ORCID Profile
0000-0002-5403-6266
Current Organisations
University of Western Australia
,
King Edward Memorial Hospital
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Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology) | Psychology | Developmental Psychology and Ageing
Child Health | Expanding Knowledge in Psychology and Cognitive Sciences |
Publisher: Elsevier BV
Date: 12-1999
Abstract: Increased production of prostaglandins and cytokines by amnion, particularly prostaglandin (PG) E2, interleukin (IL)-6 and IL-8, is thought to be an important event in infection-associated preterm labour. We characterized the amnion-derived AV3 cell line to determine its appropriateness as a model for investigation of the regulation of amnion cytokine and PG production. Amnion-derived AV3 cells were treated with tumour necrosis factor-alpha (TNF-alpha, interleukin-1beta (IL-1beta), epidermal growth factor (EGF) and phorbol 12-myristate 13-acetate (PMA) and IL-6, IL-8 and prostaglandin production was determined by immunoassay. Production of IL-6 and IL-8 rose dramatically with all treatments. PGE2, but not PGF2alpha or 6-keto-PGF1alpha, biosynthesis was also increased in a concentration-dependent manner with all treatments. A rapid increase in PGHS-2 (but not PGHS-1) mRNA expression was observed in response to TNF-alpha and IL-1beta. We conclude that the AV3 cell line inflammatory response profile is similar to those observed in primary amnion and other amnion-derived cell lines, and is an appropriate model for human amnion.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Elsevier BV
Date: 2000
Abstract: The effects of pro-inflammatory cytokines on 15-hydroxyprostaglandin dehydrogenase (PGDH) expression and prostaglandin (PG) metabolizing activity were investigated in placental tissue. Treatment of trophoblast cells in primary culture with interleukin-1beta (IL-1beta) or tumour necrosis factor-alpha (TNF-alpha) resulted in decreased prostaglandin metabolizing activity. This was assessed both by determining the ratio of production of prostaglandins to their metabolites, and by Northern blot analysis of PGDH mRNA abundance. Dexamethasone had similar inhibitory effect. We hypothesize that proinflammatory cytokines act to enhance prostaglandin actions through coordinated effects on activities of enzymes of both prostaglandin biosynthesis and metabolism, perhaps in concert with effects on receptor function.
Publisher: Oxford University Press (OUP)
Date: 10-01-2012
Abstract: Oxidized cholesterol metabolites (oxysterols) promote inflammation in a variety of cell types and are thought to be involved in a number of disease pathologies. Oxysterol concentrations are increased in pregnancy, together with systemic oxidative stress and inflammation. We tested the hypothesis that oxysterols 25-hydroxycholesterol (25-OHC) and 7-ketocholesterol (7-ketoC) promote placental trophoblast inflammation, and determined the mechanisms involved. Treatment of primary trophoblasts in culture with 25-OHC and 7-ketoC increased the production of proinflammatory cytokines (interleukin-6, macrophage inflammatory protein-1β and tumour necrosis factor-α) in a concentration-dependent fashion. Inhibition of TLR4 activation using selective inhibitors of TLR4 complex formation (OxPAPC) or signalling transmission (CLI095) prevented lipopolysaccharide (LPS)- and oxysterol-induced inflammatory cytokine production. Pretreatment of trophoblasts with selective inhibitors of I-kB kinase activity (parthenolide and TPCA-1) reduced oxysterol- and LPS-stimulated inflammatory responses, consistent with the involvement of the nuclear factor kappa B (NF-κB) pathway downstream of TLR4 signalling. Both oxysterols also increased the phosphorylation and nuclear localization of NF-κB subunit p65/RelA. Oxysterols are also known to activate liver X receptors (LXRs) which can inhibit inflammatory signalling, either directly or indirectly via membrane cholesterol reduction. Treatment with the LXR agonist, T0901317, exerted significant anti-inflammatory effects, reducing LPS- and oxysterol-driven cytokine production. Treatment with methyl-β-cyclodextrin to deplete membrane microdomain cholesterol and thereby disrupt TLR4 signalling, similarly abrogated their effects. Together, these findings indicate that although oxysterols likely activate both pro- and anti-inflammatory pathways in the placenta, the predominant effect is the promotion of placental inflammation via TLR4-dependent activation of NF-κB.
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.PLACENTA.2009.12.008
Abstract: Workshops are an important part of the annual meeting of the International Federation of Placenta Associations (IFPA). At IFPA Meeting 2009 erse topics were discussed in twelve themed workshops. Topics covered included: immune response to pregnancy signaling between fetus and placenta bioactive lipids in placenta placenta in agricultural species epigenetics and placentation trophoblast deportation glucocorticoids and placental function endothelium placental transport genes and placenta uteroplacental blood flow and placental stem cells. This report is a full summary of the various topics covered.
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.AJOG.2010.02.031
Abstract: The purpose of this study was to test the hypothesis that periodontopathic bacteria exert potent proinflammatory effects in human decidua. The immunostimulatory effects of Gram-positive and negative periodontopathic bacteria and their lipopolysaccharides were tested in human decidual cell cultures in comparison with Escherichia coli. Cytokine production was measured by enzyme-linked immunosorbent assay inflammatory gene expression was measured by oligonucleotide arrays and quantitative real time-polymerase chain reaction. All bacteria that were tested elicited an inflammatory response, although concentration-dependence and efficacy varied considerably with organism and culture. Lipopolysaccharides were more potent stimuli than intact bacterial cells, although bacteria exerted greater effects at high concentrations. Of 112 genes on the arrays, 18 genes were stimulated significantly by one or more lipopolysaccharide preparation. The ability of periodontopathic bacteria to stimulate a decidual inflammatory response is highly variable and partly dependent on the presence and structure of constituent lipopolysaccharides. This adds to our understanding of the causal association between periodontal disease and preterm birth.
Publisher: Oxford University Press (OUP)
Date: 27-09-2022
Abstract: Does mental health and behaviour differ between those conceived with and those conceived without ART? Our study observed less externalizing behaviour (delinquent/aggressive), and more parent-reported internalizing behaviour, as well as more (clinical) depression at age 14 years, in adolescents conceived after ART compared to their non-ART counterparts. Health outcomes of ART-conceived offspring may differ from those conceived without ART, and previous studies have reported differences in behaviour and mental health, particularly in childhood. The Growing Up Healthy Study (GUHS) is a prospective cohort study, investigating the long-term health of offspring conceived after ART (aged 14, 17 and 20 years), in the two operational fertility clinics in Western Australia 1991–2001 (n = 303). Their long-term health outcomes were compared to those of offspring conceived without ART from the Raine Study Generation 2 (Gen2) born 1989–1991 (n = 2868). Both cohorts are representative of the local adolescent population. Mental health parameters and behaviour were assessed at ages 14 and 17 years, through the parent completed ‘Child Behaviour Checklist’ (CBCL ART versus non-ART: age 14 years: N = 150 versus N = 1781, age 17 years: N = 160 versus N = 1351), and the adolescent completed equivalent ‘Youth Self-Report’ (YSR age 14 years: by N = 151 versus N = 1557, age 17 years: N = 161 and N = 1232). Both tools generate a T-score (standardized for age and sex) for internalizing (withdrawn, somatic complaints, anxious/depressed), externalizing (delinquent/aggressive behaviour) and total behaviour. Adolescents also completed the ‘Beck Depression Inventory for Youth’ (BDI-Y age 14 years: N = 151 versus N = 1563, age 17 years: N = 161 versus N = 1219). Higher scores indicate poorer mental health and behaviour on all the above tools. Parent-reported doctor-diagnosed conditions (anxiety, behavioural problems, attention problems and depression) were also univariately compared between the cohorts. In addition, univariate comparisons were conducted between the GUHS adolescents and Gen2 adolescents born to subfertile parents (time to pregnancy & months), as well as between offspring born to subfertile versus fertile parents within the Gen2 cohort. A subgroup analysis excluding offspring born preterm (& weeks’ gestation) or at low birthweight (& g) was also performed. Generalized estimating equations that account for correlated familial data were adjusted for the following covariates: non-singleton, primiparity, primary caregiver smoking, family financial problems, socio-economic status and both maternal and paternal ages at conception. At both 14 and 17 years of age, ART versus non-ART-conceived adolescents reported lower mean T-scores for externalizing problems (age 14 years: 49 versus 51, P = 0.045, age 17 years: 49 versus 52, P & 0.001). A similar effect was reported by parents, although not significant (age 14 years: P = 0.293, age 17 years: P = 0.148). Fewer ART-conceived adolescents reported a T-score above the clinical cut-off for externalizing behaviour (≥60 age 14 years: 7.3% versus 16.3%, P = 0.003, age 17 years: 8.1% versus 19.7%, P & 0.001). At both ages, no differences in internalizing behaviour were reported by adolescents (age 14 years: P = 0.218, age 17 years: P = 0.717) however, higher mean scores were reported by parents of the ART-conceived adolescents than by parents of the non-ART conceived adolescents (age 14 years: 51 versus 48, P = 0.027, age 17 years: 50 versus 46, P & 0.001). No differences in internalizing behaviour above the clinical cut-off (T-score ≥ 60) were observed. At age 17 years, parents who conceived through ART reported higher total behaviour scores than those parents who conceived without ART (48 versus 45, P = 0.002). At age 14 years, ART versus non-ART-conceived adolescents reported significantly higher mean scores on the BDI-Y (9 versus 6, P = 0.005) a higher percentage of adolescents with a score indicating clinical depression (≥17 12.6% versus 8.5%, aOR 2.37 (1.18–4.77), P = 0.016), as well as more moderate/severe depression (≥21 9.3% versus 4.0%, P = 0.009). At age 17 years, no differences were reported on the BDI-Y. There was also a higher percentage of parent-reported doctor-diagnosed anxiety in the ART cohort (age 14 years: 8.6% versus 3.5%, P = 0.002, at age 17 years: 12.0% versus 4.5%, P & 0.001). Removing adolescents born preterm or at low birthweight did not alter the above results. Comparing outcomes between GUHS adolescents and Gen2 adolescents born to subfertile parents, as well as between those born to subfertile versus fertile parents within Gen2, did not alter results for CBCL and YSR outcomes. Those born to subfertile parents showed higher rates of clinical depression than those born to fertile parents at age 14 years (13.7% versus 6.9%, P = 0.035). The main limitation of the study is the time difference between the GUHS and Gen2 assessments. Even though we have adjusted for covariates, additional socio-economic and lifestyle factors affecting behaviour and mental well-being could have changed. We were unable to differentiate between different types of ART (e.g. IVF versus ICSI), owing to the low number of ICSI cycles at the time of study. Fertility sub-analyses need to be replicated in larger cohorts to increase power, potentially using siblingship designs. Lastly, selection bias may be present. The reported lower prevalence of externalizing behaviour (delinquent/aggressive), and higher prevalence of internalizing behaviour, as well as more (clinical) depression at age 14 years, in ART versus non-ART-conceived adolescents, is in line with some previous studies, mostly conducted in childhood. It is reassuring that differences in the rates of depression were not observed at age 17 years, however, these findings require replication. As the use of ART is common, and mental health disorders are increasing, knowledge about a potential association is important for parents and healthcare providers alike. This project was funded by an NHMRC Grant (Hart et al., ID 1042269). R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director of PIVET Medical Centre, Perth, Western Australia. N/A.
Publisher: The American Association of Immunologists
Date: 2003
DOI: 10.4049/JIMMUNOL.170.1.158
Abstract: Increased production of PGs by gestational membranes is believed to be a principal initiator of term and preterm labor. Intrauterine infection is associated with an inflammatory response in the choriodecidua characterized by elevated production of cytokines and PGs. The precise physiological significance of enhanced choriodecidual cytokine production in the mechanism of preterm labor remains uncertain. These studies were undertaken to dissect the roles and regulation of endogenous cytokines in regulating PG production by human choriodecidua. We used LPS treatment of human choriodecidual explants as our model system. In choriodecidual explant cultures, LPS (5 μg/ml) induced a rapid increase in TNF-α production, peaking at 4 h. In contrast, IL-10, IL-1β, and PGE2 production rates peaked 8, 12, and 24 h, respectively, after LPS stimulation. Immunoneutralization studies indicated that TNF-α was a primary regulator of IL-1β, IL-10, and PGE2 production, while IL-1β stimulated only PGE2 production. Neutralization of endogenous IL-10 resulted in increased TNF-α and PGE2 production. IL-10 treatment markedly decreased TNF-α and IL-1β production, but had no effect on PGE2 production. Taken together, these results demonstrate that the effects of LPS on choriodecidual cytokine and PG production are modulated by both positive and negative feedback loops. In the setting of an infection of the intrauterine, TNF-α may be a potential target for treatment intervention IL-10 could be one such therapeutic.
Publisher: Elsevier BV
Date: 12-2022
DOI: 10.1016/J.RBMO.2022.07.007
Abstract: Are asthma and allergies more common in adolescents conceived with assisted reproductive technologies (ART) compared with adolescents conceived without? The Growing Up Healthy Study (GUHS) is a prospective cohort study including ART-conceived offspring born between 1991 and 2001 in Perth, Australia. Their long-term health outcomes, including asthma and allergy parameters, were compared with those of their counterparts conceived without ART from the Raine Study Generation 2 (Gen2), born in 1989-1991. At age 14, 152 GUHS and 1845 Gen2 participants completed the following assessments: the International Studies of Asthma and Allergies in Childhood (ISAAC) questionnaire, spirometry, methacholine challenge testing and skin prick testing (SPT). No differences were detected in the prevalence of current asthma (7.7% versus 10.8%, adjusted odds ratio [aOR] 0.82 (95% CI 0.44-1.52), P = 0.530). Spirometry-measured lung volumes were larger in the ART adolescents. Bronchial hyperresponsiveness was less prevalent in the ART cohort (8.8 versus 18.6%, P = 0.006). Current allergic rhinoconjunctivitis (ARC) rates were significantly higher in the ART cohort (32.4% versus 25.2%, aOR 1.52 [95% CI 1.03-2.26], P = 0.036), with no cohort differences in atopic dermatitis. Food allergies were more prevalent in the ART cohort (20.7 versus 10.9%, aOR 1.89 [95% CI 1.17-3.06], P = 0.010) with more adolescents having a positive SPT (68.0% versus 45.4%, aOR 3.03 [95% 1.99-4.63], P < 0.001). This study reports no differences in asthma prevalence, slightly altered lung function, an increase in ARC, food allergies and positive SPT in the ART-conceived adolescents. These findings are important to families and healthcare providers and may open up possibilities for targeted screening and treatment. Further studies are required to confirm these findings.
Publisher: American Physiological Society
Date: 02-2008
DOI: 10.1152/AJPENDO.00495.2007
Abstract: Endocannabinoids have been implicated in the mechanisms of implantation, maintenance of pregnancy, and parturition in women. Intrauterine prostaglandin production and actions are also critical in each of these mechanisms. Hence, we have evaluated the effects of cannabinoids on prostaglandin biosynthesis by human gestational membranes. Explants of term amnion and choriodecidua were established and treated with the endogenous endocannabinoids 2-arachidonoyl glycerol and anandamide, as well as the synthetic cannabinoid CP55,940, to determine their ability to modulate PGE 2 production. The explants were also treated with CP55,940 in the presence of either SR141716A (a potent and selective antagonist of the cannabinoid receptor CB1) or NS398 [a cyclooxygenase (COX)-2 inhibitor] to determine whether any observed stimulation of PGE 2 production was mediated through the CB1-receptor and/or COX-2 activity. All three cannabinoids caused a significant increase in PGE 2 production in the amnion but not in the choriodecidua. However, separated fetal (chorion) explants responded to cannabinoid treatment in a similar manner to amnion, whereas maternal (decidual) explants did not. The enhanced PGE 2 production caused by CP55,940 was abrogated by cotreatment with either SR141716A or NS398, illustrating that the cannabinoid action on prostaglandin production in fetal membranes is mediated by CB1 agonism and COX-2. Data from Western blotting show that cannabinoid treatment results in the upregulation of COX-2 expression. This study demonstrates a potential role for endocannabinoids in the modulation of prostaglandin production in late human pregnancy, with potentially important implications for the timing and progression of term and preterm labor and membrane rupture.
Publisher: Elsevier BV
Date: 10-1997
DOI: 10.1016/S0169-328X(97)00181-2
Abstract: The breakdown of membrane phospholipids and subsequent arachidonic acid metabolism to prostanoids is a well-documented brain response to cerebral ischemia. To further elucidate the components of this signal transduction pathway, immunocytochemistry was used to determine the levels of two potentially important enzymes, cytosolic phospholipase A2 (cPLA2) and prostaglandin H synthase-2 (PGHS-2), in the immature rat brain following moderate unilateral hypoxic-ischemia (HI). The CA1 pyramidal cells of the hippoc us which undergo delayed neuronal death on the injured side following HI demonstrated a significant induction of PGHS-2 immunoreactivity 48 h post-insult. However, a consistent increase in PGHS-2 was also evident in the resistant dentate granule cells at an earlier time point. Although PGHS-2 is present in both susceptible and resistant cell populations following HI, the possibility remains that ergence further down-stream in the pathway is responsible for selective vulnerability. In contrast to the neuronal PGHS-2 expression, cPLA2 immunoreactivity appears to be of glial origin with increases in and around the CAI-2 pyramidal cell layer at the 72-168-h time points. These results suggest that prostanoids are likely to serve important roles in HI brain damage and repair in infant brain.
Publisher: Springer Science and Business Media LLC
Date: 30-09-2014
Publisher: Elsevier BV
Date: 12-2021
Publisher: Elsevier BV
Date: 2023
DOI: 10.2139/SSRN.4362559
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.BIOPSYCHO.2014.08.009
Abstract: Two competing theories address the influence of foetal testosterone on cerebral laterality: one proposing exposure to high foetal testosterone concentrations is related to atypical lateralisation (Geschwind-Galaburda hypothesis), the other that high foetal testosterone concentrations exaggerate typical lateralisation (callosal hypothesis). The current study examined the relationship between cord testosterone concentrations and cerebral laterality for language and spatial memory in adulthood. Male participants with high (>0.15nmol) and low (<0.10nmol) cord testosterone levels were invited to take part in the study (n=18 in each group). Cerebral laterality was measured using functional Transcranial Doppler ultrasonography, while participants completed word generation and visual short-term memory tasks. Typical left lateralisation of language was more common in the high-testosterone group than in the low-testosterone group, χ(2)=4.50, df=1, p=034. Spatial memory laterality was unrelated to cord testosterone level. Our findings indicate that foetal testosterone exposure is related to language laterality in a direction that supports the callosal hypothesis.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.FERTNSTERT.2016.08.014
Abstract: To study whether the size and texture of oocytes/zygotes differ between in vitro maturation (IVM) and traditional IVF and to determine whether these affect the rate of fertilization and blastocyst development. Prospective case-control study. Fertility clinic. The study involved 83 participants/cycles of IVF with intracytoplasmic sperm injection (ICSI) or IVM treatment. Participants were allocated to the following groups: patients with and without polycystic ovary syndrome (PCOS) undergoing ICSI (PCOS-ICSI and Control-ICSI), and patients with PCOS undergoing IVM (PCOS-IVM). All oocytes were cultured in an Embryoscope incubator. Oocyte/zygote sizes were recorded and texture parameters of the ooplasm were analyzed using ImageJ and maZda software. Measurements were recorded at five developmental stages: sperm injection, second polar body extrusion, the first pronuclei appearance, pronuclei disappearance, and immediately before cytokinesis. Normally fertilized PCOS-IVM oocytes were significantly larger at the sperm injection and second polar body extrusion stages, compared with both the PCOS-ICSI and Control-ICSI groups. The PCOS-IVM oocytes were significantly larger at the pronuclei disappearance stage compared with the Control-ICSI group. Oocyte texture parameters were significantly different from both other treatment groups in the early developmental stages, although these were predominantly seen when compared with the Control-ICSI group. There were no significant differences in size or texture by the final stage of immediately before cytokinesis between any of the treatment groups. This study suggests that oocyte size and texture differ in the early stages of the first cell cycle.
Publisher: MDPI AG
Date: 29-04-2021
Abstract: Phthalates are ubiquitous environmental chemicals with endocrine disrupting properties and potentially obesogenic effects. We hypothesised that antenatal phthalate exposure may influence growth and adiposity patterns in girls through childhood into adolescence. Among 1342 Raine Study singleton females, 462 had maternal serum and at least one outcome available up to 20 years of age. In iduals’ maternal serum collected at 18 and 34 weeks gestation was pooled and analyzed for concentrations of 32 metabolites of 15 phthalate diesters. Cox regression and linear models were used to determine associations between maternal phthalate levels and age at menarche, change in height and weight z-scores between birth and two years, height from birth to 20 years, BMI from two to 20 years, deviation from mid-parental height at age 20 and DEXA scan measures at age 20. Weak negative associations were detected with some phthalate metabolites and change in height and weight z-score during infancy. Weak positive associations between some of the high molecular weight phthalate metabolites and height z-score were detected during childhood. While still within the normal range, age at menarche was slightly delayed in girls with higher prenatal exposure to the higher molecular weight phthalate metabolites. We derived some associations between prenatal phthalate exposure with early growth patterns and age at menarche.
Publisher: Bentham Science Publishers Ltd.
Date: 18-05-2018
DOI: 10.2174/1381612824666180130122450
Abstract: Inflammatory activation, a major driver of preterm birth and subsequent neonatal morbidity, is an attractive pharmacological target for new preterm birth therapeutics. Inflammation elicited by intraamniotic infection is causally associated with preterm birth, particularly in infants delivered ≤34 weeks’ gestation. However, sterile triggers of PTB, including placental ischaemic injury, uterine distention, cervical disease, or imbalance in the immune response, also act through inflammatory mediators released in response to tissue damage. Toll-like Receptors (TLRs) are critical upstream gate-keepers controlling the inflammatory activation that precedes preterm delivery, as well as in normal term labour. In particular, TLR4 is implicated for its capacity to sense and integrate a range of disparate infectious and sterile pro-inflammatory triggers, and so acts as a point-ofconvergence through which a range of infectious and sterile agents can activate and accelerate the parturition cascade. Recent studies point to the TLR4 signalling complex as a tractable target for the inhibition of fetal, placental & intraamniotic inflammatory cytokine production. Moreover, studies on mice show that novel small molecule antagonists of TLR4 signalling are highly effective in preventing preterm birth induced by bacterial mimetic LPS, heat-killed E. coli or the TLR4-dependent pro-inflammatory lipid, Platelet Activating Factor (PAF). In this review, we discuss the role of TLR4 in regulating the timing of birth and the potential utility of TLR4 antagonists as novel therapeutics for preterm delivery.
Publisher: Wiley
Date: 26-06-2007
Abstract: The efflux pump ATP binding cassette superfamily member G2 (ABCG2)/breast cancer resistance protein (BCRP) is highly expressed in human placenta. We have investigated the role of BCRP in the protection of the human placental trophoblasts from apoptosis and its expression in idiopathic fetal growth restriction, a condition associated with abnormal placental apoptosis. Inhibition of BCRP activity with the selective inhibitor Ko143 augmented cytokine (tumor necrosis factor-alpha/interferon-gamma)-induced apoptosis and phosphatidylserine externalization in primary trophoblast and trophoblast-like BeWo cells. Silencing of BCRP expression in BeWo cells significantly increased their sensitivity to apoptotic injury in response to cytokines and exogenous C6 and C8 ceramides. BCRP silencing also increased intracellular ceramide levels after cytokine exposure but did not affect cellular protoporphyrin IX concentrations or sensitivity to activators of the intrinsic apoptotic pathway. BCRP expression in placentas from pregnancies complicated by idiopathic fetal growth restriction was decreased compared with controls, suggesting reduced transport of its substrates from the placenta. We conclude that BCRP may play a hitherto unrecognized survival role in the placenta, protecting the trophoblast against cytokine-induced apoptosis and possibly other extrinsic activators via modulation of ceramide signaling. Decreased placental BCRP expression may result in reduced viability and hence functional deficit, contributing to the fetal growth restriction phenotype.
Publisher: The Endocrine Society
Date: 08-2003
Abstract: We have studied TNF-related apoptosis-inducing ligand (TRAIL) and its membrane-bound (R1-R4) and soluble receptors [osteoprotegerin (OPG)] in gestational membranes to assess their significance in preterm parturition and premature rupture of membranes (PROM). TRAIL was detected by ELISA in extracts of term choriodecidual (but not amnion) tissues and explant-conditioned media. Concentrations of OPG (determined using ELISA) in gestational membranes were 20- to 50-fold greater than those of TRAIL. Median OPG concentrations in amniotic fluid (AF) at 15-17 wk gestation were similar to those at term before and during labor, whereas levels in pregnancies s led preterm were significantly elevated. OPG levels in AF from women with preterm PROM were similar to those from women in preterm labor. In contrast, in pooled AF s les (n = 23-33), TRAIL concentrations at term with and without labor were elevated compared with s les from preterm deliveries. TRAIL-R3 and -R4 decoy receptors were detected in term amnion and choriodecidual extracts by immunoblotting and were localized by immunohistochemistry to amnion epithelial cells and chorionic trophoblasts. TRAIL (100 ng/ml) had little or no effect on amnion or choriodecidual cell viability or apoptosis, although these tissues responded to TNF-alpha with increased prostaglandin E(2) production. Our findings suggest that OPG is abundant in gestational membranes and, in concert with TRAIL decoy receptors, may protect resident cells of the fetal membranes against the proapoptotic effects of TRAIL and other related ligands during pregnancy.
Publisher: Wiley
Date: 16-02-2022
DOI: 10.1111/JPC.15899
Abstract: Following trials of inhaled antibiotics in adults, this study investigates the efficacy of nebulised gentamicin to improve respiratory function in children with bronchiectasis. This is a randomised, double‐blind, placebo‐controlled, crossover trial of 12‐week nebulised placebo/gentamicin, 6‐week washout, 12‐week gentamicin lacebo. Participants were children (5–15 years) with bronchiectasis, chronic infection (any pathogen), and able to perform spirometry from a hospital bronchiectasis clinic. Primary outcomes were change in forced expiratory volume in 1 s (FEV 1 ) and hospitalisation days. Secondary outcomes included sputum bacterial density, sputum inflammatory markers, additional antibiotics and symptom severity. Analyses were on an intention‐to‐treat basis. Fifteen children (mean 11.7‐years‐old) completed the study. There was no significant change in mean FEV 1 (56%/55%, P = 0.38) or annual rate of hospital admissions (1.1/0, P = 0.12) between gentamicin and placebo, respectively. However, Haemophilus influenza e sputum growth (27% vs. 80%, P = 0.002) and bacterial density (2.4 log 10 cfu/mL lower P 0.001) improved with gentamicin. Sputum inflammatory markers interleukin‐1β ( P 0.001), interleukin‐8 ( P 0.001) and tumour necrosis factor‐α ( P = 0.003) were lower with gentamicin. Poor recruitment limited study power and treatment adherence was challenging for this cohort. In this crossover study of nebulised gentamicin in children with bronchiectasis, there was a reduction in sputum bacterial density and inflammation. However, there were no major improvements in clinical outcomes and adherence was a challenge.
Publisher: Oxford University Press (OUP)
Date: 02-2013
DOI: 10.1095/BIOLREPROD.112.103754
Abstract: Placental oxidative stress plays a key role in the pathophysiology of several placenta-related disorders including intrauterine growth restriction. Oxidative stress occurs when accumulation of reactive oxygen species damages DNA, proteins, and lipids, an outcome normally limited by antioxidant defenses. Dietary supplementation with omega-3 polyunsaturated fatty acids (n-3 PUFAs) may limit oxidative stress by increasing antioxidant capacity, but n-3 PUFAs are also highly susceptible to lipid peroxidation so n-3 PUFA supplementation is potentially harmful. Here we examined the effect of n-3 PUFAs on placental oxidative stress and on placental and fetal growth in the rat. We also investigated whether diet-induced changes in maternal plasma fatty acid profiles are associated with comparable changes in placental and fetal tissues. Rats were fed either standard or high n-3 PUFA diets from Day 1 of pregnancy, and tissues were collected on Day 17 or 22 (term = Day 23). Dietary supplementation with n-3 PUFAs increased fetal (6%) and placental (12%) weights at Day 22, the latter attributable primarily to growth of the labyrinth zone (LZ). Increased LZ weight was accompanied by reduced LZ F(2)-isoprostanes (by 31% and 11% at Days 17 and 22, respectively), a marker of oxidative damage. Maternal plasma PUFA profiles were altered by dietary fatty acid intake and were strongly predictive of corresponding profiles in placental and fetal tissues. Our data indicate that n-3 PUFA supplementation reduces placental oxidative stress and enhances placental and fetal growth. Moreover, fatty acid profiles in the mother, placenta, and fetus are highly dependent on dietary fatty acid intake.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2014
DOI: 10.1158/1055-9965.EPI-13-1321
Abstract: Background: Prenatal estrogen exposure is thought to contribute to later life diseases such as breast cancer. However, few studies have directly measured prenatal estrogens and most have relied on proposed “markers” of estrogen exposure. We used a large population-based birth cohort to directly measure the relationship between prenatal estrogens and perinatal characteristics, including putative markers of estrogen exposure. Methods: Total estrone (E1), estradiol (E2), estriol (E3), and estetrol (E4) were assayed by liquid chromatography/tandem mass spectrometry from archived mixed arterial and venous serum from 860 umbilical cord blood s les. Results: Values for all estrogens were strongly intercorrelated. Cord estrogen concentrations did not differ between males and females. Levels of all estrogens were reduced in twins and concentrations increased with gestational age. Neither E1 nor E2 was correlated with birth weight, but E3 and E4 levels correlated weakly, whereas onset of labor was associated with higher estrogen concentrations. E1 and E2 concentrations were not associated with preecl sia in the current pregnancy, but E3 and E4 concentrations were lower in pregnancies complicated by preecl sia and antepartum hemorrhage. Conclusions: Umbilical cord estrogen concentrations vary with gestational age, mode of delivery, pregnancy complications, and twinning, but not with infant sex. Putative markers of prenatal estrogen exposure, preecl sia, and birth weight did not correlate with direct fetal measures of the most potent estrogen (E2) but were associated with weaker estrogens (E3 and E4). Twins had lower concentrations of all estrogens. Impact: This is the largest and best characterized dataset of prenatal estrogen concentrations, measured using highly accurate mass spectrometry/spectroscopy. These observations represent the new “gold standard” for umbilical cord estrogens, and will inform the interpretation of other datasets and the early life origins of health and disease. Cancer Epidemiol Biomarkers Prev 23(6) 946–52. ©2014 AACR.
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.VETPAR.2015.02.009
Abstract: This experiment tested the hypothesis that persistent challenge with anthelmintic susceptible Trichostrongylus colubriformis and Haemonchus contortus larvae would not affect growth of grazing, meat-breed lambs when suppressively treated with anthelmintics. The experiment was a 2×2 factorial design using 6-7 months old White Suffolk X Border Leicester/Merino (meat-breed) lambs which were either infected with 2000 T. colubriformis and 300 H. contortus L3/week (IF) or remained uninfected (UIF) for 9 weeks and were either treated (TX) with a combination of short and long-acting anthelmintics or remained untreated (UTX). Lambs grazed as one flock and were rotated between paddocks to avoid autoinfection from pasture. Lambs were humanely euthanised on day 63 and the abomasum and small intestine collected to determine total worm burdens and tissue antibody response specific to T. colubriformis. As expected, worm egg count (WEC) and worm burden were significantly higher in IF UTX lambs (p<0.001). WEC was dominated by H. contortus and peaked at 2,325 epg on day 63 but remained at zero for the other treatment groups for the duration of the experiment. Tissue antibody responses were evident in IF lambs (titres 9982 vs 2767, p=0.012) but treatment had no effect (titres 5912 vs 5349, p=0.829). Lambs grew an average of 2.6 kg during the experiment with no difference between IF TX and UIF TX groups (p=0.432). Elevated tissue antibody responses were not associated with differences in growth. Results from this experiment support the hypothesis that persistent larval challenge with anthelmintic susceptible H. contortus and T. colubriformis will not affect growth of grazing, meat-breed lambs when suppressively treated with effective anthelmintics. Therefore the use of sheep suppressively treated with effective anthelmintics appears to be a valid substitute for gastrointestinal nematode-free lambs in field experiments.
Publisher: Oxford University Press (OUP)
Date: 03-2021
DOI: 10.1093/AF/VFAB005
Publisher: Public Library of Science (PLoS)
Date: 20-08-2012
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.AJOG.2014.02.025
Abstract: Ureaplasma spp are the most commonly isolated microorganisms in association with preterm birth. Maternal erythromycin administration is a standard treatment for preterm prelabor rupture of membranes. There is little evidence of its effectiveness in eradicating Ureaplasma spp from the intrauterine cavity and fetus. We used a sheep model of intrauterine Ureaplasma spp infection to investigate the efficacy of repeated maternal intramuscular and intraamniotic erythromycin treatment to eradicate such an infection. Thirty ewes with singleton pregnancies received an intraamniotic injection of 10(7) color change units of erythromycin-sensitive Ureaplasma parvum serovar 3 at 55 days' gestation. At 116 days' gestation, 28 ewes with viable fetuses were randomized to receive (1) intraamniotic and maternal intramuscular saline solution treatment (n = 8), (2) single intraamniotic and repeated maternal intramuscular erythromycin treatment (n = 10), or (3) single maternal intramuscular and repeated intraamniotic erythromycin treatment (n = 10). Fetuses were surgically delivered at 125 days' gestation. Treatment efficacy was assessed by culture, quantitative polymerase chain reaction, and histopathologic evaluation. Animals treated with intraamniotic erythromycin had significantly less viable U parvum serovar 3 in the amniotic fluid at delivery. However, neither combination of maternal intramuscular and intraamniotic erythromycin treatment successfully cleared U parvum serovar 3 from the amniotic fluid or fetal tissues. Three de novo erythromycin-resistant U parvum isolates were identified in erythromycin-treated animals. Erythromycin treatment, given both to the ewe and into the amniotic cavity, fails to eradicate intrauterine and fetal U parvum serovar 3 infection and may lead to development of erythromycin resistant U parvum.
Publisher: Frontiers Media SA
Date: 24-03-2020
Publisher: American Society for Microbiology
Date: 2014
DOI: 10.1128/AAC.01743-13
Abstract: Solithromycin (CEM-101) is a new antibiotic that is highly potent against Ureaplasma and Mycoplasma spp. and active against many other antibiotic-resistant organisms. We have explored the maternal-amniotic-fetal pharmacokinetics of CEM-101 in a pregnant sheep model to assess its potential for treating intrauterine and antenatal infection. Chronically catheterized pregnant ewes ( n = 6 or 7) received either a single maternal intravenous (i.v.) infusion of CEM-101 (10 mg/kg of body weight), a single intra-amniotic (i.a.) injection (1.4 mg/kg of estimated fetal weight), or a combined i.v. and i.a. dose. Maternal plasma (MP), fetal plasma (FP), and amniotic fluid (AF) s les were taken via catheter at intervals of 0 to 72 h postadministration, and concentrations of solithromycin and its bioactive polar metabolites ( N -acetyl [NAc]–CEM-101 and CEM-214) were determined. Following maternal i.v. infusion, peak CEM-101 concentrations in MP, FP, and AF were 1,073, 353, and 214 ng/ml, respectively, representing a maternal-to-fetal plasma transfer efficiency of 34%. A single maternal dose resulted in effective concentrations ( ng/ml) in MP, FP, and AF sustained for h. NAc–CEM-101 and CEM-214 exhibited delayed accumulation and clearance in FP and AF, resulting in an additive antimicrobial effect ( h). Intra-amniotic solithromycin injection resulted in elevated (∼50 μg/ml) and sustained CEM-101 concentrations in AF and significant levels in FP, although the efficiency of amniotic-to-fetal transfer was low (∼1.5%). Combined i.v. and i.a. administration resulted in primarily additive concentrations of CEM-101 in all three compartments. Our findings suggest that CEM-101 may provide, for the first time, an effective antimicrobial approach for the prevention and treatment of intrauterine infection and early prevention of preterm birth.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2018
Publisher: Oxford University Press (OUP)
Date: 04-2002
Abstract: Inflammatory processes are implicated in preterm labour (PTL). To identify potential novel markers for PTL, we have used commercial cDNA arrays to generate profiles of differential expression of inflammation-associated genes in gestational membranes with term and PTL. RNA for cDNA probe synthesis was isolated from reflected human amnion and choriodecidua membranes delivered following Caesarean section at term before the onset of labour (TNL, n = 4), spontaneous labour at term (TSL, n = 4), and PTL with and without chorioamnionitis (PTL(+INF) and PTL(-INF) respectively, n = 4 each). Profiles were displayed relative to TNL and statistical comparisons of TSL versus TNL and PTL(+INF) versus PTL(-INF) were performed. Elevated expression of chemokines macrophage inflammatory protein 1beta(MIP-1beta) and pulmonary and activation-regulated chemokine (PARC) was observed in PTL(+INF) compared to PTL(-INF) amnion and choriodecidua respectively (P = 0.03). Likewise, the cytokines oncostatin-M and pre-B cell enhancing factor (PBEF) were more highly expressed in PTL(+INF) compared with PTL(-INF) and in TSL compared with TNL respectively (P = 0.03). Conversely, inhibin A, tissue inhibitors of matrix metalloproteinase (TIMP)-3 and TIMP-4 were all significantly elevated in PTL(-INF) compared with PTL(+INF) (P = 0.03). Furthermore, differential expression patterns of classes of genes, grouped according to function (e.g. chemokines), were noted. The cDNA array approach holds promise for identification of new candidate markers or combinations thereof for prediction or diagnosis of PTL, as well as for increasing our understanding of the particular aetiologies involved.
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1121
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.JRI.2017.12.004
Abstract: The central role of inflammatory processes in labour and delivery is now well-recognised. However, the biomolecular, immunological and endocrine mechanisms involved in the labour process, and the clinical manifestations of inflammation in pregnancy, are complex, variable and modulated by factors such as aetiology, ethnicity and gestational age. In this review, evidence is presented of the pivotal relationship between progesterone and inflammation in pregnancy in terms of determining the timing of labour and delivery. The maternal inflammatory burden increases with advancing gestational age in response to endocrine, maturational, physical, metabolic and biochemical drivers, leading to functional progesterone withdrawal necessary for labour and delivery. Variability in the nature, timing and magnitude of these drivers influence the timing of delivery and the likelihood of preterm birth. Pathological inflammatory insults in pregnancy, such as infection, oxidative stress, senescence and maternal allograft rejection, can precipitate preterm birth, often involving common signalling pathways. Intrauterine infection is an important cause of early preterm birth, associated with delivery of the infants at greatest risk of death and disability however, most preterm deliveries with intrauterine inflammatory activation are not infection-associated. This observation has important diagnostic and therapeutic implications and challenges. The key differences and similarities between infection-associated and sterile inflammation in this context are highlighted, and the clinical implications and significance of these processes and how they might be exploited are discussed.
Publisher: Elsevier BV
Date: 1996
DOI: 10.1016/S0143-4004(96)80078-6
Abstract: Transforming growth factor-beta (TGF-beta) and activin-A, two members of a ubiquitous family of regulators of growth, differentiation and hormonogenesis, are produced by the human placenta. Their effects on placental hCG, inhibin, and oestrogen production in vitro, either alone or in combination, were investigated using cultured Percoll-purified placental trophoblasts. Inhibin and hCG were measured by immunoassay, while aromatase activity (i.e. oestrogen production) was measured using the tritiated water method. Aromatase activity and production of hCG, but not inhibin, were inhibited (up to approximately 30 per cent) in a dose-dependent fashion by 48 h treatment with TGF-beta. The effects were significant at all doses tested, from 0.1-10 ng/ml. In contrast, activin stimulated hCG production and aromatase activity over the doses tested (0.25-25 ng/ml). The maximum effect (approximately 50 per cent stimulation above control) was seen at the 2.5 ng/ml dose, with lesser effects seen at the lower and higher doses. This characteristic bell-shaped dose-response curve was maintained in the presence of TGF-beta (10 ng/ml) or a maximally-effective dose of forskolin (6.7 microM). This suggests that the actions of activin were independent of those of TGF-beta, and were not mediated by the protein kinase-A pathway. Activin had a weak stimulatory effect on inhibin production. The results indicate that in the placenta activin and TGF-beta have opposing actions on hormonogenesis. Both factors may play a role in regulating placental function and the timing and progression of labour.
Publisher: Springer Science and Business Media LLC
Date: 30-10-2012
Publisher: Wiley
Date: 13-01-2017
DOI: 10.1111/AOGS.13065
Abstract: Preterm birth is the major cause of perinatal mortality and morbidity worldwide. Infection/inflammation is responsible for a significant percentage of preterm birth, particularly at early gestations. A recent clinical recommendation by a guidelines group of the Danish Society of Obstetrics and Gynecology advised against the use of clindamycin for the treatment of bacterial vaginosis in pregnancy to reduce the risk of spontaneous preterm birth based on lack of evidence of efficacy. We believe that the evidence for the use of clindamycin for this indication is robust and that this recommendation was reached erroneously on the basis of flawed inclusion criteria: the inclusion of an unpublished study with poorly diagnosed bacterial vaginosis and the exclusion of an important pivotal study on the use of clindamycin in early pregnancy for the prevention of preterm birth. Had these errors been corrected, the conclusions would have been different.
Publisher: Elsevier BV
Date: 04-2001
DOI: 10.1016/S0301-2115(00)00450-4
Abstract: To compare the cervicovaginal cytokines IL-1beta, IL-6 and IL-8 with fetal fibronectin (fFN) and cervical dilatation in the prediction of preterm delivery. Cervicovaginal cytokine concentration and fFN status were measured in 104 women with symptoms of preterm labour and intact membranes between 24(0) and 33(6) weeks and related to delivery within 2 and 7 days. A group of 18% had cervical dilatation > or = 1cm and 18% were positive for fFN. Preterm delivery within 2 and 7 days occurred in 5 and 12%, respectively. Only IL-6 demonstrated any ability to predict delivery within 2 and 7 days (area under the ROC curve = 0.63 and 0.75, respectively). Using 35pg/ml (75th centile) as a cut-off, IL-6 had a sensitivity and specificity of 60 and 77% for predicting delivery within 2 days, and 62 and 80% for predicting delivery within 7 days. This is similar to the performance of cervical dilatation or fFN status. Measurement of cervicovaginal cytokines has limited ability to predict imminent delivery apart from cervicovaginal IL-6 concentrations, which, in this population, is equivalent to that of fFN status and cervical dilatation > or = 1cm.
Publisher: Elsevier BV
Date: 09-1999
Publisher: Elsevier BV
Date: 11-2014
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.IJANTIMICAG.2015.04.015
Abstract: There is a strong association between vaginal and/or amniotic fluid Ureaplasma spp. colonisation and risk of preterm birth. The novel fluoroketolide antibiotic solithromycin (CEM-101) is active against Ureaplasma spp. in vitro. Evidence from ex vivo and in vivo models suggests that, unlike most macrolide antibiotics, solithromycin readily crosses the placenta. Solithromycin metabolism varies according to species in pregnant sheep, the bioactive metabolites CEM-214 and N-acetyl-CEM-101 (NAc-CEM-101) have been shown to accumulate in the amniotic cavity following maternal solithromycin administration, potentially contributing to its antimicrobial effects. To determine the antimicrobial activity of these metabolites against Ureaplasma spp., the effects of solithromycin, CEM-214, NAc-CEM-101 and the comparator azithromycin were tested on a collection of 100 clinical Ureaplasma spp. isolates from the UK and Australia using a modified 96-well broth microdilution method. MIC90 values observed for the combined cohort were: solithromycin, 0.125 mg/L CEM-214, 0.5mg/L NAc-CEM-101, 0.5mg/L and azithromycin, 2mg/L. Solithromycin showed 34-fold greater activity against Ureaplasma spp. isolates than azithromycin, whilst CEM-214 and NAc-CEM-101 possessed ca. 22% and 17% of the activity of solithromycin, respectively, significantly greater than that of azithromycin. One bacterial isolate showed resistance to azithromycin (MIC=16 mg/L) but had a much lower MIC for solithromycin (MIC=0.25mg/L). In conclusion, the metabolites of solithromycin had reduced, but still potent, activity against 100 clinical Ureaplasma spp. isolates in vitro. This may be important in some instances such as pregnancy, however studies to determine levels of the metabolites in these settings are required.
Publisher: Springer Science and Business Media LLC
Date: 12-2018
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 16-07-2004
DOI: 10.1124/DMD.32.8.813
Abstract: These studies were performed to characterize the contribution of the uridine diphosphate glucuronosyltransferase (UGT) enzymes to the clearance of 3'-azido-3'-deoxythymidine (AZT) in vivo and to assess the regulation of UGT activity [including the disposition of the cofactor uridine diphosphate glucuronic acid (UDPGA)] in the placenta. Transport of AZT and the cofactor UDPGA across the human placenta and the glucuronidation capacity of the placenta for AZT were assessed using a human placental cell line (JEG-3), primary cultures of villous term placenta, placental subcellular fractions, and a recirculating perfusion model. Glucuronidation of AZT was consistently observed at approximately 2% of the dose administered. High levels of AZT in cultured primary placental cells and lines caused autoinhibition of AZT metabolism. AZT crossed the perfused placenta in a bidirectional fashion and was at equilibrium after 3 h, whereas the AZT-glucuronide metabolite was excreted preferentially into the maternal compartment. In contrast, UDPGA (10 microM) was rapidly transferred from the maternal to the fetal circulation, being complete after 4 h of perfusion. AZT is transported and glucuronidated by the human placenta, but that placental metabolism of the drug is not significant for whole-body clearance. Likewise therapeutic failure of AZT (5-15%) is not due to placental obstruction of drug passage. Finally, the activity of the UGT enzymes in the placenta is not rate-limited by the supply of UDPGA cofactor, whereas the preferential transport of UDPGA toward the fetus observed here may indicate a role in fetal development.
Publisher: Elsevier BV
Date: 09-2011
Publisher: Wiley
Date: 22-08-2014
DOI: 10.1111/DMCN.12576
Publisher: Springer Science and Business Media LLC
Date: 15-04-2020
DOI: 10.1038/S41598-020-63705-1
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.MCE.2015.02.003
Abstract: Wnt signalling has important roles in decidualisation, implantation and placentation. We investigated the role of decidua-trophoblast communication and Wnt signalling in the placenta using a co-culture model. Expression of a wide range of Wnt-related genes was observed in both decidual and trophoblast cells using PCR array, with remarkably similar expression profiles. Co-culture induced altered expression of several Wnt-related proteins, with the Wnt inhibitors sFPR4 and DKK1 being among the most differentially expressed genes. Media concentrations of sFRP4 and DKK1 were increased with co-culture, coincident with a decrease in canonical Wnt signalling activity. Expression of PTGS1 mRNA and COX1 protein was also increased with co-culture as were media PGE2 concentrations these changes were replicated by addition of exogenous DKK1 and sFRP4. Collectively, these data suggest that paracrine interactions between decidua and trophoblast stimulate Wnt antagonist secretion leading to increased placental prostaglandin production. This may be important for implantation and placental function.
Publisher: Elsevier BV
Date: 2002
DOI: 10.1016/S0301-2115(01)00466-3
Abstract: To test the effect of selective and non-selective inhibitors of prostaglandin H synthase-2 (PGHS-II) on basal and cytokine-stimulated prostaglandin (PG) production by the immortalized human myometrial cell line, UTLRp16. UTLRp16 cells were treated with interleukin (IL)-1beta (0.1, 1, 10ng/ml) and tumor necrosis factor (TNF)-alpha (1, 3, 10ng/ml) in the presence or absence of indomethacin, etodolac, 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2 (5H)-furanone (DFU) or nimesulide for 16h (1.6-1000nM). PG production was then measured by radioimmunoassay. IL-1beta and TNF-alpha both stimulated production of PGE(2) and 6-keto-PGF(1alpha) in a concentration-dependent manner. DFU showed the most PGHS-II selectivity with IL-beta-stimulated PG production, with a IC(50)(basal)/IC(50)(stimulated) ratio of 177.8, followed by nimesulide (122.5), etodolac (23.5) and indomethacin (2.7). DFU was not as selective in TNF-alpha stimulated cells (ratio 99.5). PGHS-II-selective inhibitors may be effective in the prevention of cytokine-driven myometrial PG production associated with preterm labor.
Publisher: Oxford University Press (OUP)
Date: 12-1997
DOI: 10.1095/BIOLREPROD57.6.1438
Abstract: Amniotic fluid at term contains high concentrations of interleukin (IL)-6 and IL-8. The source of these cytokines has not been identified, although the fetal membranes (amnion and chorion) are likely contributors. Amnion cytokine production was investigated by using amnion cells isolated by enzymatic digestion (from placentas delivered at term before labor) and cultured in vitro. IL-6 and IL-8 were measured in conditioned media by ELISA. Amnion cells produced detectable amounts of both IL-6 and IL-8 throughout the 7-day culture period. The ratio of IL-8 to IL-6 was approximately 5:1, similar to the ratio found in amniotic fluid. Production of both IL-6 and IL-8 was stimulated in a concentration-dependent fashion by interleukin-1beta (0.1-10 ng/ml), tumor necrosis factor-alpha (1-100 ng/ml), and bacterial lipopolysaccharide (0.1-10 microg/ml), and also by 100 nM phorbol 12-myristate 13-acetate. Epidermal growth factor (1-25 ng/ml) had only minimal effects on amnion cytokine production. Dexamethasone (10 nM) inhibited IL-6/-8 production by approximately 50% throughout the culture period. Production of IL-6/-8 by cultured amniotic fibroblasts, which under basal conditions was much lower than that by epithelial cells, was regulated by all the agents tested in a fashion similar to that of the epithelial cells. These findings suggest that the amnion contributes to the pool of IL-6 and IL-8 in amniotic fluid. We speculate that amnion-derived cytokines might have functions during normal human parturition that are distinct from their conventional roles as inflammatory mediators.
Publisher: Elsevier BV
Date: 04-2002
Publisher: Elsevier BV
Date: 08-2023
Publisher: Elsevier BV
Date: 04-2002
Publisher: Frontiers Media SA
Date: 19-11-2014
Publisher: Elsevier BV
Date: 11-2023
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.VETPAR.2021.109589
Abstract: Australian livestock are challenged by liver fluke (Fasciola hepatica) in grazing regions endemic to the intermediate snail host. Liver fluke infests a wide range of herbivores including free-roaming wildlife such as kangaroos (Macropods). The role played by Macropods in cross-species transmission and as vectors for anthelmintic resistance is largely unknown. In Phase 1 of this study, liver fluke of Eastern grey kangaroo (Macropus giganteus Shaw, 1790) origin (Kangaroo isolate) were artificially infected in sheep to confirm establishment and cross-species transmission. In Phase 2, the efficacy of triclabendazole (TCBZ) was assessed in vivo against the Kangaroo isolate to identify any drug resistance. Forty (40) merino sheep were housed in pens and allocated to one of 4 groups (Groups 1-4). Groups 1 and 2 were artificially infected with a TCBZ resistant liver fluke isolate (Oberon) originating from sheep whilst Groups 3 and 4 were infected with the Kangaroo isolate (Phase 1). At 9 weeks post infection (wpi), sheep in Groups 2 and 4 were treated with 10 mg/kg TCBZ (Phase 2). Sheep were subsequently euthanased at 11 wpi to conduct total fluke counts (TFC) in the liver. Faecal s les were collected fortnightly to measure fluke egg counts and coproantigens. In idual blood s les were collected, concurrently with faecal s ling, to monitor haematocrit and plasma proteins levels. Liver fluke of kangaroo origin established to patent infections in sheep with similar establishment and pathogenicity to the Oberon isolate. TCBZ achieved an 86 % reduction in TFC (99.8 % - adult fluke, 0 % - immature fluke) in sheep with the Kangaroo isolate and a 28 % reduction in the Oberon isolate (37 % - adult, 0 % - immature fluke). An 89 % reduction in faecal coproantigens was observed in sheep with the Kangaroo isolate and no reduction in sheep with Oberon. This study confirmed cross-species transmission of liver fluke from a kangaroo to sheep. When cohabiting the livestock grazing environment, kangaroos may act as reservoirs for liver fluke and vectors for drug resistance within liver fluke endemic areas.
Publisher: SAGE Publications
Date: 08-08-2014
Abstract: The relationships were investigated between the prickle discomfort scores, assessed by human response from wearer trial garment assessment, and sleeve trial, Wool ComfortMeter (WCM) and Wool HandleMeter (WHM) assessments of fabrics, and fiber diameter characteristics including mean fiber diameter (MFD). Sleeve trial assessment followed exercise, the use of a control sleeve to reduce participant variance and four sensory traits. WHM provides eight handle parameters calibrated against a panel of experts. Four scenarios were evaluated: sleeve trial assessment with MFD sleeve trial assessment with MFD and WCM sleeve trial assessment with MFD, WCM and WHM parameters and sleeve trial assessment with WCM and WHM parameters. Data were analyzed using correlation and forward stepwise general linear modeling. There was no evidence that the incidence of fibers coarser than 30 µm aided the prediction of prickle discomfort once MFD had been accounted for in the models. There were significant correlations between the WCM measurement and each sleeve trial attribute. There was no significant correlation between WHM parameters and sleeve trial assessments. The sleeve trial attribute of ‘skin feel’ offers potential to improve the predictions made of wearer trial prickle discomfort when used in association of the WCM with or without data on fabric MFD. There was little evidence to support using WHM parameters with or without the WCM in predicting wearer assessed prickle discomfort of fabrics. These results indicate that the rapid evaluation of fabrics using sleeve trial assessment can provide cost effective ranking of consumer preferences.
Publisher: SAGE Publications
Date: 30-11-2016
Abstract: Intrauterine inflammation, the major cause of early preterm birth, can have microbial and sterile aetiologies. We assessed in a Transwell model the anti-inflammatory efficacies of five drugs on human extraplacental membranes delivered after preterm spontaneous labour (30–34 wk). Drugs [TPCA1 (IKKβ inhibitor), 5 z-7-oxozeaenol (OxZ, TAK1 inhibitor), inhibitor of NF-κB essential modulator binding domain (iNBD), SB239063 (p38 MAPK inhibitor) and N-acetyl cysteine (free radical scavenger free radicals)] were added after 12 h equilibration to the amniotic compartment. Concentrations of IL-6, TNF-α, MCP-1, IL-1β and PGE 2 in the media, and IL6, TNFA and PTGS2 mRNA expression levels in membranes, were determined after 12 h. Data were analysed using mixed models analyses. Thirteen of the 28 membranes had histological chorioamnionitis (HCA + ) five were positive for bacterial culture and six for fetal inflammatory reaction. Baseline PGE 2 and cytokine production was similar between HCA – and HCA + membranes. Anti-inflammatory effects were also similar between HCA – and HCA + membranes. TPCA1 and OxZ were the most effective drugs each inhibited amniotic secretion of 4/5 pro-inflammatory mediators and mRNA levels of 2/3, regardless of stimulus. We conclude that treatment with TPCA1 or OxZ, in combination with antibiotics, may minimise the adverse effects of intrauterine inflammation in pregnancy.
Publisher: Oxford University Press (OUP)
Date: 15-02-2019
DOI: 10.1111/LAM.13119
Abstract: Numerous studies have reported bacterial DNA in first-pass meconium s les, suggesting that the human gut microbiome is seeded prior to birth. However, these studies have not been able to discriminate between DNA from living bacterial cells, DNA from dead bacterial cells or cell-free DNA. Here we have used propidium monoazide (PMA) together with 16S rRNA gene sequencing to determine whether there are intact bacterial cells in the fetal gut. DNA was extracted from first-pass meconium (n = 5) and subjected to 16S rRNA gene sequencing with/without PMA treatment. All meconium s les, regardless of PMA treatment, contained detectable levels of bacterial DNA however, treatment with PMA prior to DNA extraction decreased the DNA yield by approximately 20%. PMA-treated meconium s les did not differ significantly from untreated s les in terms of observed number of OTUs (P = 0·945) although they did differ taxonomically, with around one quarter of OTUs identified in untreated s les only, suggesting that they have originated from cell-free/nonviable DNA. The mean Sørensen coefficient for treated vs untreated s les was 0·527. Our findings suggest that the fetal gut is seeded with intact bacterial cells prior to birth. This is an important finding, as exposure to live bacteria during gestation might have a significant impact on the developing fetus. SIGNIFICANCE AND IMPACT OF THE STUDY: DNA-based microbiome studies performed using 16S rRNA gene sequencing are limited by their inability to discriminate between live bacterial cells, dead bacterial cells and cell-free DNA. Here we use propidium monoazide (PMA) to exclude nonviable bacteria from microbiome analysis of first-pass meconium s les and thereby reveal that the majority of the purported fetal gut microbiome is from intact bacterial cells. This work demonstrates the importance of excluding nonviable bacteria when analysing the microbial community in low-biomass s les such as meconium.
Publisher: CSIRO Publishing
Date: 2014
DOI: 10.1071/RD14079
Abstract: The integration of a complex network of signalling molecules promotes implantation of the blastocyst and development of the placenta. These processes are crucial for a successful pregnancy and fetal growth and development. The signalling network involves both cell–cell and cell–extracellular matrix communication. The family of secreted glycoprotein ligands, the Wnts, plays a major role in regulating a wide range of biological processes, including embryonic development, cell fate, proliferation, migration, stem cell maintenance, tumour suppression, oncogenesis and tissue homeostasis. Recent studies have provided evidence that Wnt signalling pathways play an important role in reproductive tissues and in early pregnancy events. The focus of this review is to summarise our present knowledge of expression, regulation and function of the Wnt signalling pathways in early pregnancy events of human and other model systems, and its association with pathological conditions. Despite our recent progress, much remains to be learned about Wnt signalling in human reproduction. The advancement of knowledge in this area has applications in the reduction of infertility and the incidence and morbidity of gestational diseases.
Publisher: Elsevier BV
Date: 12-1999
DOI: 10.1016/S0002-9378(99)70400-X
Abstract: This study of the changes in cytokine concentrations in gestational tissues from women with term and preterm labor was undertaken to assess the extent of inflammatory activation associated with spontaneous labor and delivery. Extracts of amniotic, chorionic-decidual, and placental tissues from women delivered at term before labor (n = 15), at term after labor (n = 15), and preterm (n = 31) were assayed for interleukin 1beta, interleukin 6, and interleukin 8. In amniotic tissues of women delivered by spontaneous labor at term the median interleukin-6, interleukin-8, and interleukin-1beta concentrations were 3.8 to 5.4 times those of tissues from women delivered at term without labor (P <.05, Mann-Whitney U test). Interleukin-6 and interleukin-8 concentrations were also significantly increased (3. 3-4 times) in chorionic-decidual tissues. Marked increases (approximately 3-6 times) in the concentrations of all 3 cytokines were observed in both amniotic and chorionic-decidual tissues from women with preterm deliveries with respect to those from women with term deliveries after labor. Cytokine concentrations were significantly correlated within amniotic tissues from both women with term delivery after labor and women with preterm delivery and also in preterm chorionic-decidual tissues but not preterm placental tissues. Concentrations of cytokines in the tissues of women delivered preterm were not significantly affected by mode of delivery, treatment with antibiotics, or twin birth. In preterm tissues with evidence of intrauterine infection only amniotic interleukin-1beta concentrations were significantly elevated (P <. 05). Little or no labor-related change in cytokine concentrations was seen within placental tissues. Increased cytokine abundance in gestational membranes associated with labor supports the view that an inflammatory process is involved in both term and preterm labor. This process does not, however, appear to be evident in the villous placenta.
Publisher: Elsevier BV
Date: 09-2002
Publisher: Wiley
Date: 11-1998
DOI: 10.1111/J.1600-0897.1998.TB00062.X
Abstract: In hematopoietic cells, interleukin (IL)-13 shares many actions with IL-4. The effects of IL-13 in gestational tissues have yet to be reported, however. We compared the effects of IL-4 and IL-13 on the production of cytokines and prostaglandin E2 (PGE2) in epithelial amnion-derived WISH cells. WISH cells were treated with IL-4 or IL-13 (0.08-10 ng/ml) with/without cotreatment with IL-1 beta (0.2 ng/ml), tumor necrosis factor-alpha (10 ng/ml) or epidermal growth factor (5 ng/ml). The production of IL-6, IL-8, and PGE2 was measured by immunoassay after 16 hr. Both IL-4 and IL-13 inhibited PGE2 production with indistinguishable concentration-response curves, under basal or stimulated conditions. The maximal inhibition of IL-1 beta-stimulated PGE2 production (to 28% +/- 10% of control) was seen at 10 ng/ml of IL-4 or IL-13. Basal IL-6 production was stimulated approximately twofold by IL-4 and IL-13, whereas IL-4 and IL-13 both inhibited cytokine-stimulated (but not basal) IL-8 production by approximately 50%. In the presence of 1 ng/ml of IL-4, IL-13 was unable to further inhibit PGE2 production. The inhibition of PGE2 and IL-8 production by IL-4 in WISH cells is mimicked by IL-13. Both cytokines, probably through binding to a common receptor complex, may share a role in suppressing inflammatory reactions within intrauterine tissues.
Publisher: Wiley
Date: 02-10-2023
DOI: 10.1111/RESP.14386
Abstract: Environmental exposure to phthalates and bisphenol A (BPA), chemicals used in the production of plastics, may increase risk for asthma and allergies. However, little is known about the long‐term effects of early life exposure to these compounds. We investigated if prenatal exposure to these compounds was associated with asthma, allergy and lung function outcomes from early childhood into adulthood in a cohort study. Maternal serum s les collected from 846 pregnant women in the Raine Study were assayed for BPA and phthalate metabolites. The children of these women were followed up at 5, 13 and 22 years where spirometry and respiratory questionnaires were conducted to determine asthma and allergy status. Lung function trajectories were derived from longitudinal spirometry measurements. Multinomial logistic regression and weighted quantile sum regression was used to test associations of in idual and chemical mixtures with asthma phenotypes and lung function trajectories. Effects of prenatal BPA and phthalates on asthma phenotypes were seen in male offspring, where BPA was associated with increased risk for persistent asthma, while mono‐iso‐butyl phthalate and mono‐iso‐decyl phthalate was associated with increased risk for adult asthma. Prenatal BPA had no effect on lung function trajectories, but prenatal phthalate exposure was associated with improved lung function. Prenatal BPA exposure was associated with increased likelihood of persistent asthma in males, while prenatal phthalate exposure was associated with increased likelihood of adult asthma in males. Results suggest that prenatal exposure to prenatal BPA and phthalates affect asthma risk, particularly in males, however lung function was not adversely affected.
Publisher: IEEE
Date: 18-12-2022
Publisher: Frontiers Media SA
Date: 04-06-2018
Publisher: Informa UK Limited
Date: 02-2006
Abstract: The human placenta expresses a large number of transport proteins. The ATP-binding cassette (ABC) family of active efflux pumps, predominantly localised to the maternal-facing syncytial membrane of placental microvilli, comprise the major placental drug efflux transporters. A variety of other transporters are also expressed in the placenta that can facilitate xenobiotic transfer in both the maternal and fetal directions. Many drugs administered in pregnancy are ABC transporter substrates, and many are either teratogenic or fetotoxic. The in vitro, in vivo and clinical evidence reviewed in this article argues that active efflux of drugs by placental transporters helps to maintain its barrier function, reducing the incidence of adverse fetal effects. ABC transporter polymorphisms may explain the wide variability observed in fetal drug concentrations, incidence of teratogenesis or drug failure in pregnancies exposed to therapeutic agents. Although our understanding of the molecular mechanics and dynamics of placental drug transfer is advancing, much work is needed to fully appreciate the significance of placental drug transporters in the face of increasing drug administration in pregnancy.
Publisher: Elsevier BV
Date: 05-2000
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1016/J.PLACENTA.2007.03.001
Abstract: Placental ATP-binding cassette (ABC) transporters limit fetal exposure to xenobiotics by regulating transplacental passage into the fetal circulation their expression and function in fetal membranes, however, has not been studied. In the present study the expression, localisation and function of ABC transporters in human amnion was examined to explore their potential role in modulating amniotic fluid drug disposition in pregnancy. Single-assay oligo-microarrays were used to profile amnion gene expression, and drug transporters expressed at significant levels were identified and selected for further studies. The expression of ABCG2/breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRP) 1 (ABCC1), 2 (ABCC2) and 5 (ABCC5) was detected on the arrays, and verified by RT-PCR and immunoblotting. On confocal microscopy of fetal membrane cryosections, MRP1 and MRP5 were immunolocalised to both apical and basolateral surfaces of the amniotic epithelium, while MRP2 was expressed at low levels only in the apical membrane. BCRP in contrast showed cytoplasmic staining throughout the amniotic epithelium. In addition to the amnion, MRP1 and BCRP immunostaining was observed in the chorion and the decidua. Cell accumulation studies using selective MRP and BCRP inhibitors showed the transporters to be functionally active in amnion epithelial monolayer cultures. In contrast, transwell transport studies using intact amnion membranes did not show significant vectorial transport. These findings identify the amnion as a novel site of ABC drug transporter expression. Functional studies indicate that they may act primarily to prevent cellular xenobiotic accumulation, rather than to confer fetal protection through reduced accumulation in amniotic fluid.
Publisher: Wiley
Date: 05-2000
DOI: 10.1111/J.8755-8920.2000.430508.X
Abstract: To determine whether leptin exhibits cytokine-like properties in gestational tissues in light of its homologies with the class I family of cytokines. WISH and JEG3 cells, and amnion and choriodecidua explants, were treated inflammatory modulators (interleukin-1beta [IL-1beta], tumor necrosis factor-alpha [TNF-alpha] and bacterial lipopolysaccharide [LPS]) and leptin production was measured by immunoassay. Other agents known to regulate adipocyte leptin production were also tested for comparative purposes. In addition, WISH cells, JAR cells and placental explants were treated with leptin to assess its effects on production of IL-8, IL-6 and prostaglandin E2 (PGE2). Leptin production by all cells and tissues studied was unaffected by treatment with IL-1beta (2.5 ng/mL), TNF-alpha (25 ng/mL) and LPS (2.5 microg/mL). Dexamethasone stimulated leptin production over two-fold by WISH and JEG3 cells, whereas insulin also stimulated a two-fold increase in leptin production in JEG3 cells. IL-6 production by JAR cells and placental explants was stimulated (two- to three-fold) by leptin (300 ng/mL). PGE2 production was unaffected. Leptin derived from gestational tissues is unlikely to play a role in inflammatory reactions within the placenta, but may regulate placental cytokine production. The physiological significance of amnion-derived leptin remains to be established.
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.BIOPSYCHO.2012.10.016
Abstract: Prenatal exposure to testosterone is known to affect fetal brain maturation and later neurocognitive function. However, research on the effects of prenatal testosterone exposure has been limited by indirect measures of testosterone and small unrepresentative s les. This study investigated whether bioavailable testosterone (BioT) concentrations in umbilical cord blood are associated with expressive vocabulary development, in a large birth cohort. Cord blood s les were taken immediately after delivery and expressive vocabulary was measured at two years of age using the language development survey (LDS). BioT concentration significantly predicted vocabulary size in males (n=197), such that higher concentrations were associated with lower LDS scores, indicating smaller vocabulary. This relationship between BioT concentrations and vocabulary at aged 2 years was not observed in girls (n=176). Higher circulating prenatal testosterone concentrations at birth may be associated with reduced vocabulary in early childhood among boys.
Publisher: Oxford University Press (OUP)
Date: 02-2004
Publisher: Frontiers Media SA
Date: 30-06-2016
Publisher: Oxford University Press (OUP)
Date: 2004
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.TOXLET.2014.07.030
Abstract: Gold nanoparticles (GNPs) have considerable applications in biomedicine, such as in bio-sensing, bio-imaging, drug delivery and photothermal therapeutics. However, currently there are limited information regarding the impact of pregnancy on their biodistribution, elimination and toxicity. In this study, we investigated the biodistribution and potential toxic effects of different-sized GNPs (1.5, 4.5, 13, 30 and 70 nm in diameter) in non-pregnant and pregnant mice at different gestational ages (E5.5, 7.5, 9.5, 11.5 and 13.5). 5h after intravenous injection, GNPs exhibited size-dependent biodistribution profiles however, regardless of size, no significant biodistribution changes were observed between non-pregnant and pregnant mice. Kinetic studies showed that 4.5 nm GNPs were primarily excreted through urine within 5h, whereas 30 nm GNPs had a more prolonged blood circulation time. No apparent toxic effects (e.g., increased mortality, altered behavior, reduced animal weight, abnormal organ morphology or reduced pregnancy duration) were observed with different-sized GNPs in pregnant mice. However, treatment with 30 nm GNPs induced mild emphysema-like changes in lungs of pregnant mice. These results indicated that the maternal biodistribution patterns of GNPs in pregnant mice depended on particle size, but not gestational age organ-specific adverse effects may arise with treatment with some GNPs according to their size.
Publisher: Mary Ann Liebert Inc
Date: 10-2012
DOI: 10.1089/ADT.2011.441
Abstract: Human choriocarcinoma-derived BeWo cells express high levels of breast cancer resistance protein (BCRP/ABCG2) with no functional P-glycoprotein (P-gp) (ABCB1) activity, making them a potential model to study bidirectional ABCG2-mediated drug transport. However, the original BeWo clone (B24) available to researchers does not form confluent monolayers with tight junctions required by the model. Our aim was to adapt culture conditions to attempt to generate confluent BeWo monolayers for drug transport studies using the standard B24 clone. BeWo cells (B24 American Type Culture collection [ATCC]) were cultured in six-well plates or polycarbonate millicell inserts in a number of media formulations, growth supplements, and basement membrane substitutes. Cells were examined for confluence by microscopy, and transepithelial electrical resistance (TEER) was measured daily monolayer permeability was assessed when TEER had stabilized. Optimal growth rates were achieved in culture conditions consisting of Medium 199 (M199) supplemented with epidermal growth factor (EGF 20 ng/mL), vitamin supplements, and 10% fetal calf serum (FCS) with collagen coating. A TEER of 170 Ω in 0.6 cm(2) inserts was achieved 2 weeks after seeding under optimal conditions. The cell-impermeable diffusion marker 5(6) carboxy-2,7dichlorodihydrofluorescein (C-DCDHF) had a permeability coefficient of 3.5×10(-6) cm/s, indicative of minimal paracellular permeability. ABCG2 expression, as determined by immunoblotting, remained unaffected by confluency. In conclusion, we describe culture conditions for the B24 BeWo clone that facilitate the formation of monolayers with tighter junctions and reduced paracellular transport compared to previously published models. These growth conditions provide a good model of ABCG2-mediated drug transport in a human placental cell line.
Publisher: Oxford University Press (OUP)
Date: 27-04-2017
Publisher: Elsevier BV
Date: 08-2001
DOI: 10.1016/S0090-6980(01)00122-8
Abstract: These studies were undertaken to evaluate the changes in mRNA expression of prostaglandin H synthase (PGHS)-1 and -2 in murine gestational tissues during the latter half of pregnancy. Gestational tissues (decidual caps, membranes surrounding the fetus, and placentae), uterus, and cervix were collected from pregnant mice at days 12, 14, 16, 18, and 19 (am and pm) of gestation (n = 4), and total RNA was isolated and evaluated for PGHS-1 and PGHS-2 expression by northern blot analysis. Expression was normalized to GAPDH. There were no significant increases in PGHS-2 mRNA expression in any of the tissues studied through gestation. In contrast, expression of PGHS-1 mRNA increased significantly at term in the uterus and fetal membranes. In the placenta, mRNA for PGHS-1 was elevated at day 18 and remained elevated over the remainder of the study. These findings suggest that, in the mouse, increased production of PGs by uterine and intrauterine tissues during pregnancy is associated with up-regulation of PGHS-1 and not PGHS-2.
Publisher: Elsevier BV
Date: 02-1998
Publisher: Oxford University Press (OUP)
Date: 29-10-2014
Abstract: Is in vitro maturation (IVM) as successful as standard in vitro fertilization (IVF) for the treatment of patients with polycystic ovaries (PCO) in terms of fresh, frozen and cumulative pregnancy outcomes? There was no difference in clinical pregnancy rates in fresh or frozen embryo transfer (FET) cycles between the two treatment groups however, the IVM group showed a lower clinical pregnancy rate cumulatively. There was significantly fewer live births resulting from IVM treatment for both fresh and cumulative cycle outcomes however, there was no difference in live birth rates resulting from FETs between IVM and IVF treatment. IVM is well recognized as the only treatment option to eliminate completely the incidence of ovarian hyperstimulation syndrome. However, historically IVM has been less successful than standard IVF in terms of clinical pregnancy, implantation and live birth rates. This paper represents a retrospective case-control study. The study involved 121 participants who underwent 178 treatment cycles. Cycles were completed between March 2007 and December 2012. All fresh cycles and subsequent FET cycles were included in the analysis to calculate cumulative outcomes. All participants were prospectively diagnosed with PCO morphology or polycystic ovarian syndrome (PCOS) and underwent either IVM or standard IVF treatment. Their treatment outcomes were analysed with regard to embryological data, and the rate of biochemical pregnancy, clinical pregnancy and live birth, in addition maternal and neonatal outcomes were assessed. Fifty-six patients underwent 80 cycles of IVM treatment and 65 patients underwent 98 cycles of standard IVF treatment. For fresh cycles, the differences in the biochemical pregnancy, clinical pregnancy or miscarriage rates between the two treatment groups were not statistically significant. The IVM group showed significantly lower live birth rates in fresh cycles in comparison to standard IVF treatment (18.8 versus 31.0%, P = 0.021). For frozen embryo transfer (FET) cycles the differences in biochemical pregnancy, clinical pregnancy, live birth or miscarriage rates between the two treatments groups were not statistically significant. The cumulative biochemical pregnancy (67.5 versus 83.7%, P = 0.018), clinical pregnancy (51.3 versus 65.3%, P = 0.021) and live birth rates (41.3 versus 55.1%, P = 0.005) were significantly lower in the IVM group in comparison to the standard IVF treatment group. There was no overall difference in the cumulative miscarriage rates between the two treatment groups. There was no difference between treatment methods with regard to the neonatal outcomes, and the IVM group had a significantly lower rate of ovarian hyperstimulation syndrome (0 versus 7.1%, P < 0.001). This was an observational study and further randomized clinical trials are required to clarify the difference in outcomes between standard IVF and IVM for patients with PCO/PCOS. This is the first study to compare IVM with standard IVF in PCO/PCOS patients using blastocyst development and single embryo transfer. Furthermore, it is the first study to show the results of fresh, frozen and cumulative treatment cycle outcomes between the two groups. Our results show similar success rates to those reported from other groups, particularly in relation to the incidence of miscarriage in fresh IVM cycles and improved success from FET cycles. Maternal and neonatal outcomes are consistent with the limited literature available. The study was supported by the Women's and Infant's Research Foundation of Western Australia. Professor Hart is Medical Director of Fertility Specialists of Western Australia (FSWA) and a shareholder Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. T.H. is a consultant with FSWA and a shareholder in Western IVF. She has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. The other authors have no competing interests.
Publisher: Oxford University Press (OUP)
Date: 28-05-2022
Abstract: Is the cardiometabolic health of adolescents conceived through ART worse than that of their counterparts conceived without ART? The majority of cardiometabolic and vascular health parameters of adolescents conceived through ART are similar or more favourable, than those of their counterparts of similar age and conceived without ART. It has been proposed that the cardiometabolic health of offspring conceived with ART may be unfavourable compared to that of their counterparts conceived without ART. The literature pertaining to cardiometabolic health of offspring conceived after ART is contradictory, but generally suggests unfavourable cardiometabolic health parameters, such as an increase in blood pressure (BP), vascular dysfunction and adiposity, as well as unfavourable glucose and lipid profiles. With over 8 million children and adults born through ART worldwide, it is important to investigate whether these early signs of adverse cardiometabolic differences persist into adolescence and beyond. The Growing Up Healthy Study (GUHS) is a prospective cohort study that recruited 303 adolescents and young adults conceived after ART (aged 13–21 years) and born between 1991 and 2001 in Western Australia. Their health parameters, including cardiometabolic factors, were assessed and compared with counterparts from the Raine Study Generation 2 (Gen2). The 2868 Gen2 participants were born 1989–1992 and are representative of the Western Australian adolescent population. At ∼17 years of age (2013–2017), 163 GUHS participants replicated assessments previously completed by Gen2 at a similar age. Cardiometabolic parameters were compared between a total of 163 GUHS and 1457 Gen2 adolescents. Separate male (GUHS n = 81, Gen2 n = 735) and female (GUHS n = 82, Gen2 n = 722) analyses were conducted. Assessments consisted of a detailed questionnaire including health, lifestyle and demographic parameters, anthropometric assessments (height, weight, BMI, waist circumference and skinfold thickness), fasting serum biochemistry, arterial stiffness and BP (assessed using applanation tonometry). Abdominal ultrasonography was used to assess the presence and severity of hepatic steatosis, and thickness of abdominal fat compartments. Non-alcoholic fatty liver disease (NAFLD) was diagnosed if there was sonographic fatty liver in the absence of significant alcohol consumption. Chi2, Fisher’s exact and Mann–Whitney U tests, performed in SPSS V25, examined cohort differences and generalized estimating equations adjusted for the following covariates: singleton vs non-singleton pregnancy, birthweight (z-score), gestational age, BMI, smoking, alcohol consumption in the past 6 months and parent cardiovascular status. Arterial stiffness measures and waist circumference were additionally adjusted for height, and female analyses were additionally adjusted for use of oral contraceptives in the preceding 6 months. In adjusted analyses, GUHS females had a lower BMI (22.1 vs 23.3 kg/m2, P = 0.014), and thinner skinfolds (triceps, subscapular, mid-abdominal 16.9 vs 18.7 mm, P = 0.021, 13.4 vs 15.0 mm, P = 0.027, 19.7 vs 23.2 mm, P & 0.001, respectively), whereas males were not significantly different. Waist circumference was lower in GUHS adolescents (males: 78.1 vs 81.3 cm, P = 0.008, females: 76.7 vs 83.3 cm, P = 0.007). There were no significant differences between the two groups in glucose, insulin, homeostatic model assessment for insulin resistance, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), alanine aminotransferase and high-sensitivity C-reactive protein in both sexes. In females, serum triglycerides were lower in GUHS adolescents (1.0 vs 1.2 mmol/l, P = 0.029). GUHS males had higher serum HDL-C (1.1 vs 1.0 mmol/l, P = 0.004) and a lower TC/HDL-C ratio (3.2 vs 3.6, P = 0.036). There were no significant differences in the prevalence of NAFLD or steatosis severity scores between the cohorts in males and females. GUHS females had less subcutaneous adipose tissue (9.4 vs 17.9 mm, P & 0.001), whereas GUHS males had greater visceral adipose thickness (44.7 vs 36.3 mm, P & 0.001). There was no significant difference in pre-peritoneal adipose thickness. Pulse wave velocity was lower in GUHS males (5.8 vs 6.3 m/s, P & 0.001) and heart rate corrected augmentation index was lower in GUHS females (−8.4 vs −2.7%, P = 0.048). There were no significant differences in BP or heart rate in males or females between the two groups. Despite the substantial study size and the unique study design of the ART cohort, we were unable to differentiate between different types of ART, due to the low number of ICSI cycles (e.g. IVF vs ICSI), draw definite conclusions, or relate the outcomes to the cause of infertility. Considering the differences in time points when both cohorts were studied, external factors could have changed, which could not be accounted for. Given the observational nature of this study, causation cannot be proven. Contrary to our hypothesis and previous findings focussing mainly on childhood, this study reports mostly similar or favourable cardiometabolic markers in adolescents conceived with ART compared to those conceived without ART. The greater visceral adipose thickness, particularly present in males, requires further investigation. While these findings are generally reassuring, future well-designed and appropriately powered studies are required to definitively address the issue of cardiometabolic health in ART adults. This project was supported by NHMRC project grant number 1042269 and R.J.H. received education grant funding support from Ferring Pharmaceuticals. R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director of PIVET Medical Centre, Perth, Western Australia. N/A.
Publisher: Proceedings of the National Academy of Sciences
Date: 29-10-2015
Publisher: Springer Science and Business Media LLC
Date: 2004
DOI: 10.2165/00003088-200443080-00001
Abstract: The major function of the placenta is to transfer nutrients and oxygen from the mother to the foetus and to assist in the removal of waste products from the foetus to the mother. In addition, it plays an important role in the synthesis of hormones, peptides and steroids that are vital for a successful pregnancy. The placenta provides a link between the circulations of two distinct in iduals but also acts as a barrier to protect the foetus from xenobiotics in the maternal blood. However, the impression that the placenta forms an impenetrable obstacle against most drugs is now widely regarded as false. It has been shown that that nearly all drugs that are administered during pregnancy will enter, to some degree, the circulation of the foetus via passive diffusion. In addition, some drugs are pumped across the placenta by various active transporters located on both the fetal and maternal side of the trophoblast layer. It is only in recent years that the impact of active transporters such as P-glycoprotein on the disposition of drugs has been demonstrated. Facilitated diffusion appears to be a minor transfer mechanism for some drugs, and pinocytosis and phagocytosis are considered too slow to have any significant effect on fetal drug concentrations. The extent to which drugs cross the placenta is also modulated by the actions of placental phase I and II drug-metabolising enzymes, which are present at levels that fluctuate throughout gestation. Cytochrome P450 (CYP) enzymes in particular have been well characterised in the placenta at the level of mRNA, protein, and enzyme activity. CYP1A1, 2E1, 3A4, 3A5, 3A7 and 4B1 have been detected in the term placenta. While much less is known about phase II enzymes in the placenta, some enzymes, in particular uridine diphosphate glucuronosyltransferases, have been detected and shown to have specific activity towards marker substrates, suggesting a significant role of this enzyme in placental drug detoxification. The increasing experimental data on placental drug transfer has enabled clinicians to make better informed decisions about which drugs significantly cross the placenta and develop dosage regimens that minimise fetal exposure to potentially toxic concentrations. Indeed, the foetus has now become the object of intended drug treatment. Extensive research on the placental transfer of drugs such as digoxin and zidovudine has assisted with the safe treatment of the foetus with these drugs in utero. Improved knowledge regarding transplacental drug transfer and metabolism will result in further expansion of pharmacological treatment of fetal conditions.
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.METABOL.2017.08.003
Abstract: Cytokines produced by adipose and placental tissues (adipokines) have been implicated in the development of gestational diabetes mellitus (GDM). There is, however, limited research regarding the relationship between advancing pregnancy, maternal adipokine profile, insulin resistance and the development of GDM. Furthermore, no studies have investigated these parameters in women with a history of GDM who are at the highest risk of recurrence. This study examined the circulating concentrations of a number of adipokines associated with insulin resistance at two points in pregnancy, and determined whether they were altered in women who developed GDM. Non-diabetic women with a history of GDM in a previous pregnancy (n=123) had blood drawn at 14 and 28weeks of pregnancy for GDM diagnosis, together with assessment of a range of adipokine concentrations by multiplex assay (fatty acid-binding protein 4 [FABP4], leptin, chemerin, adiponectin and resistin). With advancing pregnancy, maternal adiponectin concentrations decreased, while leptin and resistin levels increased (p<0.05). In women who developed GDM at 28weeks of pregnancy (42%), fasting and postprandial glucose levels were already significantly elevated by 14weeks (p<0.05), while adiponectin concentrations were lower (p<0.05). Adiponectin remained lower at the time of GDM diagnosis (p<0.05), while the other adipokines were similar between groups at each timepoint. Maternal glucose and adipokine profile is altered early in pregnancy in women with a history of GDM who subsequently develop recurrent disease.
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.JRI.2016.03.002
Abstract: Ureaplasma spp. are a common vaginal microorganism causally linked to inflammation-driven preterm birth (PTB). The nature of the immune response to Ureaplasma spp. may influence PTB risk. This study sought to define maternal T cell cytokine responses to in vitro stimulation with Ureaplasma parvum serovar 3 (UpSV3) in vaginally colonised (UP+) and non-colonised (UP-) pregnant women. Whole blood flow cytometry demonstrated an increase (p=0.027) in the baseline frequency of IFNγ-positive CD3(+)CD4(-)(CD8(+)) T cells in UP+ women. UpSV3 stimulation resulted in a significant and specific increase (p=0.001) in the frequency of IFNγ-positive CD3(+)CD4(-)(CD8(+)) T cells, regardless of vaginal colonisation status. UpSV3 stimulation also increased the frequency of IFNγ-positive CD3(+)CD4(+) T cells, particularly in the UP+ group (p=0.003). This is the first published study to examine T cell responses to Ureaplasma spp. Future appropriately-powered studies are needed to assess whether insufficient priming or a loss of tolerance to Ureaplasma spp. is occurring in UP+ women at risk of PTB.
Publisher: Bioscientifica
Date: 10-1999
Abstract: To investigate labour-associated changes in production of activin and related hormones by gestational tissues we prepared extracts from amnion, choriodecidual and placental tissues delivered at term before labour (TNL n=15), at term after spontaneous labour (TSL n=15) or preterm (PTD n=31) and measured concentrations of inhibin A, activin A and follistatin by ELISA. Activin concentrations in placental tissues were significantly (Mann-Whitney U-test P .05) elevated with term labour (pg/mg protein, median 1313 vs 2591), but in the PTD tissues concentrations were lower than those delivered spontaneously at term (3650 vs 2649). Inhibin concentrations also increased with term labour in the placenta (480 vs 686), but paradoxically decreased in amnion (188 vs 64) and choriodecidua (657 vs 358). Little or no significant changes in follistatin concentrations were observed. Concentrations of all three proteins were significantly correlated between amnion and choriodecidual tissues, and were significantly correlated with each other in most tissues (Spearman's ranked correlation P .05). The activin:inhibin ratio in term amnion and choriodecidual tissues was increased 2 to 3-fold (P .0005 by Mann-Whitney U-test) after term labour, with similar trends also observed in the activin:follistatin ratio in placental tissue. These data suggest that a modest increase in placental activin and inhibin production may occur with labour at term. In addition, an increase in activin bioactivity may occur with labour, potentiating any paracrine effects of activin during parturition. The data, however, do not support an association between increased intrauterine activin biosynthesis and preterm delivery.
Publisher: IMR Press
Date: 2007
DOI: 10.2741/2266
Abstract: Preecl sia is a serious and life-threatening pregnancy complication. Reduced uteroplacental perfusion and oxygen tension, impaired trophoblast differentiation and invasion, and altered placental production of immunomodulators and growth factors are all considered to be important aspects in the aetiology of the condition. The placenta expresses a variety of pro and anti-inflammatory cytokines, adipokines and cytokine-like angiogenic growth factors, production of which is altered in preecl sia, driven (at least in part) by hypoxia. Altered levels of cytokines have been measured in the circulation of women with preecl sia, although for reasons that are not always apparent much of the data are disturbingly inconsistent. While the placenta undoubtedly makes an important contribution to plasma cytokine levels, production by maternal peripheral blood mononuclear cells (PBMCs) and other tissues is also likely to be significant, although to what extent remains undetermined. Increased placental expression of soluble receptors occurs with preecl sia, resulting in elevated circulating concentrations which confer impaired angiogenesis, deficient placental vascularisation, increased placental apoptosis and endothelial dysfunction. The extent to which these changes reflect a response to the disorder, as opposed to being a causative factor in the development of maternal disease, is a matter of some debate. Nevertheless, convincing evidence is now accruing that autocrine aracrine interactions between placental cytokines/growth factors and the maternal endothelium play a central role in the pathogenesis of preecl sia.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Elsevier BV
Date: 03-2003
DOI: 10.1067/MOB.2003.173
Abstract: The purpose of this study was to determine whether, in women who are at high risk of the development of preecl sia, serum activin A concentrations are elevated before the disease and whether activin A is a useful predictor of preecl sia. Sera were collected on five occasions throughout pregnancy from women with chronic hypertension, renal disease, or previous early-onset preecl sia (n = 80 women). Women were classified as control subjects (normotensive or stable chronic hypertension), gestational hypertensive, or preecl tic (de novo or superimposed). Serum activin A concentrations were measured by immunoassay. Differences in activin A concentrations between groups were analyzed with the use of a mixed-models procedure screening test characteristics were calculated. Twenty-six women (33%) had gestational hypertension, and 17 women (21%) had preecl sia or superimposed preecl sia. Serum activin A levels increased with gestation in all groups (P =.0001), but there were no significant difference in activin A levels between groups (P =.75). In women who were at high risk of the development of preecl sia, serum activin A levels are not elevated with preecl sia. Activin A is not a useful predictor of preecl sia in this setting.
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.EARLHUMDEV.2014.12.011
Abstract: Ratio of second digit length to fourth digit length (2D:4D) has been extensively used in human and experimental research as a marker of fetal sex steroid exposure. However, very few human studies have measured the direct relationship between fetal androgen or estrogen concentrations and digit ratio. We investigated the relationships between both androgen and estrogen concentrations in umbilical cord blood and digit ratio in young adulthood. In addition we calculated measures of total serum androgen and total estrogen bioactivity and investigated their relationship to digit ratio. Prospective cohort study. An unselected subset of the Western Australian Pregnancy Cohort (Raine) Study (159 female 182 male). Cord serum s les were collected immediately after delivery. S les were assayed for androgen (testosterone, Δ4-androstenedione, dehydroepiandrosterone) and estrogen (estrone, estradiol, estriol, estetrol) concentrations using liquid-chromatography mass-spectrometry. Digit ratio measurements were taken from hand photocopies at age 19-22years. For both males and females, there were no significant correlations between digit ratio and any androgen or estrogen concentrations considered in idually, the testosterone to estradiol ratio, total androgen bioactivity measure or ratio of androgen to estrogen bioactivity (all p>.05). In males, but not females, total estrogen bioactivity was negatively correlated with left hand digit ratio (r=-.172, p=.02), but this relationship was no longer significant when adjusted for variables known to affect sex steroid concentrations in cord blood. Our findings indicate that digit ratio is not related to fetal androgens or estrogens at late gestation.
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.JRI.2015.05.002
Abstract: Periodontal disease (PD) in pregnancy is associated with an increased risk of adverse pregnancy outcomes including miscarriage and preterm birth. Evidence exists that periodontal disease treatment may reduce inflammatory mediators in gingival crevicular fluid (GCF) and the risk of inflammation-associated pregnancy complications. The aim was to determine if periodontal disease treatment during mid-pregnancy alters local inflammation in GCF and has beneficial effects on clinical dental parameters. Eighty pregnant women with clinically diagnosed PD were recruited from a randomised controlled trial on the treatment of periodontal disease in pregnancy conducted in Perth, Australia. The treatment group underwent intensive PD treatment (20-28 weeks' GA), while the control group underwent the same treatment postnatally. GCF was collected at 20 and 28 weeks' gestation and concentrations of cytokines determined by multiplex assay: IL-1β, IL-6, IL-8, IL-10, IL-12p70, IL-17, TNF-α and MCP-1. Periodontal treatment significantly reduced the GCF levels of IL-1β, IL-10, IL-12p70 and IL-6 at 28 weeks' GA compared with controls, while levels of MCP-1, IL-8 and TNF-α exhibited a significant gestational age-dependent increase, but no treatment response. Post-treatment clinical parameters improved with significant reductions in bleeding on probing, clinical attachment loss, and probing depth. No changes in pregnancy-related outcomes were observed, although the severity of periodontal disease was significantly associated with an increased risk of infants born small for gestational age. PD treatment in pregnancy reduces the levels of some inflammatory mediators in the GCF and improves dental parameters, with no overt effects on pregnancy outcome.
Publisher: SAGE Publications
Date: 15-10-2014
Abstract: This paper describes a protocol in which female participants scored a range of sensory attributes and applied a financial value to sleeves made from knitted fabric after undertaking a 30 minute circuit training program in a gym. Each participant wore a test and a control sleeve which they scored a line scale for breathability (anchored by the words ‘doesn’t breathe well’/‘breathes well’), skin feel (anchored by the words ‘prickly itchy’/‘soft smooth’), feel after exercise (anchored by the words ‘d sweaty’/‘dry’) and overall comfort (anchored by the words ‘very uncomfortable’/‘very comfortable’). Participants also estimated their willingness to pay (WTP) for two long-sleeved next-to-skin garments made from the test and the control fabrics. All sensory scores and WTP estimates were positively correlated. Participant and sleeve fit impacted on sensory scores and WTP estimates. However, the significance of participant and fit effects were reduced if differences between the test and control sleeves were analysed and therefore this difference was a better measure of the fabric attributes than simply meaning the test fabric score. The sleeve protocol provided a relatively inexpensive and simple means to score fabrics on sensory attributes and WTP.
Publisher: Oxford University Press (OUP)
Date: 03-06-2015
Abstract: Does polycystic ovarian syndrome (PCOS) or in vitro maturation (IVM) treatment affect embryo development events and morphokinetic parameters after time-lapse incubation? There was an increase in some abnormal phenotypic events in PCOS-IVM embryos as well as an increase in early arrest of PCOS-IVM and PCOS-ICSI embryos however, IVM treatment or PCOS status did not alter morphokinetic development of embryos suitable for transfer of vitrification. IVM has been less successful than standard IVF in terms of clinical pregnancy, implantation and live birth rates. There is currently no information available about the development of IVM embryos according to time-lapse analysis. This article represents a prospective case-control study. The study involved 93 participants who underwent 93 treatment cycles. Cycles were completed between January 2013 and July 2014. Participants were recruited for the study at Fertility Specialists of WA and Fertility Specialists South, Perth, Western Australia. Of the PCOS diagnosed patients, 32 underwent IVM treatment (PCOS-IVM) and 23 had standard ICSI treatment (PCOS-ICSI). There were 38 patients without PCOS who underwent standard ICSI treatment comprising the control group (control-ICSI). The PCOS-IVM group showed significantly more embryos with multinucleated two cells (P = 0.041), multinucleated four cells (P = 0.001) and uneven two cells (P = 0.033) compared with the control-ICSI group, but not the PCOS-ICSI group. There were no significant differences in the rates of any abnormal events between the PCOS-ICSI and control-ICSI groups. Embryo arrest between Days 2 and 3 was higher in the PCOS-IVM and PCOS-ICSI groups compared with the control-ICSI group (P < 0.001 and P = 0.001). Embryo arrest from Days 3 to 4 was higher in the PCOS-IVM group compared with both the PCOS-ICSI and control-ICSI groups (P < 0.001). There were no differences in embryo arrest rates across all three groups at the compaction or blastulation stages. Cumulative rates of embryo arrest, from the time to second polar body extrusion (tPB2) to the time to formation of a blastocyst (tB), result in a decreased proportion of useable PCOS-IVM blastocysts compared with the other two treatment groups however, of the embryos remaining, there was no significant difference in morphokinetic development between the three groups. This was a small study using time-lapse analysis of embryo development as the primary end-point. Larger, randomized, clinical trials are required to clarify the implications of time-lapse incubation of IVM embryos and the effects on implantation and ongoing pregnancy. This is the first study to compare the time-lapse analysis of IVM with standard ICSI for patients with and without PCOS. This allows for a more detailed and specific timeline of events from embryos generated using this approach for patients diagnosed with PCOS and shows that embryos generated from IVM have an increased rate of early embryo arrest, however morphokinetic development is not impaired in embryos that progress to the useable blastocyst stage. The study was supported by the Women's and Infant's Research Foundation of Western Australia. R.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. The other authors have no competing interests.
Publisher: Oxford University Press (OUP)
Date: 12-2004
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1016/J.CBI.2009.04.012
Abstract: Members of the ATP-binding cassette (ABC) family of membrane-bound transporters are involved in multiple aspects of transport and redistribution of various lipids and their conjugates. Most ABC transporters localize to the plasma membrane some are associated with liquid-ordered cholesterol-/sphingolipid-rich microdomains, and to a lesser extent the membranes of the Golgi and endoplasmic reticulum. Hence, ABC transporters are well placed to regulate plasma membrane lipid composition and the efflux and redistribution of structural phospholipids and sphingolipids during periods of cellular stress and recovery. ABC transporters can also modulate cellular sensitivity to extrinsic pro-apoptotic signals through regulation of sphingomyelin-ceramide biosynthesis and metabolism. The functionality of ABC transporters is, in turn, modulated by the lipid content of the microdomains in which they reside. Cholesterol, a major membrane microdomain component, is not only a substrate of several ABC transporters, but also regulates ABC activity through its effects on microdomain structure. Several important bioactive lipid mediators and toxic lipid metabolites are also effluxed by ABC transporters. In this review, the complex interactions between ABC transporters and their lipid/sterol substrates will be discussed and analyzed in the context of their relevance to cellular function, toxicity and apoptosis.
Publisher: Oxford University Press (OUP)
Date: 25-09-2015
Abstract: By investigating a birth cohort with a high ongoing participation rate to derive an unbiased population, what are the parameters and influences upon testicular function for a population not selected with regard to fertility? While varicocele, cryptorchidism and obesity may impact on human testicular function, most common drug exposures and the presence of epididymal cysts appear to have no or minimal adverse impact. The majority of previous attempts to develop valid reference populations for spermatogenesis have relied on potentially biased sources such as recruits from infertility clinics, self-selected volunteer sperm donors for research or artificial insemination or once-fertile men seeking vasectomy. It is well known that studies requiring semen analysis have low recruitment rates which consequently question their validity. However, there has been some concern that a surprisingly high proportion of young men may have semen variables that do not meet all the WHO reference range criteria for fertile men, with some studies reporting that up to one half of participants have not meet the reference range for fertile men. Reported median sperm concentrations have ranged from 40 to 60 million sperm/ml. The Western Australian Pregnancy Cohort (Raine) was established in 1989. At 20-22 years of age, members of the cohort were contacted to attend for a general follow-up, with 753 participating out of the 913 contactable men. Of these, 423 men (56% of participants in the 20-22 years cohort study, 46% of contactable men) participated in a testicular function study. Of the 423 men, 404 had a testicular ultrasound, 365 provided at least one semen s le, 287 provided a second semen s le and 384 provided a blood s le. Testicular ultrasound examinations were performed at King Edward Memorial Hospital, Subiaco, Perth, for testicular volume and presence of epididymal cysts and varicoceles. Semen s les were provided and analysed by standard semen assessment and a sperm chromatin structural assay (SCSA) at Fertility Specialists of Western Australia, Claremont, Perth. Serum blood s les were provided at the University of Western Australia, Crawley, Perth and were analysed for serum luteinizing hormone (LH), follicular stimulating hormone (FSH), inhibin B, testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), estradiol, estrone and the primary metabolites of DHT: 5α-androstane-3α,17β-diol (3α-diol) and 5-α androstane-3-β-17-beta-diol (3β-diol). Serum steroids were measured by liquid chromatography, mass spectrometry and LH, FSH and inhibin B were measured by ELISA assays. Cryptorchidism was associated with a significant reduction in testicular (P = 0.047) and semen (P = 0.027) volume, sperm concentration (P = 0.007) and sperm output (P = 0.003). Varicocele was associated with smaller testis volume (P < 0.001), lower sperm concentration (P = 0.012) and total sperm output (P = 0.030) and lower serum inhibin B levels (P = 0.046). Smoking, alcohol intake, herniorrhaphy, an epididymal cyst, medication and illicit drugs were not associated with any significant semen variables, testicular volume or circulating reproductive hormones. BMI had a significantly negative correlation with semen volume (r = -0.12, P = 0.048), sperm output (r = -0.13, P = 0.02), serum LH (r = -0.16, P = 0.002), inhibin B (r = -0.16, P < 0.001), testosterone (r = -0.23, P < 0.001) and DHT (r = -0.22, P < 0.001) and a positive correlation with 3αD (r = 0.13, P = 0.041) and DHEA (r = 0.11, P = 0.03). Second semen s les compared with the first semen s les in the 287 participants who provided two s les, with no significant bias by Bland-Altman analysis. Testis volume was significantly correlated positively with sperm concentration (r = 0.25, P < 0.001) and sperm output (r = 0.29, P < 0.001) and inhibin B (r = 0.42, P < 0.001), and negatively correlated with serum LH (r = -0.24, P < 0.001) and FSH (r = -0.32, P < 0.001). SCSA was inversely correlated with sperm motility (r = -0.20, P < 0.001) and morphology (r = -0.16, P = 0.005). WHO semen reference criteria were all met by only 52 men (14.4%). Some criteria were not met at first analysis in 15-20% of men, including semen volume (<1.5 ml, 14.8%), total sperm output (<39 million, 18.9%), sperm concentration (<15 million/ml, 17.5%), progressive motility (<32%, 14.4%) and morphologically normal sperm (<4%, 26.4%), while all five WHO criteria were not met in four participants (1.1%). This was a large cohort study however, potential for recruitment bias still exists. Men who did not participate in the testicular evaluation study (n = 282) did not differ from those who did (n = 423) with regard to age, weight, BMI, smoking or circulating reproductive hormones (LH, FSH, inhibin B, T, DHT, E2, E1, DHEA, 3α-diol, 3β-diol), but were significantly shorter (178 versus 180 cm, P = 0.008) and had lower alcohol consumption (P = 0.019) than those who did participate. This study demonstrated the feasibility of establishing a birth cohort to provide a relatively unbiased insight into population-representative sperm output and function and of investigating its determinants from common exposures. While varicocele, cryptorchidism and obesity may impact on human testicular function, most common drug exposures and the presence of epididymal cysts appear to have little adverse impact, and this study suggests that discrepancies from the WHO reference ranges are expected, due to its derivation from non-population-representative fertile populations.
Publisher: The Royal Society
Date: 07-10-2015
Abstract: Prenatal testosterone may have a powerful masculinizing effect on postnatal physical characteristics. However, no study has directly tested this hypothesis. Here, we report a 20-year follow-up study that measured testosterone concentrations from the umbilical cord blood of 97 male and 86 female newborns, and procured three-dimensional facial images on these participants in adulthood (range: 21–24 years). Twenty-three Euclidean and geodesic distances were measured from the facial images and an algorithm identified a set of six distances that most effectively distinguished adult males from females. From these distances, a ‘gender score’ was calculated for each face, indicating the degree of masculinity or femininity. Higher cord testosterone levels were associated with masculinized facial features when males and females were analysed together ( n = 183 r = −0.59), as well as when males ( n = 86 r = −0.55) and females ( n = 97 r = −0.48) were examined separately ( p -values 0.001). The relationships remained significant and substantial after adjusting for potentially confounding variables. Adult circulating testosterone concentrations were available for males but showed no statistically significant relationship with gendered facial morphology ( n = 85, r = 0.01, p = 0.93). This study provides the first direct evidence of a link between prenatal testosterone exposure and human facial structure.
Publisher: Springer Science and Business Media LLC
Date: 10-2000
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.MCE.2012.05.009
Abstract: Sphingolipid mediators such as ceramide are pleiotropic regulators of cellular growth, differentiation and apoptosis. We investigated the role of ceramide biosynthesis, metabolism and actions in term human cytotrophoblasts syncytialized over 7 days in culture. Intracellular C16 ceramide levels increased modestly after 3 days in culture, then declined. Ceramidase was present at particularly high levels in syncytialized trophoblasts inhibition of ceramidase reduced the degree of cell fusion. Exposure to short chain C8 ceramide or aSMase enhanced secretion of the differentiation marker hCG without affecting fusion or cell viability. In contrast, pharmacological inhibition of ceramidase reduced the extent of fusion. Inhibition of the ceramide-responsive JNK and PP2A pathways did not abolish the effects of ceramide, and JNK phosphorylation was unresponsive to ceramide however, ceramide significantly inhibited phosphorylation of Akt. This study suggests that changes in ceramide biosynthesis and metabolism play a differential role in the biochemical and morphological features of trophoblast differentiation.
Publisher: Wiley
Date: 22-08-2013
DOI: 10.1002/ICD.1771
Publisher: Wiley
Date: 03-05-2010
DOI: 10.1111/J.1476-5381.2010.00839.X
Abstract: Inflammation of the extraplacental membranes plays a key role in the pathogenesis of preterm labour. The aim of this study was to screen a number of commercially available small molecule nuclear factor‐kappa B inhibitors to identify candidates suitable for clinical evaluation as anti‐inflammatory agents for the prevention of preterm birth. Nine inhibitors were evaluated across a range of concentrations for their ability to inhibit lipopolysaccharide (LPS)‐stimulated cytokine production in primary term choriodecidual cells in culture without affecting cell viability. Expression of 112 inflammation‐ and apoptosis‐related genes was evaluated using boutique oligonucleotide arrays. Two IKKβ inhibitors were found to be highly effective and non‐toxic inhibitors of choriodecidual cytokine production: parthenolide and [5‐(p‐fluorophenyl)‐2‐ureido] thiophene‐3‐carboxamide (TPCA‐1). Both compounds also inhibited LPS‐stimulated nuclear translocation of p65/RelA. Expression of 38 genes on the arrays (34%) was significantly ( P 0.05) inhibited by TPCA‐1 or parthenolide. Of the 14 genes significantly stimulated by LPS, all were inhibited by TPCA‐1 and 12 were inhibited by parthenolide. Overall, gene expression was more robustly inhibited by TPCA‐1 than parthenolide however, expression of two genes was only inhibited by parthenolide. Neither compound significantly altered the expression profile of anti‐apoptosis genes on the arrays. These studies provide evidence that pharmacological inhibition of IKKβ activity holds promise as a potential strategy for the prevention and/or treatment of inflammation‐driven preterm birth. TPCA‐1 appeared the most promising compound among those tested in this study. Different inhibitors may have subtly different effect profiles despite having similar modes of action.
Publisher: Future Medicine Ltd
Date: 07-2015
DOI: 10.2217/NNM.15.48
Abstract: Advances in nanotechnology have resulted in the design of effective, safe and tissue-selective nanocarriers for delivering therapeutics to treat malignancies, infections and other diseases. In pregnancy, nanoparticle-based drug formulations could have the potential to selectively target either the placenta and/or fetus, enabling ‘fetal-friendly’ drugs to be administered in pregnancy with minimal risk of off-target effects. A considerable amount of research has been carried out on maternal-placental-fetal nanoparticle uptake, transfer and toxicity using rodent and ex vivo models. However, the development of placental targeting strategies and the therapeutic evaluation of nanoformulations in pregnancy remains in its infancy. While some promising avenues are currently under investigation, much work is needed to bring the advantages of nanoparticle-based drug therapy in pregnancy to clinical reality.
Publisher: Elsevier BV
Date: 08-2010
Publisher: The Endocrine Society
Date: 02-2006
DOI: 10.1210/JC.2005-1982
Abstract: The importance of prostaglandin (PG) signaling pathways to the maintenance of pregnancy and initiation of labor is well recognized. However, the complexity of these pathways and the mechanism(s) of their coordinated regulation in physiological and pathological conditions are only now being appreciated. In this report we provide new evidence of a complete pathway for the biosynthesis and actions of PGD(2) and its metabolites within human gestational tissues. Using immunohistochemistry and Northern and Western blotting, we demonstrate the dynamic regulation of H-type PGD synthase (PGDS) in placenta during gestation in contrast, L-type PGDS and its PG products were detected in amniotic fluid, with increased amounts associated with labor. Placental tissues were shown to express both forms of the PGD(2) receptor identified to date, D prostanoid(1) (DP(1)) and DP(2)/chemotactic receptor on type 2 helper T cells, with a distribution consistent with the villous placenta being a major target, as well as source, of PGD(2). In vitro, placental PGD(2) production was shown to be stimulated upon inflammatory activation, whereas PGD(2) and its J series metabolites exerted potent inhibitory effects on placental cytokine production. These findings suggest that PGDS-derived prostanoids play important physiological roles in the placenta, such as immunoregulation and feto-placental communication, while potentially having a regulatory role in the processes of parturition.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 08-04-2005
Abstract: 15-Deoxy delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), an activator of peroxisome proliferator-activated receptor (PPAR)-gamma and -delta, is a prostanoid metabolite with anti-inflammatory actions. In intrauterine tissues, proinflammatory cytokines and prostaglandins have been identified as playing key roles in the maintenance of pregnancy and the onset of labor. We investigated and compared the early (<3 h) effects of 15d-PGJ(2) with rosiglitazone (PPAR-gamma ligand) and 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (GW501516) (PPAR-delta ligand) on interleukin (IL)-1beta-induced prostaglandin and cytokine production by amnion-derived WISH cells. We show that 15d-PGJ(2) exerts differential effects depending on concentration. At low concentrations ( 1 microM).
Publisher: Frontiers Media SA
Date: 02-05-2014
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.VETPAR.2014.06.028
Abstract: This research was designed to determine if ergent genetic selection for resistance to Haemonchus contortus had produced correlated changes in the metabolism of amino-nitrogen in the absence or presence of H. contortus infection. Partitioning of amino acid-nitrogen between tissues was determined in 42 Merino weaner wethers from the CSIRO Haemonchus selection flock, increased resistance to Haemonchus (IRH), decreased resistance to Haemonchus (DRH) and random bred control (C) selection lines. Weaner wethers were fed a restricted diet (9.8 MJ ME/kgDM, 86 gMP/kg DM) calculated to allow a gain of 125 g/d bodyweight throughout the experimental period and were either worm-free or trickle infected with H. contortus. At 8 weeks post-infection animals were injected with (15)N-labelled duckweed directly into the abomasums. Animals were euthanased at either 6 or 24h after the injection to collect tissue s les for calculation of percentage recovery of (15)N in tissue and to determine abomasal worm counts. Worm egg count and worm counts at week 8 of infection were lower in animals from the IRH line. IRH animals had a lower N digestibility, increased oxidation of amino acids and lower N balance but whole-body protein flux was unaffected. Amino acid metabolism, as assessed from (15)N uptake and excretion in response to H. contortus infection, differed between IRH and DRH animals. In IRH animals a greater recovery of (15)N in the thymus and abomasal smooth muscle indicated greater partitioning of amino acids towards the immune response. In DRH animals an increased recovery of (15)N in the spleen, in response to infection, may be a possible adaptation. It appears that ergent selection for worm egg count has not been associated with symmetrical changes in amino acid metabolism, but rather the partitioning of amino acid resources reflects each selection line's independent response to infection.
Publisher: MDPI AG
Date: 29-06-2023
DOI: 10.3390/MICROORGANISMS11071698
Abstract: A well-established association exists between intrauterine bacteria and preterm birth. This study aimed to explore this further through documenting bacterial and cytokine profiles in Australian mid-gestation amniotic fluid s les from preterm and term births. S les were collected during amniocenteses. DNA was extracted and the full-length 16S rRNA gene was lified and sequenced. Levels of the cytokines IL-1β, IL-6, IL-10, TNF-α and MCP-1 were determined using the Milliplex MAGPIX system. Bacterial DNA profiles were low in ersity and richness, with no significant differences observed between term and preterm s les. No differences in the relative abundance of in idual OTUs between s les were identified. IL-1β and TNF-α levels were significantly higher in s les containing reads mapping to Sphingomonas sp. however, this result should be interpreted with caution as similar reads were also identified in extraction controls. IL-6 levels were significantly increased in s les with reads that mapped to Pelomonas sp., whilst TNF-α levels were elevated in fluid s les from pregnancies that subsequently delivered preterm. Bacterial DNA unlikely to have originated from extraction controls was identified in 20/31 (64.5%) mid-gestation amniotic fluid s les. Bacterial DNA profiles, however, were not predictive of preterm birth, and although cytokine levels were elevated in the presence of certain genera, the biological relevance of this remains unknown.
Publisher: Oxford University Press (OUP)
Date: 09-2003
Abstract: The placenta and fetal membranes are the site of expression of macrophage inhibitory cytokine (MIC-1), a member of the transforming growth factor (TGF)-beta superfamily. We hypothesized that MIC-1 may act as an immune regulator in pregnancy complications associated with intrauterine inflammation. Decidual cells, chorionic trophoblasts and amnion epithelial cells were identified by immunohistochemistry as the predominant MIC-1-containing cell type in term membranes. Amnion and choriodecidual explants all produced MIC-1 in culture, the latter having the greatest production rate (206 +/- 74.5 pg/mg tissue/24 h, n=6 mean +/- SEM). Production was not responsive to stimulation by pro-inflammatory cytokines. MIC-1 was detectable in 217 transabdominal amniotic fluid (AF) s les taken from 15 to 41 weeks gestation, concentrations ranging from 0.9-51.1 ng/ml. AF MIC-1 concentrations in pregnancies with premature rupture of membranes (PROM) or preterm labour, either with or without microbial invasion of the amniotic cavity, were not significantly different from those delivered at term either with or without labour. Treatment with MIC-1 (0.25-25 ng/ml) did not alter production of interleukin-6 or -8 by amnion or choriodecidual cells in vitro. We conclude that AF MIC-1 is derived from the fetal membranes and decidua, but that MIC-1 is unlikely to be involved in the pathophysiology of preterm birth or PROM.
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.PLACENTA.2013.04.006
Abstract: Inflammation plays central roles in key aspects of successful reproduction: ovulation, implantation and parturition. In this study we characterised the inflammatory profile of the rat placenta in late gestation with and without maternal glucocorticoid (dexamethasone) treatment. Placentas (n = 6/group) were collected from untreated (Con) rats at days 16 and 22 (term = day 23) and from dexamethasone-treated (Dex) rats at day 22. mRNA and protein expression was determined for enzymes of prostaglandin synthesis and metabolism (Ptgs-1, Ptgs-2, 15-Pgdh), pro-inflammatory cytokines (Tnf-α, Il-1β, Il-6), and the macrophage marker Emr-1 in the junctional (JZ) and labyrinth (LZ) zones of the placenta. Tnf-α, Il-1β and Il-6 mRNAs all increased (2- to 4-fold) in both placental zones between days 16 and 22 (P < 0.01). Ptgs-2 mRNA (30-fold P < 0.01) and PTGS-2 protein (2.4-fold P < 0.05) similarly increased in LZ. In contrast, 15-Pdgh expression increased in JZ but decreased in LZ these changes were accompanied by decreased levels of PGE2 in the JZ and a trend towards increased LZ levels. Dex treatment inhibited fetal and placental growth, but had minimal effects on expression of Ptgs-1, Ptgs-2 or 15-Pdgh. Nevertheless, Dex treatment increased LZ PGE2 levels (5-fold, P < 0.01) at the end of gestation. Dex treatment increased Tnf-α mRNA expression in LZ (40% P < 0.05), but modestly suppressed cytokine protein expression in JZ. These data demonstrate that the inflammatory state of the LZ increases near term coincident with the known increase in local glucocorticoid levels. This suggests the classic anti-inflammatory actions of glucocorticoids do not occur in the placental LZ.
Publisher: Frontiers Media SA
Date: 04-05-2018
Publisher: Public Library of Science (PLoS)
Date: 24-09-2021
DOI: 10.1371/JOURNAL.PONE.0257847
Abstract: Intraamniotic inflammation is associated with up to 40% of preterm births, most notably in deliveries occurring prior to 32 weeks’ gestation. Despite this, there are few treatment options allowing the prevention of preterm birth and associated fetal injury. Recent studies have shown that the small, non-competitive allosteric interleukin (IL)-1 receptor inhibitor, rytvela, may be of use in resolving inflammation associated with preterm birth (PTB) and fetal injury. We aimed to use an extremely preterm sheep model of chorioamnionitis to investigate the anti-inflammatory efficacy of rytvela in response to established intra-amniotic (IA) lipopolysaccharide (LPS) exposure. We hypothesized that rytvela would reduce LPS-induced IA inflammation in amniotic fluid (AF) and fetal tissues. Sheep with a single fetus at 95 days gestation (estimated fetal weight 1.0 kg) had surgery to place fetal jugular and IA catheters. Animals were recovered for 48 hours before being randomized to either: i) IA administration of 2 ml saline 24 hours before 2 ml IA and 2 ml fetal intravenous (IV) administration of saline (Saline Group, n = 7) ii) IA administration of 10 mg LPS in 2 ml saline 24 hours before 2 ml IA and 2 ml fetal IV saline (LPS Group, n = 10) 3) IA administration of 10 mg LPS in 2 ml saline 24 hours before 0.3 mg/fetal kg IA and 1 mg/fetal kg fetal IV rytvela in 2 ml saline, respectively (LPS + rytvela Group, n = 7). Serial AF s les were collected for 120 h. Inflammatory responses were characterized by quantitative polymerase chain reaction (qPCR), histology, fluorescent immunohistochemistry, enzyme-linked inmmunosorbent assay (ELISA), fluorescent western blotting and blood chemistry analysis. LPS-treated animals had endotoxin and AF monocyte chemoattractant protein (MCP)-1 concentrations that were significantly higher at 24 hours (immediately prior to rytvela administration) relative to values from Saline Group animals. Following rytvela administration, the average MCP-1 concentrations in the AF were significantly lower in the LPS + rytvela Group relative to in the LPS Group. In delivery s les, the expression of IL-1β in fetal skin was significantly lower in the LPS + rytvela Group compared to the LPS Group. A single dose of rytvela was associated with partial, modest inhibition in the expression of a panel of cytokines/chemokines in fetal tissues undergoing an active inflammatory response.
Publisher: Frontiers Media SA
Date: 04-2016
Publisher: Elsevier BV
Date: 04-2021
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.AJOG.2011.02.035
Abstract: The objective of the study was to explore the maternal-fetal pharmacokinetics of intraamniotic (IA), intravenous (IV), or intramuscular (IM) administration of erythromycin or azithromycin in a pregnant sheep model. Pregnant ewes of 115-121 days' gestation received a single maternal IV infusion (5 mg/kg over 60 min), a single IM injection, or a single IA injection (3.2 mg/kg fetal weight) of either erythromycin lactobionate or azithromycin. Maternal/fetal blood and amniotic fluid (AF) s les were collected across 48 h for macrolide assay by liquid chromatography and tandem mass spectrometry. Maternal administration achieved therapeutic maternal plasma macrolide concentrations (≥0.5 μg/mL) with low concentrations in AF equivalent to less than 7% transfer fetal plasma levels were even lower (<1.5% transfer). The IA administration achieved therapeutic concentrations in AF and sustained for 48 h, with poor maternal-fetal transfer (<1% maternal, <0.3% fetal). Modest pharmacokinetic differences were evident between erythromycin and azithromycin. Maternal macrolide administration achieves subtherapeutic concentrations in AF or fetal plasma, whereas a single IA injection achieves therapeutic concentrations in AF but not in maternal-fetal circulations. Combined maternal and single IA administration of macrolides may be a more effective regimen for treatment of intrauterine, but not fetal, infection.
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.PLACENTA.2014.10.013
Abstract: Dietary supplementation with omega-3 long chain polyunsaturated fatty acids (n-3 PUFAs) may exert benefits in pregnancy through inhibition of placental inflammation. However, studies on the anti-inflammatory effects of n-3 PUFAs in the placenta are lacking. We compared the cytokine responses of human placental explants in vitro after 4 days pre-incubation with either: a) in idual n-3 or n-6 PUFAs (20 μM), or b) physiologically relevant combinations of low, medium or high n-3 or n-6 PUFA concentrations. Placental cytokine (IL-6 and TNF-α) mRNA expression and protein production were assessed at 4 h and 12 h, respectively. Cytokine and fatty acid concentrations were also measured in placentas delivered at term by women who ingested either low (n = 12) or high (n = 10) amounts of fish/fish oil in the month prior to delivery. Pre-exposure to n-3 PUFAs as in idual fatty acids results in reduced placental IL-6 production (P < 0.05), whereas exposure to complex fatty acid mixtures enriched in n-3 PUFAs (high n-3:n-6 ratios) results in a significant stimulation of IL-6 production (P < 0.05). There were no differences in placental n-3 or n-6 PUFA levels between women with either high or low dietary fish oil intake and no differences in cytokine expression. In summary, data from our complex lipid explant model and an observational cohort study do not support a role for n3 PUFAs in the suppression of pro-inflammatory cytokine expression in the human placenta. Results from studies of placental tissues exposed to single n-3 and n-6 PUFAs should be interpreted with considerable caution.
Publisher: Springer Science and Business Media LLC
Date: 13-11-2012
DOI: 10.1038/SREP00847
Publisher: Wiley
Date: 08-1996
DOI: 10.1111/J.1479-828X.1996.TB02722.X
Abstract: Serum concentrations of immunoreactive inhibin (ir-inhibin) and human chorionic gonadotrophin (HCG) have been measured during the first trimester in a longitudinal study of pregnant women attending a recurrent miscarriage clinic. In 30 singleton pregnancies (Group 1) that continued successfully to term, the median concentration of ir-inhibin initially declined from 1,140 pg/mL at week 4-5 then rose back to comparable values between weeks 7 and 10 but to decline again to reach the significantly lower level of 840 pg/mL (p < 0.01) at week 15-16. Serum levels of HCG showed the classical profile of normal pregnancy reaching a median peak value of 65,600 IU/L (1st IRP) at week 8-9. In 7 pregnancies that miscarried but earlier had evidence on ultrasound of an active fetal heart, HCG levels in the first 9 weeks were consistently below the 10th percentile for Group 1 pregnancies (p < 0.001). Levels of ir-inhibin were also suppressed but to a lesser extent. In 6 of 7 a fetal pregnancies, HCG levels during the first 9 weeks were again markedly subnormal. The levels of ir-inhibin varied between high normal and subnormal. In none of the pregnancy groups was a correlation found between ir-inhibin and HCG concentrations. In a single pregnancy with an anencephalic fetus, while levels of ir-inhibin and HCG were not depressed, peak values were not reached until week 12. The study shows that the level of ir-inhibin in the maternal serum in early pregnancy is of little value as a prognostic indicator of pregnancy outcome. It confirms that a subnormal HCG level is a useful predictor of early pregnancy failure.
Publisher: Springer Science and Business Media LLC
Date: 05-2014
Abstract: Intrauterine infection is a leading cause of preterm birth (PTB), most notably in deliveries occurring before 32 weeks gestation. Preterm infants exposed to intrauterine inflammation are more likely to have a host of neurological, respiratory, gastrointestinal, and visual pathologies. Preventing preterm delivery and protecting the fetus from injury is thus likely to require treatment of both intrauterine infection and inflammation. Polymyxin B (PMXB) is a cationic peptide antibiotic that binds Escherichia coli lipopolysaccharides (LPS) and prevents inflammatory activation. We hypothesized that intraamniotic administration of PMXB would selectively inhibit LPS-driven inflammation, serving as a proof-of-principle for targeted agonist capture therapy as a treatment for PTB and fetal injury. In vitro studies with primary fetal ovine keratinocytes demonstrated a significant and sustained reduction in tumor necrosis factor α and interleukin 8 messenger RNA expression after treatment with PMXB and LPS, relative to cells treated with LPS alone. In vivo studies with fetal sheep demonstrated a significant reduction in proinflammatory cytokines in the amniotic fluid and fetal lung (but not fetal skin or chorioamnion) in LPS + PMXB-treated animals, relative to those treated with LPS alone. These data are consistent with a partial resolution of LPS-driven intrauterine inflammation. They suggest the potential for agonist capture as a conceptual means of resolving the proparturition inflammation caused by infection of the amniotic cavity.
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1194/JLR.M039842
Publisher: Springer Science and Business Media LLC
Date: 12-02-2019
Publisher: Wiley
Date: 22-05-2017
Publisher: MDPI AG
Date: 18-11-2022
Abstract: Phthalate metabolites are detectable within the majority of the population. Evidence suggests that a prenatal exposure to phthalates may be associated with the subsequent risks of obesity and elevated blood pressure. We hypothesised that a prenatal exposure to phthalates would lead to an increase in adverse cardiometabolic parameters through childhood and adulthood. The maternal serum phthalate measurements from the stored s les taken from Gen1 mothers at 18 and 34 weeks gestation were examined in relation to the cardiometabolic measures in 387 male offspring from the Raine Study. Data from the Gen2 follow-ups between 3 and 27 years were used. The primary outcomes were analysed longitudinally using linear mixed models for the repeated measures. Non-alcoholic fatty liver disease (NAFLD) was assessed at 17 years using logistic regression. A consistent positive relationship was observed between a prenatal exposure to mono-carboxy-iso-octyl phthalate (MCiOP) through adolescence into adulthood with systolic blood pressure. There were no other consistent cardiovascular associations. Mid-levels of prenatal exposures to Mono-n-butyl phthalate (MnBP) were associated with a greater incidence of NAFLD. Detectable Mono-3-carboxypropyl phthalate (MCPP) was associated with a lower serum HDL-C through late childhood into adulthood, while a higher prenatal exposure to mono-iso-butyl phthalate (MiBP), was associated with a higher LDL-C at 22 years of age. A mid-level prenatal exposure to mono-2-ethylhexyl phthalate (MEHP) metabolites was associated with higher insulin in adulthood, while a higher prenatal exposure to the sum of the Di-(2-ethyl-hexyl) phthalate (DEHP) and Di-iso-nonyl phthalate (DiNP) metabolites was associated with higher fasting serum glucose in adulthood. In conclusion, our study demonstrated that higher prenatal phthalate exposures to some phthalate metabolites was associated with some adverse metabolic profiles through adolescence into adulthood, although the consistent themes were limited to a few metabolites and the outcomes of systolic blood pressure, fasting insulin and glucose.
Publisher: CSIRO Publishing
Date: 2019
DOI: 10.1071/MA19053
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.VETPAR.2011.01.043
Abstract: This research was designed to determine if ergent selection for resistance to Haemonchus contortus had produced correlated changes in voluntary feed intake and diet selection. Voluntary feed intake, diet selection and production were determined in 54 Merino weaner rams from the CSIRO Haemonchus selection flock, increased resistance to Haemonchus (IRH), decreased resistance to Haemonchus (DRH) and random bred control (C) selection lines. Weaner rams were fed ad libitum either a high (9.2 MJ ME/kg DM, 90 g MP/kg DM) or moderate (6.3 MJ ME/kg DM, 30 g MP/kg DM) quality diet and given the choice between the two diets, when uninfected (NIL) or infected with H. contortus (INF). Symmetrical response to ergent selection for worm egg count (WEC) was not matched by a symmetrical change in feed intake and there was no difference in diet selection between selection lines. Feed intake, growth and wool production of DRH animals remained the same as that of IRH, yet DRH animals had five times greater WEC than IRH. This study begins to explain the mechanisms that allow resistant animals to effectively prevent establishment and/or development of H. contortus, by maintaining a greater immune response to infection through higher circulating eosinophils, plasma globulin and IgG(1) antibody titres. Susceptible animals have displayed resilience by improving feed conversion efficiency and increasing protein synthesis.
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1016/J.PLACENTA.2006.12.003
Abstract: Trophoblast cells undergo loss of plasma membrane lipid asymmetry during cell fusion without further progression to terminal phases of apoptosis. The nature of the anti-apoptotic mechanisms providing cell survival during this process is unknown. Using a BeWo cell model, we explored the role of the xenobiotic/lipid transporter ABCG2 in promoting cell survival during forskolin-induced differentiation. Suppression of ABCG2 expression by siRNA led to a marked increase in phosphatidylserine externalisation followed by accumulation of ceramides and increased apoptosis. Expression of markers of syncytial formation (beta-hCG and HERV-W) was decreased by ABCG2 silencing, although fusion was unaffected. These findings suggest that ABCG2 protects cells during the period of transient membrane instability associated with cell differentiation and fusion, highlighting a novel, previously unrecognised role of ABCG2 as a survival factor during the formation of the placental syncytium.
Publisher: F1000 Research Ltd
Date: 18-07-2017
DOI: 10.12688/F1000RESEARCH.11385.1
Abstract: Preterm birth (PTB) remains a major obstetric healthcare problem and a significant contributor to perinatal morbidity, mortality, and long-term disability. Over the past few decades, the perinatal outcomes of preterm neonates have improved markedly through research and advances in neonatal care, whereas rates of spontaneous PTB have essentially remained static. However, research into causal pathways and new diagnostic and treatment modalities is now bearing fruit and translational initiatives are beginning to impact upon PTB rates. Successful PTB prevention requires a multifaceted approach, combining public health and educational programs, lifestyle modification, access to/optimisation of obstetric healthcare, effective prediction and diagnostic modalities, and the application of effective, targeted interventions. Progress has been made in some of these areas, although there remain areas of controversy and uncertainty. Attention is now being directed to areas where greater gains can be achieved. In this mini-review, we will briefly and selectively review a range of PTB prevention strategies and initiatives where progress has been made and where exciting opportunities await exploitation, evaluation, and implementation.
Publisher: Frontiers Media SA
Date: 20-02-2018
Publisher: CSIRO Publishing
Date: 07-10-2021
DOI: 10.1071/AN21056
Abstract: Context The sheep and wool industry is an important and established primary production entity for Australia. Specialised tertiary education in the field of sheep and wool is pivotal to the advancement of the industry. Sheep and wool education has evolved over time synchronously with changes in the presentation of tertiary teaching. The face-to-face teaching and 4-year specialised degree in animal and wool science has now developed into an online learning system, with in idual units made available to students across the country. This is delivered using a hub institute, University of New England and spoke universities across Australia. Aims The study evaluated the development and delivery of the hub and spoke method of tertiary education in sheep and wool science. Methods The data for this study comprised routine information gathered during university enrolment and specific student survey data from two questionnaires. The first questionnaire was an annual (2010–2017) survey of enrolled students (n = 289) and the second questionnaire was a survey of graduates from 2012 to 2015 (n = 128) from sheep and wool science. Key results Student numbers studying sheep and wool science in the hub and spoke program have increased three and a half fold in 10 years. The employment success of students studying the sheep and wool units is over 50%. Conclusions Utilising a hub and spoke model for online education delivery allows one university to specialise in a specific curriculum that can be offered across multi-institutions. Implications The tertiary training package, developed by the sheep and wool industry, has provided an estimated 400 graduates into the industry in 10 years.
Publisher: Wiley
Date: 26-01-2012
DOI: 10.1111/J.1469-7610.2011.02523.X
Abstract: Preliminary evidence suggests that prenatal testosterone exposure may be associated with language delay. However, no study has examined a large s le of children at multiple time-points. Umbilical cord blood s les were obtained at 861 births and analysed for bioavailable testosterone (BioT) concentrations. When participating offspring were 1, 2 and 3 years of age, parents of 767 children (males = 395 females = 372) completed the Infant Monitoring Questionnaire (IMQ), which measures Communication, Gross Motor, Fine Motor, Adaptive and Personal-Social development. Cut-off scores are available for each scale at each age to identify children with 'clinically significant' developmental delays. Chi-square analyses and generalized estimating equations examined longitudinal associations between sex-specific quartiles of BioT concentrations and the rate of developmental delay. Significantly more males than females had language delay (Communication scale) at age 1, 2 and 3 years (p-values ≤. 01). Males were also more likely to be classified as delayed on the Fine-Motor (p = .04) and Personal-Social (p < .01) scales at age 3 years. Chi-square analyses found a significant difference between BioT quartiles in the rate of language delay (but not Fine-Motor and Personal-Social delay) for males (age 3) and females (age 1 and 3). Generalized estimating equations, incorporating a range of sociodemographic and obstetric variables, found that males in the highest BioT quartile were at increased risk for a clinically significant language delay during the first 3 years of life, with an odds ratio (OR) of 2.47 (95% CI: 1.12, 5.47). By contrast, increasing levels of BioT reduced the risk of language delay among females (Quartile 2: OR = 0.23, 95% CI: 0.09, 0.59 Quartile 4: 0.46, 95% CI: 0.21, 0.99). These data suggest that high prenatal testosterone levels are a risk factor for language delay in males, but may be a protective factor for females.
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1016/J.RBMO.2011.10.012
Abstract: Sphingosine and sphingosine-1-phosphate (S1P) are involved in regulating cell differentiation. This study postulated that changes in sphingolipid biosynthesis and metabolism are important in trophoblast syncytialization and therefore examined the production, metabolism and actions of sphingosine and S1P during spontaneous trophoblast differentiation and fusion in vitro. Significant declines in intracellular sphingosine concentration (P≤0.05) and sphingosine kinase 1 (SPHK1) expression (P≤0.01) were observed during trophoblast syncytialization. Secreted S1P concentrations dropped steeply after 72h, before rising to basal concentrations with syncytialization. Intracellular S1P concentrations were undetectable throughout. Treating cells with exogenous sphingosine (P≤0.01), S1P (P≤0.001) or a specific SPHK1 inhibitor (P≤0.05) for up to 72h in culture significantly inhibited trophoblast differentiation (measured as reduced human chorionic gonadotrophin production) effects on other biochemical and morphological markers of differentiation were absent or inconsistent. Phosphorylation of Akt, an established down-stream target of S1P that spontaneously declines with trophoblast differentiation, was markedly reduced by S1P (P≤0.05). In conclusion, changes in the sphingosine-S1P pathway are involved in the regulation of trophoblast differentiation in term human placenta. Dysregulation of sphingolipid homeostasis could, therefore, disrupt placental formation and function with deleterious consequences for pregnancy outcome.
Publisher: Oxford University Press (OUP)
Date: 03-02-2015
Abstract: Intrauterine inflammation (IUI) associated with infection is the major cause of preterm birth (PTB) at <32 weeks' gestation and accounts for ∼40% of all spontaneous PTBs. Pharmacological strategies to prevent PTB and improve fetal outcomes will likely require both antimicrobial and anti-inflammatory therapies. Here we investigated the effects of two cytokine-suppressive anti-inflammatory drugs (CSAIDs), compounds that specifically target inflammatory signalling pathways, in an ovine model of lipopolysaccharide (LPS)-induced chorioamnionitis. Chronically catheterized ewes at 116 days gestation (n = 7/group) received an intra-amniotic (IA) bolus of LPS (10 mg) plus vehicle or CSAIDS: TPCA-1 (1.2 mg/kg fetal weight) or 5z-7-oxozeaenol (OxZnl 0.4 mg/kg fetal weight) controls received vehicle (dimethylsulphoxide). Amniotic fluid (AF), fetal and maternal blood s les were taken 0, 2, 6, 12, 24 and 48 h later tissues were taken at autopsy (48 h). Administration of TPCA-1 or OxZnl abrogated the stimulatory effects of LPS (P < 0.01 versus vehicle control) on production of PGE2 in AF, with lesser (non-significant) effects on IL-6 production. Fetal membrane polymorphonuclear cell infiltration score was significantly higher in LPS versus vehicle control animals (P < 0.01), and this difference was absent with TPCA-1 and OxZnl treatment. LPS-induced systemic fetal inflammation was highly variable, with no significant effects of CSAIDs observed. Lung inflammation was evident with LPS exposure, but unaffected by CSAID treatment. We have shown in a large animal model that IA administration of a single dose of CSAIDs can suppress LPS-induced IA inflammatory responses, while fetal effects were minimal. Further development and investigation of these compounds in infectious models is warranted.
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.RBMO.2010.04.004
Abstract: Although placental trophoblast migration is tightly controlled in an autocrine aracrine manner, the nature of chemoattractive factors facilitating and directing this biological activity remains largely elusive. Neural regeneration peptides (NRP), a recently discovered peptide family, stimulate neuronal migration, differentiation and survival of post-natal neurons within the murine central nervous system. Based on the neural-repair related activities of these peptides and parallels between neuronal and placental cell behaviour patterns, this study postulated that they play a role in placental development, in particular trophoblast migration and survival and investigated the role of a newly discovered NRP motif (NNZ-4920), which exhibits about 70% homology to the mouse NRP motif sequence and is homologous to a 13-mer fragment within the N-terminus of human CAPS2, in trophoblast migration and survival regulation. NNZ-4920 significantly enhanced trophoblast migration by 51% (P<0.01) compared with controls and protected against stress induced by serum withdrawal and tumour necrosis factor-alpha/interferon-gamma treatment, at femtomolar concentrations, with efficacy similar to epidermal growth factor. CAPS2 expression was detected in purified term trophoblast and decidual cells. In conclusion, the placenta may be a source of NRP-related gene expression. Its encoded peptide products exert biological effects on term trophoblast migration and survival in vitro.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.FERTNSTERT.2018.06.008
Abstract: To study the role of the prenatal environment in regulating reproductive development by measuring the prospective association between umbilical cord concentrations of sex hormone binding globulin (SHBG principal regulator of sex steroid activity), bioavailable sex steroids, and age at menarche. Prospective population-based cohort. Not applicable. In 286 female members of the Western Australian Pregnancy (Raine) cohort, concentrations of SHBG and steroids (estrogens: estrone, estradiol, estriol and estetrol [E4] androgens: total testosterone, Δ4-androstenedione, androstenedione and dehydroepiandrosterone) were measured by liquid chromatography-tandem mass spectrometry from archived umbilical cord blood s les collected at birth. Bioavailable concentrations of testosterone and estradiol were calculated along with total composite measures of androgen and estrogen bioactivity. SHBG was measured by ELISA. None. Age of menarche was calculated from date of menarche, collected prospectively by questionnaire sent home with participants at the year 10 follow-up. Higher maternal education, higher body mass index, and the presence of antepartum hemorrhage were all significantly associated with earlier age at menarche. The bioavailable sex steroid measures accounted for 8.3% of the variance in age at menarche. Further, both SHBG and E4 concentrations accounted for a significant proportion of unique variance in age at menarche. Lower SHBG and higher E4 concentrations in umbilical cord blood were associated with earlier age at menarche. These results suggest that the prenatal sex steroid environment contributes toward pubertal development and age at menarche.
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.VETPAR.2011.01.063
Abstract: The aim of this experiment was to investigate the effect of Haemonchus contortus infection on rumen function and digestion of Merino sheep from lines ergently selected for genetic resistance to H. contortus. Rumen function and whole-tract digestibility were determined in 29 Merino weaner wethers from the CSIRO Haemonchus selection flock, increased resistance to Haemonchus (IRH), decreased resistance to Haemonchus (DRH) and random bred control (C) selection lines. Wethers were fed a restricted low quality roughage diet (5.9 MJ ME/kg DM, 29 g MP/kg DM) to maintain weight and were either uninfected (NIL) or infected with H. contortus (INF). Measurements were taken at week 7 of infection, while animals were housed in metabolic crates. Animals were then euthanased to determine abomasal worm counts. IRH had significantly lower worm egg count than DRH and C lines however, adult worm and larval counts, though lower in IRH animals, did not differ significantly. DM and OM digestibility and in sacco degradability of IRH and DRH selection lines were greater than C animals. Rumen function of animals from the IRH line was altered in response to H. contortus infection with an increase in fluid outflow and turnover rate and a decrease in propionic acid concentration. These changes may be a component of a greater host resistance and begin to explain the failure of IRH animals to translate lower worm egg count into greater bodyweight gain.
Publisher: Elsevier BV
Date: 2000
Publisher: Springer Science and Business Media LLC
Date: 02-2000
DOI: 10.1016/S1071-5576(99)00065-9
Abstract: To test the hypothesis that amnion cytokine production might be regulated by prostanoids. Amnion-derived WISH cells were treated with a range of prostanoids and their effects on production of interleukin (IL)-6 and IL-8 were determined by enzyme-linked immunosorbent assay and Northern analysis. The effects of thromboxane inhibitors on cytokine production by term primary amnion explants also were examined. Prostaglandin (PG)A2, PGD2, PGF2 alpha, PGE2, PGJ2, and the PGI2 analogue carbaprostacyclin (1-1000 nmol/L) exhibited no significant effects on cytokine production. However, the thromboxane A2 (TXA2) agonist U46619 and carbocyclic (c)TXA2 both stimulated WISH cytokine production with similar potencies under basal or cytokine-stimulated conditions. Significant stimulation of IL-6 production was observed at concentrations > or = 8 nmol/L (P < .05 by analysis of variance), whereas IL-8 production was stimulated significantly but to a lesser extent. The effects of U46619 and cTXA2 were rapid maximal stimulation of cytokine production occurred within 4 to 8 hours of treatment. U46619 augmented IL-1 beta-stimulated IL-6 and IL-8 mRNA expression within 2 hours of treatment. In amnion explants inhibitors of TX synthesis and action abrogated the stimulatory effects of IL-1 beta on cytokine production. These results are consistent with the presence of a feed-forward loop in amnion involving TXA2 and cytokines, which could play a significant role in the progression of the inflammatory response involved in the mechanism of infection-driven preterm labor.
Publisher: Elsevier BV
Date: 2000
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.THERIOGENOLOGY.2022.11.001
Abstract: Dystocia, a prolonged or non-progressive birth event, is the main contributor to lamb mortality in Australia and across the world. Dystocia can cause neonatal hypoxia, central nervous system (CNS) damage leading to increased risk of starvation, exposure and mismothering, and death. These prolonged birth events can also cause fatigue, injury and death in the ewe. Dystocia may interrupt the expression of maternal behaviour and the strength of the ewe-lamb bond, and consequently lamb survival. This study focused on the effect of dystocia on ewe behaviour in the 2 h post-lambing. A total of 18 ewes were chosen for continuous behaviour annotation and analysis (dystocic (n = 9) and eutocic (n = 9)) based on the quality of video recordings, length of stage 2 parturition and classification by a single experienced observer. Dystocic ewes showed significantly lower expression of maternal behaviours and a significantly greater expression of avoidance behaviours compared to eutocic ewes. Additionally, dystocic ewes performed fewer behaviours in total compared to eutocic ewes. Dystocia can significantly affect the quality and quantity of ewe maternal behaviour expression, leading to increased avoidance of the lamb, increased risk of maternal disinterest, and increased risk of death for the lamb. If dystocic events can be identified quickly and accurately, measures can be taken to ensure the ewe and lamb recover successfully.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2002
DOI: 10.1016/S0029-7844(01)01674-X
Abstract: To determine whether maternal serum activin A, inhibin A, and follistatin concentrations in idiopathic small for gestational age (SGA) pregnancies are similar to those in normal pregnancies or elevated as in preecl sia. Maternal serum activin A, inhibin A, and follistatin concentrations were determined in 1) nulliparous women with idiopathic SGA (birth weight or =140 mmHg or diastolic blood pressure > or =90 mmHg plus proteinuria > or =2+ or >0.3 g/24h n = 22), and normotensive controls, matched for gestational age at s ling (n = 22), and 2) a longitudinal series of s les collected at five intervals throughout pregnancy from nulliparous women with idiopathic SGA (n = 19), preecl sia (n = 22), preecl sia plus SGA (n = 15), or who had uncomplicated pregnancies (n = 20). Serum concentrations of activin A and inhibin A were similar in idiopathic SGA pregnancies to controls. In preecl sia, activin A and inhibin A levels were markedly increased compared with controls or women with idiopathic SGA (P <.001), particularly in those with early-onset disease. Follistatin concentrations were only modestly (<twofold) elevated in preecl sia (P <.001). In the longitudinal study, serum activin A or inhibin A concentrations were increased in women who later developed preecl sia, whereas in women with idiopathic SGA pregnancy, a small overall increase in activin A levels was observed. In contrast to women with preecl sia, normotensive women with SGA pregnancies do not have markedly elevated circulating levels of activin A and inhibin A. These data support the hypothesis that increased serum activin A concentrations in preecl sia may be a manifestation of maternal disease rather than just a marker of abnormal placentation.
Publisher: CSIRO Publishing
Date: 1999
DOI: 10.1071/RD99066
Abstract: To evaluate the association between intercellular adhesion molecule-1 (ICAM-1) in the chorio-decidua and preterm labour and delivery, ICAM-1 mRNA abundance was assessed by northern analysis, and protein levels by ELISA, in s les of this tissue after term and preterm delivery. The median ICAM-1 mRNA expression following preterm delivery (PTD) was 4.8 and 3.8 times (P .05), respectively, those following elective Caesarean section prior to labour at term (CST) and following vaginal delivery after spontaneous labour at term (SLT). The concentration of ICAM-1 protein in the PTD s les was 2.2 and 3.0 times (P .05) those in CST and SLT s les, respectively. The differences between the term groups were not significant. The results were substantially the same when a preterm spontaneous labour (PTL) subgroup, exclusive of deliveries complicated by pre-ecl sia or intrauterine growth restriction, was compared with the term groups. Choriodecidual ICAM-1 mRNA expression, but not ICAM-1 protein concentration, significantly correlated to the degree of leukocyte infiltration of the PTD gestational membranes. Neither correlated significantly to clinical indications of intrauterine or neonatal infection. These findings indicate that ICAM-1 is expressed by the human choriodecidua and that this expression is elevated with preterm labour and delivery, particularly with increased leukocyte infiltration.
Publisher: Elsevier BV
Date: 09-2000
Abstract: The aim of this study was to determine prospectively whether serum concentrations of corticotropin-releasing hormone, corticotropin-releasing hormone-binding protein, and activin A (1) predict preterm birth within 10 days of hospital admission or at <37 weeks' gestation among women with symptoms of preterm labor and (2) are affected by glucocorticoid therapy. Serum concentrations of corticotropin-releasing hormone and activin A were measured in 94 women with symptoms of preterm labor between 24 and 34 weeks' gestation, and delivery outcomes were monitored. Corticotropin-releasing hormone-binding protein concentrations were measured in 71 of these women. In a subgroup of 15 women the serum analytes were assayed in conjunction with estriol before and 12 to 24 hours after administration of dexamethasone. Forty-six percent (6/13) of the women who were delivered within 10 days of hospital admission had a raised serum corticotropin-releasing hormone level, but the predictive relationship was not significant (chi(2) = 1.7 P =.2). Among the 31 women (including the 6 previously mentioned) who were delivered at <37 weeks' gestation, 39% (12/31) had a raised corticotropin-releasing hormone level. Although a raised corticotropin-releasing hormone concentration was positively associated with delivery at <37 weeks' gestation (chi(2) = 9 P =.003), the predictive diagnostic value was poor, with sensitivity, specificity, and positive and negative predictive values of 39%, 90%, 67%, and 75%, respectively. The serum concentrations of corticotropin-releasing hormone-binding protein and activin A were unrelated to gestational age at delivery. Dexamethasone markedly lowered the serum estriol level (P <.001) but had no effect on concentrations of corticotropinreleasing hormone, corticotropin-releasing hormone-binding protein, and activin A. Serum concentrations of corticotropin-releasing hormone, corticotropin-releasing hormone-binding protein, and activin A are not clinically useful for the prediction of preterm delivery among women with symptoms of preterm labor and are not affected by administration of glucocorticoids.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-1997
DOI: 10.1097/00003081-199709000-00004
Abstract: Current tocolytic protocols rely largely on the use of beta-mimetics to induce myometrial quiescence and delay delivery. Unfortunately, the rapid transplacental passage and poor receptor specificity of the commonly used beta-mimetics results in widespread activation of intrauterine and extrauterine beta 1 and beta 2 receptors. The use of beta-mimetics is associated with a range of well-recognized and potentially dangerous side effects for mother and fetus. The value of continued use of beta-agonists after obtaining uterine quiescence also has been the subject of recent debate. In this article we have attempted to explore the biochemical and molecular rationale for the use of alternative therapeutic modalities in the treatment and prevention of PTL. In the light of the current view that the term "preterm labor" covers a considerable ersity of causes, we propose that a range of treatment regimes should be chosen on the basis of the diagnosis and classification of the patient according to the their particular condition. Although the measurement of several biochemical parameters have been suggested to be of use in predicting PTL, we believe that a panel of diagnostic indicators (e.g., free or total CRH, IL-6, extracellular matrix proteases, fetal fibronectin) is more likely to provide useful diagnostic information on which appropriate treatment modalities can be selected (Table 1). Because of the complex and interactive nature of the mechanisms operating within the intrauterine environment to regulate myometrial activation and uterotonin production, we speculate that a combination of tocolytics, anti-inflammatory agents, uterotonic antagonists, and receptor blockers is likely to be more effective than a monotherapeutic approach, which focuses on only one facet of the process of uterine activation for pharmacologic intervention. For ex le, the use of antibiotics, PGHS inhibitors, and/or beta-mimetics might be an appropriate first line of treatment for infection-associated PTL in extreme prematurity. If it is successful, this treatment might be followed by longer term use of a progestagen and/or NO donor to maintain myometrial quiescence until closer to term. Alternatively, use of progesterone or oxytocin antagonists may be effective in augmenting the actions of beta-mimetics while reducing their side effects, whereas other combinations may be useful as long-term prophylactics in women with a high risk of developing PTL. Improvements continue in our diagnostic ability to correctly identify the different causes of preterm labor. We anticipate that careful selection of differing combinations of therapeutic options will result in significant reductions in the morbidity, mortality, and healthcare costs associated with preterm birth.
Publisher: Elsevier BV
Date: 07-1998
DOI: 10.1016/S0143-4004(98)90084-4
Abstract: Activin-betaA subunits are expressed by the human placenta and extraplacental membranes at term and preterm. The regulation of activin-A production by these tissues has not been characterized to date, however. To determine the effects on activin-A production of pro-inflammatory cytokines, amnion, decidual and placental cells were isolated by enzyme dispersion and treated in primary culture with interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha). Activin-A production (determined by ELISA) by amnion, decidual and placental cultures was 1.2 +/-0.27, 31.1+/-9.9, and 50.7+/-28.5 pg/microg protein/16 h, respectively (mean+/-SEM n=5-7 experiments). Both IL-1beta and TNF-alpha stimulated activin-A production in a concentration-dependent fashion in all cultures maximal stimulation was achieved at 0.25-1.0 ng/ml IL-1beta and 25-50 ng/ml TNF-alpha, respectively. In amnion, decidual and placental cultures IL-1beta stimulated activin-A production to 747+/-274, 190+/-11, and 254+/-60.2 per cent of controls, while TNF-alpha stimulated production to 312+/-81.5, 194+/-22.5, and 193+/-12.5 per cent, respectively (mean+/-SEM n=5 P<0.05 by ANOVA). These studies show for the first time that pro-inflammatory cytokines are potent stimulators of activin-A production by intrauterine tissues. This may provide an explanation for the elevated concentrations of activin-A measured in the sera of some women in preterm labour.
Publisher: Elsevier BV
Date: 05-1999
Abstract: The metabolism of arachidonic acid results in the production of prostaglandins (PGs), which are involved in the initiation of labour at term and preterm. The fetal membranes are a source of pro-inflammatory cytokines which promote increased PG biosynthesis via increased release of arachidonic acid and its conversion to biologically active metabolites such as PGE2 and PGF2alpha. In the amnion, the liberation of arachidonic acid from membrane glycerophospholipid stores can be catalysed by cytosolic phospholipase A2 (cPLA2). In amnion-derived WISH cells, the addition of tumour-necrosis factor alpha (TNF-alpha) (50 ng/ml) provoked a time-dependent increase in the expression of the cPLA2 mRNA which was greatest at 8 and 16 h post-treatment (3.62+/-0.52 and 3.15+/-0.45-fold of control, n=3). The increase in cPLA2 mRNA expression by TNF-alpha was unaffected by the prior addition of interleukin-4 (IL-4) (10 ng/ml), a known inhibitor of prostaglandin endoperoxide H synthase (PGHS)-2 mRNA and protein expression in WISH cells. TNF-alpha also increased the level of immunoreactive cPLA2 protein in a time-dependent manner with the highest levels evident after 8 and 16 h. As with the mRNA, cPLA2 protein levels were unaffected by pre-incubation with IL-4. The inclusion of the cPLA2-specific inhibitor arachidonyl trifluoromethyl ketone (AACOCF3) resulted in a concentration-dependent inhibition of PGE2 biosynthesis in WISH cells treated with TNF-alpha (>95 per cent at 2 microM). We conclude that TNF-alpha increases the abundance of the cPLA2 mRNA and protein in amnion epithelial cells, an effect which plays an important role in amnion PG biosynthesis in the presence of intrauterine infection.
Publisher: MDPI AG
Date: 09-09-2020
DOI: 10.3390/ANI10091605
Abstract: A common strategy to reduce predator attack on livestock is the deployment of guardian alpacas. However, little research has been conducted on the behaviour of this species while housed with other livestock. This study monitored two male alpacas cohabitating with 180 lambing ewes in order to quantify field behaviour in two phases. Phase one assessed diurnal patterns of alpacas and lambing ewes using Global Navigation Satellite System (GNSS) collars recording data over 41 days, in combination with observational recordings. Phase two developed an alpaca behavioural ethogram through continuous observations from 05:30 to 19:30 h over a 3-day period. The two alpacas shared similar behaviours with commonality of distance travelled, and both species exhibited an increase in activity level based on speed between the times of 05:00 and 17:00 h. The GNSS data indicated that the alpacas flocked with the ewes at night sharing the same resting location, however, would spend time during the day on the outskirts of the paddock. Alpacas were observed to spend the majority of the observation period in two behavioural states: grazing (57%) and resting (27%). As a result of this study we were able to catalogue a range and frequency of field behaviours which alpacas exhibit while cohabitating with lambing ewes. However, further research is needed to determine in more detail how these behaviours correspond with the effectiveness of this species as a livestock guardian.
Publisher: The Endocrine Society
Date: 08-2004
DOI: 10.1210/JC.2004-0373
Publisher: Public Library of Science (PLoS)
Date: 04-2013
Publisher: American Physiological Society
Date: 05-2006
DOI: 10.1152/AJPREGU.00630.2005
Abstract: ATP-binding cassette (ABC) efflux transporters are expressed in the human placenta where they are thought to help protect the fetus from xenobiotics. To evaluate models for analysis of ABC transporter function and regulation in the placenta, we have characterized the expression and activity of multidrug resistance (MDR) 1/P glycoprotein (Pgp), MDR3/Pgp, breast cancer resistance protein (BCRP), and multidrug resistance proteins 1 and 2 (MRPs 1, 2) in differentiating primary trophoblast cells and BeWo and Jar cell lines. Real-time PCR and immunoblotting were used for analysis of mRNA and protein expression, respectively. Functional activity was measured using selective inhibitors of efflux of fluorescent substrates, calcein-AM (Pgp and MRPs) and Hoechst 33342 (BCRP). The levels of MDR1 mRNA and protein expression were much higher in trophoblast than in Jar and especially BeWo cells. Expression of MDR3 protein was also lower in BeWo cells. Levels of MDR3 expression were markedly higher than MDR1 levels in all tested cell types. Levels of both MDR1 and MDR3 expression decreased during trophoblast differentiation/syncytialization. BCRP was highly expressed in all cell types and increased with trophoblast differentiation. MRP1 expression was much lower in trophoblasts compared with both cell lines. In contrast to its abundant mRNA expression, MRP2 protein was practically undetectable in BeWo and Jar cells and was present only at very low levels in trophoblast. Functional studies confirmed the presence of active Pgp and BCRP in all studied cell types, whereas MRP functional activity was detected only in BeWo and Jar cells. Both cell lines may be useful models for studying various aspects of placental ABC transporter expression and function, but also have significant limitations. With respect to their ABC protein expression profile, Jar cells are more similar to nondifferentiated cytotrophoblast, whereas BeWo appear to more closely reflect differentiated syncytiotrophoblast.
Publisher: Bioscientifica
Date: 02-2015
DOI: 10.1530/REP-14-0549
Abstract: The aim of this study was to determine whether supplementation with fish oil-derived n-3 polyunsaturated fatty acids (n-3 PUFA) during pregnancy modifies placental PUFA composition, the accumulation of specialised pro-resolving lipid mediators (SPMs, specifically resolvins (Rv), protectins (PD) and upstream precursors) and inflammatory gene expression. Placentas were collected from women ( n =51) enrolled in a randomised, placebo controlled trial of n-3 PUFA supplementation from 20-week gestation. Lipids were extracted for fatty acid analysis and SPMs were quantitated by mass spectrometry. Gene expression was determined by qRT-PCR. Using multiple regression analysis, data were correlated for placental n-3 PUFA and SPM levels with PUFA levels in maternal and cord blood erythrocytes. Supplementation with n-3 PUFAs increased placental docosahexaenoic acid (DHA) levels, but not eicosapentaenoic acid (EPA) levels ( P .05), and increased the levels of the SPM precursors 18-hydroxyeicosapentaenoic acid and 17-hydroxydocosahexaenoic acid (17-HDHA) by two- to threefold ( P .0005). RvD1, 17R-RvD1, RvD2 and PD1 were detectable in all placentas, but concentrations were not significantly increased by n-3 PUFA supplementation. Placental DHA levels were positively associated with maternal and cord DHA levels ( P .005), and with placental 17-HDHA concentrations ( P .0001). Placental mRNA expression of PTGS2 , IL1 β , IL6 and IL10 was unaffected by n-3 PUFA supplementation, but TNF α expression was increased by 14-fold ( P .05). We conclude that n-3 PUFA supplementation in pregnancy i) enhances placental accumulation of DHA and SPM precursors, ii) does not alter placental EPA levels, and iii) has no stimulatory effects on inflammatory gene expression. Further studies are required to ascertain the biological significance of SPMs in the placenta and the potential immunomodulatory effects of elevating placental SPM levels.
Publisher: Springer Science and Business Media LLC
Date: 18-10-2016
Publisher: Frontiers Media SA
Date: 09-12-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2021
DOI: 10.1161/HYPERTENSIONAHA.120.16256
Abstract: Preclinical evidence suggests that adult blood pressure (BP) may be modified by the prenatal endocrine environment. Specifically, in several animal models, higher prenatal testosterone exposure increases the risk of hypertension in later life. We investigated the prospective association between prenatal testosterone levels (as measured in umbilical cord blood) and BP at 20 to 27 years in 434 participants from the Raine Study. As expected, median bioavailable testosterone, the fraction of total testosterone either free or bound to serum albumin, was higher in males than females (0.12 [Q1–Q3, 0.09–0.19] versus 0.07 [Q1–Q3, 0.05–0.1] nmol/L P .001). Mean (SD) systolic BP was 122.9 (±12.3) and 110.9 (±9.5) mm Hg at age 20 years and 122.4 (±11) and 111.2 (±9.1) mm Hg at 27 years in males and females, respectively. Using hierarchical mixed-effects models, higher cord blood bioavailable testosterone concentrations were associated with higher levels of systolic BP ( P =0.007) and diastolic BP ( P =0.002) in young adults at 20 and 27 years, after adjusting for change in BP over time and potential confounders. In these models, one SD increase in bioavailable testosterone equated to a 1 mm Hg increase in systolic BP (regression coefficient, 11.1 [95% CI, 4.1–21.11]) and diastolic BP (regression coefficient, 10.15 [95% CI, 3.67–15.93]). There was no significant difference detected between males and females in the association between bioavailable testosterone and adult BP. These data from a large unselected population indicate that higher fetal testosterone levels in late pregnancy are associated with higher BP in young adulthood.
Publisher: Bioscientifica
Date: 03-2014
DOI: 10.1530/REP-13-0576
Abstract: Intrauterine infection and inflammation are responsible for the majority of early ( weeks) spontaneous preterm births (PTBs). Anti-inflammatory agents, delivered intra-amniotically together with antibiotics, may be an effective strategy for preventing PTB. In this study, the effects of four cytokine-suppressive anti-inflammatory drugs (CSAIDs: N -acetyl cysteine (NAC), SB239063, TPCA-1 and NEMO binding domain inhibitor (NBDI)) were assessed on human and ovine gestational membrane inflammation. Full-thickness membranes were collected from healthy, term, human placentas delivered by Caesarean section ( n =5). Using a Transwell model, they were stimulated ex vivo with γ-irradiation-killed Escherichia coli applied to the amniotic face. Membranes from near-term, ovine placentas were stimulated in utero with lipopolysaccharide, Ureaplasma parvum or saline control and subjected to explant culture. The effects of treatment with CSAIDs or vehicle (1% DMSO) on accumulation of PGE 2 and cytokines (human interleukin 6 (IL6), IL10 and TNFα ovine IL8 (oIL8)) were assessed in conditioned media at various time points (3–20 h). In human membranes, the IKKβ inhibitor TPCA-1 (7 μM) and p38 MAPK inhibitor SB239063 (20 μM) administered to the amniotic compartment were the most effective in inhibiting accumulation of cytokines and PGE 2 in the fetal compartment. NAC (10 mM) inhibited accumulation of PGE 2 and IL10 only NBDI (10 μM) had no significant effect. In addition to the fetal compartment, SB239063 also exerted consistent and significant inhibitory effects in the maternal compartment. TPCA-1 and SB239063 suppressed oIL8 production, while all CSAIDs tested suppressed ovine PGE 2 production. These results support the further investigation of intra-amniotically delivered CSAIDs for the prevention of inflammation-mediated PTB.
Publisher: Elsevier BV
Date: 12-1994
DOI: 10.1016/S0143-4004(05)80183-3
Abstract: In the present study, we investigated the roles of cyclic adenosine monophosphate (cAMP), intracellular calcium, glucocorticoids, protein kinase-C and gonadotrophin-releasing hormone (GnRH) in regulating human chorionic gonadotrophin (hCG), inhibin and activin production in cultured human term placental trophoblast cells. Inhibin and hCG were measured in conditioned media by radioimmunoassay, while putative forms of inhibin and activin were characterized by western blotting using affinity-purified antisera directed against the inhibin alpha- and beta A-subunits. Inhibin and hCG secretion were stimulated by dexamethasone (0.2 microM), GnRH (5-25 microM), calcium ionophore A23187 (0.2-1 microM), phorbol-12-myristate-13-acetate (22 nM) and epinephrine (1 microM), with increasing response over successive 24-h treatment periods. Two molecules Mr approximately 30 and 32 kDa appeared to be the predominant dimeric forms of inhibin secreted by the cells, while 26 kDa activin was present in excess over inhibin. Large amounts of 40-44 kDa protein were detected by the alpha-directed antisera only, which may be a form of the inhibin alpha-subunit precursor protein. Secretion of activin was responsive to phorbol ester-mediated stimulation but not to the presence of GnRH or elevated cAMP concentrations. The ergence in maternal serum inhibin and hCG concentrations during late pregnancy remains unexplained by these findings.
Publisher: Springer Science and Business Media LLC
Date: 08-08-2018
DOI: 10.1038/S41598-018-30087-4
Abstract: Antenatal inflammation as seen with chorioamnionitis is harmful to foetal/neonatal organ development including to eyes. Although the major pro-inflammatory cytokine IL-1β participates in retinopathy induced by hyperoxia (a predisposing factor to retinopathy of prematurity), the specific role of antenatal IL-1β associated with preterm birth (PTB) in retinal vasculopathy (independent of hyperoxia) is unknown. Using a murine model of PTB induced with IL-1β injection in utero , we studied consequent retinal and choroidal vascular development in this process we evaluated the efficacy of IL-1R antagonists. Eyes of foetuses exposed only to IL-1β displayed high levels of pro-inflammatory genes, and a persistent postnatal infiltration of inflammatory cells. This prolonged inflammatory response was associated with: (1) a marked delay in retinal vessel growth (2) long-lasting thinning of the choroid and (3) long-term morphological and functional alterations of the retina. Antenatal administration of IL-1R antagonists – 101.10 (a modulator of IL-1R) more so than Kineret (competitive IL-1R antagonist) – prevented all deleterious effects of inflammation. This study unveils a key role for IL-1β, a major mediator of chorioamnionitis, in causing sustained ocular inflammation and perinatal vascular eye injury, and highlights the efficacy of antenatal 101.10 to suppress deleterious inflammation.
Publisher: Springer Science and Business Media LLC
Date: 31-01-2017
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.AJOG.2016.11.1037
Abstract: A comprehensive preterm birth prevention program was introduced in the state of Western Australia encompassing new clinical guidelines, an outreach program for health care practitioners, a public health program for women and their families based on print and social media, and a new clinic at the state's sole tertiary level perinatal center for referral of those pregnant women at highest risk. The initiative had the single aim of safely lowering the rate of preterm birth. The objective of the study was to evaluate the outcomes of the initiative on the rates of preterm birth both statewide and in the single tertiary level perinatal referral center. This was a prospective population-based cohort study of perinatal outcomes before and after 1 full year of implementation of the preterm birth prevention program. In the state overall, the rate of singleton preterm birth was reduced by 7.6% and was lower than in any of the preceding 6 years. This reduction amounted to 196 cases relative to the year before the introduction of the initiative and the effect extended from the 28-31 week gestational age group onward. Within the tertiary level center, the rate of preterm birth in 2015 was also significantly lower than in the preceding years. A comprehensive and multifaceted preterm birth prevention program aimed at both health care practitioners and the general public, operating within the environment of a government-funded universal health care system can significantly lower the rate of early birth. Further research is now required to increase the effect and to determine the relative contributions of each of the interventions.
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.JRI.2010.11.003
Abstract: The major cause of spontaneous preterm birth (sPTB) at less than 32 weeks of gestation is intrauterine inflammation as a consequence of colonisation of the gestational membranes by pathogenic microorganisms which trigger activation of the local innate immune system. This results in release of inflammatory mediators, leukocytosis (chorioamnionitis), apoptosis, membrane rupture, cervical ripening and onset of uterine contractions. Recent PCR evidence suggests that in the majority of cases of inflammation-driven preterm birth, microorganisms are present in the amniotic fluid, but these are not always cultured by standard techniques. The nature of the organism and its cell wall constituents, residence time in utero, microbial load, route of infection and extent of tissue penetration are all factors which can modulate the timing and magnitude of the inflammatory response and likelihood of progression to sPTB. Administration of anti-inflammatory drugs could be a viable therapeutic option to prevent sPTB and improve fetal outcomes in women at risk of intrauterine inflammation. Preventing fetal inflammation via administration of placenta-permeable drugs could also have significant perinatal benefits in addition to those related to extension of gestational age, as a fetal inflammatory response is associated with a range of significant morbidities. A number of potential drugs are available, effective against different aspects of the inflammatory process, although the pathways actually activated in spontaneous preterm labour have yet to be confirmed. Several pharmacological candidates are discussed, together with clinical and toxicological considerations associated with administration of anti-inflammatory agents in pregnancy.
Publisher: CSIRO Publishing
Date: 15-06-2021
DOI: 10.1071/MA21023
Abstract: Preterm birth (PTB) is a significant health problem globally, with an estimate of 15 million cases annually. Approximately 10% of neonates born early will die prematurely, while a subset will develop severe life-long morbidities. Unfortunately, preterm birth’s syndromic nature has evaded prevention strategies, and it continues to impose a high burden on healthcare systems and families. The role of vaginal bacteria in triggering biomolecular causes of PTB has been recognised for years. However, translating this knowledge to practical diagnostic and therapeutic strategies has remained elusive. New techniques in high-throughput sequencing have improved our understanding of the nature and role of the vaginal microbiome during pregnancy. Several multi-ethnic and multi-geographical studies into the vaginal microbiome have identified five distinct bacterial profiles termed community state types (CSTs), one of which is positively associated with dysbiosis and increased risk of PTB. In a small pilot study of first-trimester vaginal microbial DNA obtained from pregnant women at high-risk of PTB, we compared the CST profiles generated using standard 16S licon sequencing with shallow shotgun metagenomics (SSM). Both methods identified the presence of the five CSTs as has been reported previously, although the metagenomic data showed greater taxonomic resolution and more accurate CST assignation. These findings suggest that SSM is a cost-effective and potentially superior alternative to 16S sequencing for vaginal microbiome analysis.
Publisher: Oxford University Press (OUP)
Date: 10-2002
DOI: 10.1093/HUMREP/17.10.2564
Abstract: The rationale for this study was to assess the expression, activity and localization of the enzymes uridine diphosphate glucuronosyltransferase (UGT), beta-glucuronidase, cytochrome P450 1A (CYP1A) and cytochrome P450 2E1 (CYP2E1) in first trimester human placenta and to gauge the effects of maternal variables on placental metabolism. CYP1A, CYP2E1, UGT and beta-glucuronidase activities were assessed in 25 placentas using ethoxyresorufin, chlorzoxazone, 4-methylumbelliferone and 4-methylumbelliferone glucuronide respectively. Protein expression and localization were detected by immunoblot and immunohistochemistry. All statistics were non-parametric. UGT, beta-glucuronidase and CYP1A activities were detected in all placentas s led CYP2E1 was undetectable. CYP1A, UGT1A UGT2B proteins were detected in all placentas (n = 6) tested and CYP2E1 in 4/6 placentas s led and were localized to the syncytium. UGT and CYP1A activities were significantly elevated in the placentas of mothers who smoked (P < 0.05 and P < 0.001 respectively) and were greatest in women who both smoked and drank alcohol (P < 0.05 and P < 0.01 respectively). Enzyme activities were significantly negatively correlated with gestational age (P < 0.05, r = 0.54, UGT) and maternal age respectively (P < 0.001, r = 0.63, CYP1A). beta-Glucuronidase activity did not differ with patient variables. Metabolism of compounds by the human placenta in the first trimester may be affected by maternal and environmental factors altering the activity of constitutive metabolizing enzymes.
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.PLACENTA.2019.08.079
Abstract: High-grade placental inflammation is associated with preterm birth and poor neonatal outcomes. Recent reports suggest that low-grade placental inflammation is common in uncomplicated pregnancies. The relationship between placental inflammation and innate immune anti-microbial responses is unknown. In this study we sought to identify any association between placental inflammation and fetal immune responses. Cord blood s les collected from late preterm and full-term Caesarean section deliveries (n = 44) were exposed to various immune challenges (resiquimod, LPS, PGN, poly (I:C), cGAMP, and 5'ppp-dsRNA) and production of inflammatory mediators (G-CSF, IFN-γ, IL-1β, IL-6, IL-8, IL-10, and TNF-α) was measured by multiplex assay. Hospital histology reports were used to assess the extent of inflammation in the placenta. Almost half (47.7%) of placentae examined here showed histological evidence of inflammation. Resiquimod, LPS, and PGN elicited strong inflammatory responses in neonatal cord blood, while poly (I:C), cGAMP, and 5'ppp-dsRNA elicited weaker responses. Fetuses with evidence of chorioamnionitis and fetal inflammatory reaction in their placentae had significantly increased immune responses to cGAMP and 5'ppp-dsRNA (ligands for STING and RIG-I, respectively) and significantly decreased immune responses to poly (I:C) (a TLR3 agonist). Interestingly, STING, RIG-I, and TLR3 are all involved in viral response pathways, suggesting that fetuses exposed to chorioamnionitis or fetal inflammatory reaction might respond differently to viruses postnatally. Our data suggest that low-level placental inflammation is associated with altered innate cytokine responses at birth.
Publisher: S. Karger AG
Date: 1994
DOI: 10.1159/000244074
Abstract: The contribution of the fetus to inhibin production in human pregnancy is unclear. Previous studies have reported inhibin concentrations in cord blood but on limited s le numbers. The present study is a more extensive examination of sex differences in immunoreactive inhibin and steroidal hormones in term umbilical cord blood. Venous serum concentrations of inhibin were found to be significantly higher in males (mean ± SD 2,168 ± 914 pg/ml, n = 62) than in females (1,761 ± 951 pg/ml, n = 63) (p 0.01). Male concentrations of total testosterone (p 0.005), free testosterone (p 0.005), and estradiol (p 0.05) were also significantly higher. The concentration of dehydroepiandrosterone sulphate (DHEAS) and the sex hormone-binding globulin (SHBG) capacity were similar in males and females. Multivariate regression analysis showed that the inhibin concentration in males correlated with the testosterone concentration and in females it correlated not only with testosterone concentration but also with gestational age at delivery and SHBG capacity (all p 0.001). Inhibin concentrations in cord arterial serum in a subgroup of 24 males and 31 females were higher than in the venous serum in both sexes but the differences were not statistically significant. Concentrations of DHEAS determined in 22 female cord arterial blood s les (6.0 ± 2.5 μmol/l) were significantly higher than the venous concentrations (5.2 ± 1.8 μmol/l) (p 0.05). Inhibin did not correlate with DHEAS either in their arterial serum concentrations or in the arteriovenous concentration differences. The findings of this study are consistent with the placenta being the principal source of inhibin circulating in the human fetus in late pregnancy. Further, they suggest that there are minor sex differences in placental metabolism of inhibin and the steroidal sex hormones.
Publisher: The American Association of Immunologists
Date: 15-10-2009
Abstract: Intrauterine inflammation plays a major role in the etiology of preterm labor and birth. We established an ex vivo model employing perfused full-thickness term gestational membranes to study membrane transport, function, and inflammatory responses. Exposure of the maternal (decidual) face of the membranes to LPS (5 μg/ml) resulted in increased accumulation of proinflammatory cytokines in the maternal compartment within 4 h, followed by a response in the fetal (amniotic) compartment. Using cytokine arrays, exposure to LPS was found to result in increased secretion of a large number of cytokines and chemokines in both compartments, most notably IL-5, IL-6, IL-7, MDC (macrophage-derived chemokine), MIG (monokine induced by IFN-γ), TARC (thymus and activation-regulated chemokine), TGF-β, and TNF-α. PGE2 accumulation also increased in response to LPS, particularly in the fetal compartment. Cotreatment with sulfasalazine, which inhibited nuclear translocation of NF-κB p65, had a rapid and marked inhibitory effect on the rate of cytokine accumulation in the maternal compartment, with lesser but significant effects observed in the fetal compartment. While membrane integrity was not discernibly impaired with LPS or sulfasalazine exposure, rates of chorionic apoptosis after 20 h were doubled in sulfasalazine-treated tissues. We conclude that the system described provides a means of accurately modeling human gestational membrane functions and inflammatory activation ex vivo. Decidual LPS exposure was shown to elicit a robust inflammatory response in both the maternal and fetal compartments. Sulfasalazine was an effective antiinflammatory agent in this model, but also exerted proapoptotic effects that raise concerns regarding its placental effects when administered in pregnancy.
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.BBALIP.2010.05.015
Abstract: ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 mediate the efflux of cholesterol and other sterols. Both transporters are expressed on the fetal capillaries of the placenta and are involved in maternal-to-fetal cholesterol delivery. In this study, we report that ABCA1 and ABCG1 are also present on the syncytiotrophoblast, the maternal facing placental membrane. Syncytial ABCA1 expression is apical, suggesting a role in cholesterol efflux to the mother, while ABCG1 is expressed basolaterally indicating transport to the fetus. Silencing of ABCA1 expression in primary trophoblasts in culture, or pharmacological antagonism by glyburide, decreased cholesterol efflux to apolipoprotein A-I (apoA-I) compared to controls, while ABCG1-silencing decreased cholesterol efflux to high density lipoproteins (HDL). In contrast, treatment with endogenous or synthetic LXR alpha/beta ligands such as T0901317 increased ABCA1 and ABCG1 expression and enhanced cholesterol efflux to apoA-I and HDL, respectively, while treatment with pharmacological PPAR-alpha or -gamma ligands was without effect. Trophoblasts transfected with ABCA1 or ABCG1 siRNA were more sensitive to toxic oxysterols substrates (25-hydroxycholesterol and 7-ketocholesterol) compared to mock-transfected cells, while prior treatment with T0901317 reduced oxysterol-mediated toxicity. These results identify syncytial ABCA1 and ABCG1 as important, inducible cholesterol transporters which also prevent placental accumulation of cytotoxic oxysterols.
Publisher: Elsevier BV
Date: 02-2021
Publisher: Frontiers Media SA
Date: 20-04-2015
Publisher: Springer Science and Business Media LLC
Date: 08-10-2018
DOI: 10.1038/S41565-018-0272-2
Abstract: Gold nanorods are one of the most widely explored inorganic materials in nanomedicine for diagnostics, therapeutics and sensing
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.PLACENTA.2016.01.003
Abstract: Workshops are an important part of the IFPA annual meeting, as they allow for discussion of specialized topics. At the IFPA meeting 2015 there were twelve themed workshops, three of which are summarized in this report. These workshops were related to various aspects of placental biology but collectively covered areas of pregnancy pathologies and placental metabolism: 1) nanomedicine applications and exosome biology 2) xenobiotics and endocrine disruptors and pregnancy 3) lipid mediators and placental function.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.PLACENTA.2014.09.009
Abstract: Solithromycin is a 4th generation macrolide/fluoroketolide antibiotic that has potential applications in the treatment and prevention of intrauterine and fetal infections in pregnancy it has also been reported to exert anti-inflammatory effects. The objective of the present study was to determine its ability to cross the human placenta and inhibit cytokine production by placental and decidual cells in culture. Maternal-to-fetal passage of solithromycin was determined using the dual recycling ex vivo placental perfusion model normal healthy term placentas delivered by Caesarean section were employed for the study. Creatinine transfer was also assessed as a diffusion-limited perfusion control. Purified primary decidual and trophoblast cells were treated in vitro for 20 h with solithromycin (0-100 μg/mL) and cytokine production and cell viability were assessed. The mean ± SD maternal-to-fetal transfer ratio (TRf: concentration in maternal ÷ fetal circuit) of solithromycin after 3 h perfusion was 40.3 ± 23.6% (n = 4 placentas), with values from in idual experiments ranging from 18 to 65%. The peak TRf of creatinine was 54%, and the clearance index for solithromycin (TRfsoli/TRfcreat) was 87% at 3 h. Solithromycin did not inhibit production of IL-6 and TNF-α by trophoblasts and decidual cells at non-toxic pharmacological concentrations (≤ 11 μg/mL). Solithromycin is the first antibiotic of its class to exhibit efficient maternal-to-fetal transfer across the human placenta and is thus an ideal candidate for evaluation for the treatment of intrauterine and fetal infections in pregnancy. At pharmacological concentrations it does not appear to inhibit pro-inflammatory cytokine production by placental cells.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Springer Science and Business Media LLC
Date: 05-2011
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 19-01-2007
Abstract: Placental ATP binding cassette (ABC) transporters protect placental and fetal tissues by effluxing xenobiotics and endogenous metabolites. We have investigated the effects of cytokines and survival/growth factors, implicated in various placental pathologies, on ABC transporter expression and function in primary placental trophoblast cells. Treatment of primary term trophoblasts in vitro with tumor necrosis factor-alpha (TNF-alpha) or interleukin (IL)-1beta decreased mRNA and protein expression of apical transporters ABCB1/multidrug resistance gene product 1 (MDR1) and ABCG2/breast cancer resistance protein (BCRP) protein by 40 to 50% (P < 0.05). In contrast, IL-6 increased mRNA and protein expression of the basolateral transporter ABCB4/MDR3 (P < 0.05), whereas ABCC1/MRP1 expression was unaltered. Pretreatment of trophoblasts with TNF-alpha over 48 h resulted in significantly decreased BCRP efflux activity (increased mitoxantrone accumulation) with minimal changes in MDR1/3 activity. Epidermal growth factor (EGF) and insulin-like growth factor II, on the other hand, significantly increased BCRP expression at the mRNA and protein level (P < 0.05) EGF treatment also increased BCRP functional activity. Estradiol stimulated BCRP, MDR1, and MDR3 mRNA and protein expression by 40 to 60% and increased MDR1/3 functional activity (P < 0.05). Progesterone had modest positive effects on MRP1 mRNA and MDR1 protein expression (P < 0.05). In conclusion, this study shows that proinflammatory cytokines, sex steroids, and growth factors exert independent effects on expression of apical and basolateral placental ABC transporters in primary trophoblast. Such changes could alter placental drug disposition, increase fetal susceptibility to toxic xenobiotics, and impact on placental viability and function.
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.CBI.2013.03.007
Abstract: The human placenta, in addition to its roles as a nutrient transfer and endocrine organ, functions as a selective barrier to protect the fetus against the harmful effects of exogenous and endogenous toxins. Members of the ATP-binding cassette (ABC) family of transport proteins limit the entry of xenobiotics into the fetal circulation via vectorial efflux from the placenta to the maternal circulation. Several members of the ABC family, including proteins from the ABCA, ABCB, ABCC and ABCG subfamilies, have been shown to be functional in the placenta with clinically significant roles in xenobiotic efflux. However, recent findings suggest that these transporters also protect placental tissue by preventing the cellular accumulation of cytotoxic compounds such as lipids, sterols and their derivatives. Such protective functions are likely to be particularly important in pregnancies complicated by inflammatory or oxidative stress, where the generation of toxic metabolites is enhanced. For ex le, ABC transporters have been shown to protect against the harmful effects of hypoxia and oxidative stress through increased expression and efflux of oxysterols and glutathione conjugated xenobiotics. However, this protective capacity may be diminished in response to the same stressors. Several studies in primary human trophoblast cells and animal models have demonstrated decreased expression and activity of placental ABC transporters with inflammatory, oxidative or metabolic stress. Several clinical studies in pregnancies complicated by inflammatory conditions such as preecl sia and gestational diabetes support these findings, although further studies are required to determine the clinical relevance of the relationships between placental ABC transporter expression and activity, and placental function in stressed pregnancies. Such studies are necessary to fully understand the consequences of pregnancy disorders on placental function and viability in order to optimise pregnancy care and maximise fetal growth and health.
Publisher: Elsevier BV
Date: 02-2001
Publisher: Informa UK Limited
Date: 08-12-2016
Publisher: Oxford University Press (OUP)
Date: 2019
DOI: 10.1111/LAM.13091
Abstract: Reagent-derived contamination can compromise the integrity of microbiome data, particularly in low microbial biomass s les. This contamination has recently been attributed to the ‘kitome’ (contamination introduced by the DNA extraction kit), prior to which attention was mostly paid to potential contamination introduced by PCR reagents. In this study, we assessed the proportion to which our DNA extraction kit and PCR master mix introduce contaminating microbial DNA to bacterial microbial profiles generated by 16S rRNA gene sequencing. Utilizing a commercial dsDNase treatment protocol to decontaminate the PCR master mix, we demonstrated that the vast majority of contaminating DNA was derived from the PCR master mix. Importantly, this contamination was almost completely eliminated using the simple dsDNase treatment, resulting in a 99% reduction in contaminating bacterial reads. We suggest that dsDNase treatment of PCR reagents should be explored as a simple and effective way of reducing contamination in low-biomass microbiome studies and producing more robust and reliable data. Reagent contamination with microbial DNA is a major problem in microbiome studies of low microbial biomass s les. Levels of such contaminating DNA often outweigh what is present in the s le and heavily confound subsequent data analysis. Previous studies have suggested this contamination is primarily derived from DNA extraction kits. Here, we identified the PCR master mix as the primary source of contamination, and showed that enzymatic removal of the contamination drastically reduced the blank signal and improved precision. Decontamination of PCR master mixes may have the potential to improve the sensitivity and accuracy of low-biomass microbiome studies.
Publisher: Elsevier BV
Date: 04-1999
Abstract: Cytokines and growth factors have been proposed to act as in vivo modulators of amnion prostaglandin production at parturition. To characterize the effects of the 'anti-inflammatory' cytokine interleukin (IL)-4 on amnion prostaglandin production, amnion epithelium-derived WISH cells were treated with IL-4 in the presence/absence of IL-1beta, tumour necrosis factor-alpha (TNF-alpha) or epidermal growth factor (EGF). IL-4 (0.08-10 ng/ml) potently inhibited cytokine-stimulated PGE2 production over 16 h (maximal inhibition approximately 66% at 2.0 ng/ml IL-4). Delaying addition of IL-4 (1 ng/ml) by up to 8 h after IL-1beta addition only slightly attenuated its inhibitory effects, from approximately 65% to approximately 50%. EGF-stimulated PGE2 production was either not inhibited or slightly stimulated by IL-4. Immunoblotting studies revealed that IL-4 (10 ng/ml) significantly suppressed prostaglandin-H synthase-2 (PGHS-2) levels in cells stimulated with IL-1beta and TNF-alpha over 16 h, but had no consistent effects on cytosolic phospholipase A2 (cPLA2) levels under any condition. In the presence of arachidonic acid (10 microM), IL-4 again inhibited cytokine-stimulated, but not EGF-stimulated, PGE2 production. The presence of IL-4 also failed to alter the amount of arachidonic acid released in response to EGF. These findings suggest a role and potential therapeutic application for IL-4 in inhibiting amnion PGHS-2 expression and hence prostaglandin production in infection-driven preterm labour, but not labour in the absence of inflammatory initiators.
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.VETPAR.2015.11.017
Abstract: The hypothesis tested in this experiment was that Trichostrongylus colubriformis infection would reduce growth rates of grazing meat-breed lambs however production loss would be reduced by suppression of the host immune response. The experiment had a 3×2 factorial design using 6-7 month old meat-breed lambs which remained uninfected or infected (IFY) with 2000 or 4000 T. colubriformis L3/week for 12 weeks and were immunosuppressed (SUPY) using methylprednisolone acetate once weekly or remained non-immunosuppressed (SUPN). Immunosuppression increased worm egg counts (WEC) of infected lambs (SUPY 2421 eggs per gram (epg), SUPN 1154 epg on day 84, p<0.05) and T. colubriformis burdens (p<0.05-0.10) and reduced circulating eosinophils (p<0.05 on days 11, 42, 56 and 84) and intestinal total antibody titres (p<0.02). There was a significant (p<0.05) interaction between the main effects of infection and immunosuppression with infection having a larger negative effect on the liveweight of non-immunosuppressed lambs. The immunological response of the host to T. colubriformis infection accounted for 75% of the overall cost of infection (3.1kg) with the majority of this cost occurring during the first 35 days of infection. In contrast, most of the cost associated with the direct effect of infection occurred after day 35. These results confirm in grazing meat-breed lambs that the host's immunological response to T. colubriformis infection is the major component of production loss.
Publisher: Bioscientifica
Date: 12-1998
Abstract: Increased prostaglandin biosynthesis during intrauterine infection may be a possible mechanism by which preterm labour is initiated. Inflammatory cytokines and growth factors are known to stimulate prostaglandin production through an increase in prostaglandin endoperoxide H synthase (PGHS)-2 synthesis and activity. Interleukin-4 (IL-4), an anti-inflammatory cytokine, can downregulate PGHS-2 expression and inhibit prostaglandin production. Therefore, the aims of the current study were to determine the effects of IL-4 on PGHS-1 and PGHS-2 expression in amion-derived WISH cells treated with inflammatory cytokines and growth factors. In WISH cells, near-maximal production of the PGHS-2 mRNA occurred using 5 ng/ml EGF, 1 ng/ml IL-1beta or 50 ng/ml TNF-alpha. Time-course experiments determined that the PGHS-2 mRNA was induced maximally by these stimuli by 1 h. Pretreatment of WISH cells with IL-4 reduced PGHS-2 mRNA levels at 1 h by 67% in cells treated with EGF, 62% in cells treated with IL-1beta and 54% in cells treated with TNF-alpha. Pretreatment with IL-4 more effectively inhibited PGHS-2 expression than simultaneous addition with EGF or IL-1beta but not TNF-alpha. Immunoblot analysis showed a correlation between inhibition of mRNA levels and levels of PGHS-2 protein, although stimulation of PGHS-2 protein production by EGF was undetectable. Levels of PGHS-1 protein and mRNA remained unchanged in all experiments. Increased production of prostaglandin E2 (PGE2) in response to TNF-alpha and IL-1beta treatment was attenuated by IL-4 pretreatment, by 52% and 72%, respectively. No attenuation of EGF-stimulated PGE2 levels was seen. We conclude that IL-4 inhibits PGHS-2 mRNA and protein production in cytokine-stimulated WISH cells, but does not affect EGF-stimulated PGE2 production, suggesting that EGF can induce prostaglandin biosynthesis by a mechanism other than through increased PGHS-2 expression.
Publisher: Elsevier BV
Date: 12-2001
DOI: 10.1016/S0090-6980(01)00164-2
Abstract: Apoptosis at the site of rupture has been proposed to play a role in premature rupture of the fetal membranes, a condition associated with increased risk of neonatal sepsis and preterm birth. We investigated the ability of peroxisome proliferator-activated receptor (PPAR)-gamma ligands 15-deoxy-delta12,14PGJ2 (15d-PGJ2), delta12PGJ2, ciglitizone and rosiglitazone to induce apoptosis in the amnion-like WISH cell line. 15d-PGJ2 (10 microM) induced morphological characteristics of apoptosis within 2 h, with biochemical indices (caspase activation and substrate cleavage) following shortly after maximum cell death (approximately 60%) was observed by 16 h, with an EC50) of approximately 7 microM 15d-PGJ2. Delta12-PGJ2 also induced apoptosis but was less potent and acted at a much slower rate. While ciglitizone also induced apoptosis, rosiglitazone had no effect on cell viability. The mechanism of induction of apoptosis by 15d-PGJ2 and delta12PGJ2, which may be independent of PPAR-gamma activation, requires further elucidation.
Publisher: Elsevier BV
Date: 2021
DOI: 10.1016/J.VETPAR.2021.109637
Abstract: This study was conducted to investigate whether co-administration of Barbervax® (Bvax) with Haemonchus contortus surface larval antigen (HcsL3) would increase the protective efficacy and duration of protection against H. contortus infection in weaner Merino sheep. A total of 132 10-month-old weaned Merino ewe lambs were randomly allocated into six treatment groups (n = 22). Sheep were vaccinated four times with either Barbervax® (Bvax), H. contortus L3 surface larval antigen (HcsL3), combined vaccination (Bvax + HcsL3), Bvax + AlOH, HcsL3 + Saponin or remained as unvaccinated controls. Aluminium hydroxide (AlOH) and saponin adjuvants were included in HcsL3 and Bvax vaccines respectively. The first three vaccinations were given at 4 week intervals and the fourth vaccination provided as booster, 9 weeks later. All animals were treated with Zolvix™ (monepantel 25 mg/mL, Elanco) at the third vaccination and commencing two weeks later, artificially trickle infected with H. contortus L3. Worm egg count (WEC), packed cell volume (PCV), antibody titre and bodyweight were measured throughout the study as was specific antibody directed against each antigen using ELISA. The administration of Bvax and HcsL3, alone or in combination, induced an antibody response against HcsL3 but only the Bvax and the combined treatment elicited an antibody response to the Bvax antigen. The targeting of HcsL3 by each vaccine was confirmed by immunofluorescence staining of H. contortus L3. However, only the booster vaccination in the Bvax treatments reduced WEC to levels below untreated controls. The HcsL3 vaccine did not reduce WEC in this experiment and co-administration with Bvax did not improve the efficacy and duration of protection against H. contortus infection.
Publisher: Oxford University Press (OUP)
Date: 08-2010
DOI: 10.1095/BIOLREPROD.110.083907
Abstract: Placental oxidative stress plays a key role in the pathophysiology of placenta-related disorders, most notably preecl sia (PE) and intrauterine growth restriction (IUGR). Oxidative stress occurs when accumulation of reactive oxygen species (ROS) damages DNA, proteins and lipids, an outcome that is limited by antioxidant enzymes mitochondrial uncoupling protein 2 (UCP2) may also limit oxidative stress by reducing ROS production. Here we characterized placental antioxidant defenses during normal gestation and following glucocorticoid-induced IUGR. Placentas were collected on Days 16 and 22 of normal rat pregnancy (term = Day 23) and at Day 22 after dexamethasone treatment from Day 13. Expression of several genes encoding antioxidant enzymes (Sod1, Sod2, Sod3, Cat, Gpx3, Txn1, Txnrd1, Txnrd2, and Txnrd3) and Ucp2 was measured by quantitative RT-PCR in the labyrinth (LZ) and junctional zones (JZ) of the placenta. Expression of Sod1 and Ucp2 mRNAs and the activity of xanthine oxidase, a source of ROS, all increased from Days 16 to 22 in both placental zones, whereas Sod2 and Gpx3 increased only in the rapidly growing LZ. In contrast, Sod3 and Txnrd1 expression fell in the LZ over this period, whereas total superoxide dismutase activity remained stable. Dexamethasone treatment reduced fetal-placental growth and LZ expression of Ucp2 but increased JZ expression of Txn1. Indices of placental oxidative damage (TBARS, F(2)-isoprostanes, and 8-OHdG) did not change with gestational age or dexamethasone, indicative of adequate antioxidant protection. Overall, our data suggest that the rat placenta is protected from oxidative stress by the dynamic zone- and stage-dependent expression of antioxidant defense genes.
Publisher: Public Library of Science (PLoS)
Date: 09-03-2017
Publisher: Hindawi Limited
Date: 03-2004
Publisher: Elsevier BV
Date: 02-2006
DOI: 10.1016/J.PLACENTA.2005.03.002
Abstract: Bovine nuclear transfer pregnancies are characterized by a high incidence of placental abnormalities, notably, increased placentome size and deficiencies in trophoblast cell function and establishment of placental vasculature. Alterations in gene expression during placental growth and development may contribute to the appearance of large placentomes in pregnancies derived from nuclear transfer. The placenta synthesizes a number of cytokines and growth factors, including the transforming growth factor-betas (TGF-betas) that are involved in the establishment, maintenance and/or regulation of pregnancy. All forms of TGF-beta and their receptors are present at the fetal-maternal interface of the bovine placentome, where they are thought to play an important role in regulating growth, differentiation, and function of the placenta. Using real-time RT-PCR, we have examined the expression of TGF-beta1, TGF-beta2, TGF-beta3 and the receptors TGF-betaRI and TGF-betaRII in placentomes of artificially inseminated (AI) and nuclear transfer (NT)-derived bovine pregnancies at days 50, 100 and 150 of gestation. TGF-beta1, TGF-beta2 and TGF-beta3 mRNA expression increased by 2.0-2.8-fold, while TGF-betaRI and TGF-betaRII mRNA expression decreased by 1.7-2.0-fold in NT placentomes compared to AI controls at all gestational ages examined. These findings indicate that NT placentomes may be resistant to the growth suppressive effects of TGF-betas and could contribute to the placental proliferative abnormalities observed in NT-derived placentas. Alternatively, deficiencies in placentation may provide a mechanism whereby TGF-betas are dysregulated in NT pregnancies.
Publisher: Bentham Science Publishers Ltd.
Date: 05-2011
DOI: 10.2174/138920111795471010
Abstract: During the past decade there has been an explosion in the number of nanoparticulate drugs or drug delivery systems being explored, developed and marketed for the treatment and prevention of human diseases. While the potential dangers of drug administration in pregnancy are well known, there are circumstances where the benefits of maternal drug administration are perceived to outweigh the risks to the fetus. Hence, the administration of potentially harmful drugs in pregnancy is surprisingly common. Nanoparticulate delivery systems offer a potential avenue for delivering therapeutics to maternal tissues with minimal risk of incidental fetal exposure, depending on the ability of the nanoparticle in question to cross the placenta. As the conduit to the fetus, the placenta is both a drug target and a drug barrier, as well as a potential target of any toxicity. Limited studies on this topic show considerable uncertainty regarding the transplacental passage of nanoparticles, and our understanding of the criteria that determine transferability is poor. Despite the fact that the toxicity caused by environmental and man-made nanoparticulates has been widely studied in various organ systems, data on the effects of maternal nanoparticle exposure on human fetal tissues are lacking, although studies in rodents indicate that caution is justified. In this review, we examine the evidence relating to the potential toxicity of nanoparticles in pregnancy, the ability of the placenta to take up and transfer nanoparticles to the fetus, and the theoretical benefits and risks of administration of nanoparticle-based therapeutics in pregnancy.
Publisher: Bioscientifica
Date: 04-2014
DOI: 10.1530/REP-13-0331
Abstract: We hypothesised that antenatal exposure to ubiquitous phthalates may lead to an earlier menarche and a lower prevalence of polycystic ovarian syndrome (PCOS) and polycystic ovarian morphology (PCO) in adolescence. The Western Australian Pregnancy Cohort (Raine) Study recruited 3000 women at 18 weeks of gestation in 1989–1991, 1377 had antenatal serum stored without thawing at −80 °C. An unselected subset was evaluated in the early follicular phase for PCO and PCOS by ultrasound and serum evaluation in adolescence. Serum was analysed for anti-Müllerian hormone (AMH), inhibin B, sex hormone binding globulin (SHBG), testosterone, androstenedione and DHEAS. Four hundred microlitres of the frozen maternal serum underwent isotope-diluted liquid chromatography–tandem mass spectrometry, with preceding enzymatic deconjugation followed by solid-phase extraction to determine phthalate exposure. Two hundred and forty four girls attended assessment and most common phthalate metabolites were detectable in the majority of the 123 s les available. Several phthalates were negatively associated with maternal SHBG, and associations with maternal androgens were less consistent. The sum of the metabolites of di-(2-ethylhexyl) phthalate was associated with a non-significant tendency towards an earlier age at menarche ( P =0.069). Uterine volume was positively associated with mono-(carboxy-iso-octyl) phthalate ( P =0.018). Exposure to monoethyl phthalate (MEP) and the sum of all phthalate metabolites (Σall phth.m) were protective against PCOS in adolescence ( P =0.001 and P =0.005 respectively). There were negative associations of MEP with PCO ( P =0.022) and of MEP with serum AMH ( P =0.031). Consequently, our data suggest that antenatal exposure to environmental phthalates may be associated with oestrogenic and/or anti-androgenic reproductive effects in adolescent girls.
Publisher: Springer Science and Business Media LLC
Date: 07-06-2015
Publisher: Wiley
Date: 27-02-2022
DOI: 10.1111/AVJ.13156
Abstract: Infectious disease has a significant impact on livestock production. Availability of alternatives to antibiotics to prevent and treat disease is required to reduce reliance on antibiotics while not impacting animal welfare. Innate immune stimulants, such as mycobacterium cell wall fractions (MCWF), are used as alternatives to antibiotics for the treatment and prevention of infectious disease in a number of species including cattle, horses and dogs. This study aimed to evaluate the safety of Amplimune®, an MCWF‐based immune stimulant, for weaner Angus cattle. On day −1 and 0, sixty mixed‐sex Angus weaner cattle were transported for 6 h before being inducted and housed in a large single pen, simulating feedlot induction conditions. The cattle were assigned to one of six treatment groups (n = 10 per group): 2 mL Amplimune intramuscularly (2IM) 2 mL Amplimune subcutaneously (2SC) 5 mL Amplimune intramuscularly (5IM) 5 mL Amplimune subcutaneously (5SC) 5 mL saline intramuscularly (SalIM) and 5 mL saline subcutaneously (SalSC) on day 0 following transportation. Body temperature, body weight, concentrations of circulating pro‐inflammatory cytokines (TNFα, IL‐1β, IL‐6 and IL‐12) and haematology parameters were measured at various times up to 96 h post‐treatment. No adverse effects from Amplimune treatment were observed. Amplimune induced an increase in circulating cytokine TNFα concentrations, total white blood cell count and lymphocyte counts indicative of activation of the innate immune system without causing an excessive inflammatory response. Results confirm that Amplimune can be safely administered to beef cattle at the dose rates and via the routes of administration investigated here.
Publisher: Elsevier BV
Date: 05-2020
Publisher: Wiley
Date: 05-2000
DOI: 10.1111/J.8755-8920.2000.430504.X
Abstract: Clinically useful tests for the prediction and diagnosis of preterm labor and delivery remain to be established. We have hypothesized that soluble intercellular adhesion molecule-1 (sICAM-1) in the cervicovaginal fluid of women with preterm labor may be a useful diagnostic tool. The cervicovaginal fluid of 103 women between 24(0) and 33(6) weeks gestation with preterm contractions and intact membranes was assayed for sICAM-1. Elevated sICAM-1 concentrations predicted short intervals to delivery (area under receiver operator characteristic (ROC) curves, 0.70-0.72 for delivery within 3, 7 and 10 days), with high specificity. Characteristics for delivery within 3 days at a 3 ng/mL threshold for a positive test were sensitivity 33.3%, specificity 98.9%, and positive and negative predictive values of 75.0% and 93.9%, respectively. Predictive ability was independent of and complementary to that of fetal fibronectin (fFN). Measurement of sICAM-1 in cervicovaginal fluid has potential as a predictor of preterm delivery in women with symptoms of preterm labor, particularly in conjunction with fFN testing.
Publisher: American Society for Microbiology
Date: 02-2014
DOI: 10.1128/JCM.03036-13
Abstract: Ureaplasma sp. infection in neonates and adults underlies a variety of disease pathologies. Of the two human Ureaplasma spp., Ureaplasma parvum is clinically the most common. We have developed a high-resolution melt (HRM) PCR assay for the differentiation of the four serovars of U. parvum in a single step. Currently U. parvum strains are separated into four serovars by sequencing the promoter and coding region of the multiple-banded antigen (MBA) gene. We designed primers to conserved sequences within this region for PCR lification and HRM analysis to generate reproducible and distinct melt profiles that distinguish clonal representatives of serovars 1, 3, 6, and 14. Furthermore, our HRM PCR assay could classify DNA extracted from 74 known (MBA-sequenced) test strains with 100% accuracy. Importantly, HRM PCR was also able to identify U. parvum serovars directly from 16 clinical swabs. HRM PCR performed with DNA consisting of mixtures of combined known serovars yielded profiles that were easily distinguished from those for single-serovar controls. These profiles mirrored clinical s les that contained mixed serovars. Unfortunately, melt curve analysis software is not yet robust enough to identify the composition of mixed serovar s les, only that more than one serovar is present. HRM PCR provides a single-step, rapid, cost-effective means to differentiate the four serovars of U. parvum that did not lify any of the known 10 serovars of Ureaplasma urealyticum tested in parallel. Choice of reaction reagents was found to be crucial to allow sufficient sensitivity to differentiate U. parvum serovars directly from clinical swabs rather than requiring cell enrichment using microbial culture techniques.
Publisher: Frontiers Media SA
Date: 04-04-2017
Publisher: Elsevier BV
Date: 07-2021
DOI: 10.1016/J.PNPBP.2020.110218
Abstract: Antidepressant treatment of perinatal depression is increasingly common and accepted in clinical guidelines. It has been suggested that serotonergic antidepressants may effect changes in the oxytocinergic system, including oxytocin levels, and that this may be one of the beneficial mechanisms of action for these drugs. Furthermore, oxytocin has been associated with the quality of the parent-child relationship, which may be important in treatment of perinatal depression. This study will explore if there is a relationship between antidepressant use over the perinatal period and oxytocin levels. Data from a pregnancy cohort study are used from 279 women across three groups: women taking antidepressants in pregnancy (n = 48), women with untreated depression (n = 31) and healthy control women (n = 200). Data included antidepressant use, maternal depression and oxytocin plasma concentrations in pregnancy and up to 12 months postpartum. We found that concurrent oxytocin blood concentrations were not associated with perinatal antidepressant use. However, oxytocin blood concentrations increased more steeply in those on antidepressants across the perinatal period compared to control women. A steeper increase for Selective Serotonergic Reuptake Inhibitors was observed, however, this effect was on the boarder of statistical significance. In conclusion, although antidepressant use and oxytocin was not associated at any time point, women taking antidepressants during pregnancy had larger increases in oxytocin over the perinatal period. Future research could examine specific agents and class of antidepressant and the relationship to parenting.
Publisher: The Endocrine Society
Date: 24-06-2016
DOI: 10.1210/JC.2016-1646
Abstract: The impact of early life events on testicular function in adulthood is not well understood. To study the early influences of fetal growth, exposures to cigarette smoke in utero and cord blood estrogens, and the influences of growth and adiposity in childhood through adolescence on testicular function in adulthood. Male members of the Western Australian Pregnancy Cohort (Raine) were contacted at 20-22 years of age. Of 913 contacted, 423 (56%) agreed to participate 404 underwent a testicular ultrasound, 365 provided a semen s le, and reproductive hormones were measured (384). Fetal growth measurements (n = 137), umbilical cord estrogen concentrations (n = 128), cord testosterone (T) (n = 125), and child-adulthood growth charts (n = 395) were available. Median sperm output for the 18.6% of men exposed in utero to smoking was lower than nonexposed (82.4 × 10(6) vs 123.1 × 10(6) P = .029). Sperm output in adulthood was inversely correlated with cord serum estradiol (P = .019) and estrone (P = .018). The sperm output of men whose cord blood estradiol and estrone were less than 50th percentile vs more than 50th percentile was 191.1 × 10(6) vs 100.5 × 10(6) (P = .002) and 190.0 × 10(6) vs 106.0 × 10(6) (P = .012), respectively. Men with favorable fetal growth patterns in utero were less likely to have total motile sperm counts within the lowest quartile (P = .011), and men born prematurely had reduced serum T levels in adulthood (13.4 vs 16.6nmol/L, P = .024). Consistent height above the 50th percentile for age through childhood was associated with larger adult mean testicular volume (P < .001). Optimal body mass index trajectory through childhood and adolescence was associated with larger testicular volume (P = .009) and higher serum inhibin B (P = .010) and T (P = .003) in adulthood. Exposures to maternal smoking and higher cord blood estrogens at delivery were associated with a reduced sperm output in adulthood. Optimal adult testicular function depends on being born at or above average weight, and maintaining optimal growth and adiposity into adulthood.
Publisher: CSIRO Publishing
Date: 2017
DOI: 10.1071/AN15805
Abstract: This experiment tested the hypothesis that integrated parasite management (IPM) programs would reduce the effects of gastrointestinal nematodes (GIN) in meat-breed lamb production systems on the Northern Tablelands of New South Wales. The experiment was a longitudinal experiment using twin-bearing Border Leicester × Merino ewes on farms managed in accordance to either regional WormBoss IPM programs (n = 3 farms) or typical (TYP) regional GIN control (n = 2 farms). Ewes on each farm were either GIN-suppressed (SUP n = 120 ewes) or not (NSUP n = 120 ewes) and were managed in two groups (n = 120/group) balanced for GIN control. Ewes lambed in September and at lamb marking, 120 lambs (Dorset sires) from each ewe GIN control group were enrolled in the experiment to investigate the effect of ewe GIN control on lamb performance up to weaning. Overall mean worm egg count (WEC) of ewes (P = 0.004) was lower with IPM (IPM 766 vs TYP 931 epg) and was achieved with fewer drenches (IPM 4.5 vs TYP 5.5/year). Despite lower WEC, GIN infection reduced liveweight (IPM –2.1 kg vs TYP –1.1 kg, P = 0.0006) and clean fleece weight (IPM –0.11 kg vs TYP –0.01 kg, P = 0.03) of ewes to a greater extent on IPM farms. The annual rate of apparent ewe mortality was 6.5% and this was unaffected by GIN infection. WEC of lambs at weaning was lower on IPM farms (IPM 159 epg vs TYP 322, P 0.0001) but the difference in weaning weights of lambs reared by NSUP and SUP ewes was greater on IPM farms (IPM –1.1 kg vs TYP 0.2 kg, P 0.0001). Overall, the production loss due to GIN infection in these sheep-meat production systems, on the Northern Tablelands of New South Wales, was small and treatment frequency can be reduced by IPM programs.
Publisher: CSIRO Publishing
Date: 2017
DOI: 10.1071/AN15806
Abstract: The hypothesis tested in this experiment was that the effects of gastrointestinal nematodes (GIN) on growth of meat-breed lambs would be absent during the suckling period and greatest after weaning. The experiment was a single factor design conducted on five farms over 2012–2014, using meat-breed lambs (Poll Dorset × Border Leicester/Merino), which were either GIN-suppressed (SUP) or not (NSUP). The experiment commenced at lamb marking and continued for 5 months. SUP lambs were serially treated with short- and long-acting anthelmintics. NSUP lambs were not treated before weaning and at weaning received a short-acting multi-active drench with subsequent treatments varying between farms. Worm egg count (WEC) of NSUP lambs were significantly higher (P 0.0001) than SUP lambs at weaning (1170 and 10 epg) and thereafter (P 0.0001) reaching 920 epg 2 months after weaning. Haemonchus contortus was the predominant species present in NSUP lambs with smaller contributions from Trichostrongylus spp. There was no effect of GIN control on lamb growth during the pre-weaning period (SUP 17.2 kg vs NSUP 17.0 kg, P = 0.093), whereas GIN reduced growth of lambs by 0.5 kg (SUP 7.1 kg vs NSUP 6.6 kg, P = 0.002) in the last month of observation. There was no effect of GIN control on lamb mortality. GIN did not affect growth of suckling meat-breed lambs despite high WEC at weaning indicating resilience to GIN infection in lambs growing at 200 g/day. In contrast, post-weaning growth was reduced by GIN infection, despite effective treatment at weaning and movement to GIN ‘safe’ pastures. The susceptibility of weaned lambs to the effects of GIN infection highlights the importance of effective control measures at this time.
Publisher: Oxford University Press (OUP)
Date: 08-05-2022
Abstract: Are there differences in thyroid function between adolescents and young adults conceived with and without ART? This study demonstrated no evidence of clinically relevant differences in thyroid function between adolescents and young adults conceived with and without ART. Studies to date have reported an increase in subclinical hypothyroidism in offspring conceived after ART. It has been suggested that the increase in maternal estrogen (E2) after fresh embryo transfers could affect thyroid function of the offspring. Suboptimal thyroid function at a young age can cause irreversible damage to the central nervous system, which makes early detection and correct treatment essential. The Growing Up Healthy Study (GUHS) is a prospective cohort study, which aimed to recruit all adolescents born after conception with ART between 1991 and 2001 in the study area. The included participants (n = 303, aged 13–20 years) completed various health assessments. Depending on the age at enrolment, participants completed thyroid assessments at the 14- or 20-year follow-up. The outcomes of these replicated thyroid assessments were compared to those of participants conceived without ART from the Raine Study Generation 2 (Gen2). The Gen2 participants (n = 2868) were born between 1989 and 1992 and have been recognized to be representative of the local population. Thyroid function assessments were compared between n = 134 GUHS and n = 1359 Gen2 adolescents at age 14 years and between n = 47 GUHS and n = 914 Gen2 young adults at age 20 years. The following mean thyroid hormone concentrations were compared between the cohorts: thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4) and thyroid peroxidase antibodies (TPOAb). The prevalence of the following thyroid hormone profiles, based on in idual thyroid hormone concentrations, was compared: euthyroidism, subclinical and overt hypo- and hyperthyroidism and thyroid autoimmunity. Outcomes were compared between the cohorts, and univariately between fresh embryo transfers (ET) and frozen ET (FET) within the GUHS. The correlation between maternal peak E2 concentrations (pE2) and fT4 was assessed within the GUHS. All mean thyroid function outcomes fell within the normal range. At both ages, we report no differences in TSH concentrations. At age 14 years, lower fT3 concentrations (4.80 versus 5.35 pmol/L, P & 0.001) and higher fT4 concentrations (12.76 versus 12.19 pmol/L, P & 0.001) were detected in the GUHS adolescents compared to Gen2 adolescents. At age 20 years, higher fT3 and fT4 concentrations were reported in GUHS adolescents (4.91 versus 4.63 pmol/L, P = 0.012 13.43 versus 12.45 pmol/L, P & 0.001, respectively) compared to Gen2 participants. No differences in the prevalence of subclinical and overt hypo- and hyperthyroidism or thyroid autoimmunity were demonstrated between the cohorts at age 14 and 20 years. Thyroid function did not differ between ET and FET, and no correlation between pE2 and fT4 was reported. The observational nature of the study limits the ability to prove causation. Furthermore, the comparison of ET and FET offspring at age 20 years may be lacking power. We were unable to differentiate between different types of ART (e.g. IVF versus ICSI) owing to the low number of ICSI cycles at the time of study. As ART laboratory and clinic data were collected contemporaneously with the time of treatment, no other data pertaining to the ART cycles were sought retrospectively hence, some factors could not be accounted for. This study does not support previous findings of clinically relevant differences in thyroid function when comparing a cohort of adolescents conceived after ART to counterparts conceived without ART. The minor differences detected in fT3 and fT4 were considered not biologically relevant. Although these findings appear reassuring, they warrant reinvestigation in adulthood. This project was funded by an NHMRC Grant (Hart et al., ID 1042269). R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director and a shareholder of PIVET Medical Centre, Perth, Western Australia. N/A.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.RBMO.2017.11.009
Abstract: Bisphenol A (BPA) is a ubiquitous chemical suspected to possess oestrogenic hormonal activities. Male population studies suggest a negative impact on testicular function. As Sertoli cell proliferation occurs during fetal or early postnatal life, it is speculated that oestrogenic environmental exposures may influence mature testicular function. Among 705 Western Australian Pregnancy Cohort (Raine) Study men aged 20-22 years, 404 underwent testicular ultrasound examination (149 had maternal serum available), and/or 365 provided semen (136 had maternal serum) and/or 609 serum s les for sex steroids, gonadotrophins and inhibin B analysis (244 had maternal serum). Maternal serum collected at 18 and 34 weeks' gestation was pooled and assayed for concentrations of total BPA (free plus conjugated) as an estimate of antenatal exposure. Testicular volume was calculated by ultrasonography, and semen analysis performed. Serum LH, FSH and inhibin B were measured by immunoassay testosterone, oestradiol, oestrone andBPA were measured by liquid chromatography-mass spectrometry. BPA levels were detectable in most (89%) maternal serum s les. After adjustment for maternal smoking, abstinence and varicocele, sperm concentration and motility were significantly correlated to maternal serum BPA (r = 0.18 P = 0.04 for both). No other associations of maternal serum BPA with testicular function were observed.
Publisher: American Society for Microbiology
Date: 11-2014
DOI: 10.1128/AAC.03721-14
Abstract: Treatment of intrauterine infection is likely key to preventing a significant proportion of preterm deliveries before 32 weeks of gestation. Azithromycin (AZ) may be an effective antimicrobial in pregnancy however, few gestation age-approriate data are available to inform the design of AZ-based treatment regimens in early pregnancy. We aimed to determine whether a single intra-amniotic AZ dose or repeated maternal intravenous (i.v.) AZ doses would safely yield therapeutic levels of AZ in an 80-day-gestation (term is 150 days) ovine fetus. Fifty sheep carrying single pregnancies at 80 days gestation were randomized to receive either: (i) a single intra-amniotic AZ administration or (ii) maternal intravenous AZ administration every 12 h. Amniotic fluid, maternal plasma, and fetal AZ concentrations were determined over a 5-day treatment regimen. Markers of liver injury and amniotic fluid inflammation were measured to assess fetal injury in response to drug exposure. A single intra-amniotic administration yielded significant AZ accumulation in the amniotic fluid and fetal lung. In contrast, repeated maternal intravenous administrations achieved high levels of AZ accumulation in the fetal lung and liver and a statistically significant increase in the fetal plasma drug concentration at 120 h. There was no evidence of fetal injury in response to drug exposure. These data suggest that (i) repeated maternal i.v. AZ dosing yields substantial fetal tissue uptake, although fetal plasma drug levels remain low (ii) transfer of AZ from the amniotic fluid is less than transplacental transfer and (iii) exposure to high concentrations of AZ did not elicit overt changes in fetal white blood cell counts, amniotic fluid monocyte chemoattractant protein 1 concentrations, or hepatotoxicity, all consistent with an absence of fetal injury.
Publisher: Elsevier BV
Date: 06-1999
DOI: 10.1016/S0090-6980(99)00008-8
Abstract: Preterm labor is frequently associated with ascending intrauterine infection, accompanied by leukocytes infiltration and enhanced local production of cytokines and other inflammatory mediators. The resulting lification of the inflammatory response, and of prostanoid production in particular, is postulated to be a principal mechanism of infection-driven preterm labor. In this review the effects of pro- and anti-inflammatory cytokines are discussed with respect to the expression of enzymes involved in three key steps of prostanoid biosynthesis and metabolism: liberation of arachidonic acid (AA), conversion of AA to bioactive prostanoids, and prostanoid catabolism. We suggest that by exerting coordinate actions on all three key steps, through multiple molecular mechanisms, inflammatory cytokines acutely up-regulate prostanoid production in intrauterine tissues.
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.VETPAR.2015.01.016
Abstract: This experiment tested the hypothesis that growth rates of meat-breed lambs would not be affected by infection with tapeworm (Monieza spp.). Two experiments, conducted in successive years (2012 and 2013) on a commercial sheep farm on the Northern Tablelands of NSW, assessed growth rates of meat-breed lambs, between 4 and 6 months of age, following the removal of the cestode, Monieza spp. (or commonly referred to as tapeworm). In 2012 and 2013, 93 and 85 lambs respectively were randomly allocated to two treatment groups. One group (Prazi) was treated with praziquantel, levamisole and abamectin to remove tapeworm and gastrointestinal nematode infection (GIN) while the second group (Control) was treated with levamisole and abamectin to remove only GIN. Tapeworm prevalence and egg counts of Control lambs ranged from 25 to 77% and 7 to 730 eggs per gram (epg) respectively and were significantly (p<0.005) reduced in Prazi lambs, following treatment, at all time-points in both years. Pre-treatment GIN worm egg counts ranged between 1684 and 3368 epg with Haemonchus contortus the dominant species. Post-treatment GIN worm egg counts were similar between Prazi and Control groups, expect on one occasion (Day 65, 2013) when GIN worm egg counts were expectantly higher (p<0.005) in Control lambs. No significant difference in growth rates were observed between treatment groups in either year with overall group mean daily bodyweight gains being 95 and 81 g/day (p=0.053) in 2012 and 132 and 134 g/day (p=0.784) in 2013 for the Prazi and Control groups respectively. This experiment confirmed that removal of tapeworm burdens did not increase growth rates in meat-breed lambs on a commercial sheep farm in the Northern Tablelands of NSW.
Publisher: American Physiological Society
Date: 12-2014
Publisher: Wiley
Date: 14-06-2016
Abstract: To undertake a survey of the world's clinical trial registries to provide current data on the number, nature, funding source and geographical distribution of pregnancy drug trials (PDT). Comprehensive analysis of WHO-certified clinical trial registries. Sixteen registries containing 301 538 trials (168 826 active in 2013-2014) were analysed to identify the numbers, location, funding sources, and areas of interest/development of PDTs. The percentage of PDTs varied from 0 to 7.4% across registries. Overall, just 0.32% (534) of all active registered studies were PDTs. The US registry (Clinicaltrials.gov) was the largest database, but contributed just 14% of all active PDTs. The majority of PDTs focused on anaesthesia/analgesia, preterm birth/tocolysis, labour induction, endocrine and hypertensive disorders. Less than 6% of active PDTs focused on maternal or fetal health as a specific primary outcome, and only 4.4% included a preplanned pharmacokinetic analysis of the trial medications. A third of all active PDTs involved repurposing of existing medicines for applications in pregnancy, whereas only three new investigational drugs had been developed for a pregnancy indication. Seven percent of all active PDTs identified were pharmaceutical industry-funded. Inter-disease comparisons identified a ~50-fold disparity in trial activity between pregnancy and other comparable areas. This study demonstrates unequivocally the marked under-representation of medication development, evaluation and safety trials in pregnancy. The likelihood that the current pharmaceutical landscape in pregnancy will improve in the foreseeable future is slim. Advocacy and increased awareness of the issue is necessary to achieve positive change. Pregnant women are significantly under-represented in global clinical drug trials.
Publisher: Wiley
Date: 14-06-2023
DOI: 10.1111/AVJ.13264
Abstract: Fasciolosis is an endemic zoonotic parasitic disease with significant impacts on human health and both animal health and production. Early post‐infection impacts on the host remain unclear. The objective of this study was to determine the changes, if any, to levels of endotoxin in cattle plasma in response to early‐stage infection with Fasciola hepatica . Thirty‐six (36) commercial bred cattle were experimentally infected with approximately 400 viable metacercariae. Plasma lipopolysaccharide (endotoxin) levels were examined on 24 occasions from 0 h before infection to 336 h after infection using the Limulus Amoebocyte Lysate chromogenic end point assay and compared with that of six (6) uninfected control animals. Peak lipopolysaccharide levels in infected animals were reached at 52 h after infection and returned to pre‐infection levels at time 144 h after infection. Infected animals had significantly elevated lipopolysaccharide levels between 24 and 120 h after infection when compared to uninfected animals. The mean change in endotoxin units (EU)/mL over time after infection was statistically significant in infected animals. Elevations of lipopolysaccharide occurred in all infected animals suggesting a possible repeatable and titratable endotoxemia conducive to therapeutic agent model development.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Elsevier BV
Date: 04-2007
Publisher: Springer Science and Business Media LLC
Date: 06-06-2017
DOI: 10.1038/S41598-017-03128-7
Abstract: Multimodal polymeric nanoparticles have many exciting diagnostic and therapeutic applications, yet their uptake and passage by the placenta, and applications in the treatment of pregnancy complications have not been thoroughly investigated. In this work, the maternal-fetal-placental biodistribution of anionic and cationic multimodal poly(glycidyl methacrylate) (PGMA) nanoparticles in pregnant rats at mid (ED10) and late (ED20) gestation was examined. Fluorescently-labelled and superparamagnetic PGMA nanoparticles functionalized with/without poly(ethyleneimine) (PEI) were administered to pregnant rats at a clinically-relevant dose and biodistribution and tissue uptake assessed. Quantitative measurement of fluorescence intensity or magnetic resonance relaxometry in tissue homogenates lacked the sensitivity to quantify tissue uptake. Confocal microscopy, however, identified uptake by maternal organs and the decidua (ectoplacental cone) and trophoblast giant cells of conceptuses at ED10. At ED20, preferential accumulation of cationic vs. anionic nanoparticles was observed in the placenta, with PGMA-PEI nanoparticles localised mainly within the chorionic plate. These findings highlight the significant impact of surface charge and gestational age in the biodistribution of nanoparticles in pregnancy, and demonstrate the importance of using highly sensitive measurement techniques to evaluate nanomaterial biodistribution and maternal-fetal exposure.
Publisher: Bioscientifica
Date: 05-2015
DOI: 10.1530/REP-14-0622
Abstract: Abnormal trophoblast function is associated with fetal growth restriction (FGR). The JAK–STAT pathway is one of the principal signalling mechanisms by which cytokines and growth factors modulate cell proliferation, differentiation, cell migration and apoptosis. The expression of placental JAK–STAT genes in human idiopathic FGR is unknown. In this study, we propose the hypothesis that JAK–STAT pathway genes are differentially expressed in idiopathic FGR-affected pregnancies and contribute to abnormal feto-placental growth by modulating the expression of the amino acid transporter SNAT2 , differentiation marker CGB /human chorionic gonadotrophin beta-subunit (β-hCG) and apoptosis markers caspases 3 and 8, and TP53 . Expression profiling of FGR-affected placentae revealed that mRNA levels of STAT3 , STAT2 and STAT5B decreased by 69, 52 and 50%, respectively, compared with gestational-age-matched controls. Further validation by real-time PCR and immunoblotting confirmed significantly lower STAT3 mRNA and STAT3 protein (total and phosphorylated) levels in FGR placentae. STAT3 protein was localised to the syncytiotrophoblast (ST) in both FGR and control placentae. ST differentiation was modelled by in vitro differentiation of primary villous trophoblast cells from first-trimester and term placentae, and by treating choriocarcinoma-derived BeWo cells with forskolin in cell culture. Differentiation in these models was associated with increased STAT3 mRNA and protein levels. In BeWo cells treated with siRNA targeting STAT3 , the mRNA and protein levels of CGB/β-hCG, caspases 3 and 8, and TP53 were significantly increased, while that of SNAT2 was significantly decreased compared with the negative control siRNA. In conclusion, we report that decreased STAT3 expression in placentae may contribute to abnormal trophoblast function in idiopathic FGR-affected pregnancies.
Publisher: Elsevier BV
Date: 04-2001
Publisher: Wiley
Date: 12-2001
DOI: 10.1034/J.1600-0897.2001.D01-33.X
Abstract: The pro-inflammatory cytokine interleukin (IL)-1beta has been shown to stimulate the production of prostaglandins (PG) in gestational tissues. Increased PG synthesis is considered a key step in the initiation of labor both at term and preterm. In this study. IL-1beta mRNA in the uterus and gestational tissues of mice during mid to late pregnancy was studied to characterize its tissue specific as well as gestational age expression. Gestational tissues (placenta. decidual cap and fetal membranes). uterus, and cervix were collected from pregnant mice during gestation. Total RNA was isolated and probed for the expression of IL-1beta mRNA. There was a significantly increased expression of IL-1beta mRNA in the uterus on day 18 of pregnancy. In the decidual caps, there was increased expression of IL-1beta mRNA on day 14 of pregnancy and a decrease in expression with the onset of labor. In the fetal membranes and placenta, IL-1beta mRNA expression significantly increased on days 14 and 18 of pregnancy. respectively, and then remained elevated for the duration of pregnancy. In the cervix, there was a decrease in expression with labor onset. The increases in IL-1beta mRNA in the fetal membranes and placenta late in pregnancy are consistent with a localized, tissue specific inflammatory activation involved in the initiation of parturition.
Publisher: Springer Science and Business Media LLC
Date: 09-2005
Publisher: American Society for Microbiology
Date: 09-2014
DOI: 10.1128/AAC.03187-14
Abstract: Intrauterine infection with Ureaplasma spp. is strongly associated with preterm birth and adverse neonatal outcomes. We assessed whether combined intraamniotic (IA) and maternal intravenous (IV) treatment with one of two candidate antibiotics, azithromycin (AZ) or solithromycin (SOLI), would eradicate intrauterine Ureaplasma parvum infection in a sheep model of pregnancy. Sheep with singleton pregnancies received an IA injection of U. parvum serovar 3 at 85 days of gestational age (GA). At 120 days of GA, animals ( n = 5 to 8/group) received one of the following treatments: (i) maternal IV SOLI with a single IA injection of vehicle (IV SOLI only) (ii) maternal IV SOLI with a single IA injection of SOLI (IV+IA SOLI) (iii) maternal IV AZ and a single IA injection of vehicle (IV AZ only) (iv) maternal IV AZ and a single IA injection of AZ (IV+IA AZ) or (v) maternal IV and single IA injection of vehicle (control). Lambs were surgically delivered at 125 days of GA. Treatment efficacies were assessed by U. parvum culture, quantitative PCR, enzyme-linked immunosorbent assay, and histopathology. Amniotic fluid (AF) from all control animals contained culturable U. parvum . AF, lung, and chorioamnion from all AZ- or SOLI-treated animals (IV only or IV plus IA) were negative for culturable U. parvum . Relative to the results for the control, the levels of expression of interleukin 1β (IL-1β), IL-6, IL-8, and monocyte chemoattractant protein 2 (MCP-2) in fetal skin were significantly decreased in the IV SOLI-only group, the MCP-1 protein concentration in the amniotic fluid was significantly increased in the IV+IA SOLI group, and there was no significant difference in the histological inflammation scoring of lung or chorioamnion among the five groups. In the present study, treatment with either AZ or SOLI (IV only or IV+IA) effectively eradicated macrolide-sensitive U. parvum from the AF. There was no discernible difference in antibiotic therapy efficacy between IV-only and IV+IA treatment regimens relative to the results for the control.
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.PLACENTA.2011.07.007
Abstract: Dlx3, a member of the large homeobox gene family of transcription factors, is important for murine placental development. Targeted deletion of Dlx3 in the mouse results in embryonic death due to placental failure. This study investigated the role of human DLX3 in villous cytotrophoblast (VCT) differentiation in the placenta. Primary VCT from human term placentae, which spontaneously differentiate when maintained in culture over 72 h, showed a significant increase in mRNA and protein expression of DLX3 and 3βHSD. The functional role of DLX3 was determined using trophoblast derived-cell line, BeWo. Forskolin treated BeWo cells showed significantly increased DLX3 mRNA and protein expression. Forskolin stimulation also showed a significant increase in syncytin and 3βHSD mRNA expression, and increased release of βhCG into the cell culture supernatant. To determine whether DLX3 had a direct or indirect effect on VCT differentiation, mRNA and protein expression of DLX3 was increased using a plasmid DLX3 over-expression construct. Over-expression of DLX3 resulted in increased mRNA expression of 3βHSD and syncytin, as well as increased secretion of β-hCG protein in the cell culture medium. In conclusion, we provide evidence that DLX3 acts upstream of syncytin, 3βHSD and βhCG and that DLX3 has a regulatory role in VCT differentiation.
Publisher: MDPI AG
Date: 27-01-2022
Abstract: Dystocia is the greatest contributor to neonatal lamb mortality in Australia and poses significant welfare and economic concerns worldwide. In this study, we set out to investigate whether pen-side analysis technology could be employed to detect blood parameters predictive of dystocic labour events in sheep. In a pilot trial, we collected and analysed blood s les in pen-side assays for glucose, lactate, pH, pCO2, pO2, base excess, HCO3, TCO2, sO2, lactate, sodium, potassium, chloride, calcium, urea nitrogen, creatinine, haematocrit, haemoglobin and anion gap. From the pilot data, we identified creatinine, TCO2, chloride and calcium as potentially useful markers. To develop a time course and to establish variability of the selected blood parameters, a time series of s les was collected from 12 ewes, from mid-gestation to 48 h after birth. For the main trial, blood s les were collected at mid- and late gestation for glucose determination and for the full set of blood parameters at three time points before, at and after birth. Possible predictors of lambing difficulty were chloride, haematocrit and haemoglobin, s led one week before birth creatinine, s led at birth and blood pH and base excess after birth. In conclusion, we found that pen-side analysis of blood markers showed promise in identifying dystocic lambing events.
Publisher: Elsevier BV
Date: 15-10-2003
DOI: 10.1016/S0041-008X(03)00274-6
Abstract: The anti-HIV drug 3'-azido-3'-deoxythymidine (AZT) is the drug of choice for preventing maternal-fetal HIV transmission during pregnancy. Our aim was to assess the cytotoxic effects of AZT on human placenta in vitro. The mechanisms of AZT-induced effects were investigated using JEG-3 choriocarcinoma cells and primary explant cultures from term and first-trimester human placentas. Cytotoxicity measures included trypan blue exclusion, MTT, and reactive oxygen species (ROS) assays. Apoptosis was measured with an antibody specific to cleaved caspase-3 and by rescue of cells by the general caspase inhibitor Boc-D-FMK. The effect of AZT on the activities of glutathione-S-transferase, beta-glucuronidase, UDP-glucuronosyl transferase, cytochrome P450 (CYP) 1A, and CYP reductase (CYPR) in the placenta was assessed using biochemical assays and immunoblotting. AZT increased ROS levels, decreased cellular proliferation rates, was toxic to mitochondria, and initiated cell death by a caspase-dependent mechanism in the human placenta in vitro. In the absence of serum, the effects of AZT were lified in all the models used. AZT also increased the amounts of activity of GST, beta-glucuronidase, and CYP1A, whereas UGT and CYPR were decreased. We conclude that AZT causes apoptosis in the placenta and alters metabolizing enzymes in human placental cells. These findings have implications for the safe administration of AZT in pregnancy with respect to the maintenance of integrity of the maternal-fetal barrier.
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.PLACENTA.2010.12.007
Abstract: Oxygenated cholesterol metabolites known as oxysterols display potent biological activities ranging from regulation of lipid homeostasis to cytotoxicity. Oxysterols have previously been shown to inhibit the invasion of first trimester trophoblasts, an effect which involves activation of the nuclear liver X receptors (LXRs). In the present study, we investigated the effects of several oxysterols on syncytialisation (differentiation and fusion) in term placental trophoblasts. Treatment of cultured term primary trophoblast cells with oxysterols [25-hydroxycholesterol, 7-ketocholesterol, 22(R)-hydroxycholesterol] and the synthetic LXR agonist T0901317 at non-toxic doses decreased expression of GCM-1 and HERV-W mRNA and reduced hCG secretion and placental alkaline phosphatase activity, indicative of diminished trophoblast differentiation. Furthermore, treatment with these compounds also decreased cell fusion measured by E-cadherin immunostaining and quantification of syncytialised nuclei. Treatment with an LXR antagonist (geranylgeranyl diphosphate) abrogated the inhibitory effects of oxysterols and T0901317 on trophoblast syncytialisation indicating that these effects are mediated by LXR. These findings suggest that oxysterols impair differentiation and fusion of term trophoblast cells via an LXR-dependent mechanism.
Publisher: MDPI AG
Date: 02-07-2022
DOI: 10.3390/NU14132753
Abstract: Infant allergy is the most common early manifestation of an increasing propensity for inflammation and immune dysregulation in modern environments. Refined low-fibre diets are a major risk for inflammatory diseases through adverse effects on the composition and function of gut microbiota. This has focused attention on the potential of prebiotic dietary fibres to favourably change gut microbiota, for local and systemic anti-inflammatory effects. In pregnancy, the immunomodulatory effects of prebiotics may also have benefits for the developing fetal immune system, and provide a potential dietary strategy to reduce the risk of allergic disease. Here, we present the study protocol for a double-blinded, randomised controlled trial investigating the effects of maternal prebiotics supplementation on child allergic disease outcomes. Eligible pregnant women have infants with a first-degree relative with a history of medically diagnosed allergic disease. Consented women are randomised to consume either prebiotics (galacto-oligosaccharides and fructo-oligosaccharides) or placebo (maltodextrin) powder daily from 18–20 weeks’ gestation to six months’ post-partum. The target s le size is 652 women. The primary outcome is infant medically diagnosed eczema secondary outcomes include allergen sensitisation, food allergies and recurrent wheeze. Breast milk, stool and blood s les are collected at multiple timepoints for further analysis.
Publisher: Frontiers Media SA
Date: 04-06-2019
Publisher: Burleigh Dodds Science Publishing
Date: 15-09-2017
Publisher: Elsevier BV
Date: 2023
DOI: 10.2139/SSRN.4362587
Publisher: Springer Science and Business Media LLC
Date: 12-2001
Abstract: Ecteinascidin 743 (ET-743) is a novel, marine-derived anticancer agent currently under clinical development for the treatment of solid tumors. The aim of this study was to develop and validate limited s ling strategies for the prediction of ET-743 clearance in phase II studies, using two techniques: the stepwise linear regression approach and the Bayesian estimation approach. Data from a phase I dose-finding study were used with ET-743 administered as a 24-h infusion. Plasma concentration time data from 34 patients treated with 1200. 1500 or 1800 microg/m2 ET-743 were randomly ided into an index data set, used for the development of the strategies, and a validation data set. With the linear regression approach, clearance (obtained by non-compartmental analysis) was correlated with the ratios of dose to the observed concentrations. For the Bayesian approach a three-compartment population pharmacokinetic model was developed optimal time-points were selected using the D-optimality algorithm. The strategies were compared by assessment of their predictive performance of CL in the validation data set. The linear regression method yielded a single-point s ling schedule with no significant bias and acceptable precision (-0.03% and 21%, respectively). With the Bayesian approach, a three-s le strategy was selected which resulted in less-accurate, but unbiased, predictions (bias 13%, precision 34%). Optimal s ling strategies were developed and validated for estimation of ET-743 clearance. Although the linear regression approach showed slightly better predictive performance, the Bayesian approach is preferred for the current phase II studies as it is more robust and flexible and allows the description of the full pharmacokinetic profile.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Elsevier BV
Date: 09-1986
DOI: 10.1016/0022-4731(86)90250-5
Abstract: We describe a method for the measurement of plasma dehydroepiandrosterone sulphate (DHAS) which incorporates a Triton X-100 solubilised preparation of human placental steroid sulphatase as a hydrolysing agent and a direct radioimmunoassay of liberated DHA using a specific antiserum. The hydrolysis procedure is carried out at 50 degrees C for 1 h and an assay run can be completed in 4 h. As determined by the method, plasma concentrations of DHAS in 32 normal adult men (ages 23-58 yr) had a mean value +/- SD of 5.5 +/- 1.89 mumol/l. For 30 normal adult cyclic women (ages 22-35 yr) the mean plasma concentration of DHAS +/- SD was 3.1 +/- 1.35 mumol/l which was significantly lower (P less than 0.01) than found for men. Plasma DHAS concentration were also measured in 50 hirsute female patients. The mean value +/- SD was 5.03 +/- 2.52 mumol/l which was significantly higher (P less than 0.01) than the value for the normal female group. Some 42% of the hirsute patients had DHAS concentrations above the upper 95% probability limit of the normal range for premenopausal women.
Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.JRI.2014.12.008
Abstract: We hypothesised that circulating monocytes of women with vaginal colonisation with Ureaplasma spp., genital microorganisms known to cause inflammation-driven preterm birth, would elicit a tolerised cytokine response to subsequent in vitro Ureaplasma parvum serovar 3 (UpSV3) stimulation. Using multi-parameter flow cytometry, we found no differences with regard to maternal colonisation status in the frequency of TNF-α-, IL-6-, IL-8- and IL-1β-expressing monocytes in response to subsequent UpSV3 stimulation (P > 0.10 for all cytokines). We conclude that vaginal Ureaplasma spp. colonisation does not specifically tolerise monocytes of pregnant women towards decreased responses to subsequent stimulation.
Start Date: 09-2016
End Date: 09-2021
Amount: $415,000.00
Funder: Australian Research Council
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