The risk tolerance and decision-making processes of Australian women regarding medication trials in pregnancy.

Background: Pregnant women have historically been excluded from participation in medication trials, in part due to the perceived risks of drug exposure to mothers and fetuses. However, little is known about pregnant women's attitudes toward risk and participation in such trials.

Aims: To address this knowledge gap and to identify factors that influence trial participation.

Maternal Reports of Preterm and Sick Term Infants' Settling, Sleeping and Feeding in the 9 Months after Discharge from Neonatal Nursery: An Observational Study.

The effects of preterm birth, neonatal morbidities and environmental influences on infant sleep development is an important yet under-researched topic, with little known about normative sleep for infants born sick or preterm. The aim of this prospective, observational longitudinal study was to evaluate maternal perceptions and degree of bother with infant sleep behaviours and feeding outcomes across the first 9 months after discharge for sick/preterm infants cared for in the neonatal intensive care unit (NICU) and for healthy term-born infants. This paper reports outcomes for the sick/preterm cohort ( = 94) that were recruited from two NICUs in Perth, Western Australia.

Respiratory benefit in preterm lambs is progressively lost when the concentration of fetal plasma betamethasone is titrated below two nanograms per milliliter.

Antenatal steroid therapy is the standard of care for women at imminent risk of preterm delivery. Current dosing regimens use suprapharmacological doses to achieve extended fetal steroid exposures. We aimed to determine the lowest fetal plasma betamethasone concentration sufficient to achieve functional preterm lung maturation.

The Vaginal Microbiome in Health and Disease-What Role Do Common Intimate Hygiene Practices Play?

The vaginal microbiome is a dynamic, sensitive microenvironment. The hallmark of a 'healthy' vaginal microbiome is currently believed to be one dominated by spp., which acidifies the vaginal environment and help to protect against invading pathogens.

Preclinical evaluation of drugs to block inflammation-driven preterm birth.

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.

Ureaplasma parvum genotype, combined vaginal colonisation with Candida albicans, and spontaneous preterm birth in an Australian cohort of pregnant women.

Background: Detection of Ureaplasma, Mycoplasma and Candida spp. in the vagina during pregnancy has previously been associated with preterm birth (PTB). However, the prevalence of these microorganisms and the associated obstetric risks (likely to be population-specific) have not been determined in Australian women; furthermore, in the case of Ureaplasma spp.

T cell cytokine responses to stimulation with Ureaplasma parvum in pregnancy.

Unlabelled: Ureaplasma spp. are a common vaginal microorganism causally linked to inflammation-driven preterm birth (PTB). The nature of the immune response to Ureaplasma spp.

Intrauterine Candida albicans Infection Causes Systemic Fetal Candidiasis With Progressive Cardiac Dysfunction in a Sheep Model of Early Pregnancy.

Introduction: Several recent studies have identified a potential role for intrauterine Candida albicans in adverse pregnancy outcomes, including preterm birth. There is, however, a limited understanding of the impact of intrauterine candida infection on fetal well-being in early pregnancy. Using a sheep model of early pregnancy, the aims of this study were to determine (1) the ability of experimentally induced intrauterine C albicans to infect the fetus and (2) whether C albicans exposure in early pregnancy is associated with alterations in fetal cardiac function, as measured by spectral tissue Doppler imaging analysis of fetal cardiac function.

A New, Potent, and Placenta-Permeable Macrolide Antibiotic, Solithromycin, for the Prevention and Treatment of Bacterial Infections in Pregnancy.

Intrauterine infection-inflammation is a major cause of early preterm birth and subsequent neonatal mortality and acute or long-term morbidity. Antibiotics can be administered in pregnancy to prevent preterm birth either prophylactically to women at high risk for preterm delivery, or to women with diagnosed intrauterine infection, prelabor rupture of membranes, or in suspected preterm labor. The therapeutic goals of each of these scenarios are different, with different pharmacological considerations, although effective antimicrobial therapy is an essential requirement.

Outside-in? Acute fetal systemic inflammation in very preterm chronically catheterized sheep fetuses is not driven by cells in the fetal blood.

Background: The preterm birth syndrome (delivery before 37 weeks gestation) is a major contributor to the global burden of perinatal morbidity and death. The cause of preterm birth is complex, multifactorial, and likely dependent, at least in part, on the gestational age of the fetus. Intrauterine infection is frequent in preterm deliveries that occur at <32 weeks gestation; understanding how the fetus responds to proinflammatory insult will be an important step towards early preterm birth prevention.

Drugs to block cytokine signaling for the prevention and treatment of inflammation-induced preterm birth.

Preterm birth (PTB) at less than 37 weeks of gestation is the leading cause of neonatal morbidity and mortality. Intrauterine infection (IUI) due to microbial invasion of the amniotic cavity is the leading cause of early PTB (<32 weeks). Commensal genital tract Ureaplasma and Mycoplasma species, as well as Gram-positive and Gram-negative bacteria, have been associated with IUI-induced PTB.

Whole blood flow cytometric analysis of Ureaplasma-stimulated monocytes from pregnant women.

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.

The Maternal Serological Response to Intrauterine Ureaplasma sp. Infection and Prediction of Risk of Pre-Term Birth.

Pre-term birth (PTB) associated with intrauterine infection and inflammation (IUI) is the major cause of early PTB less than 32 weeks of gestation. Ureaplasma spp. are common commensals of the urogenital tract in pregnancy and are the most commonly identified microorganisms in amniotic fluid of pre-term pregnancies.

Successful combined intratumoral immunotherapy of established murine mesotheliomas requires B-cell involvement.

Combination immunotherapy has resulted in a number of impressive outcomes in mouse models and clinical settings. In this study, we report that a timed triple immunotherapy (TTI) protocol using 3 agonist antibodies (anti-CD25mAb, anti-TGF-βmAb, and anti-CTLA-4mAb) produced complete clearance of established AB1 murine mesothelioma tumors. Combining all 3 agonist antibodies into a single cocktail for intratumoral injection was as effective as the TTI in tumor eradication.

Maternal intravenous administration of azithromycin results in significant fetal uptake in a sheep model of second trimester pregnancy.

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.

Intrauterine Candida albicans infection elicits severe inflammation in fetal sheep.

Background: Preventing preterm birth and subsequent adverse neonatal sequelae is among the greatest clinical challenges of our time. Recent studies suggest a role for Candida spp. in preterm birth and fetal injury, as a result of their colonization of either the vagina and/or the amniotic cavity.

Effects of cytokine-suppressive anti-inflammatory drugs on inflammatory activation in ex vivo human and ovine fetal membranes.

Intrauterine infection and inflammation are responsible for the majority of early (<32 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.

Polymyxin B agonist capture therapy for intrauterine inflammation: proof-of-principle in a fetal ovine model.

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.

Topically applied Melaleuca alternifolia (tea tree) oil causes direct anti-cancer cytotoxicity in subcutaneous tumour bearing mice.

Background: Melaleuca alternifolia (tea tree) oil (TTO) applied topically in a dilute (10%) dimethyl sulphoxide (DMSO) formulation exerts a rapid anti-cancer effect after a short treatment protocol. Tumour clearance is associated with skin irritation mediated by neutrophils which quickly and completely resolves upon treatment cessation.

Objective: To examine the mechanism of action underlying the anti-cancer activity of TTO.

Tumour eradication and induction of memory against murine mesothelioma by combined immunotherapy.

Numerous immunotherapy treatments for cancer are undergoing clinical trials or are already approved for use. One particular area of interest is targeting mechanisms of immune tolerance. Using a murine model of mesothelioma, we investigated the roles of regulatory T-cells, intratumoural transforming growth factor (TGF)-β and the negative regulator molecule cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) in immune tolerance to tumours.

The Role of Regulatory T Cells in Mesothelioma.

Malignant mesothelioma (MM) appears to be responsive to immunotherapy. The lack of complete tumour cure as a result of many immunotherapies tested to date suggests that the immune response to MM is complex and multi-parametric. Regulatory T (Treg) cells are prevalent within murine and human mesotheliomas with their removal shown to result in tumour growth inhibition and the release of anti-tumour effector T cells from immunosuppression.

Mechanisms of immune suppression exerted by regulatory T-cells in subcutaneous AE17 murine mesothelioma.

We have reported previously that a combined intratumoral treatment with anti-CD25mAb/transforming growth factor-β (TGF-β) soluble receptor induced regression of established and subcutaneous AE17 murine mesotheliomas. Here, we have investigated the mechanisms underlying this observation by analyzing the concentrations of interferon-γ (IFN-γ) and TGF-β within tumors at various time points following single regulatory T-cell (T(reg)) depleting anti-CD25mAb, TGF-β soluble receptor, or combined anti-CD25mAb/TGF-β soluble receptor treatment. The combined treatment maintains the intratumoral TGF-β concentration at a significantly lower level than either the untreated controls or the single anti-CD25mAb treatment alone.

Inhibition of established subcutaneous murine tumour growth with topical Melaleuca alternifolia (tea tree) oil.

Purpose: Systemic toxicity coupled with long treatment regimes of approved topical chemotherapeutic agents such as imiquimod and 5-fluorouracil (5-FU) are limiting. There is now more focus on the potential use of topical terpene agents as skin cancer treatments. Here, we show for the first time that topical Melaleuca alternifolia (tea tree) oil (TTO), abundant in terpenes, has in vivo antitumour activity.

Combined intratumoral regulatory T-cell depletion and transforming growth factor-β neutralization induces regression of established AE17 murine mesothelioma tumors.

Suppression of an anti-tumor immune response by regulatory T cells (T(regs)) in tumor-bearing hosts is now well established. Previously, we have reported that the intratumoral administration of T(reg)-depleting anti-CD25 monoclonal antibody every 10 days is highly effective at inhibiting the further development of established murine mesotheliomas. Here we investigate the dosage, kinetics, and immunology of this treatment.