assess the adherence to antenatal care plans regarding timing of assisted delivery. Cardiac parameters were measured in a subset of women to investigate any differences between the passive and active SS of labour.Study designCohort study of 73 women with CD, classified into mWHO Class Groups I–IV. Women were matched with an equal number of women controlling for gestational age, maternal age (+/− five years), parity, use of regional anaesthesia, and spontaneous versus assisted delivery. 12 of the 73 women with cardiac disease had cardiac parameters and oxygen saturations measured in the active and passive SS of labours.ResultsLength of passive SS was longer and the active component of the SS was significantly shorter in women with CD, because of a policy of elective assisted delivery. However, thirty four percent pushed for longer than was recommended. No adverse cardiac events were reported. Analysis of Holters showed no evidence of maternal arrhythmia in the active SS. Maternal heart rate increased at a modest but significant rate in the active SS.ConclusionCompliance with antenatal recommendations was poor; prolonged pushing was not associated with an increase in cardiac events. A restrictive policy for the duration of the active SS of labour in women with CD is currently based entirely on expert opinion and more prospective studies are needed justify this policy.
Sliwa K, van Hagen IM, Budts W, et al., 2016, Pulmonary hypertension and pregnancy outcomes: data from the Registry Of Pregnancy and Cardiac Disease (ROPAC) of the European Society of Cardiology, European Journal of Heart Failure, Vol: 18, Pages: 1119-1128, ISSN: 1879-0844
AIMS: To describe the outcomes of pregnancy in women with pulmonary hypertension. METHODS AND RESULTS: In 2007 the European Registry on Pregnancy and Heart Disease was initiated by the European Society of Cardiology. Consecutive patients with all forms of cardiovascular disease, presenting with pregnancy, were enrolled with the aim of investigating the pregnancy outcomes. This subgroup of the cohort included 151 women with pulmonary hypertension (PH) either diagnosed by right heart catheterization or diagnosed as possible PH by echocardiographic signs, with 26% having pulmonary arterial hypertension (PAH), in three subgroups: idiopathic (iPAH), associated with congenital heart disease (CHD-PAH), or associated with other disease (oPAH), and 74% having PH caused by left heart disease (LHD-PH, n = 112). Maternal mean age was 29.2 ± 5.6 years and 37% were nulliparous. Right ventricular systolic pressure was <50 mmHg in 59.6% of patients, 50-70 mmHg in 28.5% and >70 mmHg in 11.9%. In more than 75% of patients, the diagnosis of PH had been made before pregnancy. Maternal death up to 1 week after delivery occurred in five patients (3.3%), with another two out of 78 patients who presented for follow-up (2.6%), dying within 6 months after delivery. The highest mortality was found in iPAH (3/7, 43%). During pregnancy, heart failure occurred in 27%. Caesarean section was performed in 63.4% (23.9% as emergency). Therapeutic abortion was performed in 4.0%. Complications included miscarriage (5.6%), fetal mortality (2%), premature delivery (21.7%), low birth weight (19.0%), and neonatal mortality (0.7%). CONCLUSION: Mortality in this group of patients with various forms of PH was lower than previously reported as specialized care during pregnancy and delivery was available. However, maternal and fetal mortality remains prohibitively high in women with iPAH, although this conclusion is restricted by limite
Xu H, van Deel E, Johnson M, et al., 2016, Pregnancy mitigates cardiac pathology in a mouse model of left ventricular pressure overload, American Journal of Physiology - Heart and Circulatory Physiology, Vol: 311, Pages: H807-H814, ISSN: 0363-6135
In western countries heart disease is the leading cause of maternal death during pregnancy. The effect of pregnancy on the heart is difficult to study in patients with preexisting heart disease. Since experimental studies are scarce, we investigated the effect of pressure-overload, produced by transverse aortic constriction (TAC) in mice, on the ability to conceive, pregnancy outcome, and maternal cardiac structure and function. Four weeks of TAC produced left ventricular (LV) hypertrophy and dysfunction with marked interstitial fibrosis, decreased capillary density and induced pathological cardiac gene expression. Pregnancy increased relative LV and right ventricular weight without affecting the deterioration of LV function following TAC. Surprisingly, the TAC-induced increase in relative heart and lung weight was mitigated by pregnancy, which was accompanied by a partial normalization of capillary density and natriuretic peptide type A expression. Additionally, the combination of pregnancy and TAC increased the cardiac phosphorylation of c-Jun, and STAT1, but reduced PI3K phosphorylation. Finally, TAC did not significantly affect conception rate, pregnancy duration, uterus size, litter size and pup weight. In conclusion, we found that, rather than exacerbating the changes associated with cardiac pressure-overload, pregnancy actually attenuated pathological LV remodeling and mitigated pulmonary congestion, capillary rarefaction and pathological gene expression produced by TAC, suggesting a positive effect of pregnancy on the pressure-overloaded heart.
Feng Y, Chen S, Li C, et al., 2016, Curettage after uterine artery embolization combined with methotrexate treatment for caesarean scar pregnancy., Experimental and Therapeutic Medicine, Vol: 12, Pages: 1469-1475, ISSN: 1792-1015
In the present study, we evaluated the diagnosis and management modalities of caesarean scar pregnancy (CSP). Thirty patients diagnosed with CSP were retrospectively studied between February, 2010 and February, 2012. Twenty-five patients were offered prophylactic uterine artery embolization (UAE) and methotrexate (MTX) prior to uterine suction curettage. Five cases were referred from other hospitals where the initial management with uterine suction curettage had resulted in uncontrollable massive haemorrhage, 4 of the cases had UAE and one proceeded immediately to hysterectomy. In the 25 patients treated with prophylactic UAE and MTX, 12 had laparoscopy-guided curettage and 13 had ultrasound-guided curettage without complication. The results showed that the 25 patients with CSP, who received prophylactic UAE and MTX prior to uterine curettage, recovered without complications. Five patients referred from other hospitals, where uterine curettage was the primary procedure, had severe complications including uncontrolled vaginal bleeding and uterine rupture. Four of the five patients were treated successfully with emergency UAE and the remaining patient underwent emergency hysterectomy as ultrasound examination detected significant haemorrhage between the uterus and the bladder. Of the 25 patients who received prophylactic UAE combined with MTX, there were no reports of irregular menstruation or serious adverse effects. Notably, the decrease in serum human chorionic gonadotropin (HCG) levels 3 days post-surgery was greater with ultrasound-guided curettage (84.3±5.5%) than with laparoscopy-guided curettage (76.3±10.2%). In summary, the data suggested that prophylactic UAE with MTX followed by ultrasound-guided curettage is the most effective therapeutic approach in CSP.
Ertekin E, van Hagen IM, Salam AM, et al., 2016, Ventricular tachyarrhythmia during pregnancy in women with heart disease: Data from the ROPAC, a registry from the European Society of Cardiology, International Journal of Cardiology, Vol: 220, Pages: 131-136, ISSN: 1874-1754
OBJECTIVES: To describe the incidence, onset, predictors and outcome of ventricular tachyarrhythmia (VTA) in pregnant women with heart disease. BACKGROUND: VTA during pregnancy will cause maternal morbidity and even mortality and will have impact on fetal outcome. Insufficient data exist on the incidence and outcome of VTA in pregnancy. METHODS AND RESULTS: From January 2007 up to October 2013, 99 hospitals in 39 countries enrolled 2966 pregnancies in women with structural heart disease. Forty-two women (1.4%) developed clinically relevant VTA during pregnancy, which occurred mainly in the third trimester (48%). NYHA class >1 before pregnancy was an independent predictor for VTA. Heart failure during pregnancy was more common in women with VTA than in women without VTA (24% vs. 12%, p=0.03) and maternal mortality was respectively 2.4% and 0.3% (p=0.15). More women with VTA delivered by Cesarean section than women without VTA (68% vs. 47%, p=0.01). Neonatal death, preterm birth (<37weeks), low birthweight (<2500g) and Apgar score <7 occurred more often in women with VTA (4.8% vs. 0.3%, p=0.01; 36% vs. 16%, p=0.001; 33% vs. 15%, p=0.001 and 25% vs. 7.3%, p=0.001, respectively). CONCLUSIONS: VTA occurred in 1.4% of pregnant women with cardiovascular disease, mainly in the third trimester, and was associated with heart failure during pregnancy. NYHA class before pregnancy was predictive. VTA during pregnancy had clear impact on fetal outcome.
Migale R, MacIntyre DA, Cacciatore S, et al., 2016, Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics, BMC Medicine, Vol: 14, ISSN: 1741-7015
BACKGROUND: Preterm birth is now recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; however, the relative contribution of each remains unclear. In this study we aimed to characterize temporal transcriptome changes in the uterus preceding term labor and preterm labor (PTL) induced by progesterone withdrawal or inflammation in the mouse and compare these findings with human data. METHODS: Myometrium was collected at multiple time points during gestation and labor from three murine models of parturition: (1) term gestation; (2) PTL induced by RU486; and (3) PTL induced by lipopolysaccharide (LPS). RNA was extracted and cDNA libraries were prepared and sequenced using the Illumina HiSeq 2000 system. Resulting RNA-Seq data were analyzed using multivariate modeling approaches as well as pathway and causal network analyses and compared against human myometrial transcriptome data. RESULTS: We identified a core set of temporal myometrial gene changes associated with term labor and PTL in the mouse induced by either inflammation or progesterone withdrawal. Progesterone withdrawal initiated labor without inflammatory gene activation, yet LPS activation of uterine inflammation was sufficient to override the repressive effects of progesterone and induce a laboring phenotype. Comparison of human and mouse uterine transcriptomic datasets revealed that human labor more closely resembles inflammation-induced PTL in the mouse. CONCLUSIONS: Labor in the mouse can be achieved through inflammatory gene activation yet these changes are not a requisite for labor itself. Human labor more closely resembles LPS-induced PTL in the mouse, supporting an essential role for inflammatory mediators in human "functional progesterone withdrawal." This improved understanding of inflammatory and progesterone influence on the uterine transcriptome has important implications for
Schofield SJ, Doughty VL, van Stiphout N, et al., 2016, Assisted conception and the risk of CHD: a case-control study, Cardiology in the Young, Vol: 27, Pages: 473-479, ISSN: 1467-1107
Epidemiological studies suggest a higher prevalence of congenital malformations in children conceived through assisted reproductive technologies. There are a few studies that address CHD specifically and most have examined data from registries. We examined the relationship between CHD and assisted conception using data collected in a specialist paediatric cardiac service in the United Kingdom. Between April, 2010 and July, 2011, the parents of children attending paediatric cardiology clinics at the Royal Brompton Hospital, London, were invited to complete a questionnaire that enquired about the nature of their child's conception, the route for their original referral, and a number of potential confounding exposures. "Cases" were defined as children diagnosed with one or more carefully defined CHDs and "controls" as those with normal hearts. Of 894 new attendees with complete data, half of them were cases (n=410, 45.9%). The overall prevalence of assisted conception was 5.4% (n=44). Logistic regression analysis demonstrated a non-significant increase in the crude odds for the use of assisted reproduction (odds ratio 1.21, 95% confidence interval 0.66-2.22) in this group. After adjustment for gestation, parity, year of birth, and maternal age, the odds ratio reduced (odds ratio 0.95, 95% confidence interval 0.48-1.88). Increased rates of assisted conception were observed in a number of CHD subgroups, although no significant differences were found. These findings do not suggest an overall association between CHD and assisted reproduction in this population.
Georgiou EX, Lei K, Lai PF, et al., 2016, The study of progesterone action in human myometrial explants., Molecular Human Reproduction, ISSN: 1460-2407
STUDY HYPOTHESIS: Myometrial explants represent a superior model compared with cell culture models for the study of human myometrial progesterone (P4) signalling in parturition. STUDY FINDING: Gene expression analysis showed myometrial explants closely resemble the in vivo condition and the anti-inflammatory action of P4 is not lost with labour onset. WHAT IS KNOWN ALREADY: Circulating P4 levels decline before the onset of parturition in most animals, but not in humans. This has led to the suggestion that there is a functional withdrawal of P4 action at the myometrial level prior to labour onset. However, to date, no evidence of a loss of P4 function has been provided, with studies hampered by a lack of a physiologically relevant model. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Myometrial biopsies obtained at Caesarean section were dissected into explants after a portion was immediately snap frozen (t = 0). Microarray analysis was used to compare gene expression of t = 0 with paired (i) explants, (ii) passage 4 myometrial cell cultures or (iii) the hTERT myometrial cell line. Western blotting and chemokine/cytokine assays were used to study P4 signalling in myometrial explants. MAIN RESULTS AND THE ROLE OF CHANCE: Gene expression comparison of t = 0 to the three models demonstrated that explants more closely resemble the in vivo status. At the protein level, explants maintain both P4 receptor (PR) and glucocorticoid receptor (GR) levels versus t = 0 whereas cells only maintain GR levels. Additionally, treatment with 1 µM P4 led to a reduction in interleukin-1 (IL-1) β-driven cyclooxygenase-2 in explants but not in cells. P4 signalling in explants was PR-mediated and associated with a repression of p65 and c-Jun phosphorylation. Furthermore, the anti-inflammatory action of P4 was maintained after labour onset. LIMITATIONS/REASONS FOR CAUTION: There is evidence of basal inflammation in the myometrial explant model. WIDER IMPLICATIONS OF THE FINDINGS: Myomet
Cauldwell M, Von Klemperer K, Uebing A, et al., 2016, Why is post-partum haemorrhage more common in women with congenital heart disease?, International Journal of Cardiology, Vol: 218, Pages: 285-290, ISSN: 1874-1754
ObjectiveTo identify the factors associated with an increased post-partum blood loss in women with congenital heart disease (CHD).MethodsThe study was a retrospective cohort study, which included 366 nulliparous women with CHD and a singleton pregnancy cared for in a single tertiary centre (Chelsea and Westminster Hospital) between 1994 and 2014. The women were classified into one of 12 different functional groups and univariate and multivariate regression analysis were used to identify factors associated with increased blood loss at delivery.ResultsThe average volume of blood loss in women with CHD was twice that expected. Univariate analysis showed that White European women had the lowest blood loss. Women who had been on anticoagulants, had a forceps delivery, emergency Caesarean section or general anaesthesia lost more blood than those having a spontaneous vaginal birth under regional analgesia. Higher CARPREG scores were associated strongly with increased blood loss. Women with a Fontan circulation had the highest blood loss and the difference remained significant after correcting for other significant variables.ConclusionsWomen with CHD are at increased risk of PPH. We have identified several potentially modifiable risk factors that may be targeted to reduce this risk. In addition, women with a Fontan circulation were most prone to PPH, independent of other risk factors, suggesting the existence of lesion-specific abnormalities and the need for extra vigilance in this group of women at the time of birth.
Zhao H, Mitchell S, Koumpa S, et al., 2016, Heme Oxygenase-1 mediates neuro-protection conferred by argon in combination with hypothermia in neonatal hypoxia-ischemia brain injury, Anesthesiology, Vol: 125, Pages: 180-192, ISSN: 1528-1175
Argon–hypothermia treatment reduced both neuronal death in an in vitro neuronal culture model and brain infarct size in an in vivo rat model of neonatal asphyxia. The protective effects of argon–hypothermia involve both inhibition of apoptosis and neuroinflammation mechanisms and activation of cell survival pathways.
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