ORCID Profile
0000-0002-5975-2843
Current Organisations
Sydney Local Health District
,
South Western Sydney Local Health District
,
Western Sydney University
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2013
DOI: 10.1161/HYPERTENSIONAHA.111.00698
Abstract: The microvasculature plays an important role in regulating cardiovascular changes in pregnancy, but changes in microvasculature have been difficult to document in vivo. This study objectively quantifies changes in the maternal retinal arteriolar and venular caliber over the course of healthy pregnancy. Healthy pregnant women (n=53) were recruited from Royal Prince Alfred Hospital, Sydney, Australia. Retinal images and mean arterial blood pressures (MAP) were collected at 13, 19, 29, and 38 weeks of gestation and at 6-month postpartum. Retinal vessels were analyzed and summarized as the central retinal arteriolar equivalent and central retinal venular equivalent. Central retinal arteriolar equivalent and central retinal venular equivalent were corrected for MAP. Paired t tests were performed comparing consecutive time points, with a significance level of P .01. There was a decrease in MAP between 13- and 19-week gestation ( P =0.001) followed by a return to baseline from 19 weeks to delivery. This was correlated by an increase in vessel caliber between 13- and 19-week gestation (central retinal arteriolar equivalent: P .001, central retinal venular equivalent: P =0.007) and a return to baseline from 19 weeks to delivery. There were no differences in the central retinal arteriolar equivalent or central retinal venular equivalent (both uncorrected and corrected for MAP) between nulliparous and parous women. The pattern of dilatation and constriction in the microvasculature mirrored the changes in MAP throughout pregnancy, reflecting changes in peripheral resistance. This study provides insights into physiological changes in the microvasculature throughout a healthy pregnancy. These results can be used as a baseline with which to compare the changes observed in pathological conditions of pregnancy.
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.PREGHY.2016.04.009
Abstract: The Hypertensive Disorders of Pregnancy (HDP) affect 7-10% of pregnancies worldwide and are one of the leading causes of mortality and morbidity in the perinatal period. An accurate assessment of mortality and morbidity is essential to provide effective care and treatment and benchmarking of these issues is required to enhance outcomes and define standards. To benchmark outcomes for women and babies following a diagnosis of hypertension between obstetric units in similar settings. Utilising a set of pre-defined clinical indicators, In idual Patient Data analysis techniques applied to the medical records of all women diagnosed with a HDP over a 12month period at six obstetric units within Australia and Canada. Statistical analysis included contingency table sand means testing oas appropriate utilising IBM SPSS V.18. Overall HDP rate of 7.6% of all deliveries, with a 3.0% preecl sia rate. Outcomes differed significantly between units and did not cluster within any in idual unit.
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.AJOG.2015.12.047
Abstract: There is growing evidence that hypertensive disorders of pregnancy are associated with increased long-term cardiovascular mortality in the mother. Hypertension in pregnancy, until recently, however, has been ignored largely as a risk factor for future cardiovascular disease and mortality because the link between the 2 is not fully understood. To determine the association between women with hypertension in pregnancy and long-term cardiovascular disease mortality. All women who delivered at a metropolitan hospital between the periods of January 1, 1980, and December 31, 1989, were identified by use of the International Statistical Classification of Diseases and Related Health Problems, 9th Revision, Australian Modification. The total number of deliveries in the given time period was 31,656, with 4387 (14%) of the women identified as having had hypertension in their pregnancy. Using information from the New South Wales Births, Deaths and Marriages Registry and the Australian Bureau of Statistics Death Registry, we identified a total of 651 deaths from this cohort (n = 31,656). There were 521 deaths among the women who remained normotensive in their pregnancy and 129 deaths for women who had hypertension during their pregnancy. Overall, the women with hypertensive disorders of pregnancy were at greater risk of death than the women who remained normotensive in their pregnancy (odds ratio 1.56 95% confidence interval 1.28-1.89 P < .001). Women with a history of hypertension in their pregnancy are at an increased risk of future cardiovascular mortality, and this work identifies a group of women who may benefit from early screening and intervention strategies to help decrease their risk of future cardiovascular disease.
Publisher: Informa UK Limited
Date: 2008
DOI: 10.1080/10641950802020552
Abstract: To test the hypothesis that vascular endothelial growth factor receptor 1 (Flt1) is negatively correlated with apoptosis in preecl sia placentae, and to examine the effects of antihypertensive medication on apoptosis. Flt1 and TUNEL immunoreactivity were quantitatively compared in the stromal decidual cells, villous trophoblasts, and endothelial cells of placentae from uncomplicated pregnancies (NP, n = 34) to those in patients with preecl sia (PE, n = 30), and those in patients with preecl sia with superimposed intrauterine growth restriction (PE + IUGR, n = 7). Further analyses determined any correlations with the antepartum use of the antihypertensives clonidine and hydralazine. There was no difference in either Flt1 or TUNEL when comparing PE placentae (with or without IUGR) with NP. There were no correlations with the use of the antihypertensives. Apoptotic levels do not correlate with Flt1 in preecl sia placentae and are not regulated by in vivo exposure to the antihypertensives clonidine and hydralazine.
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.PLACENTA.2018.09.008
Abstract: Cigarette smoking (CS) and preecl sia (PE), regulate the expression of nicotinic acetylcholine receptor (nAChR) subunits in the placenta, yet no data exist at the histological level. Using immunohistochemistry of formalin fixed and paraffin embedded placental tissue, this study quantified the expression of nine nAChR subunits (α2, α3, α4, α5, α7, α9, β1, β2, δ) and compared the expression amongst four groups of non-smoker non-PE (controls, n = 8), smokers (n = 8), PE (n = 8), and those who were smokers with PE (smoke + PE, n = 4). Quantification was of the percentage of villi with positive cells stained (% villi with +ve), percentage of positive stained cells per villous (% +ve cells/villous), percentage of positive cells in the decidua (%+ve Decidua), and intensity of staining in the outer villous trophoblast layer. Changes were restricted to the villi (as opposed to the decidua), and were specific to the α9 (smoke + PE), β1 (smokers), and β2 (PE) subunits when compared to controls. CS seemed to have a protective effect for the β2 subunit and an additive effect for the α9 and β1 subunits within the villous core/stroma cells and not the trophoblast layer. These findings support that both CS and PE affect nAChRs in the placenta, but that this is restricted to the villi.
Publisher: Wiley
Date: 08-12-2014
Publisher: Wiley
Date: 28-07-2009
DOI: 10.1111/J.1440-1681.2009.05160.X
Abstract: 1. There are currently limited diagnostic methods for assessing the integrity of the pulmonary microvasculature. We hypothesized that a novel, invasively determined physiological index of 'pulmonary flow reserve' (PFR = maximal hyperaemic pulmonary blood flow ided by basal pulmonary flow) may facilitate microvascular assessment in the lung. Therefore, we developed a baboon model in which to: (i) validate the use of Doppler flow velocity for PFR assessment (ii) define the optimal drug and dose regimen for attainment of maximal pulmonary hyperaemia and (iii) demonstrate the feasibility of measuring PFR in healthy higher primates. 2. Doppler sensor guidewires were placed in segmental pulmonary arteries of 11 ketamine-anaesthetized baboons. Vessel diameter, flow velocity and haemodynamics were recorded before and after direct intrapulmonary artery administration of saline, adenosine (50-500 microg/kg per min) and papaverine (3-60 mg), enabling calculation of PFR. 3. Saline (either bolus injection or infusion) did not alter vessel diameter or flow velocity (P > 0.1), validating local drug administration. Both adenosine and papaverine induced dose-dependent increases in flow velocity from baseline (from 22.5 +/- 2.3 to 32.7 +/- 4.8 cm/s for 400-500 microg/kg per min adenosine and from 23.9 +/- 1.1 to 34.6 +/- 4.0 cm/s for 24 mg papaverine both P 0.3). Healthy primate PFR values were 1.35 +/- 0.10 and 1.39 +/- 0.10 using 200 microg/kg per min adenosine and 24 mg papaverine, respectively (P > 0.8). 4. In conclusion, pulmonary flow reserve in higher primates can be assessed using Doppler sensor guidewire and either adenosine or papaverine as microvascular hyperaemic agents. Measurements of PFR may facilitate pulmonary microvascular assessments.
Publisher: Wiley
Date: 08-2008
DOI: 10.1111/J.1440-1797.2008.00938.X
Abstract: Patients with significant renal impairment have difficulties maintaining a viable pregnancy due to maternal and fetal complications. Both peritoneal dialysis and hemodialysis support throughout pregnancy has been reported to assist in these pregnancies. We report our experience with the use of peritoneal dialysis in five cases leading to successful deliveries with minimal complications.
Publisher: BMJ
Date: 04-10-2011
Publisher: Public Library of Science (PLoS)
Date: 26-03-2013
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.CYTO.2009.04.006
Abstract: The placenta plays a pivotal role in the pathophysiology of preecl sia. Insufficient trophoblast invasion within the placenta can cause focal regions of ischaemia/hypoxia that, in turn, may stimulate the production of inflammatory cytokines. These cytokines are thought to cause endothelial cell activation and dysfunction, resulting in the clinical signs of preecl sia. In addition to insufficient trophoblast invasion, the presence of inadequate maternal vasculature remodelling by trophoblasts also leads to changes in angiogenesis that may result from variations in the inflammatory cytokine profile. This study examined changes in the protein levels of IL-10 (immunoregulatory), TNF-alpha (pro-inflammatory) and sFlt-1 (anti-angiogenic) in normal term placentas under different oxygen tensions. The second aim was to determine if the link between varying levels of the cytokine, IL-10, and the expression/release of TNF-alpha was oxygen dependent, and whether there was a concurrent change in sFlt-1. Normal term placentas (n=6) were cultured at three different oxygen tensions (2%, 8% or 21%) in the presence or absence of exogenous IL-10. Protein (TNF-alpha and sFlt-1) secretion was measured using commercial ELISA kits, and qRT-PCR was used to examine gene expression. Placental IL-10 release was significantly reduced at 2% oxygen when compared to 8% (p=0.045) and 21% (p=0.013). Expression of TNF-alpha and sFlt-1 was not significantly different. Exogenous IL-10 significantly reduced TNF-alpha protein levels only when explants were cultured in 2% oxygen (p=0.05). Soluble Flt-1 protein secretion was unaffected by the addition of IL-10 at any of the oxygen tensions tested. TNF-alpha release can be inhibited in vitro by IL-10 under hypoxic conditions. However, IL-10 has no affect on sFlt-1 in term placentas, suggesting that these molecules act either via different pathways, or if linked, may be so at different stages of placental development.
Publisher: Wiley
Date: 02-2008
Publisher: Springer Science and Business Media LLC
Date: 16-07-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2013
DOI: 10.1161/HYPERTENSIONAHA.113.01890
Abstract: Preecl sia is a leading cause of maternal morbidity and mortality. The degree of maternal cardiovascular dysfunction that precedes the onset of preecl sia is largely unknown. This prospective cohort study aimed to characterize differences in vivo in retinal microvascular caliber and blood pressure throughout pregnancy in relation to preecl sia development. Women were recruited from Royal Prince Alfred Hospital, Sydney, Australia, of which 92 women were included in the study. Retinal images and blood pressures were collected at 13, 19, 29, and 38 weeks of gestation. Retinal vessels were analyzed as the central retinal arteriolar equivalent corrected for mean arterial blood pressure and the central retinal venular equivalent corrected for mean arterial blood pressure, using generalized linear models adjusted for age and body mass index. The preecl sia group were significantly older ( P =0.002) and had a significantly higher mean body mass index ( P =0.005). The central retinal arteriolar equivalent corrected for mean arterial blood pressure was significantly reduced at 13 ( P =0.03), 19 ( P =0.007), and 38 ( P =0.03) weeks of gestation in the preecl sia group. The central retinal venular equivalent corrected for mean arterial blood pressure was also significantly lower at 13 ( P =0.04) and 19 ( P =0.001) weeks of gestation in the women who progressed to preecl sia. This study directly documents increased peripheral resistance in vivo, observed as the combination of constricted retinal arterioles or venules and elevated blood pressure, in women who later developed preecl sia. This difference preceded the clinical signs of preecl sia.
Publisher: The American Association of Immunologists
Date: 07-2013
Abstract: Transplacental immune regulation refers to the concept that during pregnancy, significant cross-talk occurs between the maternal and fetal immune system with potential long-term effects for both the mother and child. In this study, we made the surprising observation that there is a strong correlation of peripheral blood regulatory T (Treg) cells between the mother and the fetus. In contrast, there is no significant Treg cell correlation between paternal fetal dyads (pairs), suggesting that the specific context of pregnancy, rather than the genetic parental similarity to the fetus, is responsible for this correlation. Gene microarray analysis of Treg cells identified a typical IL-10–dependent signature in maternal and fetal Treg cells. In addition, a direct correlation of serum IL-10 protein levels between maternal fetal dyads was observed. Furthermore, we show that maternal serum IL-10 levels correlate with serum estradiol and estriol, implicating hormonal involvement in this alignment. Interestingly, we show that Treg cells possess higher expression of IL-10 receptor α and that Treg cell IL-10 receptor α expression directly correlates with their Bcl-2 expression. Indeed, in vitro data in both humans and mice demonstrate that IL-10 upregulates Bcl-2 specifically in Treg cells but not non-Treg cells. Our results provide evidence for transplacental regulation of cellular immunity and suggest that IL-10 may influence Treg cell homeostasis through its effect on Treg cell Bcl-2 expression. These novel findings have important implications on immune tolerance in pregnancy and beyond in areas of autoimmunity, allergy, and transplantation.
Publisher: Wiley
Date: 04-11-1999
DOI: 10.1046/J.1440-1681.1999.03158.X
Abstract: 1. The purpose of the present study was to examine the effect of nitric oxide (NO) inhibition on mean arterial pressure (MAP), endothelin (ET) and the renin-aldosterone system in pregnancy in the non-human primate (baboon). 2. Twenty pregnant baboons (Papio hamadryas) were examined prospectively after the administration of an oral NO inhibitor in different phases of pregnancy. Haemodynamic responses to NO inhibition, evidence of pre-ecl sia and the renin-aldosterone system were examined under anaesthesia. 3. Oral NL-nitro-L-arginine (NOLA 5 or 10 mg/kg) was given for 1 week in early (6-8 weeks gestation), middle (14-16 weeks gestation) and late (22-24 weeks gestation) pregnancy and while non-pregnant. Mean arterial pressure, heart rate, haematology, biochemistry, ET, plasma renin activity (PRA) and aldosterone were measured. Foetal effects of NOLA were also examined by ultrasound and neonatal measurements. 4. Nitric oxide inhibition led to an increase in MAP in non-pregnant animals (9 mmHg) and in middle and later pregnancy (6 and 7 mmHg, respectively). Mean arterial pressure in early pregnancy was not affected. A reduction in PRA occurred after NO inhibition in all stages of pregnancy. Significant proteinuria occurred only in late pregnancy. 5. Nitric oxide is involved in the maintenance of lower blood pressure in late pregnancy and inhibition leads to an increase in blood pressure and proteinuria in the baboon. Nitric oxide insufficiency may contribute to the clinical manifestations of human pre-ecl sia. Nitric oxide was not involved in the normal vasodilation of early primate pregnancy.
Publisher: Wiley
Date: 10-09-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2015
Publisher: Informa UK Limited
Date: 04-04-2014
DOI: 10.3109/10641955.2014.903963
Abstract: Gene expression studies often pool tissues from multiple placentas when using animal models of preecl sia without accounting for the potential confounders of litter origin or pup sex. We aimed to determine whether placental gene expression differs based on sex or litter. We examined the differential expression of soluble fms-like tyrosine kinase 1 (Flt-1) using 35 pups from six normal pregnant mice. Expression of sFlt-1 (p = 0.003) was significantly different between litters but not between sexes (p = 0.17). These findings highlight the importance of adequate s ling from multiple litters in expression studies when using animal models in clinical research.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2014
Publisher: Wiley
Date: 02-2006
DOI: 10.1111/J.1440-1797.2006.00546.X
Abstract: Renal artery stenosis is a common, correctable cause of hypertension and renal impairment, with multiple screening tests available to aid diagnosis. Data assessing the accuracy of screening tests are mostly derived from tight 'experimental' protocols and the application of these tests to large-scale clinical practice is not clear. Our aim was to investigate physician preferences and diagnostic accuracy of screening tests for renal artery stenosis when applied to clinical practice in a large, Australian tertiary referral centre. We investigated all renal angiograms performed at our institution between September 2002 and September 2004, as referred by renal physicians. We accessed hospital and physician records of all patients to document demographics, clinical history, screening investigations, source of screening and angiogram results. The series involved 75 consecutive patients who had 79 screening investigations (four patients had two screening tests). The case series showed that 19 (24%) patients did not have any screening investigations prior to angiography. Duplex ultrasonography was the most utilised screening test, being used in 20 (33%) of the remaining 60 screening tests. Computed tomographic angiography (CTA) was used in 19 (32%), magnetic resonance imaging in 13 (22%) and renal scintigraphy was used in four (7%) screening procedures. Magnetic resonance angiography was the most accurate screening test with a positive predictive value of 92%, followed by duplex ultrasonography with 88% and CTA was relatively inaccurate, with a positive predictive value (PPV) of 58% (P = 0.036). Clinical suspicion alone was inaccurate with a PPV of 40%, except in previously treated renal artery stenosis (PPV 89%). Duplex ultrasonography was the most utilised screening investigation amongst the physicians of our referral base. Magnetic resonance angiography and duplex ultrasonography had good positive predictive values, while CTA may not be as reliable as previously reported when applied to a large, non-selective clinical practice.
Publisher: Wiley
Date: 12-2004
Publisher: Informa UK Limited
Date: 2007
DOI: 10.1080/10641950701380958
Abstract: Antihypertensive drugs are administered to women with preecl sia to control blood pressure and fluid overload. Whether they modulate placental or circulating cytokine production in women with preecl sia is unknown. This study examines the effect of pharmacological doses of antihypertensive drugs on the production of IL-10, tumor necrosis factor alpha (TNF-alpha), and IL-6 in placental tissue and peripheral blood mononuclear cells (PBMCs) from women with preecl sia. Term placenta s les (n = 6) and PBMCs from whole blood (n = 6) were obtained from women with preecl sia. Both villous explants and PBMCs were cultured with increasing concentrations of antihypertensive drugs (clonidine, diazoxide, hydralazine, and furosemide). The dose effect of drugs on the production of placental and circulating cytokines IL-10, TNF-alpha, and IL-6 was examined by enzyme-linked immunosorbent assay (ELISA). Our data suggest that clonidine can stimulate anti-inflammatory IL-10 production from PBMC while decreasing pro-inflammatory TNF-alpha, whereas low doses of hydralazine increased the production of IL-10, TNF-alpha, and IL-6 from preecl tic PBMCs. There was a reduction in IL-10, TNF-alpha, and IL-6 production with increasing doses of clonidine and hydralazine by placentas in preecl sia. IL-10, TNF-alpha, and IL-6 production from preecl tic placenta and PBMCs were inhibited by diazoxide and furosemide. Antihypertensive drugs may alter Th1/Th2 cytokine balance in preecl tic tissues in vitro.
Publisher: Wiley
Date: 06-12-2010
DOI: 10.1111/J.1600-0897.2010.00929.X
Abstract: The cardinal features of human pre-ecl sia, hypertension and proteinuria, are mimicked in animal models. Increasingly, the accuracy of inducing 'pure' systemic endothelial dysfunction is regarded as critical in differentiating mechanisms of pre-ecl sia from other conditions which induce hypertension (e.g. glomerulonephritis, renal denervation or manipulation of the renin-angiotensin system). A recent study in baboons has identified the timing of induction of maternal endothelial damage after acute uteroplacental ischaemia (UPI). The endothelial changes in the glomerulus are indicative of a direct endothelial toxin and mimic the lesions seen in human pre-ecl sia the extent of hypertension and proteinuria are also similar. This animal model identifies systemic and placental sFLT-1 (soluble fms-like tyrosine kinase-1) as a potential mediator of endothelial damage. This research involving primates with haemomonochorial placentas makes translation of these results to humans very compelling for understanding the mechanisms of human disease. Similar endothelial dysfunction has been identified in baboons treated with anti-inflammatory inhibitors. Similar studies in rodents have identified a relationship between angiotensin II agonistic antibodies, UPI/reduced uteroplacental perfusion pressure, angiogenic markers, and cytokines. We can now identify vasoconstrictive mediators of the hypertensive and endothelial response such as endothelin 1, the renin-angiotensin system, or other hormones such as oestrogens in primate models.
Publisher: Wiley
Date: 22-08-2011
Publisher: Elsevier BV
Date: 06-2015
Abstract: To identify differences in patterns of adverse health behaviours among people with type 2 diabetes according to country or region of birth. Population-based study of 23,112 in iduals with type 2 diabetes aged 45 years and older, from New South Wales, Australia. Self-reported questionnaire data and logistic regression models were used to estimate odds ratios for adverse health behaviours according to country or region of birth, adjusted for confounding factors. People with diabetes born in the Middle East and in the United Kingdom (UK) were more likely to be current smokers than those born in Australian, while those from Asia were less likely to be smokers. Relative to Australian-born people with diabetes, those born in the Middle East were more likely to have insufficient physical activity, while those born in Oceania, North West Europe and the UK were less likely. People with diabetes from Asia, North Africa, the Middle East and Sub-Saharan Africa were less likely to consume alcohol than those born in Australia, but people born in the UK were slightly more likely to consume alcohol. People with diabetes born in the UK, Asia, and North Africa were more likely than those born in Australia to have an inadequate intake of fruit and vegetables. Adverse health behaviours among people with type 2 diabetes varied markedly according to country or region of birth. Promoting smoking cessation and increasing physical activity levels among people with diabetes who were born in Middle Eastern countries are clear priorities.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2014
Publisher: Springer Science and Business Media LLC
Date: 07-03-2011
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.HLC.2013.10.087
Abstract: It has been widely thought that the effects of hypertension in pregnancy reversed after delivery and hypertension values returned to their pre-pregnancy level as it was seen as a disease of short duration in otherwise healthy young women. However, recent studies have demonstrated that the principal underlying abnormality, endothelial dysfunction, remains in women who had preecl sia and that it is this damage that increases the risk of developing cardiovascular disease (CVD) in later life. The contributions of hypertension and dyslipidaemia before and during the pregnancy are also important and contribute to future risk. Serum lipids are complex and change dramatically in pregnancy. In general there is an increase in most plasma lipid components, notably triglycerides, total cholesterol and the major particles of HDL and LDL. Aberrations or exaggerations in this shift (i.e. decrease HDL and a greater increase in LDL) are associated with poor outcomes of pregnancy such as preecl sia. Long term cardiovascular disease is influenced by preecl sia and in part potentially by the lipid changes which escalate late in disease. Whether we can influence the risk of preecl sia by controlling cardiovascular risk factors preceding or during preecl sia, or cardiovascular disease after preecl sia is yet to be determined. Ultimately, strategies to control lipid concentrations will only be viable when we understand the safety to the mother at the time of the pregnancy, and to the foetus both immediately and in the very long term. Strategies to control blood pressure are well established in the non-pregnant population, and previous preecl sia and gestational hypertension should be considered in any cardiovascular risk profile. Whether control of blood pressure in the pregnancy per se is of any longer term benefit is also yet to be determined.
Publisher: Elsevier BV
Date: 2010
DOI: 10.1016/J.PLACENTA.2009.10.009
Abstract: In humans, it is known that blood flow is directed to the gravid uterus from two (right and left) pelvic uterine arteries. The extent of supply from the tubo-ovarian anastomosis (joining of the ovarian and uterine arteries) is unknown. The aim of this study was to delineate the arterial blood supply to the placenta via systematic angiography in normal pregnancies in a non-human primate, the baboon (Papio hamadryas). The assessment of the distribution of blood supply with single-shot 3-vessel angiography (aorta, right and left common iliac arteries), allowed assessment of bilateral supply and possible ovarian supply (n=9). In 2-vessel pictures (aorta and left or right iliac), the contralateral supply was determined by subtraction of the ipsilateral supply from the total supply (n=7). The studies were all approved by the Institutional animal welfare committee and were conducted as part of a broader project investigating preecl sia. The animals were 9 years of age and 140 days of gestation for the 3 vessel study and 154 days of gestation for the 2 vessel study. The angiograms were more likely to have cotyledons perfused by the left uterine artery (p=0.012) than the right. Overall, 55% of placentae had 5-44% of supply overlapping and 22% had 10-15% ovarian contribution to blood supply. This study demonstrates the variation in primate uteroplacental blood flow including the contribution of ovarian arteries and left and right collateralization. Similarity to human vascular anatomy strengthens the use of primate species as a model of human placentation.
Publisher: Informa UK Limited
Date: 2003
Publisher: Elsevier BV
Date: 09-2005
DOI: 10.1016/J.PLACENTA.2004.09.011
Abstract: Glucocorticoids are used in pregnancy to enhance fetal lung maturity as well as to ameliorate antepartum and postpartum HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, but it is not clear if glucocorticoids can modulate placental cytokine production. The aim of this study is to examine the effect of glucocorticoids at equivalent doses used for fetal lung maturity on placental tissue production of cytokines (IL-10, IL-6 and TNF-alpha). Placental biopsies were taken from the decidual surface of term placentas of normal pregnancy (n = 5) and preecl sia (n = 5). Villous explants were cultured with increasing concentrations of glucocorticoids (betamethasone and methyl-prednisolone, 0.0025 microM, 0.25 microM and 25 microM). The dose effect of glucocorticoids on cytokines (TNF-alpha, IL-6 and IL-10) production was examined using ELISA. There was a stepwise reduction of TNF-alpha (23.6-97.5% reduction) and IL-6 (13.7-71% reduction) with increasing doses of betamethasone and methyl-prednisolone from placentas of women with preecl sia and normal pregnancy. However, IL-10 was not altered in conditioned medium by increasing doses of glucocorticoids. Our data suggest that the ratio of pro-inflammatory to anti-inflammatory cytokine (Th1/Th2) is potentially altered by exogenous glucocorticoids. These changes have a favourable effect on the ratio in preecl sia with a reduction in the potentially vascular active pro-inflammatory cytokines but without altering or decreasing the necessary anti-inflammatory cytokine IL-10 production in placental tissue.
Publisher: Informa UK Limited
Date: 2007
DOI: 10.1080/10715760701684809
Abstract: Increased oxidative stress is a hallmark of the autoimmune disease systemic lupus erythematosus (SLE). This study compares serum protein oxidation levels in SLE patients without and with renal involvement (lupus nephritis) the latter have a significantly poorer prognosis. Similar increases in protein carbonyls and decreases in protein thiols were observed in both SLE groups compared to controls. Protein carbonyl distribution, determined by Western blotting of 2D gels, was similar in both SLE groups, suggesting factors other than oxidation also play a role in SLE complications. 2D electrophoresis examined the serum proteome further. Six proteins were significantly decreases in non-renal SLE patients compared to controls five were identified by mass spectrometry, including one isoform of pro-atherogenic apoCIII. Total apoCIII levels (assessed by ELISA) in lupus nephritis patients were significantly elevated compared to controls or non-renal SLE patients. Thus, levels of oxidized proteins and apoCIII may be useful biomarkers in SLE studies.
Publisher: Wiley
Date: 03-10-2002
DOI: 10.1046/J.1440-1681.2002.03763.X
Abstract: 1. Pre-ecl sia is a human disease of pregnancy characterized by high blood pressure, proteinuria and end-organ damage, if severe. Pre-ecl sia is thought to be related to changes in early placental development, with the formation of a shallower than normal placental bed. 2. Transforming growth factor (TGF)-beta1 is a multifunctional fibrogenic growth factor involved in immune regulation that is elevated in some populations with a high risk of hypertensive end-organ disease related to increases in endothelin release. Transforming growth factor-beta1 is also an important factor in placental implantation. Alterations in TGF-beta1 may be related to abnormal placental development in early pregnancy and, thus, are a candidate for the development of hypertension in pre-ecl sia. 3. The aim of the present study was to examine the placental distribution and serum concentration of TGF-beta1 in patients with pre-ecl sia compared with normal pregnancy. 4. Patients with pre-ecl sia (n = 12) were compared with patients with normal pregnancy (n = 14). Transforming growth factor-beta1 was determined by TGF-beta1 Max ELISA (Promega, Madsion, WI, USA) after serum dilution (1/150) and acid activation. Placental distribution was determined by immunostaining with TGF-beta1 (Santa Cruz, Santa Cruz, CA, USA 20 ng/mL) and the villi and decidual trophoblast were scored for intensity and extent of staining. 5. Patients with pre-ecl sia had a mean gestational age of 36 weeks, whereas those with a normal pregnancy had a mean gestational age of 39.0 +/- 0.4 weeks. There was no difference in TGF-beta1 concentration between the two groups (mean (+/-SEM) 27.1 +/- 1.0 vs 26.4 +/- 0.7 pg/mL for normal pregnancy and pre-ecl sia, respectively P = 0.73, Mann-Whitney U-test). There was no correlation between systolic or diastolic blood pressure and TGF-beta1 concentration (regression analysis P = 0.4 and 0.2). Immunostaining was absent in the villous trophoblast cells and endovascular and extravillous trophoblast of term placentas. 6. Although TGF-beta1 is present in trophoblast cells in early pregnancy during placental development, TGF-beta1 concentrations were not increased in the placenta at term in pre-ecl sia and there was no correlation between blood pressure and serum TGF-beta1, suggesting that TGF-beta1 does not play a role in the development of late gestation pre-ecl sia and hypertension.
Publisher: Elsevier BV
Date: 02-2004
Publisher: Wiley
Date: 27-05-2003
DOI: 10.1034/J.1600-0897.2003.00053.X
Abstract: Reduced placental (trophoblast) cytokine interleukin-10 (IL-10) occurs in human pre-ecl sia. Along with an increase in inflammatory cytokines this may play an important role in the development of hypertension in pregnancy. It is not clear whether the changes in placental IL-10 are due to a change in the placental cell production of IL-10 or a result of changes in cytokine receptor status in adjacent tissues. This study is aimed at qualifying the presence and distribution of IL-10 receptors in women with a pre-ecl tic outcome compared to normal pregnancy and gestational hypertension. Patients at the KGV Hospital, Sydney was selected for the study. Placentas were collected fresh and paraffin serial sections made. Sections were stained with IL-10 receptor antibody (10 microgram/mL) using avidin-biotin immunohistochemistry. Tissues of patients with pre-ecl sia (n=11) were compared with normal pregnancy (n=12). Pre-ecl sia was defined as a blood pressure >140/90 mmHg on two occasions and de nova proteinuria >300 mg per day which resolved post-partum. The fetal weights, gestational ages and maternal ages at delivery were compared (ANOVA) and the differences in staining of decidual and villous tissues were graded according to density. Statistical comparisons were made using the Kruskal-Wallis test. The groups were similar for maternal gestational age but delivered at earlier gestation and with lower fetal weight. There was significantly less villous cytotrophoblast staining for IL-10 receptor in all groups (P=0.012) compared to decidual trophoblast cells. There was equal intensity and density of extravillous straining observed in normal pregnancy (45 +/- 12%) positive cells compared to pre-ecl sia (27 +/- 12%). IL-10 receptors are present in greater concentration in the extravillous (decidual) trophoblast compared to villi. The decrease in IL-10 produced by trophoblast cells in pre-ecl sia is not explained by a difference in the IL-10 receptor distribution compared to normal pregnancy.
Publisher: Informa UK Limited
Date: 21-10-2009
DOI: 10.3109/10641950902777721
Abstract: The increase of soluble VEGF-Receptor 1 (sFlt-1) is thought to contribute to the pathogenesis of preecl sia. Soluble VEGF-Receptor 1 binds to circulating free VEGF and PLGF and this cascade is associated with endothelial dysfunction, a prominent feature of preecl sia. Preecl sia is also associated with excessive maternal response to pro-inflammatory stimuli manifesting as an imbalance of Th1/Th2 cytokine production at the maternal-fetal interface. Whether increased sFlt-1 expression has any effect on placental production of Th1/Th2 cytokines IL-10 and TNF-alpha is yet to be investigated. The aim of this study is to examine if exogenous sFlt-1 can regulate Th1/Th2 cytokines IL-10 and TNF-alpha production from normal placental explants via intracellular calcium release. Placental explants were taken from the decidual surface of normal non-laboured term placentas (n = 11).Villous explants were cultured with increasing concentrations of sFlt-1. The dose effect of sFlt-1 on placental Th1 and Th2 cytokine production (TNF-alpha and IL-10) were examined. Free PLGF, VEGF and sFlt-1 concentrations in the conditioned medium were also measured. Intracellular calcium blocker, 1,2-bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, tetra(acetoxymethyl)-ester (BAPTA/AM) was applied to investigate whether the changes in cytokine concentration were mediated by intracellular free calcium. Placental IL-10 and TNF-alpha production were significantly increased after sFlt-1 incubation. The increase in IL-10 can be inhibited by BAPTA/AM. Soluble Flt-1 and free PLGF concentration in the conditioned medium was not changed. Free VEGF concentration in the conditioned medium was not detectable. Exogenous sFlt-1 can increase TNF-alpha and IL-10 production from normal placental explants. The change in Th1/Th2 cytokine level may be mediated by intracellular free calcium.
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.PLACENTA.2014.03.009
Abstract: The interaction between trophoblast cells and maternal uterine endothelium is important for placental vascular modelling. Nitric oxide (NO) is a potent vasorelaxant that regulates systemic blood pressure and is reduced in preecl sia. NO may affect placental cell interaction. This study was to examine whether NO plays a role in regulating TNF-α induced inhibition of trophoblast cell integration into endothelial cellular networks in-vitro. Red fluorescent-labelled human uterine myometrial microvascular endothelial cells (UtMVECs) were seeded on Matrigel. After endothelial cellular networks formed, green fluorescent-labelled HTR-8/SVneo trophoblast cells were co-cultured with endothelial cells, together with/without TNF-α (0.5 ng/ml) and/or NO donor, sodium nitroprusside dihydrate (SNP) (100 μM). Images were captured after 24 h. The effects on HTR-8/SVneo cell integration were quantified by Image Analysis software. The cells were then recovered from Matrigel to extract mRNA. Quantitative PCR was performed to evaluate the expression of eNOS, VCAM-1 and E-selectin. The concentrations of sVCAM-1 and sE-selectin in the conditioned medium were measured by ELISA. TNF-α inhibited HTR-8/SVneo trophoblast cell integration into endothelial cellular networks, as well as decreased eNOS mRNA expression. Increases in VCAM-1 and E-selectin in cellular mRNA and protein concentrations in the conditioned medium were also seen. The NO donor reversed the inhibitory effect of TNF-α on trophoblast integration and increased eNOS mRNA expression. SNP also reduced sE-selectin and sVCAM-1 expressions which were increased by TNF-α in the conditioned medium. Our data suggest the inhibitory effect of TNF-α on trophoblast integration may be mediated by NO, via reducing endothelial cell activation.
Publisher: Public Library of Science (PLoS)
Date: 09-03-0222
Publisher: Oxford University Press (OUP)
Date: 2013
DOI: 10.5665/SLEEP.2292
Publisher: Informa UK Limited
Date: 1993
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.AJOG.2013.02.042
Abstract: To determine the incidence of preecl sia and ecl sia and associated mortality in Australia between 2000 and 2008. Analysis of statutorily collected datasets of singleton births in New South Wales using International Classification of Disease coding. Analyzed using cross tabulation, logistic regression, and means testing, where appropriate. The overall incidence of preecl sia was 3.3% with a decrease from 4.6% to 2.3%. The overall rate of ecl sia was 8.6/10,000 births or 2.6% of preecl sia cases, with an increase from 2.3% to 4.2%. The relative risk of ecl sia in preecl tic women in 2008 was 1.9 (95% confidence interval, 1.28-2.92) when compared with the year 2000. The relative risk of a woman with preecl sia/ecl sia dying in the first 12 months following birth compared with normotensive women is 5.1 (95% confidence interval, 3.07-8.60). Falling rates of preecl sia have not equated to a decline in the incidence of ecl sia. An accurate rate of both preecl sia and ecl sia is vital considering the considerable contribution that these diseases make to maternal mortality. The identification and treatment of ecl sia should remain a priority in the clinical setting.
Publisher: Elsevier BV
Date: 07-2008
DOI: 10.1016/J.JDIACOMP.2007.07.001
Abstract: Diabetic renal disease is characterized by accumulation of extracellular matrix, glomerulosclerosis, and tubulointerstitial fibrosis. Connective tissue growth factor (CTGF) is implicated in these changes, as it contributes to new matrix synthesis and is increased in the diabetic kidney. CTGF also inhibits mesangial matrix degradation through up-regulation of the tissue inhibitor of matrix metalloproteinase 1 (TIMP-1). In a non-human primate model of diabetes, we determined whether the level of renal CTGF protein before development of albuminuria correlated with renal matrix and TIMP-1 changes and whether renal CTGF predicts progression to albuminuria. In a group of diabetic (n=9) and control (n=6) baboons after a 5-year duration of diabetes, renal tissue CTGF and TIMP-1 were detected by immunohistochemistry and compared with glomerular basement membrane (GBM) thickness and mesangial volume measurements from electron photomicrographs of renal biopsies. Urinary albumin levels were measured at 5 and 10 years of diabetes. GBM thickness, CTGF protein, and TIMP-1 protein were increased after 5 years of diabetes (each P<.05). Tubular fibronectin scores correlated with tubular CTGF scores (r=0.72, P=.002). In diabetic animals, GBM thickness correlated with tubular and total CTGF levels (P=.002 and P=.04, respectively), whereas mesangial cell and total matrix volume correlated with glomerular TIMP-1 (P=.02 and P=.01, respectively). Tubular CTGF scores (P=.008) and GBM thickness (P=.03) at 5 years in diabetes each predicted the degree of albuminuria at 10 years. These results suggest that early increases in renal CTGF protein contribute to incipient diabetic nephropathy and that renal CTGF may have utility as an early marker for progression to dysfunction in the diabetic kidney.
Publisher: BMJ
Date: 16-12-2013
DOI: 10.1136/BJOPHTHALMOL-2013-303946
Abstract: To explore effects of time following ptosis surgery on patient-reported quality-of-life outcomes. The Glasgow Benefit Inventory (GBI), a validated, postinterventional questionnaire was administered to consecutive adults undergoing ptosis surgery on the operating list of one surgeon over a 30-month period. Patients who were not contactable or unable to provide answers were excluded. Mean scores of patients grouped by time since surgery were compared (unpaired t test and Westlake intervals to test equivalence). Of 63 consecutive patients, 50 (79%) were included. Mean age was 63 years. Mean time since surgery was 561 days (range 21-973). There was no significant difference in mean total scores of patients assessed less than 18 months since surgery compared with those assessed later (p=0.544). Distributions of total scores were similar. No significant differences were found for subscores or when patients were ided into three groups according to time after surgery. Multivariate logistic regression revealed no significant effect of time since surgery. Trends were seen with regard to age and type of operation, but did not reach significance. Patient-perceived benefit following ptosis surgery shows stability with time, as assessed using the GBI. Future studies could explore correlations with age and type of surgery.
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.PLACENTA.2005.05.003
Abstract: The placenta is pivotal in the acceptance of the feto-placental unit by the maternal immune system. Imbalance at the maternal-fetal interface of tissue pro- and anti-inflammatory cytokines may be partly involved in disease causation. Previous work has shown conflicting levels of IL-10. IL-10 levels have been shown to increase, decrease, or remain unchanged in women with preecl sia. This study examines the difference in serum and placental IL-10 expression in women with preecl sia and investigates if the IL10 (-1082) A promoter polymorphism contributes to lower concentrations. In a prospective case-control study of 12 women with preecl sia and 31 controls we assessed serum IL-10 by ELISA, placental mRNA by quantitative PCR and protein by immunohistochemistry as well as placental IL10 promoter genotype. Comparisons were made with non-parametric tests where necessary and chi-square. We found a significant reduction in placental IL-10 mRNA and protein expression in women with preecl sia compared to controls. Women with the AA IL-10 promoter genotype expressed less placental IL-10 mRNA compared to women with AG or GG genotype. There was no difference in serum IL-10 concentrations between different genotypes. Preecl sia is associated with a deficiency of placental IL-10. Placental AA genotype in the promoter region results in significantly less placental IL-10.
Publisher: Informa UK Limited
Date: 2006
DOI: 10.1080/10641950600745228
Abstract: In pregnancy, absolute blood pressure (BP) limits define preecl sia. Therefore, BP in pregnancy should be measured accurately and in accordance with accepted guidelines. Accuracy of BP readings determined by rate of cuff deflation was analyzed. This study also investigated the compliance of clinical staff at Royal Prince Alfred Hospital, Australia, to guidelines for BP measurement. The study was an observational trial of 98 normotensive antenatal or recently postnatal patients. Two BP readings were taken, each with fast (>5 mm Hg/sec) and slow (<or=2 mm Hg/sec) descent of mercury and compared by Bland-Altman analysis. Also, BP techniques used by junior doctors, specialist obstetricians, and midwives were compared using a 9-point scale. Australian national guidelines recommend slow descent of mercury. Fast descent underestimated the systolic BP by 9 mm Hg (95% confidence interval [CI], -23 to +5 mm Hg) (p < 0.001). Fast descent measured the diastolic BP within 2 mm Hg (95% CI, -10 to +14 mm Hg) (not different, p = 0.151). Accuracy of fast cuff deflation was 28% for systolic BP and 50% for diastolic BP for <5 mm Hg, and respectively, 64% and 68% for <10 mm Hg, 84% and 80% for <15 mm Hg and 91% and 87% for <20 mm Hg. Compliance with guidelines was greatest for specialists and midwives (p = 0.001) and their most commonly missed feature (76% to 100%) was slow cuff deflation. Rapid cuff deflation underestimates the systolic BP compared to accepted guidelines (<or=2 mm Hg/sec). Medical and midwifery staff may not follow accepted guidelines for BP measurement, particularly with regard to rate of cuff deflation. Potential misdiagnosis and under-treatment of patients with hypertension may compromise pregnancy outcomes.
Publisher: Wiley
Date: 28-07-2009
DOI: 10.1111/J.1440-1681.2009.05155.X
Abstract: 1. Increases in soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) contribute to the pathogenesis of pre-ecl sia. Soluble Flt-1 binds to circulating free vascular endothelial growth factor and placenta growth factor and this is associated with endothelial dysfunction. Soluble endoglin, a transforming growth factor (TGF)-beta coreceptor, was reported to synergize with sFlt-1 to lify endothelial dysfunction by inhibiting TGF-beta1-mediated vasorelaxation. 2. The aim of the present study was to examine whether the antihypertensive drugs clonidine (0.08-1.3 microg/mL), diazoxide (25-300 microg/mL), frusemide (60-1000 microg/mL) and hydralazine (6.3-100 microg/mL) have any effect on placental production of sFlt-1 and sEng in placentas from normal and pre-ecl tic pregnancies. 3. Explants were taken from non-laboured term placentas of normal pregnancy (n = 5) and women with pre-ecl sia (n = 5). Villous explants were cultured with increasing doses of antihypertensive drugs. Placental sFlt-1 and sEng production was examined using ELISA. 4. Baseline sFlt-1 production was higher in placentas from women with pre-ecl sia than from normal pregnancy (4.5 +/- 1.4 vs 3.2 +/- 0.6 ng/mg of total protein, respectively P < 0.001), as was sEng production (9.0 +/- 2.3 vs 4.1 +/- 0.6 ng/mg of total protein, respectively P < 0.001). With the exception of frusemide, none of the antihypertensive drugs tested had any effect on sFlt-1 and sEng production from placental explants of normal pregnancy and women with pre-ecl sia. Increasing frusemide concentrations were correlated with increased sEng production in normal pregnancy (P < 0.005). 5. In conclusion, placental sFlt-1 and sEng production was higher in pre-ecl sia and antihypertensive drugs had no effect on placental production of sFlt-1 and sEng in vitro.
Publisher: Elsevier BV
Date: 21-02-2005
DOI: 10.1016/J.CYTO.2004.10.011
Abstract: In pregnancy, the placental contribution of cytokines to maternal immunosuppression has been established, however their role in normal maternal blood pressure regulation has not been identified. We investigate the contribution of interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNF-alpha) to the vasodilation of early pregnancy in non-human primates. We also sequenced the IL-10 baboon gene and compared it with humans. The effect of four different treatments, administered sequentially (semi-random-design) on resting 18h, night time, or hourly mean arterial pressure (MAP) and heart rate (HR) were measured using telemetry. An anti-human IL-10 monoclonal antibody (MAb, 1mg, n=7), anti-TNF-alpha antibody (n=3), a combination of anti-IL-10 and anti-TNF-alpha antibodies (n=5) or saline (n=3) control were administered intravenously to baboons in early pregnancy. Plasma and placental IL-10 concentration was measured before and after injection in all animals. Anti-human IL-10 MAb caused a significant increase in MAP of 2.6+/-0.5mmHg over the 18-h period (p<0.05). Administration of TNF-alpha alone or in combination with IL-10 did not alter MAP. There was 97% sequence homology of IL-10 cDNA between humans and baboons. IL-10 was shown to regulate the vasodilation of early pregnancy in Papio hamadryas. This partial role of IL-10 in the early BP response of primate pregnancy may be relevant to pathophysiological states of human pregnancy such as preecl sia.
Publisher: Wiley
Date: 18-05-2011
Publisher: Wiley
Date: 26-05-2009
DOI: 10.1111/J.1751-0813.2009.00434.X
Abstract: To assess the incidence of lymphoma and wasting-related deaths in the National Baboon Colony of Australia and relate it to the presence of simian T-cell lymphotrophic virus 1 (STLV-1) infection. The records of all animals that had died since establishment of the National Baboon Colony in Australia were reviewed retrospectively. The clinical signs and histopathological findings were recorded and assessed to determine the involvement of lymphoma in the deaths. The presence of STLV-1 was recorded if known and correlated with the STLV-1 status of the colony. Of the deaths from disease or illness, 53% were diagnosed as or suspected to be lymphoma, occurring in mature animals with no sex predisposition. The most common presentation was rapidly occurring generalised lymphadenomegaly. This study has described a relatively high prevalence of lymphoma in a colony of captive-bred baboons, and it is evident that STLV-1 may play a role in the disease. Management practices in baboon colonies need to take into account the possible presence of STLV-1 and aim to reduce the transmission of the virus by preventing sexual contact between positive and negative animals. Lymphoma needs to be considered as one of the more common causes of wasting and death.
Publisher: Elsevier BV
Date: 08-2004
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.TAAP.2014.02.015
Abstract: Smoking during pregnancy is associated with low birth weight, premature delivery, and neonatal morbidity and mortality. Nicotine, a major pathogenic compound of cigarette smoke, binds to the nicotinic acetylcholine receptors (nAChRs). A total of 16 nAChR subunits have been identified in mammals (9 α, 4 β, and 1 δ, γ and ε subunits). The effect of cigarette smoking on the expression of these subunits in the placenta has not yet been determined, thus constituting the aim of this study. Using RT-qPCR and western blotting, this study investigated all 16 mammalian nAChR subunits in the normal healthy human placenta, and compared mRNA and protein expressions in the placentas from smokers (n = 8) to controls (n = 8). Our data show that all 16 subunit mRNAs are expressed in the normal, non-diseased human placenta and that the expression of α2, α3, α4, α9, β2 and β4 subunits is greater than the other subunits. For mRNA, cigarette smoke exposure was associated with increased expression of the α9 subunit, and decreased expression of the δ subunit. At the protein level, expression of both α9 and δ was increased. Thus, cigarette smoking in pregnancy is sufficient to regulate nAChR subunits in the placenta, specifically α9 and δ subunits, and could contribute to the adverse effects of vasoconstriction and decreased re-epithelialisation (α9), and increased calcification and apoptosis (δ), seen in the placentas of smoking women.
Publisher: Informa UK Limited
Date: 10-11-2011
DOI: 10.3109/10641950902972140
Abstract: To determine rates of and potential causative factors for acute pulmonary oedema (APO) in hypertensive women. Statistical analysis, including logistic regression, was applied to the in idual patient data (IPD) of all hypertensive women who delivered in 2005 at two comparable units. Of 880 cases analysed, there were no women with APO in unit one and 19 women in unit two. The women with APO received larger quantities of intravenous fluids, delivered at earlier gestations, via Caesarean section, following failed induction of labour and had a longer hospital stay. The development of APO in women with hypertension during pregnancy is associated with high levels of intravenous fluid administration.
Publisher: Springer Science and Business Media LLC
Date: 26-11-2021
Publisher: Informa UK Limited
Date: 03-07-2015
DOI: 10.3109/10641955.2015.1051227
Abstract: Preecl sia remains a leading cause of maternal and neonatal morbidity and mortality. The pathophysiology of preecl sia remains poorly understood with various pathological mechanisms being implicated including the renin angiotensin system (RAAS), angiogenic pathways and various components of the immune system. Recently a pathogenic autoimmune factor has been identified in the form of auto-agonistic angiotensin II type 1 receptor antibodies (AT1-AA). AT1-AA have been studied in vitro and in vivo in various human and animal models and these data have provided compelling evidence for their role in preecl sia. This review summarises the current literature surrounding the role of AT1-AA in preecl sia and draws links between this relatively novel antibody to well-established pathological mechanisms including the immune system, the RAAS, angiogenic pathways and placental ischaemia.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2016
DOI: 10.1161/HYPERTENSIONAHA.116.07286
Abstract: An imbalance in the angiogenesis axis during pregnancy manifests as clinical preecl sia because of endothelial dysfunction. Circulating soluble fms-like tyrosine kinase 1 (sFLT-1) increases and placental growth factor (PlGF) reduces before and during disease. We investigated the clinical and biochemical effects of replenishing the reduced circulating PlGF with recombinant human PlGF (rhPlGF) and thus restoring the angiogenic balance. Hypertensive proteinuria was induced in a nonhuman primate ( Papio hamadryas ) by uterine artery ligation at 136 days gestation (of a 182-day pregnancy). Two weeks after uteroplacental ischemia, rhPlGF (rhPlGF, n=3) or normal saline (control, n=4) was administered by subcutaneous injection (100 μg/kg per day) for 5 days. Blood pressure was monitored by intra-arterial radiotelemetry and sFLT-1 and PlGF by ELISA. Uteroplacental ischemia resulted in experimental preecl sia evidenced by increased blood pressure, proteinuria, and endotheliosis on renal biopsy and elevated sFLT-1. PlGF significantly reduced after uteroplacental ischemia. rhPlGF reduced systolic blood pressure in the treated group (−5.2±0.8 mm Hg from 132.6±6.6 mm Hg to 124.1±7.6 mm Hg) compared with an increase in systolic blood pressure in controls (6.5±3 mm Hg from 131.3±1.5 mm Hg to 138.6±1.5 mm Hg). Proteinuria reduced in the treated group (−72.7±55.7 mg/mmol) but increased in the control group. Circulating levels of total sFLT-1 were not affected by the administration of PlGF however, a reduction in placental sFLT-1 mRNA expression was demonstrated. There was no significant difference between the weights or lengths of the neonates in the rhPlGF or control group however, this study was not designed to assess fetal safety or outcomes. Increasing circulating PlGF by the administration of rhPlGF improves clinical parameters in a primate animal model of experimental preecl sia.
Publisher: SAGE Publications
Date: 07-1994
DOI: 10.1258/002367794780681642
Abstract: Two juvenile baboons presented with diarrhoea, which did not resolve completely following antibiotic therapy. Ileal intussusception was identified at autopsy in both cases. Trichuris was the only gastrointestinal pathogen for which evidence could be found. This helminth is well-recognized as a cause of intussusception in human infants, but the complication has not been reported previously in non-human primates. It is likely to be fatal if undiagnosed.
Publisher: Wiley
Date: 05-2003
DOI: 10.1046/J.1440-1681.2003.03844.X
Abstract: 1. The aim of the present study was to investigate whether pre‐ecl isa, a state of placental hypoxia, is associated with placental abnormalities in the amount, distribution and expression of enothelial nitric oxide synthase (eNOS). 2. Localization and intensity of eNOS was determined by immunohistochemistry using an antibody specific for eNOS. The amount of eNOS mRNA expression was determined by reverse transcription–polymerase chain reaction (RT‐PCR) and the densitometry of gel bands was expressed as a ratio of the band density of the housekeeping gene β 2 ‐microglobulin. 3. Endothelial NOS staining was localized to syncytiotrophoblast cells within the villi and decidual trophoblast cells. It was not present in the endothelium of terminal villous vessels. There was no significant difference in eNOS villous or decidual staining intensity between normal pregnancy (NP n = 12), pre‐ecl sia ( n = 14), or gestational hypertension (GH n = 4). Staining for eNOS was not significantly different in the decidua compared with the villi in NP, GH or pre‐ecl sia. Within the decidua, the depth of eNOS staining was similar in NP, pre‐ecl isa and GH. 4. There was no significant difference in eNOS mRNA expression between NP (0.70 ± 0.11), pre‐ecl sia (0.5 ± 0.07) or GH (0.69 ± 0.26). 5. These findings suggest that the amount of eNOS in the placenta is not deficient in pre‐ecl sia, excluding a possible pathogenic role for eNOS in this disease. Furthermore, placental hypoxia, which is associated with pre‐ecl sia, did not induce an upregulation of eNOS
Publisher: American Physiological Society
Date: 15-05-2016
DOI: 10.1152/AJPHEART.00958.2015
Abstract: Preecl sia is a hypertensive disorder of pregnancy that affects 3–5% of all pregnancies. There is evidence to suggest that epigenetic mechanisms, such as DNA methylation, play a role in placental development and function. This study compared DNA methylation profiles of placentas from preecl sia-affected pregnancies with placentas from healthy pregnancies to identify gene-specific changes in DNA methylation that may contribute to the development of preecl sia. The methylation status of eight placental biopsies taken from preecl sia-affected and 16 healthy pregnancies was analyzed using the Illumina Infinium Methylation 450 BeadChip array. Bisulfite pyrosequencing was used to confirm regions found to be differentially methylated between preecl sia and healthy placentas. A total of 303 differentially methylated regions, 214 hypermethylated and 89 hypomethylated, between preecl sia cases and controls were identified, after adjusting for gestational age (adjusted P 0.05). Functional annotation found cell adhesion, wingless type MMTV Integration Site family member 2 (Wnt) signaling pathway, and regulation of transcription were significantly enriched in these gene regions. Hypermethylation of WNT2, sperm equatorial segment protein ( SPESP1), NADPH oxidase 5 ( NOX5), and activated leukocyte cell adhesion molecule ( ALCAM) in preecl sia placentas was confirmed with pyrosequencing. This study found differences in methylation in gene regions involved in cell signaling ( WNT2), fertilization and implantation ( SPESP1), reactive oxygen species signaling ( NOX5), and cell adhesion ( ALCAM). These results build on recently published studies that have reported significant differences in DNA methylation in preecl sia placentas.
Publisher: Elsevier BV
Date: 12-2022
DOI: 10.1016/J.PREGHY.2022.11.001
Abstract: This study investigated health care workers and key policy informant's knowledge, and barriers to the use of calcium and aspirin for preventing preecl sia in Blantyre and Lilongwe, Malawi. A descriptive cross-sectional formative study using semi-structured In-Depth Interview (IDIs) was conducted at Queen Elizabeth Central Hospital (QECH), Reproductive Health Directorate, and the United Nations Population Development Fund (UNFPA) Office in 2021. Data was analyzed using NVIVO™ software. Thematic content analysis was used to analyze and interpret the findings. Emerging themes were then developed inductively and deductively. Doctors had greater knowledge of the use of calcium and aspirin for prevention of preecl sia compared to nurses and key policy informants. Lack of knowledge, patient's late presentation, scarcity of calcium tablets and delays in implementing new guidelines were the barriers to use identified. This study shows that there are health care worker and policy level barriers that affect the implementation of calcium and aspirin use for the prevention of preecl sia in Malawian women.
Publisher: Elsevier BV
Date: 11-2005
DOI: 10.1016/J.PLACENTA.2004.10.019
Abstract: Preecl sia is a multisystem disorder manifest by hypertension after 20 weeks' gestation associated with end organ damage, usually proteinuria. The placenta is thought to be pivotal in the pathogenesis of the disease. Both the placenta and the maternal systemic response are characterised by heightened inflammation. Garlic has been shown to have anti-inflammatory and pro-apoptotic properties amongst others. It was hypothesised that treating placental explants with garlic may inhibit the production of inflammatory cytokines (interleukin-6 (IL-6) and tumour necrosis factor (TNFalpha)) and stimulate the production of anti-inflammatory cytokines (interleukin-10 (IL-10)) by the placental explants. Garlic, we hypothesised, would also stimulate apoptosis in the explants as measured by soluble TNF-related apoptosis-inducing ligand/Apo-2L (sTRAIL) production. Normal placental explants (n=5) and explants from women who had preecl sia (n=4) were cultured in the presence of various garlic concentrations (10-1000 microg/mL). The lowest garlic concentration (10 microg/mL) increased the normal explant production of IL-10 by 29.2% (12.2, 57.5% p<0.01) while inhibiting the production of IL-6 by 23.5% (8.9, 32.5% p<0.01) (normal explants) and TNFalpha by 19.4% (4.5, 35.3% p<0.05) (preecl tic explants). Garlic resulted in an increase in IL-10 production at lower doses (normal explants only) and inhibition of the production of IL-10 at higher doses (normal and preecl tic explants). Garlic also resulted in a dose-dependent reduction of IL-6 and TNFalpha. Initially there was no change in sTRAIL production however, at the highest garlic concentrations there was a significant increase in production. We thus conclude that garlic may have an immunomodulatory effect on normal and preecl tic placentas.
Publisher: Elsevier BV
Date: 03-1991
DOI: 10.1016/J.PLACENTA.2010.12.005
Abstract: Preecl sia has been linked to shallow trophoblast invasion and failure of uterine spiral artery transformation. Interaction between trophoblast cells and maternal uterine endothelium is critically important for this remodelling. The aim of our study was to investigate the effect of TNF-α on the interactions of trophoblast-derived JEG-3 cells into capillary-like cellular networks. We have employed an in vitro trophoblast-endothelial cell co-culture model to quantify trophoblast integration into endothelial cellular networks and to investigate the effects of TNF-α. Controlled co-cultures were also treated with anti-TNF-α antibody (5 μg/ml) to specifically block the effect of TNF-α. The invasion was evaluated by performing quantitative PCR (Q-PCR) to analyse gene expression of matrix metalloproteinases-2 (MMP-2), MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1, integrins (α(1)β(1) and α(6)β(4)), plasminogen activator inhibitor (PAI)-1, E-cadherin and VE-cadherin. JEG-3 cell integration into endothelial networks was significantly inhibited by exogenous TNF-α. The inhibition was observed in the range of 0.2-5 ng/ml, to a maximum 56% inhibition at the highest concentration. This inhibition was reversed by anti-TNF-α antibody. Q-PCR analysis showed that mRNA expression of integrins α(1)β(1) and MMP-2 was significantly decreased. VE-cadherin mRNA expression was significantly up-regulated (32-80%, p < 0.01) but its protein concentration in the cell lysates was significantly reduced (20-45%, p < 0.01). PAI-1, MMP-9, TIMP-1 and E-cadherin were not affected. In conclusion, TNF-α can inhibit trophoblast-like cells (JEG-3) integration into maternal endothelial cellular networks, and this process involves the inhibition of MMP-2 and a failure of integrins switch from α(6)β(4) to α(1)β(1.) These molecular correlations reflect the changes identified in human preecl sia.
Publisher: Portland Press Ltd.
Date: 05-2004
DOI: 10.1042/CS20040062
Abstract: One of the fundamental issues in pre-ecl sia (hypertension in pregnancy) research is to find serum proteins that can act as markers of disease predisposition, remote disease onset, imminent disease onset or disease activity at the height of its destructive powers. We make assumptions, not infrequently, that positive findings at the time of delivery reflect early changes in the maternal and fetal circulations. Very little has been defined in terms of fetal circulation, as it is, by and large, deemed to be harder to access and less likely to lend itself to useful non-invasive diagnostic tests in early pregnancy. The study published in this issue of Clinical Science by Prickett et al. shows that there is a differential expression of the precursor molecule of CNP (C-type natriuretic peptide), N-terminal proCNP, in pre-ecl sia. At term, pre-ecl tic umbilical cord plasma concentrations are decreased relative to normal pregnancy, possibly reflecting a decrease in placental production. At the same time maternal levels are increased relative to normal pregnancies and this possibly reflects an increase in myometrial/endovascular production. There is no doubt that the predominant actions of these hormones are local and whether plasma levels are a true reflection of dynamic changes in local production and effect is yet to be seen. This study represents a promising start in identifying large stable molecules which could be markers for pre-ecl sia. This study has relatively small numbers of patients and work still needs to be done to determine the utility of umbilical cord levels in early phases of the disease. Whether serum levels of N-terminal proCNP can provide an accurate reflection of normal or pathological maternal uterine adaptation to pregnancy remains a question worth evaluating.
Publisher: BMJ
Date: 07-2013
Publisher: Wiley
Date: 11-07-2007
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.AJOG.2013.02.014
Abstract: The objective of this study was to determine how parity and breastfeeding were associated with maternal high blood pressure, and how age modifies this association. Baseline data for 74,785 women were sourced from the 45 and Up Study, Australia. These women were 45 years of age or older, had an intact uterus, and had not been diagnosed with high blood pressure before pregnancy. Odds ratios (ORs) and 99% confidence intervals (CIs) for the association between giving birth, breastfeeding, lifetime breastfeeding duration, and average breastfeeding per child with high blood pressure were estimated using logistic regression. The combination of parity and breastfeeding was associated with lower odds of having high blood pressure (adjusted OR, 0.89 99% CI, 0.82-0.97 P < .001), compared with nulliparous women, whereas there was no significant difference between mothers who did not breastfeed and nulliparous women (adjusted OR, 1.06 99% CI, 0.95-1.18 P = .20). Women who breastfed for longer than 6 months in their lifetime, or greater than 3 months per child, on average, had significantly lower odds of having high blood pressure when compared with parous women who never breastfed. The odds were lower with longer breastfeeding durations and were no longer significant in the majority of women over the age of 64 years. Women should be encouraged to breastfeed for as long as possible and a woman's breastfeeding history should be taken into account when assessing her likelihood of high blood pressure in later life.
Publisher: Wiley
Date: 23-09-2008
DOI: 10.1111/J.1600-0684.2007.00277.X
Abstract: Non-human primates, particularly baboons, are valuable as animal models for reproductive research, because of their similarity to humans. Knowledge of colony-specific pregnancy and neonatal outcomes is essential for interpretation of such research. A retrospective review of the reproductive records of the Australian National Baboon Colony (ANBC) from 1994 to 2006 was performed. The overall live birth rate was over 70% of recognized pregnancies. Pregnancy loss was due to equal proportions of spontaneous abortion and stillbirth, and was not affected by maternal age or parity. Stillbirth rates were increased by the use of animals in novel late pregnancy experimental protocols. Neonatal mortality rates were low overall, but significantly higher in primiparous compared with multiparous mothers (P < 0.05). There were no cases of maternal mortality. The success of the ANBC breeding programme is demonstrated by the low rate of pregnancy loss, high neonatal survival rate and lack of maternal mortality.
Publisher: Springer Science and Business Media LLC
Date: 12-2013
Publisher: Wiley
Date: 20-03-2010
DOI: 10.1111/J.1440-1681.2009.05334.X
Abstract: 1. The presence of proteinuria is not essential to the diagnosis of pre-ecl sia under many diagnostic consensus statements. The aim of the present study was to assess maternal and perinatal outcomes after proteinuric pre-ecl sia compared with other non-proteinuric disease presentations. 2. An in idual patient data review (n = 670) was undertaken for 2003-2006 at a tertiary referral centre in Sydney (NSW, Australia). Women were diagnosed in accordance with the Australasian Society for the Study of Hypertension in Pregnancy Consensus Statement. Data were analysed with the Chi-squared test, t-tests and non-parametric tests. Statistical significance was set at P < 0.05. 3. The proteinuric cohort had higher systolic and diastolic blood pressure recordings than the non-proteinuric cohort (160/102 and 149/94 mmHg, respectively P < 0.001), and were also administered magnesium sulphate more frequently (44 vs 22%, respectively P < 0.001), delivered at earlier gestation (37 vs 38 weeks, respectively P < 0.001), required operative delivery more frequently (63 vs 48%, respectively P < 0.001) and received more antihypertensive medications during the antenatal period (72 vs 57%, respectively P < 0.001). Acute renal failure and acute pulmonary oedema were rare. Four cases of ecl sia all occurred in non-proteinuric women. The perinatal mortality rate was lower for the offspring of women with proteinuric pre-ecl sia compared with offspring of non-proteinuric women (13/1000 and 31/1000, respectively P = 0.006). 4. The results of the present study indicate that the presence of proteinuria denotes a group of women who have higher antenatal blood pressure, who deliver at earlier gestation and require operative delivery more commonly, although it is not an indicator of other markers of maternal morbidity or perinatal mortality.
Publisher: Elsevier BV
Date: 10-1996
DOI: 10.1016/S0168-8227(96)01335-6
Abstract: Extracellular matrix plays an important role in many physiological functions and its abnormalities are thought to play a key role in the pathogenesis of diabetic complications. In this paper we used the techniques of electron microscopy, immunostaining and X-ray diffraction to document some of the early events in the changes of extracellular matrix in a model of insulin dependent diabetes in baboons. Our results show that thickening of basement membrane and enlargement of mesangium are demonstrable in the glomeruli of prepubertal diabetic baboons within 2 years from the onset of diabetes. Concomitant with this was the accumulation of type IV collagen and laminin in the mesangium. By contrast, even the very sensitive technique of X-ray diffraction failed to demonstrate changes in the equatorial direction of collagen molecules of the skin and tendon. We conclude that changes of glomerular extracellular matrix are demonstrable early in insulin dependent diabetes even in prepubertal baboons. These can be used as endpoints in evaluating the efficacy of pharmacological agents such as aminoguanidine in preventing diabetic complications.
Publisher: Elsevier BV
Date: 05-2007
Abstract: Preecl sia is a complication of pregnancy with significant morbidity and mortality for the mother and the fetus. Presumptions are made that placental hypoxia has a causative role in the clinical syndrome. Furthermore, soluble fms-like tyrosine kinase 1 (sFLT-1) has been shown to have a role in the maternal syndrome of preecl sia. We investigated the relationship between uteroplacental ischemia (UPI), the maternal clinical syndrome of preecl sia and sFLT-1 in non-human primates. The induction of UPI in a pregnant non-human primate resulted in the development of a clinical entity analogous to human preecl sia. This was illustrated by the increase in blood pressure, development of proteinuria, and renal histological changes identical to human preecl sia. A significant elevation in the placental and peripheral blood mononuclear cell sFLT-1 mRNA expression was noted, translating to a significant elevation in circulating sFLT-1. Thus, this sequence suggests that a pathogenic reduction in placental perfusion results in the development of the maternal syndrome of preecl sia and an increase in circulating sFLT-1, which is derived both from placental and extra-placental sources.
Publisher: Elsevier BV
Date: 2003
DOI: 10.1046/J.1444-2892.2003.00206.X
Abstract: In early pregnancy, a substantial drop in arterial blood pressure occurs, that might be attributed to enhanced vascular nitric oxide synthesis. We investigated whether nitric oxide mediates the vasodilation that occurs in early human pregnancy. Resting and stimulated forearm vascular resistance were measured (venous occlusion plethysmograph) in six women at 10 +/- 3 weeks of uncomplicated pregnancy and in the same women 7 +/- 5 weeks after elective termination of pregnancy. Forearm vascular resistance was also measured in six non-pregnant, healthy controls. Resting forearm vascular resistance was similar during pregnancy (33 +/- 16 arbitrary units (AU)), after pregnancy (31 +/- 10 AU) and in controls (41 +/- 13 AU, P > 0.05). The decreases in forearm vascular resistance to intrabrachial infusions of acetylcholine (2 and 20 microg/min), serotonin (10 and 100 ng/min) and sodium nitroprusside (1 and 2.5 microg/min) were similar in all groups. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (16 micromol/min) produced similar increases in vascular resistance in pregnant women (38 +/- 17 AU), after pregnancy (36 +/- 14 AU) and in control subjects (42 +/- 8 AU, P = NS). These results indicate that neither basal nor stimulated nitric oxide levels are altered in the forearm circulation during first trimester pregnancy.
Publisher: Public Library of Science (PLoS)
Date: 11-07-2012
Publisher: Springer Science and Business Media LLC
Date: 2014
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1016/S1701-2163(16)32643-3
Abstract: To implement a set of clinical indicators to benchmark outcomes for women suffering from the hypertensive disorders of pregnancy. Seven clinical indicators were designed and applied retrospectively to data collected from two tertiary referral centres, Royal Prince Alfred Hospital, Sydney, Australia and British Columbia Women's Hospital and Health Centre, Vancouver BC, for all women coded as hypertensive during pregnancy under the International Classification of Disease (ICD-10) coding system in the years 2002-2004. Diagnostic categories were assigned using the Australasian Society for the Study of Hypertension in Pregnancy criteria, expressed in equivalent Canadian terms drawn from the Report of the Canadian Hypertension Society Consensus. Comparisons were made using the established clinical indicators. Data analysis using chi-square comparison was performed with significance set at P < 0.05. Seven outcome measures of maternal and neonatal mortality and morbidity were compared. Significant areas of difference between the two tertiary referral centres were seen in birth weights below the 10th centile (RPA 11% vs. BCW 20% P < 0.05) and below the 3rd centile (RPA 1.5% vs. BCW 7.5% P < 0.001). There were significantly more episodes of maternal pulmonary edema at BCW than at RPA (0.1% and 1.2%, respectively P < 0.001). Between similar centres, clinically significant differences in outcomes for HDP were identified. Further evaluation of differences may lead to analysis of possible contributors such as expectant versus urgent delivery management policies, rigidity of blood pressure control, and choice of antihypertensive drug.
Publisher: Wiley
Date: 25-01-2012
DOI: 10.1111/J.1600-0684.2011.00532.X
Abstract: To determine systolic and diastolic function using transthoracic echocardiography in the baboon (Papio hamadryas). Transthoracic echocardiography was performed in eight non-pregnant female and six pregnant baboons according to American Society of Echocardiography recommendations. Haemodynamic measurements were obtained from fourteen baboons. Compared to non-pregnant baboons, pregnant baboons demonstrated: (mean ± SD, pregnant vs. healthy) increased cardiac output (1615 ± 121 ml/minutes vs. 1317 ± 134 ml/minutes P = 0.001) due to an increased heart rate [120 ± 11 beats per minute (BPM) vs. 105 ± 6 BPM P = 0.018]. The inter-observer and intra-observer variability (mean difference ± SD) for the left ventricular outflow tract diameter was 0.05 ± 0.07 cm and 0.01 ± 0.03 cm respectively. There was minimal impact to the animal's daily activities. Transthoracic echocardiography was applicable and reproducible for the assessment of haemodynamics in baboons thus enabling translation of animal results to human studies.
Publisher: Public Library of Science (PLoS)
Date: 18-07-2016
Publisher: Wiley
Date: 17-03-2014
DOI: 10.1111/JMP.12113
Abstract: The aim of this study was to assess agreement between different methods of blood pressure measurement in anaesthetised baboons. Systolic and diastolic blood pressure (SBP and DBP) were measured in anaesthetised baboons using intra-arterial radiotelemetry, automated oscillometry and mercury sphygmomanometry. Correlation between the different methods was assessed. The correlation between intra-arterial radiotelemetry and automated oscillometry was 0.9 (P < 0.001) for SBP and 0.9 (P < 0.001) for DBP. Between-method differences were -4.4 ± 7.2 mm Hg for SBP and -3.4 ± 7.1 mm Hg for DBP. For automated oscillometry vs. mercury sphygmomanometry, correlation was 0.4 for both SBP (P < 0.001) and DBP (P < 0.001). Between-method differences were 7.9 ± 12.7 mm Hg for SBP and 7.3 ± 12.6 mm Hg for DBP. Our study demonstrates that automated oscillometry may be an appropriate alternative to telemetry for measuring blood pressure in anaesthetised baboons.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2006
Publisher: Oxford University Press (OUP)
Date: 1992
Publisher: Elsevier BV
Date: 10-2010
DOI: 10.1016/J.HLC.2010.06.1057
Abstract: Despite increasing evidence implicating the pulmonary microcirculation in the pathogenesis of lung conditions such as pulmonary vascular disease, there remain few methods for its evaluation in vivo. We recently demonstrated that the novel index of Doppler-derived pulmonary flow reserve (PFR(dopp)=maximal hyperaemic/basal pulmonary flow) could be reliably measured in high primates. Noting that the microvasculature is the chief regulator of pulmonary blood flow, we hypothesised that PFR(dopp) may detect microcirculatory loss. We therefore studied the relationship between PFR(dopp) and experimentally induced pulmonary microvascular obstruction using microspheres in higher primates. Under ketamine anaesthesia, Doppler sensor-guidewires were placed in the segmental pulmonary artery of three adult baboons. Doppler flow velocity and haemodynamics were recorded at rest and during hyperaemia [as induced by intrapulmonary artery adenosine (200 μg/kg/min)]. Serial PFR(dopp) evaluations were made after cumulative intrapulmonary artery ceramic microspheres administration. Cumulative microsphere administration progressively reduced PFR(dopp) (1.54 ± 0.26, 1.48 ± 0.20, 1.12 ± 0.04 and 1.18 ± 0.09 baseline, 10(4), 10(5) and 10(6) microspheres boluses p<0.02) without affecting pulmonary artery pressure, systemic artery pressure or heart rate. Doppler-derived PFR can detect partial, progressive pulmonary microvascular obstruction in higher primates. PFR(dopp) may thus have a potential role in the assessment of the pulmonary microcirculation in vivo.
Publisher: Wiley
Date: 10-2011
DOI: 10.1111/J.1440-1681.1994.TB02572.X
Abstract: 1. The haemodynamic effects of intravenous nitric oxide inhibitor, N-nitro-L-arginine (NOLA), were examined in four conscious non-restrained baboons (Papio hamadryas). Mean arterial pressure, (MAP), systemic vascular resistance (SVR) and cardiac output (CO) were measured at timed intervals up to 24 h after a bolus injection of NOLA. 2. N-nitro-L-arginine increased blood pressure in a dose-dependent manner up to 9.5 mg/kg. Increases in blood pressure were accompanied by increases in SVR and decreases in CO, with a significant fall in heart rate. 3. One animal received 9.5 mg/kg NOLA and became unconscious, suggesting cerebral vasospasm. 4. Vascular effects of nitric oxide contribute significantly to the regulation of arterial blood pressure under physiological conditions in the baboon.
Publisher: Elsevier BV
Date: 11-2002
DOI: 10.1016/S0966-3274(02)00078-3
Abstract: Chronic Rejection (CR) is the leading cause of renal allograft dysfunction. Upregulation of growth factors has been shown in CR but the time point at which this occurs in not known. The aim of this study was to examine the time course of upregulation of growth factors and correlate this with the macrophage and myofibroblast interstitial infiltrate. Using a rat model of CR (F344 kidney donor to Lewis recipient), infiltration by ED1 + macrophages and proliferation of alpha-smooth muscle actin (alpha-SMA) and desmin-expressing cells was examined using immunohistochemistry. In addition, expression of mRNA for interferon-gamma (IFN-gamma), transforming growth factor-beta (TGF-beta), basic-fibroblast growth factor (b-FGF) and vascular endothelial growth factor (VEGF) was studied using a semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) technique. Native Lewis rat kidney and Lewis-Lewis isografts were used as controls. Immunohistochemical staining of ED1 + cells showed a marked increase in the macrophage infiltrate of allografts compared to isografts at all time periods (P = 0.0002) peaking at weeks 8-12 after transplantation. Expression of alpha-SMA was also increased in allografts (P = 0.002). RT-PCR analysis showed that mRNA for TGF-beta was maximally upregulated in allografts in comparison to isografts at week 8 after engraftment (P = 0.05) and declined thereafter, although remained at elevated levels compared to controls. IFN-gamma and b-FGF gene expression was increased in allografts late in the post-transplantation period. Early infiltration of macrophages and production of TGF-beta1 was followed by later upregulation of fibrogenic growth factors and myofibroblasts associated with interstitial fibrosis and organ dysfunction.
Publisher: CSIRO Publishing
Date: 2013
DOI: 10.1071/PY12010
Abstract: The objective of the study was to examine associations between family history of premature cardiovascular disease (CVD), knowledge of CVD risk and protective factors, and health behaviours. The design was via administration of a questionnaire to 307 participants from four general practice centre waiting rooms in the Sydney West area. The most recognised CVD risk factor was smoking (97.7%) and the most recognised CVD protective factor was omega-3 fatty acids (78.5%). After adjustment for age, sex, education attainment and personal history of CVD, a strong family history of premature CVD was associated with being more likely to interpret a blood pressure of 130/85 as a CVD risk factor (OR 2.77, 95% CI 1.07–7.14), but less likely to identify being an ex-smoker (compared with never having smoked before) as a risk factor (OR 0.32, 95% CI 0.12–0.90). Those with a strong family history of premature CVD, on average, had smoked 0.82 pack years more than those with an average family history of premature CVD (s.e. 4.22, P = 0.04). In conclusion, there continues to be both strengths and deficits in the community’s overall knowledge of CVD risk and protective factors, and a strong family history of premature CVD appears to be an independent risk factor for smoking.
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.CYTO.2011.06.003
Abstract: Preecl sia is a common disease of pregnancy characterised by maternal hypertension and proteinuria. Abnormal placentation in early pregnancy and abnormal cytokine and anti-angiogenic factor expression are thought to contribute to the clinical syndrome of endothelial dysfunction evident in the second half of gestation. The mechanisms underlying both the placental pathology and its translation to the maternal clinical syndrome are not fully understood. A model of preecl sia manifest by clinically evident endothelial dysfunction (increased blood pressure and proteinuria) was induced by administration of low-dose TNF-α for 2weeks at mid-gestation in pregnant baboons (Papio hamadryas). Blood pressure was monitored continuously and remotely by intra-arterial radiotelemetry. Following TNF-α infusion, there was an increase in systolic and diastolic blood pressure and development of proteinuria in pregnant treated animals, but not in pregnant saline controls nor in non-pregnant TNF-α treated animals. The treated pregnant animals also developed elevated plasma soluble FMS-like tyrosine kinase-1 (sFLT-1) and increased placental mRNA expression of sFLT-1 and soluble endoglin (sEng). These results clearly demonstrate that the cytokine TNF-α can induce the clinical and biochemical features of human preecl sia. The results identify a link between cytokines, placental dysfunction and endothelial dysfunction resulting in a loss of maternal blood pressure control.
Publisher: Wiley
Date: 28-07-2015
DOI: 10.1111/AJI.12417
Abstract: Increased levels of inflammatory cytokines are demonstrated in the serum of women with pre-ecl sia. TNF-α infusion in animal models induces proteinuric hypertension similar to human pre-ecl sia. The effect of TNF-α on regulation of the immune and hypoxic pathways in the developing placenta and their relationship with experimental pre-ecl sia remains unexamined. TNF-α was infused into pregnant mice, and the effects on maternal hypertension, proteinuria, circulating levels of sFlt-1 and corresponding placental changes in molecules responding to inflammation (TLR-3 and TLR-4) and hypoxia (HIF-1α) were examined. TNF-α infusion resulted in maternal hypertension and proteinuria. Molecular changes in the placenta involved upregulation of TLR-3, TLR-4 and HIF-1α. Serum levels of sFlt-1 were high in pregnant animals, but not further upregulated by TNF-α infusion. A role for maladaptive regulation of TLR and HIF-1α induced by an imbalance in inflammatory cytokines is implicated in the pathogenesis of pre-ecl sia.
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1016/J.BPOBGYN.2011.03.002
Abstract: Hypertensive disorders of pregnancy are a major cause of morbidity and mortality worldwide. Reliable, published in idual patient data from units and countries are lacking. Without these data, clinicians are unable to benchmark their incidence, treatments and outcomes, and patient safety is unable to be routinely assessed. Available data suggest that a notable proportion of the adverse events that occur with hypertensive disease of pregnancy may be preventable. Theory and practice indicate several methods that can offer the possibility of averting these preventable adverse events. These methods include benchmarking outcomes, standardisation of care processes, simulation, and enhancement of patient knowledge. However, data on optimal methods to enhance patient safety and quality of care of pregnant women with hypertensive disease remain limited, and further research is required.
Publisher: Wiley
Date: 27-01-2011
DOI: 10.1111/J.1440-1797.2010.01411.X
Abstract: With the recent discovery of potential serum 'toxins' in human preecl sia, it is timely to consider how these might relate to preecl tic nephropathy. This review will discuss the clinical presentation of preecl sia with an emphasis on renal involvement. It will explore the nature of the renal histological changes including endothelial and the more recently discovered podocyte changes, the implications of elevated anti-angiogenic molecules, anti-angiotensin-1 receptor agonistic antibodies and other proposed mechanisms in causing or exacerbating renal lesions. It will also explore the role of pre-existing renal disease in causing preecl sia and the potential for new biomarkers, both serum and urinary, to inform clinical practice with regard to differentiating preecl sia from pre-existing renal disease. Recommendations about the future of women who have had preecl sia are unclear but the general consensus is that there are future cardiovascular risks, and to a lesser extent, future renal risks in these women. Regular review of proteinuria and glomerular filtration rate as well as overall cardiovascular risk status seems a logical step.
Publisher: Wiley
Date: 1995
DOI: 10.1111/J.1600-0684.1995.TB00141.X
Abstract: Over a period of four years, streptozocin has been used to induce diabetes in 10 baboons, all of whom are insulin dependent. We describe our experience with their husbandry, induction of diabetes, insulin therapy, metabolic control and growth rate. Streptozocin dosage of 60 mg/kg readily induces hyperglycemia with minimal hepatic or renal toxicity. Using a once daily injection of mixed short and intermediate acting insulins at a dosage of 2-4 U/kg, it is possible to maintain a degree of metabolic control similar to that attained in patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2007
Publisher: Informa UK Limited
Date: 20-02-2015
DOI: 10.3109/10641955.2015.1009545
Abstract: The role of the nicotinic acetylcholine receptors (nAChR) in pre-ecl sia is unknown. Given that ACh levels are affected in pre-ecl sia, it has been suggested that compensatory changes in nAChR expression may ensue. This study aimed to determine the effects of pre-ecl sia on the mRNA and protein expression of 12 mammalian nAChR subunits. Placentas were collected from healthy term pregnancies (n = 8) and pregnancies complicated by pre-ecl sia (n = 7), both being non-cigarette smoke exposed to rule out any role of nicotine. Using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR), 12 subunits (α2, α3, α4, α5, α6, α7, α9, β1, β2, β4, δ, and γ) were able to be studied at the mRNA level, while at the protein level using Western blotting, nine subunits (α2, α3, α4, α5, α7, α9, β1, β2, and γ) were studied. At the mRNA level, pre-ecl tic placentas showed an increase in α2 (p = 0.003), α9 (p < 0.001), β1 (p = 0.03) and β2 (p = 0.02) subunit expression, while at the protein level, α7 (p = 0.004), α9 (p = 0.02), and δ (p = 0.003) subunits were increased compared to controls. Certain nAChR subunits are increased in the pre-ecl tic placenta. Given the absence of cigarette smoking, the changes in expression are hypothesised to be due to the hypoxic environment resulting from the pathophysiology of pre-ecl sia, which subsequently affects endogenous ACh levels, yielding compensatory increases in α2, α7, α9, β1, β2, and δ nAChR subunits.
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.PREGHY.2018.04.002
Abstract: This review summarizes the literature to date on the subject of the chronobiology of blood pressure in pregnancy, and more specifically, in the common disease state of high blood pressure in pregnancy or preecl sia. While the guidelines for treating hypertension in pregnancy use absolute measures to start treatment, they do not take into account the important rhythms of hypertension including nighttime and daytime readings. These variations are likely to have strong impacts on pregnancy outcomes, risk and long-term hypertension risk.
Publisher: Springer Science and Business Media LLC
Date: 29-11-2010
DOI: 10.1007/S00125-009-1610-6
Abstract: Chronic non-healing wounds are a common complication of diabetes. Prolonged inflammation and decreased matrix accumulation may contribute. Connective tissue growth factor (CTGF) is induced during normal wound healing, but its regulation in diabetic wounds is unknown. We developed a primate model for the study of in vivo wound healing in baboons with long diabetes duration. Drum implants were placed subcutaneously into thighs of diabetic and non-diabetic control baboons. After 2 and 4 weeks the skin incision sites were removed for measurement of breaking strength and epithelial thickness. Drum implants were removed for analysis of granulation tissue and inflammatory cells, CTGF and tissue inhibitor of matrix metalloproteinase (TIMP-1). Degradation of added CTGF by wound fluid was also examined. Healed incision site skin was stiffer (less elastic) in diabetic baboons and epithelial remodelling was slower compared with controls. Granulation tissue from diabetic baboons was reduced at 2 and 4 weeks, with increased vessel lumen areas at 4 weeks. Macrophages were reduced while neutrophils persisted in diabetic tissue. In diabetic wound tissue at 4 weeks there was less CTGF induced, as shown by immunohistochemistry, compared with controls. In contrast, immunoreactive fragments of CTGF were significantly increased in whole tissue lysate in diabetic baboons, suggesting that CTGF is redistributed in diabetes from granulation tissue into wound fluid. When recombinant human CTGF was co-incubated with wound fluid, increased CTGF degradation products were observed in both control and diabetic s les. This baboon model of wound healing reflects the abnormal microenvironment seen in human diabetic wounds and provides insights into the dysregulation of CTGF in diabetic wounds.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2014
Location: Australia
No related grants have been discovered for Annemarie Hennessy.