The placental renin-angiotensin system (RAS) is involved in placentation. We have shown that pror... more The placental renin-angiotensin system (RAS) is involved in placentation. We have shown that prorenin mRNA (REN) is expressed in a first trimester trophoblast cell line (HTR-8/SVneo) but not in a choriocarcinoma cell line (BeWo). We attempted to stimulate RAS expression in these cells by cAMP, 5'-aza-2'-deoxycytidine (AZA; an inhibitor of methylation), cAMP and AZA combined, and the sex steroids medroxyprogesterone acetate (MPA) and estradiol-17β (E2) with and without cAMP. RAS mRNAs were measured by qPCR and prorenin concentration in supernatants measured by an ELISA. In HTR-8/SVneo cells, all treatments increased REN expression compared to controls and cAMP + AZA combined was more effective than either treatment alone. Prorenin levels in supernatants were similarly upregulated. In HTR-8/SVneo cells, angiotensinogen (AGT) mRNA expression was increased by MPA + E2 either with or without cAMP. AGT expression was also significantly increased by AZA. BeWo cells did not express REN or prorenin and it was not inducible with any treatment. AGT expression was significantly increased with AZA, the combination of cAMP + AZA, and MPA + E2 + cAMP treatments. Since cAMP, AZA, cAMP and AZA combined, or MPA and E2 with and without cAMP in HTR-8/SVneo cells, a cell line most similar in its RAS expression to the in vivo placenta, these factors may affect placental RAS activity. Surprisingly, these treatments also induced AGT expression in BeWo cells. Whether they are involved in regulating AGT in choriocarcinomas in vivo remains to be determined.
BV that occurs after delivery is due to renal salt and water losses. Because the natriuresis was ... more BV that occurs after delivery is due to renal salt and water losses. Because the natriuresis was greater if the lamb's arterial pressure rose after birth, it is possible that a high arterial pressure in the immediate newborn period could result in salt and volume depletion. (Pediutr Res 36: 506- 513, 1994) Abbreviations AII, angiotensin I1 ADH, antidiuretic hormone BV, blood volume BV,, blood volume at delivery FRN,P, fractional reabsorption of sodium by the proximal tubule FR,,D, fractional reabsorption of sodium by the distal tubule GFR, glomerular filtration rate This study also examines in further detail the changes in renal sodium handling that occur after delivery to determine whether proximal and distal tubular sodium reabsorption are both affected or whether, as has been seen in other situations in which glomerulotubular balance has been altered (M), proximal tubular function is depressed and distal tubular function is enhanced. In addition, the renal response of the newborn to the first feed was studied. All procedures and protocols were approved by the Animal Care and Ethics Committee, University of New South Wales. Experiments were carried out in nine chronically prepared pregnant ewes at 139-145 d gestation. Surgical preparation and animal care. Under general anesthesia at 129-133 d gestation, catheters were inserted into a maternal carotid artery and jugular vein, into the amniotic cavity, and into both recurrent tarsal veins, a femoral artery, and the bladder of a fetus as previously
The effect of oral contraceptive medication on blood pressure was studied in 74 young married wom... more The effect of oral contraceptive medication on blood pressure was studied in 74 young married women over a period ranging from 3 months to 2 years. A rise in mean systolic pressure of 7 mmHg and in mean diastolic pressure of i 8i mmHg was observed. The increase in systolic pressure was significant. Furthermore, the relation betw3en systolic pressure and age became significant during oral contraceptive therapy. Three out of 74 women developed sustained systolic and diastolic hypertension during oral contraceptive therapy. Women with a history of hypertension in pregnancy or with a history of parental hypertension showed a greater incidence of hypertensive visits during oral contraception. Earlier reports on an apparent association be- tween oral contraceptive therapy and the aggravation or onset of hypertension (Woods, I967; Laragh et al., I967) have led to studies to investigate the incidence of hypertension in women taking oral contraceptives. Goodlin and Waechter (I969), in a retrospective sur- vey, found no hypertension in women taking oral contraceptives. Wallace (I97I) found that the incidence of oral contraceptive use in women attending a hypertensive clinic was twice that expected among the population at large, and Clezy (1970) reported that, in 8 patients, resistance to conventional antihyper- tensive therapy occurred during administration of oral contraceptives. However, these surveys were not definitive studies to determine the true incidence of hypertension in women taking oral contraceptives. In a controlled study, Tyson (I968) re- ported an incidence of onset of hypertension of I5-5 per cent in 5I subjects studied for periods up to 8 months, while Saruta, Saade, and Kaplan (1970) studied 62 women (6 of whom were already hypertensive) before and after oral contraception. Of the 56 normo- tensive women in this latter study, io developed hypertension. Both of these surveys
FURIN is a pro-protein convertase previously shown to be important for placental syncytialisation... more FURIN is a pro-protein convertase previously shown to be important for placental syncytialisation (Zhou et al. [1]), a process of cell fusion whereby placental cytotrophoblast cells fuse to form a multinucleated syncytium. This finding has been broadly accepted however, we have evidence suggesting the contrary. Spontaneously syncytialising term primary human trophoblast cells and BeWo choriocarcinoma cells were treated with either FURIN siRNA or negative control siRNA or the protease inhibitor, DEC-RVKR-CMK, or vehicle. Cells were then left to either spontaneously syncytialise (primary trophoblasts) or were induced to syncytialise with forskolin (BeWo). Effects on syncytialisation were measured by determining human chorionic gonadotrophin secretion and E-cadherin protein levels. We showed that FURIN is not important for syncytialisation in either cell type. However, in primary trophoblasts another protease also inhibited by DEC-RVKR-CMK, may be involved. Our results directly contrast with those published by Zhou et al. Zhou et al. however, used first trimester villous explants to study syncytialisation, and we used term primary trophoblasts. Therefore, we suggest that FURIN may be involved in syncytialisation of first trimester trophoblasts, but not term trophoblasts. What is more concerning is that our results using BeWo cells do not agree with their results, even though for the most part, we used the same experimental design. It is unclear why these experiments yielded different results, however we wanted to draw attention to simple differences in measuring syncytialisation or flaws in method reporting (including omission of cell line source and passage numbers, siRNA concentration and protein molecular weights) and choice of immunoblot loading controls, that could impact on experimental outcomes. Our study shows that careful reporting of methods by authors and thorough scrutiny by referees are vital. Furthermore, a universal benchmark for measuring syncytialisation is required so that various studies of syncytialisation can be validated.
Context: Australian Aboriginal communities in urban, rural and remote areas are continuing to suf... more Context: Australian Aboriginal communities in urban, rural and remote areas are continuing to suffer high rates of perinatal mortality and morbidity that will impact on the future health of the community. It has been well documented that Aboriginal women have extreme distrust of mainstream pregnancy-related health care and suggested that late entry into antenatal care is as high as 50% in the Aboriginal population. Although medical and midwifery staff have long discussed strategies to improve uptake of antenatal health care for Aboriginal women, researchers in many areas have found the recruitment of Aboriginal people into scientific studies almost impossible. This article seeks to share the strategies that have been developed over a period of time by the authors that have proved useful for recruitment and retention into research. It is anticipated that these strategies would also apply for health practitioners in maintaining their patients for clinical care management.
Background We carried out a study to determine the impact of prematurity on kidney development in... more Background We carried out a study to determine the impact of prematurity on kidney development in the first 2 years of life. Methods In this prospective study, extremely preterm neonates (gestation < 28 weeks) were recruited and underwent assessments at 6, 12, and 24 months of age. A cohort of neonates born term were also recruited and followed up for 24 months. The primary outcomes measured in this study were total kidney volume (TKV) and estimated glomerular filtration rate (eGFR); albuminuria and blood pressure measurements (all provided as mean (standard deviation)) were the secondary outcomes. Results Fifty-three premature and 31 term neonates (control) were recruited. At the age of 24 months (corrected age), infants born preterm had significantly smaller TKV (56.1 (9.4) vs. 64.8 (10.2) mL; P = 0.006). There was no difference in eGFR. These preterm infants were smaller (11.25 (1.53) vs. 12.9 (1.8) kg; P = 0.002) and shorter (83.8 (3.0) vs. 86.3 (3.4) cm; P = 0.02) when compa...
Introduction Women’s choices for a sexual partner are influenced by numerous personal, cultural, ... more Introduction Women’s choices for a sexual partner are influenced by numerous personal, cultural, social, political and religious factors, and may also include aspects of penile anatomy such as male circumcision (MC) status. Aim To perform a systematic review examining (i) whether MC status influences women’s preference for sexual activity and the reasons for this, and (ii) whether women prefer MC for their sons. Methods PRISMA-compliant searches were conducted of PubMed, Google Scholar, Embase, and the Cochrane Database of Systematic Reviews. Articles that met the inclusion criteria were rated for quality using the SIGN system. Results Database searches identified 29 publications with original data for inclusion, including 22 for aim (i) and 4 of these and 7 others pertaining to aim (ii). In the overwhelming majority of studies, women expressed a preference for the circumcised penis. The main reasons given for this preference were better appearance, better hygiene, reduced risk of i...
Background: Male circumcision (MC) is proven to substantially reduce men's risk of a number of se... more Background: Male circumcision (MC) is proven to substantially reduce men's risk of a number of sexually transmitted infections (STIs). We conducted a detailed systematic review of the scientific literature to determine the relationship between MC and risk of STIs and associated conditions in women. Methods: Database searches by "circumcision women" and "circumcision female" identified 68 relevant articles for inclusion. Examination of bibliographies of these yielded 14 further publications. Each was rated for quality using a conventional rating system. Results: Evaluation of the data from the studies retrieved showed that MC is associated with a reduced risk in women of being infected by oncogenic human papillomavirus (HPV) genotypes and of contracting cervical cancer. Data from randomized controlled trials and other studies has confirmed that partner MC reduces women's risk not only of oncogenic HPV, but as well Trichomonas vaginalis, bacterial vaginosis and possibly genital ulcer disease. For herpes simplex virus type 2, Chlamydia trachomatis, Treponema pallidum, human immunodeficiency virus and candidiasis, the evidence is mixed. Male partner MC did not reduce risk of gonorrhea, Mycoplasma genitalium, dysuria or vaginal discharge in women. MC reduces risk of oncogenic HPV genotypes, cervical cancer, T. vaginalis, bacterial vaginosis and possibly genital ulcer disease in women. The reduction in risk of these STIs and cervical cancer adds to the data supporting global efforts to deploy MC as a health-promoting and life-saving public health measure and supplements other STI prevention strategies.
Preterm infants often have poor cardiovascular function that is associated with adverse neurodeve... more Preterm infants often have poor cardiovascular function that is associated with adverse neurodevelopmental outcomes. Preterm infants may be vulnerable to hypovolaemia due to excessive vasodilatation and leaky capillaries. Following reduction in blood volume, cardiac output and mean arterial pressure were reduced to the same extent in term and preterm piglets. Cerebral blood flow was maintained following blood volume reduction in term but not in preterm piglets. Effective detection and treatment of functional hypovolaemia may reduce the risk of brain injury in preterm infants. Preterm infants often have impaired cardiovascular function that may contribute to poor neurodevelopmental outcomes. The study aimed to determine the effects of reduced blood volume on cardiovascular function, including cerebral blood flow, in preterm and term piglets. In preterm (97/115 days) and term piglets, up to 10% of the estimated blood volume was removed. Removal of blood was stopped if MAP dropped belo...
Pediatric nephrology (Berlin, Germany), Jan 2, 2018
We carried out a study to determine the impact of prematurity on renal development. The primary o... more We carried out a study to determine the impact of prematurity on renal development. The primary outcomes measured were nephrinuria and albuminuria; renal volume and glomerular filtration rate were the secondary outcomes. Preterm neonates born at less than 28 weeks of gestation, with birth weight between 10th and 90th centile (appropriate for gestational age), were recruited and underwent assessments at 28, 32 and 37 weeks postmenstrual age (PMA). Fifty-three premature neonates and 31 term neonates (control) were recruited. The median gestational age of the premature neonates was 26.4 [24.7-27.4] weeks, with a mean birth weight of 886 (179) g. The mean gestational age of term neonates was 39.1 (1.2) weeks and the mean birth weight was 3406 (406) g. The median age of the term neonates was 6.5 [3.0-12.5] days. The total kidney volume (TKV) almost doubled from 10.3 (2.9) cm at 28 weeks PMA to 19.2 (3.7) cm at 37 weeks PMA (P = 0.0001). TKV at 37 weeks PMA was significantly smaller compa...
Indigenous Australians experience higher rates of renal disease and hypertension than non-Indigen... more Indigenous Australians experience higher rates of renal disease and hypertension than non-Indigenous Australians. Low birth weight is recognized as a contributing factor in chronic disease and has been shown to increase the risk of renal failure in adulthood. A smaller kidney volume with fewer nephrons places an individual at risk of hypertension and renal failure. Indigenous Australians have fewer nephrons than non-Indigenous Australians. In this study, intrauterine fetal and kidney growth were evaluated in 174 Indigenous Australian babies throughout gestation in order to record and evaluate fetal growth and kidney size, within a population that is at high risk for chronic illness.Pregnant women that identified as Indigenous, or non-Indigenous women that were pregnant with a partner who identified as an Indigenous Australian were eligible to participate. Maternal history, smoking status, blood and urine samples and fetal ultrasounds were collected throughout pregnancy. Fetal kidney...
To determine whether recent evidence-based United States policies on male circumcision (MC) apply... more To determine whether recent evidence-based United States policies on male circumcision (MC) apply to comparable Anglophone countries, Australia and New Zealand. Articles in 2005 through 2015 were retrieved from PubMed using the keyword "circumcision" together with 36 relevant subtopics. A further PubMed search was performed for articles published in 2016. Searches of the EMBASE and Cochrane databases did not yield additional citable articles. Articles were assessed for quality and those rated 2+ and above according to the Scottish Intercollegiate Grading System were studied further. The most relevant and representative of the topic were included. Bibliographies were examined to retrieve further key references. Randomized controlled trials, recent high quality systematic reviews or meta-analyses (level 1++ or 1+ evidence) were prioritized for inclusion. A risk-benefit analysis of articles rated for quality was performed. For efficiency and reliability, recent randomized con...
The preterm newborn is at high risk of developing cardiovascular compromise during the first day ... more The preterm newborn is at high risk of developing cardiovascular compromise during the first day of life and this is associated with increased risk of brain injury. Standard treatments are volume expansion and administration of inotropes, typically dopamine and/or dobutamine, but there is limited evidence that inotropes improve clinical outcomes. This study investigated the efficacy of dopamine and dobutamine for the treatment of cardiovascular compromise in the preterm newborn using a piglet model. Preterm and term piglets were assigned to either dopamine, dobutamine or control infusions. Heart rate, left ventricular contractility, cardiac output, blood pressure, and cerebral and regional blood flows were measured during baseline, low (10µg/kg/hr) and high (20µg/kg/hr) dose infusions. At baseline, preterm piglets had lower cardiac contractility, cardiac output, blood pressure, and cerebral blood flow compared to term piglets. The response of preterm piglets to either dopamine or do...
Journal of developmental origins of health and disease, Jan 15, 2016
Indigenous Australians have high rates of chronic diseases, the causes of which are complex and i... more Indigenous Australians have high rates of chronic diseases, the causes of which are complex and include social and environmental determinants. Early experiences in utero may also predispose to later-life disease development. The Gomeroi gaaynggal study was established to explore intrauterine origins of renal disease, diabetes and growth in order to inform the development of health programmes for Indigenous Australian women and children. Pregnant women are recruited from antenatal clinics in Tamworth, Newcastle and Walgett, New South Wales, Australia, by Indigenous research assistants. Measures are collected at three time points in pregnancy and from women and their children at up to eight time points in the child's first 5 years. Measures of fetal renal development and function include ultrasound and biochemical biomarkers. Dietary intake, infant feeding and anthropometric measurements are collected. Standardized procedures and validated tools are used where available. Since 201...
1. The effect of cold on vagal action at the heart was studied in sheep, dogs and an isolated gui... more 1. The effect of cold on vagal action at the heart was studied in sheep, dogs and an isolated guinea pig atrial preparation. 2. During cardiac output measurements in un-anaesthetized sheep, by the thermodilution method, bradycardia was evoked on injection of cold indicator in eight of 12 sheep studied. This bradycardia was consistently evoked when blood pressure was increased, but not at normal blood pressure levels. 3. In the guinea pig atrial preparation, which has one vagus nerve attached, bradycardia was evoked by electrical stimulation of the vagus nerve. When the preparation was cooled this bradycardia was potentiated. 4. In anaesthetized dogs, the cut peripheral end of one vagus was stimulated electrically at different frequencies. The linear relationship between pulse interval and vagal frequency was then compared at deep body temperatures of 35, 37, 39 and 41°C. This comparison showed that the vagus prolonged pulse interval more effectively when the animal was cool (35°C) t...
Here we review the international evidence for benefits and risks of infant male circumcision (MC)... more Here we review the international evidence for benefits and risks of infant male circumcision (MC) and use this to develop an evidence-based policy statement for a developed nation setting, focusing on Australia. Evidence from good quality studies that include meta-analyses and randomized controlled trials showed that MC provides strong protection against: urinary tract infections and, in infancy, renal parenchymal disease; phimosis; paraphimosis; balanoposthitis; foreskin tearing; some heterosexually transmitted infections including HPV, HSV-2, trichomonas, HIV, and genital ulcer disease; thrush; inferior hygiene; penile cancer and possibly prostate cancer. In women, circumcision of the male partner protects against HPV, HSV-2, cervical cancer, bacterial vaginosis, and possibly Chlamydia. MC has no adverse effect on sexual function, sensitivity, penile sensation or satisfaction and may enhance the male sexual experience. Adverse effects are uncommon (<1%), and virtually all are minor and easily treated. For maximum benefits, safety, convenience and cost savings, MC should be performed in infancy and with local anesthesia. A risk-benefit analysis shows benefits exceed risks by a large margin. Over their lifetime up to half of uncircumcised males will suffer a medical condition as a result of retaining their foreskin. The ethics of infant MC and childhood vaccination are comparable. Our analysis finds MC is beneficial, safe and cost-effective, and should optimally be performed in infancy. In the interests of public health and individual wellbeing, adequate parental education, and steps to facilitate access and affordability should be encouraged in developed countries.
Nephrin is a 180 KD trans-membrane protein expressed in glomerular podocytes. It was first identi... more Nephrin is a 180 KD trans-membrane protein expressed in glomerular podocytes. It was first identified in children with congenital nephrotic syndrome of the Finnish type (NPHS1). Nephrin forms an integral part of podocytes, which-together with endothelial cells and the basement-form the glomerular filtration barrier. Podocytopathies result in the detection of nephrin in the urine. We reviewed the literature to determine if urine nephrin measurements could become useful as a biomarker to detect early podocyte injury. Our search identified a total of 19 studies that have been published to date. The most common clinical conditions for which urine nephrin analyses were carried out included diabetic nephropathy, glomerulonephritis and pre-eclampsia. Nephrin measurement was carried out using commercially available ELISA kits, the messenger ribonucleic acid real-time polymerase chain Reaction, or electrophoresis. Nephrinuria showed positive correlation with proteinuria and severity of podoc...
Sudden infant death syndrome (SIDS), neonatal deaths, and deaths from infection are higher among ... more Sudden infant death syndrome (SIDS), neonatal deaths, and deaths from infection are higher among Indigenous Australians. This study aimed to determine the effects of inflammatory responses and exposure to cigarette smoke, two important factors associated with sudden death in infancy, on preterm birth, and birth weight in a cohort of Indigenous mothers. Indigenous Australian women (n = 131) were recruited as part of a longitudinal study while attending antenatal care clinics during pregnancy; blood samples were collected up to three times in pregnancy. Serum cotinine, indicating exposure to cigarette smoke, was detected in 50.4% of mothers. Compared with non-Indigenous women, the cohort had 10 times the prevalence of antibodies to Helicobacter pylori (33 vs. 3%). Levels of immunoglobulin G, antibodies to H. pylori, and C-reactive protein (CRP) were all inversely correlated with gestational age (P < 0.05). CRP levels were positively associated with maternal body mass index (BMI; ρ = 0.449, P = 0.001). The effects of cigarette smoke (cotinine) and inflammation (CRP) were assessed in relation to risk factors for SIDS: gestational age at delivery and birth weight. Serum cotinine levels were negatively associated with birth weight (ρ = -0.37, P < 0.001), this correlation held true for both male (ρ = -0.39, P = 0.002) and female (ρ = -0.30, P = 0.017) infants. Cotinine was negatively associated with gestational age at delivery (ρ = -0.199, P = 0.023). When assessed by fetal sex, this was significant only for males (ρ = -0.327, P = 0.011). CRP was negatively associated with gestational age at delivery for female infants (ρ = -0.46, P < 0.001). In contrast, maternal BMI was significantly correlated with birth weight. These data highlight the importance of putting programs in place to reduce cigarette smoke exposure in pregnancy and to treat women with chronic infections such as H. pylori to improve pregnancy outcomes and decrease risk factors for sudden death in infancy.
A number of clinical and experimental studies have examined the effects of pregnancy on the cardi... more A number of clinical and experimental studies have examined the effects of pregnancy on the cardiac baroreflex. The results obtained vary. For example, it has been reported that baroreflex sensitivity was decreased during pregnancy in women , in pregnant ewes and in pregnant rabbits . In other studies, however, it was found to be increased in women , or unchanged in pregnant sheep . We therefore decided to compare baroreflex-mediated effects on the control of the heart rate of pregnant and non-pregnant ewes, using three different methods of analysis. By selective autonomic blockade we also measured the extent to which the sympathetic and parasympathetic nerves were responsible for baroreceptor effects on the heart. First we examined the arterial pressure-heart rate reflex by fitting an equation described by to the values for mean arterial pressure (MAP) and heart rate (HR), both obtained as mean values from 100 s records. Second, using the same 100 s records we determined the relationship between MAP and heart rate variability (HRV) measured as the coefficient of variation (c.v.) of the mean
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Papers by Eugenie Forbes