Obstetrics and Gynaecology - Research Publications

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    Chemically-Induced Lipoprotein Breakdown for Improved Extracellular Vesicle Purification.
    Iannotta, D ; A, A ; Lai, A ; Nair, S ; Koifman, N ; Lappas, M ; Salomon, C ; Wolfram, J (Wiley, 2023-12-15)
    Extracellular vesicles (EVs) are nanosized biomolecular packages involved in intercellular communication. EVs are released by all cells, making them broadly applicable as therapeutic, diagnostic, and mechanistic components in (patho)physiology. Sample purity is critical for correctly attributing observed effects to EVs and for maximizing therapeutic and diagnostic performance. Lipoprotein contaminants represent a major challenge for sample purity. Lipoproteins are approximately six orders of magnitude more abundant in the blood circulation and overlap in size, shape, and density with EVs. This study represents the first example of an EV purification method based on the chemically-induced breakdown of lipoproteins. Specifically, a styrene-maleic acid (SMA) copolymer is used to selectively breakdown lipoproteins, enabling subsequent size-based separation of the breakdown products from plasma EVs. The use of the polymer followed by tangential flow filtration or size-exclusion chromatography results in improved EV yield, preservation of EV morphology, increased EV markers, and reduced contaminant markers. SMA-based EV purification enables improved fluorescent labeling, reduces interactions with macrophages, and enhances accuracy, sensitivity, and specificity to detect EV biomarkers, indicating benefits for various downstream applications. In conclusion, SMA is a simple and effective method to improve the purity and yield of plasma-derived EVs, which favorably impacts downstream applications.
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    Newborn and child-like molecular signatures in older adults stem from TCR shifts across human lifespan
    van de Sandt, CE ; Nguyen, THO ; Gherardin, NA ; Crawford, JC ; Samir, J ; Minervina, AA ; Pogorelyy, MV ; Rizzetto, S ; Szeto, C ; Kaur, J ; Ranson, N ; Sonda, S ; Harper, A ; Redmond, SJ ; McQuilten, HA ; Menon, T ; Sant, S ; Jia, X ; Pedrina, K ; Karapanagiotidis, T ; Cain, N ; Nicholson, S ; Chen, Z ; Lim, R ; Clemens, EB ; Eltahla, A ; La Gruta, NL ; Crowe, J ; Lappas, M ; Rossjohn, J ; Godfrey, DI ; Thomas, PG ; Gras, S ; Flanagan, KL ; Luciani, F ; Kedzierska, K (NATURE PORTFOLIO, 2023-11)
    CD8+ T cells provide robust antiviral immunity, but how epitope-specific T cells evolve across the human lifespan is unclear. Here we defined CD8+ T cell immunity directed at the prominent influenza epitope HLA-A*02:01-M158-66 (A2/M158) across four age groups at phenotypic, transcriptomic, clonal and functional levels. We identify a linear differentiation trajectory from newborns to children then adults, followed by divergence and a clonal reset in older adults. Gene profiles in older adults closely resemble those of newborns and children, despite being clonally distinct. Only child-derived and adult-derived A2/M158+CD8+ T cells had the potential to differentiate into highly cytotoxic epitope-specific CD8+ T cells, which was linked to highly functional public T cell receptor (TCR)αβ signatures. Suboptimal TCRαβ signatures in older adults led to less proliferation, polyfunctionality, avidity and recognition of peptide mutants, although displayed no signs of exhaustion. These data suggest that priming T cells at different stages of life might greatly affect CD8+ T cell responses toward viral infections.
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    Exploring sex differences in fetal programming for childhood emotional disorders
    Galbally, M ; Watson, SJ ; Lappas, M ; de Kloet, ER ; Wyrwoll, CS ; Mark, PJ ; Lewis, AJ (PERGAMON-ELSEVIER SCIENCE LTD, 2022-07)
    In examining maternal depression, placental 11β-HSD2 mRNA expression and offspring cortisol regulation as a potential fetal programming pathway in relation to later child emotional disorders, it has become clear that sex differences may be important to consider. This study reports on data obtained from 209 participants in the Mercy Pregnancy and Emotional Wellbeing Study (MPEWS) recruited before 20 weeks of pregnancy. Maternal depressive disorders were diagnosed using the SCID-IV and maternal childhood trauma using the Childhood Trauma Questionnaire. Placental 11β-HSD2 mRNA was measured using qRT-PCR. For assessment of stress-induced cortisol reactivity, salivary cortisol samples were taken at 12 months of age. At 4 years of age, measurement of Childhood Emotional Disorders (depression and anxiety) was based on maternal report using the Preschool Age Psychiatric Assessment (PAPA) and internalizing symptoms using the Child Behavior Checklist (CBCL). Maternal depression in pregnancy and postpartum, and infant cortisol reactivity, was associated with internalizing symptoms for females only. For female offspring only, increased 12-month cortisol reactivity was also associated with increased emotional disorders at 4 years of age; however, there was no association with placental 11β-HSD2 mRNA expression. In females only, the combination of lower placental 11β-HSD2 mRNA expression and higher cortisol reactivity at 12 months of age predicted increased internalising problems. These findings suggest there may be sex differences in prenatal predictors and pathways for early childhood depression and anxiety symptoms and disorder.
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    Examining differences in placental efficiency following exposure to antidepressants and current depression: Findings from an Australian pregnancy cohort study
    Galbally, M ; Watson, SJ ; Spigset, O ; Lappas, M ; Walker, S ; Lewis, AJ (W B SAUNDERS CO LTD, 2022-03-04)
    INTRODUCTION: Placental dysfunction and inefficiency, is important in understanding fetal growth restriction and low birth weight. Two recent studies have examined the relationship between antidepressant use in pregnancy and placental weight ratios; one found lower placental weight ratio associated with antidepressant use and the other found a higher ratio. METHODS: This study examined 342 women recruited in early pregnancy, including 75 taking antidepressants, 29 with current depression and 238 controls. Antidepressant use was measured through self-report in early and late pregnancy, hospital records at delivery and drug concentrations in umbilical cord and maternal blood obtained at delivery. Maternal depression was measured using the Structured Clinical Interview for the DSM IV (SCID) at recruitment. Placentas were collected at delivery and weighed, and infant birth weight recorded. Placental efficiency was measured using standardised placental weight residuals and included as the outcome in general linear models (ANOVA/ANCOVA) to test hypotheses. RESULTS: While placental weight was higher for those on antidepressants compared to controls (z=.30 c.f. Z=-0.08, p=.012), there were no significant differences between the three groups after adjusting for maternal body mass index at recruitment. When comparing antidepressant groups separately there were small-to-moderate positive associations between (SSRI) concentrations and placental weight (rho's > 0.20, p's > 0.05), which did not reach significance. CONCLUSION: Antidepressant use in pregnancy was not associated with significant changes in placental efficiency after adjustment for confounding variables. Future research should expand on this to examine other aspects of placental function and include a wide range of potential confounding variables to draw clinically meaningful conclusions.
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    Immune profiling of SARS-CoV-2 infection during pregnancy reveals NK cell and ?? T cell perturbations
    Habel, JR ; Chua, BY ; Kedzierski, L ; Selva, KJ ; Damelang, T ; Haycroft, ER ; Nguyen, THO ; Koay, H-F ; Nicholson, S ; McQuilten, HA ; Jia, X ; Allen, LF ; Hensen, L ; Zhang, W ; Sandt, CEVD ; Neil, JA ; Pragastis, K ; Lau, JSY ; Jumarang, J ; Allen, EK ; Amanant, F ; Krammer, F ; Wragg, KM ; Juno, JA ; Wheatley, AK ; Tan, H-X ; Pell, G ; Walker, S ; Audsley, J ; Reynaldi, A ; Thevarajan, I ; Denholm, JT ; Subbarao, K ; Davenport, MP ; Hogarth, PM ; Godfrey, DI ; Cheng, AC ; Tong, SYC ; Bond, K ; Williamson, DA ; McMahon, JH ; Thomas, PG ; Pannaraj, PS ; James, F ; Holmes, NE ; Smibert, OC ; Trubiano, JA ; Gordon, CL ; Chung, AW ; Whitehead, CL ; Kent, SJ ; Lappas, M ; Rowntree, LC ; Kedzierska, K (AMER SOC CLINICAL INVESTIGATION INC, 2023-03-22)
    Pregnancy poses a greater risk for severe COVID-19; however, underlying immunological changes associated with SARS-CoV-2 during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in unvaccinated pregnant and nonpregnant women with acute and convalescent COVID-19, quantifying 217 immunological parameters. Humoral responses to SARS-CoV-2 were similar in pregnant and nonpregnant women, although our systems serology approach revealed distinct antibody and FcγR profiles between pregnant and nonpregnant women. Cellular analyses demonstrated marked differences in NK cell and unconventional T cell activation dynamics in pregnant women. Healthy pregnant women displayed preactivated NK cells and γδ T cells when compared with healthy nonpregnant women, which remained unchanged during acute and convalescent COVID-19. Conversely, nonpregnant women had prototypical activation of NK and γδ T cells. Activation of CD4+ and CD8+ T cells and T follicular helper cells was similar in SARS-CoV-2-infected pregnant and nonpregnant women, while antibody-secreting B cells were increased in pregnant women during acute COVID-19. Elevated levels of IL-8, IL-10, and IL-18 were found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, we demonstrate perturbations in NK cell and γδ T cell activation in unvaccinated pregnant women with COVID-19, which may impact disease progression and severity during pregnancy.
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    Selenium Prevents Inflammation in Human Placenta and Adipose Tissue In Vitro: Implications for Metabolic Diseases of Pregnancy Associated with Inflammation.
    Nguyen-Ngo, C ; Perkins, AV ; Lappas, M (MDPI AG, 2022-08-11)
    Gestational diabetes mellitus (GDM) and maternal obesity are significant metabolic complications increasingly prevalent in pregnancy. Of major concern, both GDM and maternal obesity can have long-term detrimental impacts on the health of both mother and offspring. Recent research has shown that increased inflammation and oxidative stress are two features central to the pathophysiology of these metabolic conditions. Evidence suggests selenium supplementation may be linked to disease prevention in pregnancy; however, the specific effects of selenium on inflammation and oxidative stress associated with GDM and maternal obesity are unknown. Therefore, this study aimed to investigate the effect of selenium supplementation on an in vitro model of GDM and maternal obesity. Human placental tissue, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were stimulated with either the bacterial product lipopolysaccharide (LPS) or the pro-inflammatory cytokine TNF-α. Selenium pre-treatment blocked LPS and TNF-α induced mRNA expression and secretion of pro-inflammatory cytokines and chemokines, while increasing anti-inflammatory cytokine and antioxidant mRNA expression in placenta, VAT and SAT. Selenium pre-treatment was also found to inhibit LPS- and TNF-α induced phosphorylation of ERK in placenta, VAT and SAT. These findings indicate that selenium may be able to prevent inflammation and oxidative stress associated with GDM and maternal obesity. Additional in vivo studies are required to identify the efficacy of selenium supplementation in preventing inflammatory pathways activated by GDM and maternal obesity and to elucidate the mechanism involved.
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    Punicalagin Suppresses Mediators Involved in Labor Onset and Progression in vitro
    Nguyen-Ngo, C ; Willcox, JC ; Lappas, M (Science Publications, 2021-01-01)
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    Extracellular vesicles and their potential role inducing changes in maternal insulin sensitivity during gestational diabetes mellitus
    Nair, S ; Ormazabal, V ; Lappas, M ; McIntyre, HD ; Salomon, C (WILEY, 2021-02)
    Gestational diabetes mellitus (GDM) is one of the most common endocrine disorders during gestation and affects around 15% of all pregnancies worldwide, paralleling the global increase in obesity and type 2 diabetes. Normal pregnancies are critically dependent on the development of maternal insulin resistance balanced by an increased capacity to secrete insulin, which allows for the allocation of nutrients for adequate foetal growth and development. Several factors including placental hormones, inflammatory mediators and nutrients have been proposed to alter insulin sensitivity and insulin response and underpin the pathological outcomes of GDM. However, other factors may also be involved in the regulation of maternal metabolism and a complete understanding of GDM pathophysiology requires the identification of these factors, and the mechanisms associated with them. Recent studies highlight the potential utility of tissue-specific extracellular vesicles (EVs) in the diagnosis of disease onset and treatment monitoring for several pregnancy-related complications, including GDM. To date, there is a paucity of data defining changes in the release, content, bioactivity and diagnostic utility of circulating EVs in pregnancies complicated by GDM. Placental EVs may engage in paracellular interactions including local cell-to-cell communication between the cell constituents of the placenta and contiguous maternal tissues, and/or distal interactions involving the release of placental EVs into biological fluids and their transport to a remote site of action. Hence, the aim of this review is to discuss the biogenesis, isolation methods and role of EVs in the physiopathology of GDM, including changes in maternal insulin sensitivity during pregnancy.
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    Obstetric and perinatal outcomes for women with pre-existing diabetes in rural compared to metropolitan settings in Victoria, Australia
    Williamson, RL ; McCarthy, EA ; Oats, JJ ; Churilov, L ; Lappas, M ; Shub, A (WILEY, 2021-06)
    BACKGROUND: Pre-existing diabetes in pregnancy is associated with an increased risk of complications. Likewise, living in rural, regional and remote Victoria, Australia, is also associated with poorer health outcomes. There is a gap in the literature with regard to whether Victorian women with pre-existing diabetes experience a greater risk of adverse pregnancy outcomes compared to their metropolitan counterparts. AIM: Our objective is to compare obstetric and perinatal outcomes for women with pre-existing diabetes delivering in rural vs metropolitan hospitals in Victoria, Australia. MATERIALS AND METHODS: Retrospective population-based study using routinely collected state-based data of singleton births to women with type 1 and type 2 diabetes who delivered in metropolitan (n = 3233) and rural hospitals (n = 693) in Victoria, Australia, between 2006-2015. Pearson's χ2 test, Fisher's exact test and MannWhitney U-test were used to compare obstetric and perinatal outcomes between metropolitan and rural locations. RESULTS: Delivery in a rural hospital was associated with higher rates of stillbirth (2.3% vs 1.1%, P = 0.027), macrosomia (25.9% vs 16.9%, P < 0.001), shoulder dystocia (8.4% vs 3.5%, P < 0.001) and admission to the neonatal intensive care unit/special care nursery (73.2% vs 59.3%, P < 0.001). Smoking (18.0% vs 8.9%, P < 0.001), overweight/obesity (P = 0.047) and socioeconomic disadvantage (P < 0.001) were more common in rural women. CONCLUSIONS: Women with pre-existing diabetes who deliver in rural hospitals experience a greater risk of adverse perinatal outcomes and present with increased maternal risk factors. These results suggest a need to improve care for women with pre-existing diabetes in rural Victoria.
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    Hepatitis A virus cellular receptor 2 (HAVCR2) is decreased with viral infection and regulates pro-labour mediators OA
    Liong, S ; Lim, R ; Barker, G ; Lappas, M (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.