Obstetrics and Gynaecology - Research Publications
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ItemHepatitis A virus cellular receptor 2 (HAVCR2) is decreased with viral infection and regulates pro-labour mediators OA(WILEY, 2017-07)PROBLEM: Intrauterine infection caused by viral infection has been implicated to contribute to preterm birth. Hepatitis A virus cellular receptor 2 (HAVCR2) regulates inflammation in non-gestational tissues in response to viral infection. METHOD OF STUDY: The aims of this study were to determine the effect of: (i) viral dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) on HAVCR2 expression; and (ii) HAVCR2 silencing by siRNA (siHAVCR2) in primary amnion and myometrial cells on poly(I:C)-induced inflammation. RESULTS: In human foetal membranes and myometrium, HAVCR2 mRNA and protein expression was decreased when exposed to poly(I:C). Treatment of primary amnion and myometrial cells with poly(I:C) significantly increased the expression and release of pro-inflammatory cytokines TNF, IL1A, IL1B and IL6; the expression of chemokines CXCL8 and CCL2; the expression and secretion of adhesion molecules ICAM1 and VCAM1; and PTGS2 and PTGFR mRNA expression and the release of prostaglandin PGF2α . This increase was significantly augmented in cells transfected with siHAVCR2. Furthermore, mRNA expression of anti-inflammatory cytokines IL4 and IL10 was significantly decreased. CONCLUSION: Collectively, our data suggest that HAVCR2 regulates cytokines, chemokines, prostaglandins and cell adhesion molecules in the presence of viral infection. This suggests a potential for HAVCR2 activators as therapeutics for the management of preterm birth associated with viral infections.
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ItemTRADD, TRAF2, RIP1 and TAK1 are required for TNF--induced pro-labour mediators in human primary myometrial cells(WILEY, 2017-07)PROBLEM: TNF-α plays a central role in the processes of human labour and delivery. This study sought to determine the role of the adaptor proteins TNFR1-associated death domain protein (TRADD), TNF receptor-associated factor 2 (TRAF2), receptor interacting protein 1 (RIP1) and transforming growth factor beta-activated kinase 1 (TAK1) in TNF-α-induced formation of pro-labour mediators. METHOD OF STUDY: Human primary myometrial cells were transfected with siRNA against TRADD (siTRADD), TRAF2 (siTRAF2), RIP1 (siRIP1) or TAK1 (siTAK1), treated with TNF-α, and assayed for pro-inflammatory mediators expression. RESULTS: siTRADD, siTRAF2, siRIP1 and siTAK1 significantly decreased TNF-α-induced IL-1α, IL-1β, IL-6, IL-8, MCP-1 mRNA expression and release of IL-6, IL-8 and MCP-1; and cyclooxygenase (COX)-2 expression and release of prostaglandin PGF2α . There was a significant attenuation of TNF-α-induced expression of adhesion molecules ICAM-1 and VCAM-1 mRNA with siTRADD, siTRAF2 or siRIP1. siTRADD and siRIP1 significantly attenuated TNF-α-induced MMP-9 mRNA expression and release and nuclear factor κB (NF-κB) transcriptional activity. There was a significant increase in TNF-α-induced sVCAM-1 release, MMP-9 mRNA expression and NF-κB activity with siTAK1. CONCLUSION: TRADD, TRAF2, RIP1 and TAK1 are involved in TNF-α signalling in human myometrium. Further studies are required to determine whether inhibition of these proteins can prevent preterm birth.
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ItemA mobile health intervention promoting healthy gestational weight gain for women entering pregnancy at a high body mass index: the txt4two pilot randomised controlled trial(WILEY, 2017-10)OBJECTIVE: To determine the feasibility and effectiveness of an mHealth intervention promoting healthy diet, physical activity and gestational weight gain in pregnant women. DESIGN: Randomised controlled trial (RCT). SETTING: Australian tertiary obstetric hospital. POPULATION: One hundred pregnant women who were overweight or obese prior to pregnancy. METHODS: Women recruited at the first antenatal clinic visit were randomised to either an intervention or a control group. The intervention consisted of a tailored suite of strategies delivered (from first antenatal visit until 36 weeks' gestation) via multiple modalities available on mobile devices. MAIN OUTCOME MEASURES: The primary outcome was intervention feasibility and secondary outcomes were objectively measured changes in gestational weight gain (GWG) and self-reported dietary intake and physical activity. RESULTS: Ninety-one women completed the study. Delivery to protocol provides evidence of program feasibility. Most women engaged regularly with the program, with the majority (97.6%) reporting that the intervention was helpful. Secondary outcomes demonstrated a significantly lower GWG in the intervention group (7.8 kg ± 4.7 versus 9.7 kg ± 3.9; P =0.041) compared with the control group at intervention completion. Intervention group women reported significantly smaller reductions in total, light- and moderate-intensity physical activity from baseline to completion of the intervention (P = 0.001) compared with the control group, but no differences in consumption frequencies of key food groups. CONCLUSION: An intervention that aimed to deliver healthy diet, physical activity and GWG guidance utilising innovative technology can be feasibly implemented and produce positive physical activity and GWG outcomes. TWEETABLE ABSTRACT: txt4two mHealth study improved gestational weight gain and physical activity in pregnant women with high BMIs.
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ItemMaternal 25-hydroxyvitamin D is inversely correlated with foetal serotonin(WILEY, 2017-03)OBJECTIVE: Maternal vitamin D deficiency during pregnancy has been linked to impaired neurocognitive development in childhood. The mechanism by which vitamin D affects childhood neurocognition is unclear but may be via interactions with serotonin, a neurotransmitter involved in foetal brain development. In this study, we aimed to explore associations between maternal and foetal vitamin D concentrations, and foetal serotonin concentrations at term. STUDY DESIGN AND MEASUREMENTS: Serum 25-hydroxyvitamin D (25(OH)D, nmol/l) and serotonin (5-HT, nmol/l) concentrations were measured in maternal and umbilical cord blood from mother-infant pairs (n = 64). Association between maternal 25(OH)D, cord 25(OH)D and cord serotonin was explored using linear regression, before and after adjusting for maternal serotonin levels. We also assessed the effects of siRNA knockdown of the vitamin D receptor (VDR) and administration of 10 nm 1,25-dihydroxyvitamin D3 on serotonin secretion in human umbilical vein endothelial cells (HUVECs) in vitro. RESULTS: We observed an inverse relationship between both maternal and cord 25(OH)D concentrations with cord serotonin concentrations. The treatment of HUVECs with 1,25-dihydroxyvitamin D3 in vitro decreased the release of serotonin (193·9 ±14·8 nmol/l vs 458·9 ± 317·5 nmol/l, control, P < 0·05). Conversely, inactivation of VDR increased serotonin release in cultured HUVECs. CONCLUSIONS: These observations provide the first evidence of an inverse relationship between maternal 25(OH)D and foetal serotonin concentrations. We propose that maternal vitamin D deficiency increases foetal serotonin concentrations and thereby contributes to longer-term neurocognitive impairment in infants and children.
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ItemAnti-Diabetic, Anti-Inflammatory, and Anti-Oxidant Effects of Naringenin in an In Vitro Human Model and an In Vivo Murine Model of Gestational Diabetes Mellitus(WILEY, 2019-10)SCOPE: Gestational diabetes mellitus (GDM), which affects up to 20% of pregnant women, is associated with maternal peripheral insulin resistance, low-grade inflammation, and oxidative stress. The flavonoid naringenin has potent anti-diabetic, anti-inflammatory, and anti-oxidative properties; however, its effects in GDM remain unknown. The study aimed to determine the effects of naringenin on glucose metabolism, inflammation, and oxidative stress associated with GDM both in vitro and in vivo. METHODS AND RESULTS: In vitro, human tissue samples obtained at term elective Caesarean section are stimulated with tumour necrosis factor alpha (TNF) to develop a GDM-like environment. Naringenin treatment significantly improves TNF-impaired glucose uptake in skeletal muscle. In placenta and visceral adipose tissue (VAT), naringenin significantly reduces expression of pro-inflammatory cytokines and chemokines and increases antioxidant mRNA expression. Mechanistically, naringenin suppresses nuclear factor κB activation. In vivo, pregnant heterozygous db/+ mice are used to model GDM. Daily intraperitoneal injections of GDM mice with naringenin from gestational day 10-17 significantly improve glucose tolerance, reduces IL1A mRNA expression, and increases antioxidant mRNA expression in placenta, VAT, and subcutaneous adipose tissue. CONCLUSION: Naringenin is shown to improve insulin sensitivity, inflammation, and oxidative stress associated with GDM and shows promise as a novel preventive therapeutic.
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ItemObesity in older adults: Effect of degree of weight loss on cardiovascular markers and medications(WILEY, 2019-08)Obesity worsens the age-related tendency towards cardiovascular disease and diabetes. Older adults are vulnerable to medication adverse effects. Intentional weight loss in older adults with obesity has been shown to improve cardiovascular and glycaemic markers. The effect of rapid weight loss induced by very-low-calorie diets (VLCDs) on these markers has not been evaluated in this group. In this 12-week study, participants were randomized to one of healthy eating, hypocaloric diet or VLCD, all combined with three times weekly exercise (Ex/HE, Ex/Diet, Ex/VLCD, respectively). The effects of these interventions on weight, blood pressure, lipids, glucose and HbA1c , inflammatory markers and cardiovascular and diabetes medication changes were measured. Weight loss was 3.7%, 5.1% and 11.1% in Ex/HE, Ex/Diet and Ex/VLCD, respectively. There were significant improvements in HbA1c in all groups, but by the greatest degree in Ex/VLCD (0.18 ± 0.07%, 0.18 ± 0.06% and 0.59 ± 0.13%, respectively). Similar patterns were seen in total cholesterol (0.13 ± 0.15, 0.21 ± 0.11 and 0.53 ± 0.13 mmol/L, respectively, P = .047), triglycerides (0.35 ± 0.13, 0.20 ± 0.10 and 0.51 ± 0.09 mmol/L, respectively, P = .011) and systolic blood pressure (9 ± 2, 2 ± 3 and 14 ± 3 mmHg respectively, P = .025). There were no between-group differences in fasting glucose, high-density lipoprotein (HDL) cholesterol, LDL-C and inflammatory markers. Reductions in anti-hypertensive or diabetes medication were made in 4/29, 7/36 and 16/37 participants in Ex/HE, Ex/Diet and Ex/VLCD, respectively (P = .017). Significant weight loss achieved with a VLCD gave rise to improvements in multiple cardiovascular risk markers, despite reduction in medication. Weight loss is an under-utilized method of cardiovascular risk management in this group.
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ItemExpression and function of macrophage-inducible C-type lectin (Mincle) in inflammation driven parturition in fetal membranes and myometrium.(Oxford University Press (OUP), 2019-07)The pivotal role of inflammatory processes in human parturition is well known, but not completely understood. We have performed a study to examine the role of macrophage-inducible C-type lectin (Mincle) in inflammation-associated parturition. Using human samples, we show that spontaneous labour is associated with up-regulated Mincle expression in the myometrium and fetal membranes. Mincle expression was also increased in fetal membranes and myometrium in the presence of pro-labour mediators, the proinflammatory cytokines interleukin (IL)-1B and tumour necrosis factor (TNF), and Toll-like receptor (TLR) ligands fsl-1, poly(I:C), lipopolysaccharide (LPS) and flagellin. These clinical studies are supported by mouse studies, where an inflammatory challenge in a mouse model of preterm birth increased Mincle expression in the uterus. Importantly, elimination of Mincle decreased the effectiveness of proinflammatory cytokines and TLR ligands to induce the expression of pro-labour mediators; namely, proinflammatory cytokines and chemokines, contraction-associated proteins and prostaglandins, and extracellular matrix remodelling enzymes, matrix metalloproteinases. The data presented in this study suggest that Mincle is required when inflammatory activation precipitates parturition.
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ItemQuantitative Proteomics by SWATH-MS Suggest an Association Between Circulating Exosomes and Maternal Metabolic Changes in Gestational Diabetes Mellitus(WILEY, 2019-01)Several factors including placental hormones (PH) released from the human placenta have been associated with the development of insulin resistance and gestational diabetes mellitus (GDM). However, circulating levels of PH does not correlate well with maternal insulin sensitivity across gestation, suggesting that other, previously unrecognized, mechanisms may be involved. The levels of circulating exosomes are higher in GDM compared to normal. GDM derived exosomes produce greater release of pro-inflammatory cytokines from endothelial cells compared to exosomes from normal, suggesting that their contents may differ compared to normal pregnancies. Using a quantitative, information-independent acquisition (Sequential Windowed Acquisition of All Theoretical Mass Spectra [SWATH]) approach, differentially abundant circulating exosome proteins are identified in women with normal glucose tolerance (NGT) and GDM at the time of GDM diagnosis. A total of 78 statistically significant proteins in the relative expression of exosomal proteins in GDM are compared with NGT. Bioinformatic analysis shows that the exosomal proteins in GDM target pathways are mainly associated with energy production, inflammation, and metabolism. Finally, an independent cohort of patients is used to validate some of the proteins identified by SWATH. The data obtained may be of utility in elucidating the underlying physiological mechanisms associated with insulin resistance in GDM.
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ItemExpression and regulation of metallothioneins in myometrium and fetal membranes(WILEY, 2018-12)PROBLEM: Metallothioneins (MTs) play important roles in regulating oxidative stress, inflammation, and hormone signaling. These processes play a major role in labor at term and preterm. The aims of this study were to characterize (a) temporal- and labor-associated changes and (b) the effect of pro-inflammatory and pro-labor insults on the expression of MT1 isoforms, MT2A, MT3, and MT4 in fetal membranes and myometrium. METHOD OF STUDY: The expression of MTs was assessed in fetal membranes and myometrium from nonlaboring and laboring women at preterm and term by RT-qPCR. Tissue explants were used to assess the effect of pro-inflammatory cytokines and Toll-like receptor (TLR) ligands on the expression of MTs in fetal membranes and myometrium. RESULTS: In fetal membranes, the expression of MT1A, MT1E, MT1F, MT1X, and MT2A was higher at term compared with preterm. Preterm labor and preterm histological chorioamnionitis were associated with increased expression of MT1A, MT1G, MT1M, MT1X, MT2A, and MT3. Term labor was associated with increased expression of MT1A, MT1F, MT1X, MT2A, and MT3 in fetal membranes and expression of MT1A, MT1E, MT1F, MT1G, MT1M, MT1X, MT2A, and MT3 in myometrium. Pro-inflammatory cytokines and TLR ligands increased the expression of MT1A, MT1E, MT1F, MT1G, MT1H, MT1X, and MT2A in fetal membranes and myometrium. CONCLUSION: Temporal-, labor-, and infection-associated increases in MT1 isoforms, MT2A, and MT3 have been observed in fetal membranes and/or myometrium. Furthermore, pro-inflammatory cytokines and bacterial and viral products increased the expression of MT1 isoforms, MT2A, MT3, and MT4 mRNA expression in fetal membranes and myometrium.