Mercy Hospital for Women

Heidelberg, Australia

Mercy Hospital for Women

Heidelberg, Australia
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Galbally M.,Mercy Hospital for Women
Journal of Affective Disorders | Year: 2011

Objective: In weighing the risk and benefits of pharmacological treatment of depression during pregnancy it is important to consider risks of long-term as well as short-term implications for children from exposure. Hence, this article examines the evidence to date of studies which have examined longer-term neurodevelopment teratogenic effects on child outcomes (including cognitive, motor and behavioral outcome measures) following in utero exposure to antidepressants. Method: A systematic review of published literature between January, 1973 and February, 2010 was conducted using the following key-words: pregnancy, child/infant development/neurodevelopment, antidepressants. All studies (N = 12) that reported primary data on neurodevelopmental outcome of infants exposed prenatally to antidepressants were assessed and analyzed. Results: The identified studies varied considerably in their own methodology, including the age of the children studied, the scales and assessments used, and the different aspects of neurodevelopment (such as cognitive, motor and behavioral outcomes) that were examined. Despite these limitations, the majority of studies found no difference between those exposed and controls on the various neurodevelopmental outcome measures, whereas only two studies identified statistically significant differences in motor function. Conclusions: These preliminary reassuring results must be confirmed by larger studies with longer period of follow-up and providing more robust measures of neurodevelopmental outcome, in order to definitively exclude any potential risk of neurodevelopmental teratogenicity associated with antidepressant exposure in utero. © 2010 Elsevier B.V. All rights reserved.


Lappas M.,University of Melbourne | Lappas M.,Mercy Hospital for Women
Biology of Reproduction | Year: 2013

Preterm birth remains one of the most important issues facing perinatal medicine today, with chronic inflammation and/or infection being the biggest etiological factor. The nucleotide oligomerization domain (NOD) intracellular molecules recognize a wide range of microbial products as well as other intracellular danger signals, thereby initiating inflammation through activation of nuclear factor KB (NFKB), a central regulator of the terminal processes of human labor and delivery. The aims of this study were to determine the effect of 1) human labor, proinflammatory cytokines, and bacterial endotoxin LPS on NOD1 and NOD2 expression and 2) NOD1 and NOD2 activation on the expression of prolabor mediators in human fetal membranes and myometrium. NOD1 and NOD2 expression was significantly higher in fetal membranes and myometrium after spontaneous labor when compared to nonlaboring tissues. Bacterial endotoxin LPS and the proinflammatory cytokines TNF and IL1B significantly increased NOD2, but not NOD1, expression. Furthermore, LPS-induced NOD2 expression was decreased by the NFKB inhibitor BAY 11-7082. In both fetal membranes and myometrium, the NOD1 ligand bacterial iEDAP and the NOD2 ligand bacterial MDP significantly increased the expression and secretion of proinflammatory cytokines (IL6 and IL8), cyclooxygenase (PTGS2) expression and subsequent release of prostaglandins PGE2 and PGF2alpha, and the expression and activity of MMP9. The effects of these NOD1 and NOD2 ligands were mediated via NFKB, as 1) both iE-DAP and MDP significantly increased NFKB activation and 2) the NFKB inhibitor BAY 11-7082 attenuated iE-DAP- and MDP-induced expression and secretion of prolabor mediators. In conclusion, NOD1 and NOD2 are increased in laboring fetal membranes and myometrium and with bacterial infection. Agonist activation of NOD1 and NOD2 by bacterial products leads to NFKB activation and transcription of NFKB induced prolabor genes. NOD1 and NOD2 may thus represent therapeutic targets for the treatment and/or management of preterm birth. © 2013 by the Society for the Study of Reproduction, Inc.


Lappas M.,University of Melbourne | Lappas M.,Mercy Hospital for Women
Mediators of Inflammation | Year: 2012

A prominent feature of inflammatory diseases is endothelial dysfunction. Factors associated with endothelial dysfunction include proinflammatory cytokines, adhesion molecules, and matrix degrading enzymes. At the transcriptional level, they are regulated by the histone deacetylase sirtuin (SIRT) 1 via its actions on the proinflammatory transcription factor nuclear factor- κ B (NF- κ B). The role of SIRT6, also a histone deacetylase, in regulating inflammation in endothelial cells is not known. The aim of this study was to determine the effect of SIRT6 knockdown on inflammatory markers in human umbilical vein endothelial cells (HUVECs) in the presence of lipopolysaccharide (LPS). LPS decreased expression of SIRT6 in HUVECs. Knockdown of SIRT6 increased the expression of proinflammatory cytokines (IL-1 β, IL-6, IL-8), COX-prostaglandin system, ECM remodelling enzymes (MMP-2, MMP-9 and PAI-1), the adhesion molecule ICAM-1, and proangiogenic growth factors VEGF and FGF-2; cell migration; cell adhesion to leukocytes. Loss of SIRT6 increased the expression of NF- κ B, whereas overexpression of SIRT6 was associated with decreased NF- κ B transcriptional activity. Taken together, these results demonstrate that the loss of SIRT6 in endothelial cells is associated with upregulation of genes involved in inflammation, vascular remodelling, and angiogenesis. SIRT6 may be a potential pharmacological target for inflammatory vascular diseases. © 2012 Martha Lappas.


Dwyer P.L.,Mercy Hospital for Women
International Urogynecology Journal and Pelvic Floor Dysfunction | Year: 2010

The incidence of urinary tract injury is low in most gynaecological operations but, if undiagnosed, is a cause of significant postoperative morbidity for the patient and litigation for the gynaecologist. A Medline search of studies of urinary tract injury at gynaecological surgery show that only one in 10 ureteral injuries and one in three bladder injuries are detected at the time of surgery without intraoperative cystoscopy. As cystoscopy is not routinely performed by the majority of gynaecologists during surgery, even in difficult cases, failure to detect injury to the urinary tract by itself should not be seen as negligence. However, all gynaecologists performing pelvic surgery should be encouraged to become competent in cystourethroscopy and perform this intra-operatively, at least in all high-risk cases of gynaecological surgery. © The International Urogynecological Association 2010.


Brownfoot F.C.,Mercy Hospital for Women
The Cochrane database of systematic reviews | Year: 2013

Despite the widespread use of antenatal corticosteroids to prevent respiratory distress syndrome in preterm infants, there is currently no consensus as to the type of corticosteroid to use; nor the dose, frequency, timing of use or the route of administration. To assess the effects of different corticosteroid regimens for women at risk of preterm birth. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (13 February 2013). All identified published and unpublished randomised controlled trials or quasi-randomised control trials comparing any two corticosteroids (dexamethasone or betamethasone or any other corticosteroid that can cross the placenta), comparing different dose regimens (including frequency and timing of administration) in women at risk of preterm birth were included. We planned to exclude cross-over trials and cluster-randomised trials. We included studies published as abstracts only along with studies published as full-text manuscripts Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of included studies. Data were checked for accuracy. For this update, 12 trials (1557 women and 1661 infants) were included. Dexamethasone was associated with a reduced risk of intraventricular haemorrhage (IVH) compared with betamethasone (risk ratio (RR) 0.44, 95% confidence interval (CI) 0.21 to 0.92; four trials, 549 infants). No statistically significant differences were seen for other primary outcomes: respiratory distress syndrome (RDS) (RR 1.06, 95% CI 0.88 to 1.27; five trials, 753 infants) and perinatal death (neonatal death RR 1.41, 95% CI 0.54 to 3.67; four trials, 596 infants). Similarly, very few differences were seen for secondary outcomes such as rate of admission to the neonatal intensive care unit (NICU) although in one trial, those infants exposed to dexamethasone, compared with betamethasone, had a significantly shorter length of NICU admission (mean difference (MD) -0.91 days, 95% CI -1.77 to -0.05; 70 infants). Results for biophysical parameters were inconsistent, but mostly no clinically important differences were seen.Compared with intramuscular dexamethasone, oral dexamethasone significantly increased the incidence of neonatal sepsis (RR 8.48, 95% CI 1.11 to 64.93) in one trial of 183 infants. No statistically significant differences were seen for other outcomes reported.Apart from a reduced maternal postpartum length of stay for women who received betamethasone at 12-hourly intervals compared to 24-hourly intervals in one trial (MD -0.73 days, 95% CI -1.28 to -0.18; 215 women), no differences in maternal or neonatal outcomes were seen between the different betamethasone dosing intervals assessed. Similarly, no significant differences in outcomes were seen when betamethasone acetate and phosphate was compared with betamethasone phosphate in one trial. It remains unclear whether one corticosteroid (or one particular regimen) has advantages over another.Dexamethasone may have some benefits compared with betamethasone such as less IVH, and a shorter length of stay in the NICU. The intramuscular route may have advantages over the oral route for dexamethasone, as identified in one small trial. Apart from the suggestion that 12-hour dosing may be as effective as 24-hour dosing of betamethasone based on one small trial, few other conclusions about optimal antenatal corticosteroid regimens were able to be made. No long-term results were available except for a small subgroup of 18 month old children in one trial. Trials comparing the commonly used corticosteroids are most urgently needed, as are trials of dosages and other variations in treatment regimens.


Lappas M.,University of Melbourne | Lappas M.,Mercy Hospital for Women
American Journal of Reproductive Immunology | Year: 2014

Problem: Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that is involved in human parturition, especially in the context of infection-induced preterm birth. Caspase-1 is a key component of inflammasomes, which are activated upon infection to trigger the maturation of IL-1β. Method of study: To determine the effect of human labour on caspase-1 activation in human foetal membranes and myometrium. In addition, the mechanisms by which inflammasome activation regulates IL-1β production were also be assessed. Results: Higher caspase-1 gene and protein expression were detected in foetal membranes myometrium obtained from term labouring women when compared with samples taken from non labouring women. Lipopolysaccharide induced the transcription and secretion of IL-1β from foetal membranes and myometrium; both events were dependent on nuclear factor kappa B (NF-κB). However, levels of extracellular IL-1β were greatly increased by subsequent treatment with the potassium-proton ionophore Adenosine triphosphate (ATP) or nigericin; an effect that was dependent on active caspase-1. Additionally, ATP induced IL-1β secretion via the purinergic P2X7 receptor, whereas the pannexin-1 channel was required for nigericin induced IL-1β secretion. Conclusion: Taken together, these results demonstrate that caspase-1 activation is increased with human labour in foetal membranes and myometrium, and is required for infection-induced IL-1β secretion. © 2013 John Wiley & Sons Ltd.


INTRODUCTION: Independent of their role in apoptosis, cellular inhibitors of apoptosis (cIAP) 1 and 2, have emerged as regulators of inflammation. Obesity in pregnancy is characterised by maternal and placental inflammation. Thus, the aim of this study was to determine the effect of maternal obesity and pro-inflammatory mediators on cIAP expression in human placenta.METHODS: The expression of cIAP was assessed in human placenta from lean (n = 15) and obese (n = 14) patients by qRT-PCR and Western blotting. Primary trophoblast cells were used to determine the effect of pro-inflammatory cytokines on cIAP expression, and the effect of cIAP siRNA on pro-inflammatory cytokines.RESULTS: cIAP1 and cIAP2, gene and protein expression were significantly higher in placenta from women with pre-existing maternal obesity compared to placenta form lean women. Additionally, bacterial endotoxin LPS and the pro-inflammatory cytokines tumour necrosis factor (TNF)-α and interleukin (IL)-1β significantly increased the expression of both cIAP1 and cIAP2 in primary trophoblast cells isolated from human term placenta. Knockdown of cIAP1 or cIAP2 in human primary trophoblast cells significantly decreased TNF-α induced expression and secretion of pro-inflammatory cytokines IL-6 and IL-8 and of matrix metalloproteinase (MMP)-9.DISCUSSION: cIAP1 and cIAP2 expression is increased in placenta from women with pre-existing maternal obesity and in response to treatment with pro-inflammatory cytokines. Functional studies in placental trophoblast cells revealed that cIAPs are involved in TNF-α induced-expression of pro-inflammatory cytokines. Given the central role of pro-inflammatory cytokines in placental nutrient transport, this data suggest that cIAP1 and cIAP2 may play a role in fetal growth and development. Copyright © 2014 Elsevier Ltd. All rights reserved.


Lappas M.,University of Melbourne | Lappas M.,Mercy Hospital for Women
Metabolism: Clinical and Experimental | Year: 2014

Objective To determine the effect of maternal obesity and gestational diabetes mellitus (GDM) on the expression and release of genes involved in endothelial cell dysfunction in human placenta and omental adipose tissue. Materials/Methods Human placenta and omental adipose tissue were obtained from non-obese and obese normal glucose tolerant (NGT) women and women with GDM at the time of Caesarean section. Quantitative RT-PCR was performed to determine the level of expression. Tissue explants were performed to determine the release of proteins of interest. Results There was no effect of pre-existing maternal obesity or GDM on placental gene expression or secretion of members of the VEGF family members (PLGF and VEGF-A expression and secretion; sFlt-1 release; VEGFR1 and VEGFR2 mRNA expression); FGFR1 mRNA expression, FGF2 mRNA expression and secretion; endoglin mRNA expression and secretion (sEng); and the adhesion molecules ICAM-1 and VCAM-1. On the other hand, in omental adipose tissue, pre-existing maternal obesity and GDM were associated with increased gene expression of PLGF, endoglin and ICAM-1 and increased secretion of PLGF, sFlt-1, FGF2, sEng and sICAM-1. There was, however, no effect of maternal pre-existing obesity and GDM on VEGF-A, VEGFR1, VEGFR2, FGFR1 and VCAM-1 expression or secretion. Conclusions This study demonstrated the presence of abnormal expression and secretion of angiogenic proteins and adhesion molecules in omental adipose tissue, but not placenta, from pregnant women with GDM and pre-existing maternal obesity. Increased angiogenic and adhesion molecules released from adipose tissue may affect angiogenesis, inflammation and or lipid and glucose metabolism in both mum and her offspring. © 2014 Elsevier B.V. All rights reserved.


Lappas M.,University of Melbourne | Lappas M.,Mercy Hospital for Women
Journal of Endocrinology | Year: 2014

Maternal peripheral insulin resistance and increased inflammation are two features of pregnancies, complicated by gestational diabetes mellitus (GDM). The nucleotide-binding oligomerisation domain (NOD) intracellular molecules recognise a wide range of microbial products, aswell as other intracellular danger signals, thereby initiating inflammation through activation of nuclear factor κB (NFκB). The aimof this study was to determinewhether levels of NOD1 and NOD2 are increased in adipose tissue of womenwith GDM. The effect of NOD1 and NOD2 activation on inflammation and the insulin signalling pathwaywas also assessed. NOD1, but not NOD2, expression was higher in omental and subcutaneous adipose tissues obtained from women with GDM when compared with those from women with normal glucose tolerance(NGT). Inbothomentalandsubcutaneous adipose tissues fromNGTandGDMwomen, the NOD1 ligand g-D-glutamyl-meso-diaminopimelic acid (iE-DAP) significantly induced the expression and secretion of the pro-inflammatory cytokine interleukin 6 (IL6) and chemokine IL8; COX2 (PTGS2) gene expression and subsequent prostaglandin production; the expression and secretion of the extracellular matrix remodelling enzyme matrix metalloproteinase 9 (MMP9) and the gene expression and secretion of the adhesionmolecules ICAM1 and VCAM1. There was no effect of the NOD2 ligand muramyl dipeptide on any of the endpoints tested. The effects of the NOD1 ligand iE-DAP were mediated via NFκB, as the NFκB inhibitor BAY 11-7082 significantly attenuated iE-DAP-induced expression and secretion ofpro-inflammatory cytokines, COX2 gene expression and subsequent prostaglandin production, MMP9 expression and secretion and ICAM1 and VCAM1 gene expression and secretion. In conclusion, the present findings describe an important role for NOD1 in the development of insulin resistance and inflammation in pregnancies complicated by GDM. © 2014 Society for Endocrinology.


Lappas M.,University of Melbourne | Lappas M.,Mercy Hospital for Women
Molecular and Cellular Endocrinology | Year: 2014

Gestational diabetes mellitus (GDM) is characterised by maternal peripheral insulin resistance, increased inflammation, and increasing levels of circulating free fatty acids (FFAs) and advanced glycation endproducts (AGEs). Caspase-1 is a key component of the inflammasome, which is activated upon cellular infection or stress to trigger the maturation IL-1β, a pro-inflammatory cytokine that mediated insulin resistance. The aim of this study was to determine whether the inflammasome is activated in adipose tissue from women with gestational diabetes mellitus (GDM) and if it interferes with the insulin signalling pathway leading to the insulin resistance that is evident in GDM. Protein expression of active caspase-1 and mature IL-1β secretion was increased in adipose tissue of women with GDM. Treatment of adipose tissue with IL-1β decreased insulin-stimulated phosphorylation of IRS-1, GLUT-4 expression and glucose uptake. Low-grade inflammation (induced by LPS), the FFA palmitate and AGE conjugated to BSA (AGE-BSA), induced IL-1β secretion via inflammasome activation. In conclusion, the present findings describe an important role for adipose tissue inflammasome activation in the development of insulin resistance associated in pregnancies complicated by GDM. © 2013.

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