ORCID Profile
0000-0001-7114-3920
Current Organisation
University of South Australia
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Publisher: Wiley
Date: 25-01-2022
Abstract: An optical redox ratio can potentially be used to report on the dynamics of cell and tissue metabolism and define altered metabolic conditions for different pathologies. While there are methods to measure the optical redox ratio, they are not particularly suited to real‐time in situ or in vivo analysis. Here, we have developed a fiber‐optic system to measure redox ratios in cells and tissues and two mathematical models to enable real‐time, in vivo redox measurements. The optical redox ratios in tissue explants are correlated directly with endogenous NADH/FAD fluorescence emissions. We apply the mathematical models to the two‐photon microscopy data and show consistent results. We also used our fiber‐optic system to measure redox in different tissues and show consistent results between the two models, hence demonstrating proof‐of‐principle. This innovative redox monitoring system will have practical applications for defining different metabolic disease states.
Publisher: Elsevier BV
Date: 09-2020
Publisher: Wiley
Date: 30-05-2018
DOI: 10.1113/JP274948
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.LFS.2022.120521
Abstract: Maternal undernutrition during pregnancy disrupts both fetal growth and development with perturbations to certain physiological processes within the maternal-fetal-placental unit, including metabolic function. However, it is unknown if hypoglycemia during pregnancy alters maternal-fetal-placental drug metabolism as mediated by cytochrome P450 (CYP) enzymes. Despite this, hypoglycemia reduces CYP enzyme activity in non-pregnant animals. We therefore hypothesised that in a sheep model of hypoglycemia induced by late gestation undernutrition (LGUN), maternal-fetal-placental CYP activity would be reduced, and that fetal glucose infusion (LGUN+G) would rescue reduced CYP activity. At 115d gestation (term, 150d), ewes were allocated to control (100% metabolic energy requirement (MER) n = 11), LGUN (50% MER n = 7) or LGUN+G (50% MER + fetal glucose infusion n = 6) and maintained on their diets until post-mortem. Maternal-fetal-placental CYP activity assays were performed at 131-133d gestation. Microsomes were isolated from placenta and fetal liver collected at 139-142d gestation and incubated with CYP-specific probe drugs. Metabolite concentrations were measured using Liquid Chromatography - tandem mass spectrometry (LC-MS/MS). CYP2C19 and CYP3A were undetectable in placenta or fetal liver, and CYP1A2 was undetectable in the fetal liver. Placental-specific CYP1A2 and CYP2D6 activity and hepatic-specific CYP2D6 activity were unaffected by LGUN. Maternal-fetal-placental CYP1A2 activity was reduced in response to LGUN in the maternal compartment only. Reduced maternal-fetal-placental CYP1A2 activity, but not placental-specific CYP1A2 activity, may lead to the developing fetus being exposed to increased concentrations of CYP1A2-specific substrates and suggests further consideration of drug dosing is required in instances of late gestation maternal undernutrition.
Publisher: Elsevier BV
Date: 07-2023
Publisher: American Physiological Society
Date: 12-2018
DOI: 10.1152/AJPREGU.00391.2017
Abstract: Experimental studies that are relevant to human pregnancy rely on the selection of appropriate animal models as an important element in experimental design. Consideration of the strengths and weaknesses of any animal model of human disease is fundamental to effective and meaningful translation of preclinical research. Studies in sheep have made significant contributions to our understanding of the normal and abnormal development of the fetus. As a model of human pregnancy, studies in sheep have enabled scientists and clinicians to answer questions about the etiology and treatment of poor maternal, placental, and fetal health and to provide an evidence base for translation of interventions to the clinic. The aim of this review is to highlight the advances in perinatal human medicine that have been achieved following translation of research using the pregnant sheep and fetus.
Publisher: Wiley
Date: 07-2020
DOI: 10.1113/JP279631
Publisher: MDPI AG
Date: 15-06-2021
DOI: 10.3390/IJMS22126386
Abstract: It is well understood that sex differences exist between females and males even before they are born. These sex-dependent differences may contribute to altered growth and developmental outcomes for the fetus. Based on our initial observations in the human placenta, we hypothesised that the male prioritises growth pathways in order to maximise growth through to adulthood, thereby ensuring the greatest chance of reproductive success. However, this male-specific “evolutionary advantage” likely contributes to males being less adaptable to shifts in the in-utero environment, which then places them at a greater risk for intrauterine morbidities or mortality. Comparatively, females are more adaptable to changes in the in-utero environment at the cost of growth, which may reduce their risk of poor perinatal outcomes. The mechanisms that drive these sex-specific adaptations to a change in the in-utero environment remain unclear, but an increasing body of evidence within the field of developmental biology would suggest that alterations to placental function, as well as the feto-placental hormonal milieu, is an important contributing factor. Herein, we have addressed the current knowledge regarding sex-specific intrauterine growth differences and have examined how certain pregnancy complications may alter these female- and male-specific adaptations.
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.PHRS.2019.04.020
Abstract: Resveratrol (RSV) has been reported to have potential beneficial effects in the complicated pregnancy. Various pregnancy complications lead to a suboptimal in utero environment that impacts fetal growth during critical windows of development. Detrimental structural changes to key organ systems in utero persist into adult life and predispose offspring to an increased risk of chronic non-communicable metabolic diseases such as cardiovascular disease, diabetes and obesity. The aim of this systematic review was to determine the effect of gestational RSV exposure on both maternal and fetal outcomes. Publicly available databases (n = 8) were searched for original studies reporting maternal and/or fetal outcomes after RSV exposure during pregnancy irrespective of species. Of the 115 studies screened, 31 studies were included in this review. RSV exposure occurred for different durations across a range of species (Rats n = 18, Mice n = 7, Japanese Macaques n = 3 and Sheep n = 3), models of complicated pregnancy (eg. maternal dietary manipulations, gestational diabetes, maternal hypoxia, teratogen exposure, etc.), dosages and administration routes. Maternal and fetal outcomes differed not only based on the model of complicated pregnancy assessed but also as a result of species. Given the heterogenic nature of these studies, further investigation assessing RSV exposure during the complicated pregnancy is warranted. In order to make an informed decision regarding the use of RSV to intervene in pregnancy complications, we suggest a minimum data set for consideration in future studies.
Publisher: American Chemical Society (ACS)
Date: 23-05-2023
Publisher: Wiley
Date: 02-2020
DOI: 10.14814/PHY2.14365
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.LFS.2021.120133
Abstract: Non-alcoholic fatty liver disease (NAFLD) is characterised by accumulation of triglycerides and cholesterol within the liver and dysregulation of specific hepatic cytochrome P450 (CYPs) activity. CYPs are involved in the metabolism of endogenous and exogenous chemicals. Hepatic CYP activity is dysregulated in human studies and animal models of a Western diet (WD) or low birth weight (LBW) independently, but the additive effects of LBW and postnatal WD consumption are unknown. As such, the aim of this study was to determine the independent and combined effect of birthweight and postnatal diet on hepatic CYP activity in a guinea pig model. LBW was generated via uterine artery ablation at mid gestation (term = 70 days gestation). Normal birthweight (NBW) and LBW pups were allocated either a control diet (CD) or WD at weaning. After 4 months of dietary intervention, guinea pigs were humanely killed, and liver tissue collected for biochemical and functional hepatic CYP activity analyses. Independent of birthweight, functional activity of CYP3A was significantly reduced in female and male WD compared to CD animals (female, P < 0.0001 male, P = 0.004). Likewise, CYP1A2 activity was significantly reduced in male WD compared to CD animals (P = 0.020) but this same reduction was not observed in females. Diet, but not birthweight, significantly altered hepatic CYP activity in both sexes, and the effect of diet appeared to be greater in males. These findings may have clinical implications for the management of NAFLD and associated co-morbidities between the sexes.
Publisher: American Physiological Society
Date: 03-2020
DOI: 10.1152/PHYSIOLGENOMICS.00092.2019
Abstract: There are critical molecular mechanisms that can be activated to induce myocardial repair, and in humans this is most efficient during fetal development. The timing of heart development in relation to birth and the size/electrophysiology of the heart are similar in humans and sheep, providing a model to investigate the repair capacity of the mammalian heart and how this can be applied to adult heart repair. Myocardial infarction was induced by ligation of the left anterior descending coronary artery in fetal (105 days gestation when cardiomyocytes are proliferative) and adolescent sheep (6 mo of age when all cardiomyocytes have switched to an adult phenotype). An ovine gene microarray was used to compare gene expression in sham and infarcted (remote, border and infarct areas) cardiac tissue from fetal and adolescent hearts. The gene response to myocardial infarction was less pronounced in fetal compared with adolescent sheep hearts and there were unique gene responses at each age. There were also region-specific changes in gene expression between each age, in the infarct tissue, tissue bordering the infarct, and tissue remote from the infarction. In total, there were 880 genes that responded to MI uniquely in the adolescent s les compared with 170 genes in the fetal response, as well as 742 overlap genes that showed concordant direction of change responses to infarction at both ages. In response to myocardial infarction, there were specific changes in genes within pathways of mitochondrial oxidation, muscle contraction, and hematopoietic cell lineages, suggesting that the control of energy utilization and immune function are critical for effective heart repair. The more restricted gene response in the fetus may be an important factor in its enhanced capacity for cardiac repair.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Wiley
Date: 23-12-2020
Abstract: The primary metabolic pathway required to produce ATP differs as a result of tissue type, developmental stage and substrate availability. We utilized molecular and histological techniques to define the metabolic status in foetal and adult, adipose and skeletal muscle tissues. Redox ratios of these tissues were also determined optically by two-photon microscopy. Adult perirenal adipose tissue had a higher optical redox ratio than fetal perirenal adipose tissue, which aligned with glycolysis being used for ATP production whereas adult skeletal muscle had a lower optical redox ratio than fetal skeletal muscle, which aligned with oxygen demanding oxidative phosphorylation activity being utilized for ATP production. We have compared traditional molecular and microscopy techniques of metabolic tissue characterization with optical redox ratios to provide a more comprehensive report on the dynamics of tissue metabolism.
Publisher: Wiley
Date: 31-10-2023
DOI: 10.1113/JP285097
Publisher: Elsevier BV
Date: 2017
Publisher: Elsevier BV
Date: 02-2021
Publisher: Wiley
Date: 23-08-2020
DOI: 10.1113/JP280019
Publisher: Springer Science and Business Media LLC
Date: 21-01-2019
Publisher: Cambridge University Press (CUP)
Date: 13-11-2021
DOI: 10.1017/S2040174420001014
Abstract: Nutrition during the periconceptional period influences postnatal cardiovascular health. We determined whether in vitro embryo culture and transfer, which are manipulations of the nutritional environment during the periconceptional period, dysregulate postnatal blood pressure and blood pressure regulatory mechanisms. Embryos were either transferred to an intermediate recipient ewe (ET) or cultured in vitro in the absence (IVC) or presence of human serum (IVCHS) and a methyl donor (IVCHS+M) for 6 days. Basal blood pressure was recorded at 19–20 weeks after birth. Mean arterial pressure (MAP) and heart rate (HR) were measured before and after varying doses of phenylephrine (PE). mRNA expression of signaling molecules involved in blood pressure regulation was measured in the renal artery. Basal MAP did not differ between groups. Baroreflex sensitivity, set point, and upper plateau were also maintained in all groups after PE stimulation. Adrenergic receptors alpha-1A (αAR1A), alpha-1B (αAR1B), and angiotensin II receptor type 1 (AT1R) mRNA expression were not different from controls in the renal artery. These results suggest there is no programmed effect of ET or IVC on basal blood pressure or the baroreflex control mechanisms in adolescence, but future studies are required to determine the impact of ET and IVC on these mechanisms later in the life course when developmental programming effects may be unmasked by age.
Publisher: Wiley
Date: 10-01-2021
Publisher: Wiley
Date: 13-03-2023
DOI: 10.1113/JP284137
Abstract: Mammalian cardiomyocytes undergo major maturational changes in preparation for birth and postnatal life. Immature cardiomyocytes contribute to cardiac growth via proliferation and thus the heart has the capacity to regenerate. To prepare for postnatal life, structural and metabolic changes associated with increased cardiac output and function must occur. This includes exit from the cell cycle, hypertrophic growth, mitochondrial maturation and sarcomeric protein isoform switching. However, these changes come at a price: the loss of cardiac regenerative capacity such that damage to the heart in postnatal life is permanent. This is a significant barrier to the development of new treatments for cardiac repair and contributes to heart failure. The transitional period of cardiomyocyte growth is a complex and multifaceted event. In this review, we focus on studies that have investigated this critical transition period as well as novel factors that may regulate and drive this process. We also discuss the potential use of new biomarkers for the detection of myocardial infarction and, in the broader sense, cardiovascular disease. image
Publisher: Wiley
Date: 27-12-2020
DOI: 10.1113/JP280693
Publisher: Cambridge University Press (CUP)
Date: 21-09-2020
DOI: 10.1017/S2040174420000884
Abstract: Advanced imaging techniques are enhancing research capacity focussed on the developmental origins of adult health and disease (DOHaD) hypothesis, and consequently increasing awareness of future health risks across various subareas of DOHaD research themes. Understanding how these advanced imaging techniques in animal models and human population studies can be both additively and synergistically used alongside traditional techniques in DOHaD-focussed laboratories is therefore of great interest. Global experts in advanced imaging techniques congregated at the advanced imaging workshop at the 2019 DOHaD World Congress in Melbourne, Australia. This review summarizes the presentations of new imaging modalities and novel applications to DOHaD research and discussions had by DOHaD researchers that are currently utilizing advanced imaging techniques including MRI, hyperpolarized MRI, ultrasound, and synchrotron-based techniques to aid their DOHaD research focus.
Publisher: Wiley
Date: 28-08-2022
Abstract: Magnetic resonance imaging (MRI) assessment of fetal blood oxygen saturation (SO 2 ) can transform the clinical management of high‐risk pregnancies affected by fetal growth restriction (FGR). Here, a novel MRI method assesses the feasibility of identifying normally grown and FGR fetuses in sheep and is then applied to humans. MRI scans are performed in pregnant ewes at 110 and 140 days (term = 150d) gestation and in pregnant women at 28 +3 ± 2 +5 weeks to measure feto‐placental SO 2 . Birth weight is collected and, in sheep, fetal blood SO 2 is measured with a blood gas analyzer (BGA). Fetal arterial SO 2 measured by BGA predicts fetal birth weight in sheep and distinguishes between fetuses that are normally grown, small for gestational age, and FGR. MRI feto‐placental SO 2 in late gestation is related to fetal blood SO 2 measured by BGA and body weight. In sheep, MRI feto‐placental SO 2 in mid‐gestation is related to fetal SO 2 later in gestation. MRI feto‐placental SO 2 distinguishes between normally grown and FGR fetuses, as well as distinguishing FGR fetuses with and without normal Doppler in humans. Thus, a multi‐compartment placental MRI model detects low placental SO 2 and distinguishes between small hypoxemic fetuses and normally grown fetuses.
Publisher: Wiley
Date: 26-08-2021
DOI: 10.14814/PHY2.14999
Publisher: Elsevier BV
Date: 2023
Publisher: Wiley
Date: 06-2023
DOI: 10.14814/PHY2.15749
Abstract: Babies born growth restricted are at an increased risk of both poor short‐and long‐term outcomes. Current interventions to improve fetal growth are ineffective and do not lower the lifetime risk of poor health status. Maternal resveratrol (RSV) treatment increases uterine artery blood flow, fetal oxygenation, and fetal weight. However, studies suggest that diets high in polyphenols such as RSV may impair fetal hemodynamics. We aimed to characterize the effect of RSV on fetal hemodynamics to further assess its safety as an intervention strategy. Pregnant ewes underwent magnetic resonance imaging (MRI) scans to measure blood flow and oxygenation within the fetal circulation using phase contrast‐MRI and T 2 oximetry. Blood flow and oxygenation measures were performed in a basal state and then repeated while the fetus was exposed to RSV. Fetal blood pressure and heart rate were not different between states. RSV did not impact fetal oxygen delivery (DO 2 ) or consumption (VO 2 ). Blood flow and oxygen delivery throughout the major vessels of the fetal circulation were not different between basal and RSV states. As such, acute exposure of the fetus to RSV does not directly impact fetal hemodynamics. This strengthens the rationale for the use of RSV as an intervention strategy against fetal growth restriction.
Publisher: SPIE
Date: 02-01-2018
DOI: 10.1117/12.2283352
Publisher: Elsevier BV
Date: 09-2023
Publisher: Frontiers Media SA
Date: 22-07-2022
DOI: 10.3389/FPHYS.2022.925772
Abstract: The recent demonstration of normal development of preterm sheep in an artificial extrauterine environment has renewed interest in artificial placenta (AP) systems as a potential treatment strategy for extremely preterm human infants. However, the feasibility of translating this technology to the human preterm infant remains unknown. Here we report the support of 13 preterm fetal pigs delivered at 102 ± 4 days (d) gestation, weighing 616 ± 139 g with a circuit consisting of an oxygenator and a centrifugal pump, comparing these results with our previously reported pumpless circuit ( n = 12 98 ± 4 days 743 ± 350 g). The umbilical vessels were cannulated, and fetuses were supported for 46.4 ± 46.8 h using the pumped AP versus 11 ± 13 h on the pumpless AP circuit. Upon initiation of AP support on the pumped system, we observed supraphysiologic circuit flows, tachycardia, and hypertension, while animals maintained on a pumpless AP circuit exhibited subphysiologic flows. On the pumped AP circuit, there was a progressive decline in umbilical vein (UV) flow and oxygen delivery. We conclude that the addition of a centrifugal pump to the AP circuit improves survival of preterm pigs by augmenting UV flow through the reduction of right ventricular afterload. However, we continued to observe the development of heart failure within a matter of days.
Publisher: Wiley
Date: 04-2021
DOI: 10.1113/JP280803
Abstract: The margin of human viability has extended to the extremes of gestational age ( weeks) when the lungs are immature and ventilator‐induced lung injury is common. Artificial placenta technology aims to extend gestation ex utero in order to allow the lungs additional time to develop prior to entering an air‐breathing environment. We compared the haemodynamics and cerebral oxygenation of piglets in the immediate period post‐oxygenator (OXY) transition against both paired in utero measures and uniquely against piglets transitioned onto mechanical ventilation (VENT). Post‐transition, OXY piglets became hypotensive with reduced carotid blood flow in comparison with both paired in utero measures and VENT piglets. The addition of a pump to the oxygenator circuit may be required to ensure haemodynamic stability in the immediate post‐transition period. Gestational age at birth is a major predictor of wellbeing the lower the gestational age, the greater the risk of mortality and morbidity. At the margins of human viability ( weeks gestation) immature lungs combined with the need for early ventilatory support means lung injury and respiratory morbidity is common. The abrupt haemodynamic changes consequent on birth may also contribute to preterm‐associated brain injury, including intraventricular haemorrhage. Artificial placenta technology aims to support oxygenation, haemodynamic stability and ongoing fetal development ex utero until mature enough to safely transition to a true ex utero environment. We aimed to characterize the impact of birth transition onto either an oxygenator circuit or positive pressure ventilation on haemodynamic and cerebral oxygenation of the neonatal piglet. At 112 days gestation (term = 115 days), fetal pigs underwent instrumentation surgery and transitioned onto either an oxygenator (OXY, n = 5) or ventilatory support (VENT, n = 8). Blood pressure (BP), carotid blood flow and cerebral oxygenation in VENT piglets rose from in utero levels to be significantly higher than OXY piglets post‐transition. OXY piglet BP, carotid blood flow and carotid oxygen delivery (DO 2 ) decreased from in utero levels post‐transition however, cerebral regional oxygen saturation (rSO 2 ) was maintained at fetal‐like levels. OXY piglets became hypoxaemic and retained CO 2 . Whether OXY piglets are able to maintain cerebral rSO 2 under these conditions for a prolonged period is yet to be determined. Improvements to OXY piglet oxygenation may lie in maintaining piglet BP at in utero levels and enhancing oxygenator circuit flow.
Publisher: S. Karger AG
Date: 2022
DOI: 10.1159/000526972
Abstract: b i Introduction: /i /b Newborns exposed to sildenafil citrate (SC) in utero have increased rates of persistent pulmonary hypertension. The mechanism behind this has not yet been fully elucidated. We aimed to utilize a combination of clinically relevant MRI techniques to comprehensively characterize the haemodynamics of the fetal sheep whilst under the influence of SC. We hypothesized that these MRI techniques would detect SC-induced increases in pulmonary blood flow and oxygen delivery prior to birth. b i Methods: /i /b At 116–117 days gestational age (term, 150 days), pregnant Merino ewes ( i n /i = 9) underwent fetal catheterization surgery. MRI scans were performed during a basal state and then repeated during a constant umbilical vein infusion of SC to measure blood flow and oxygenation within the major vessels of the fetal circulation using phase-contrast-MRI and T sub /sub oximetry. b i Results: /i /b Right and left ventricular cardiac outputs were not different between states. Pulmonary blood flow increased during the SC state resulting in elevated pulmonary oxygen delivery. Right to left heart shunting through the foramen ovale was reduced without reducing cerebral oxygen delivery. b i Conclusion: /i /b SC induces alterations to pulmonary haemodynamics i in utero /i a characteristic that if maintained may underlie or act as a precursor towards the elevated rates of poor pulmonary outcomes after birth. These MRI techniques are the first to comprehensively characterize sildenafil’s direct impact on the pulmonary vasculature and its indirect detriment to the flow of oxygen-rich blood through the foramen ovale.
Publisher: Wiley
Date: 12-03-2022
DOI: 10.1113/JP282900
Publisher: Wiley
Date: 19-08-2022
DOI: 10.1113/JP283559
Publisher: Wiley
Date: 04-08-2020
DOI: 10.1113/JP280444
Publisher: Wiley
Date: 21-07-2022
DOI: 10.1113/JP283315
Publisher: Cambridge University Press (CUP)
Date: 07-01-2021
DOI: 10.1017/S204017442000135X
Abstract: Respiratory distress syndrome results from inadequate functional pulmonary surfactant and is a significant cause of mortality in preterm infants. Surfactant is essential for regulating alveolar interfacial surface tension, and its synthesis by Type II alveolar epithelial cells is stimulated by leptin produced by pulmonary lipofibroblasts upon activation by peroxisome proliferator-activated receptor γ (PPARγ). As it is unknown whether PPARγ stimulation or direct leptin administration can stimulate surfactant synthesis before birth, we examined the effect of continuous fetal administration of either the PPARγ agonist, rosiglitazone (RGZ Study 1) or leptin (Study 2) on surfactant protein maturation in the late gestation fetal sheep lung. We measured mRNA expression of genes involved in surfactant maturation and showed that RGZ treatment reduced mRNA expression of LPCAT1 (surfactant phospholipid synthesis) and LAMP3 (marker for lamellar bodies), but did not alter mRNA expression of PPARγ , surfactant proteins ( SFTP-A, -B, -C , and -D ), PCYT1A (surfactant phospholipid synthesis), ABCA3 (phospholipid transportation), or the PPARγ target genes SPHK-1 and PAI-1 . Leptin infusion significantly increased the expression of PPARγ and IGF2 and decreased the expression of SFTP-B . However, mRNA expression of the majority of genes involved in surfactant synthesis was not affected. These results suggest a potential decreased capacity for surfactant phospholipid and protein production in the fetal lung after RGZ and leptin administration, respectively. Therefore, targeting PPARγ may not be a feasible mechanistic approach to promote lung maturation.
Publisher: Cambridge University Press (CUP)
Date: 25-01-2021
DOI: 10.1017/S2040174420001403
Abstract: Medical care is predicated on ‘do no harm’, yet the urgency to find drugs and vaccines to treat or prevent COVID-19 has led to an extraordinary effort to develop and test new therapies. Whilst this is an essential cornerstone of a united global response to the COVID-19 pandemic, the absolute requirements for meticulous efficacy and safety data remain. This is especially pertinent to the needs of pregnant women a group traditionally poorly represented in drug trials, yet a group at heightened risk of unintended adverse materno-fetal consequences due to the unique physiology of pregnancy and the life course implications of fetal or neonatal drug exposure. However, due to the complexities of drug trial participation when pregnant (be they vaccines or therapeutics for acute disease), many clinical drug trials will exclude them. Clinicians must determine the best course of drug treatment with a dearth of evidence from either clinical or preclinical studies, where at least in the short term they may be more focused on the outcome of the mother than of her offspring.
Publisher: Springer Science and Business Media LLC
Date: 13-09-2017
Publisher: Oxford University Press (OUP)
Date: 25-06-2019
DOI: 10.1093/AF/VFZ019
Publisher: Wiley
Date: 03-2021
DOI: 10.14814/PHY2.14742
Publisher: Wiley
Date: 22-09-2021
DOI: 10.1113/JP281292
Abstract: Restriction of fetal substrate supply has an adverse effect on surfactant maturation in the lung and thus affects the transition from in utero placental oxygenation to pulmonary ventilation ex utero . The effects on surfactant maturation are mediated by alteration in mechanisms regulating surfactant protein and phospholipid synthesis. This study aimed to determine the effects of late gestation maternal undernutrition (LGUN) and LGUN plus fetal glucose infusion (LGUN+G) compared to Control on surfactant maturation and lung development, and the relationship with pulmonary blood flow and oxygen delivery ( ) measured by magnetic resonance imaging (MRI) with molecules that regulate lung development. LGUN from 115 to 140 days’ gestation significantly decreased fetal body weight, which was normalized by glucose infusion. LGUN and LGUN+G resulted in decreased fetal plasma glucose concentration, with no change in fetal arterial compared to control. There was no effect of LGUN and LGUN+G on the mRNA expression of surfactant proteins ( SFTP ) and genes regulating surfactant maturation in the fetal lung. However, blood flow in the main pulmonary artery was significantly increased in LGUN, despite no change in blood flow in the left or right pulmonary artery and to the fetal lung. There was a negative relationship between left pulmonary artery flow and to the left lung with SFTP‐B and GLUT1 mRNA expression, while their relationship with VEGFR2 was positive. These results suggest that increased pulmonary blood flow measured by MRI may have an adverse effect on surfactant maturation during fetal lung development. image Maternal undernutrition during gestation alters fetal lung development by impacting surfactant maturation. However, the direction of change remains controversial. We examined the effects of maternal late gestation maternal undernutrition (LGUN) on maternal and fetal outcomes, signalling pathways involved in fetal lung development, pulmonary haemodynamics and oxygen delivery in sheep using a combination of molecular and magnetic resonance imaging (MRI) techniques. LGUN decreased fetal plasma glucose concentration without affecting arterial . Surfactant maturation was not affected however, main pulmonary artery blood flow was significantly increased in the LGUN fetuses. This is the first study to explore the relationship between in utero MRI measures of pulmonary haemodynamics and lung development. Across all treatment groups, left pulmonary artery blood flow and oxygen delivery were negatively correlated with surfactant protein B mRNA and protein expression in late gestation.
Publisher: Wiley
Date: 28-11-2018
Abstract: The heart has high metabolic demand to maintain function. The primary source of energy supply to support correct contractile muscle function differs between a fetus and an adult. In fetal life, ATP is primarily generated by glycolysis and lactate oxidation, whereas following birth, there is a shift towards a reliance on mitochondrial metabolism and fatty acid oxidation. This change in metabolic status is an adaptation to different fuel availability, oxygenation and growth patterns. In this study, we have employed 2-photon excitation fluorescence microscopy to define the relationship between two critical metabolic cofactors nicotinamide adenine dinucleotide(P)H and flavin adenine dinucleotide, effectively utilizing a redox ratio to differentiate between the metabolic status in fetal (proliferative) and adult (quiescent/hypertrophic) hearts. Two-photon imaging was also used to visually confirm the known increase in collagen deposition in the adult heart. The changes observed were consistent with a hypertrophic growth profile and greater availability of fatty acids in the adult heart, compared to the proliferative fetal heart. Two-photon excitation fluorescence microscopy is therefore a convenient imaging technology that enables the monitoring of striated muscle architecture and the metabolic status of heart tissue. This imaging technology can potentially be employed to visualize cardiac and other muscle pathologies.
Publisher: Elsevier BV
Date: 2015
Publisher: Wiley
Date: 20-05-2018
DOI: 10.1113/JP275806
Publisher: Springer Science and Business Media LLC
Date: 29-05-2018
DOI: 10.1038/S41598-018-24672-W
Abstract: Mitochondrial morphology is important for the function of this critical organelle and, accordingly, altered mitochondrial structure is exhibited in many pathologies. Imaging of mitochondria can therefore provide important information about disease presence and progression. However, mitochondrial imaging is currently limited by the availability of agents that have the capacity to image mitochondrial morphology in both live and fixed s les. This can be particularly problematic in clinical studies or large, multi-centre cohort studies, where tissue archiving by fixation is often more practical. We previously reported the synthesis of an iridium coordination complex [Ir( ppy ) 2 ( MeTzPyPhCN )] + where ppy is a cyclometalated 2-phenylpyridine and TzPyPhCN is the 5-(5-(4-cyanophen-1-yl)pyrid-2-yl)tetrazolate ligand and showed that this complex (herein referred to as IraZolve-Mito) has a high specificity for mitochondria in live cells. Here we demonstrate that IraZolve-Mito can also effectively stain mitochondria in both live and fixed tissue s les. The staining protocol proposed is versatile, providing a universal procedure for cell biologists and pathologists to visualise mitochondria.
Publisher: Elsevier BV
Date: 11-2021
Publisher: Wiley
Date: 02-06-2020
DOI: 10.1113/JP279054
Publisher: Wiley
Date: 16-09-2021
Abstract: Intrauterine growth restriction (IUGR) is a result of limited substrate supply to the developing fetus in utero, and can be caused by either placental, genetic or environmental factors. Babies born IUGR can have poor long‐term health outcomes, including being at higher risk of developing cardiovascular disease. Limited substrate supply in the IUGR fetus not only changes the structure of the heart but may also affect metabolism and function of the developing heart. We have utilised two imaging modalities, two‐photon microscopy and phase‐contrast MRI (PC‐MRI), to assess alterations in cardiac metabolism and function using a sheep model of IUGR. Two‐photon imaging revealed that the left ventricle of IUGR fetuses (at 140–141 d GA) had a reduced optical redox ratio, suggesting a reliance on glycolysis for ATP production. Concurrently, the use of PC‐MRI to measure foetal left ventricular cardiac output (LVCO) revealed a positive correlation between LVCO and redox ratio in IUGR, but not control fetuses. These data suggest that altered heart metabolism in IUGR fetuses is indicative of reduced cardiac output, which may contribute to poor cardiac outcomes in adulthood.
Publisher: Cambridge University Press (CUP)
Date: 26-07-2022
DOI: 10.1017/S204017442100043X
Abstract: There is a strong relationship between low birth weight (LBW) and an increased risk of developing cardiovascular disease (CVD). In postnatal life, LBW offspring are becoming more commonly exposed to the additional independent CVD risk factors, such as an obesogenic diet. However, how an already detrimentally programmed LBW myocardium responds to a secondary insult, such as an obesogenic diet (western diet WD), during postnatal life is ill defined. Herein, we aimed to determine in a pre-clinical guinea pig model of CVD, both the independent and interactive effects of LBW and a postnatal WD on the molecular pathways that regulate cardiac growth and metabolism. Uterine artery ablation was used to induce placental insufficiency (PI) in pregnant guinea pigs to generate LBW offspring. Normal birth weight (NBW) and LBW offspring were weaned onto either a Control diet or WD. At ˜145 days after birth (young adulthood), male and female offspring were humanely killed, the heart weighed and left ventricle tissue collected. The mRNA expression of signalling molecules involved in a pathological hypertrophic and fibrotic response was increased in the myocardium of LBW male, but not female offspring, fed a WD as was the mRNA expression of transcription factors involved in fatty acid oxidation. The mRNA expression of glucose transporters was downregulated by LBW and WD in male, but not female hearts. This study has highlighted a sexually dimorphic cardiac pathological hypertrophic and fibrotic response to the secondary insult of postnatal WD consumption in LBW offspring.
Publisher: Frontiers Media SA
Date: 23-05-2023
DOI: 10.3389/FCVM.2023.1206138
Abstract: Over recent decades, a variety of advanced imaging techniques for assessing cardiovascular physiology and cardiac function in adults and children have been applied in the fetus. In many cases, technical development has been required to allow feasibility in the fetus, while an appreciation of the unique physiology of the fetal circulation is required for proper interpretation of the findings. This review will focus on recent advances in fetal echocardiography and cardiovascular magnetic resonance (CMR), providing ex les of their application in research and clinical settings. We will also consider future directions for these technologies, including their ongoing technical development and potential clinical value.
Publisher: Wiley
Date: 10-2019
DOI: 10.1113/JP278110
Publisher: Cambridge University Press (CUP)
Date: 28-01-2021
Publisher: Wiley
Date: 29-03-2021
DOI: 10.1113/JP281002
Abstract: Human placental function is evaluated using non‐invasive Doppler ultrasound of umbilical and uterine artery pulsatility indices as measures of resistance in placental vascular beds, while measurement of placental oxygen consumption ( ) is only possible during Caesarean delivery. This study shows the feasibility of using magnetic resonance imaging (MRI) in utero to measure blood flow and oxygen content in uterine and umbilical vessels to calculate oxygen delivery to and by the gravid uterus, uteroplacenta and fetus. Normal late gestational human uteroplacental by MRI was ∼4 ml min −1 kg −1 fetal weight, which was similar to our MRI measurements in sheep and to those previously measured using invasive techniques. Our MRI approach can quantify uteroplacental , which involves the quantification of maternal‐ and fetal‐placental blood flows, fetal oxygen delivery and , and the oxygen gradient between uterine‐ and umbilical‐venous blood, providing a comprehensive assessment of placental function with clinical potential. It has not been feasible to perform routine clinical measurement of human placental oxygen consumption ( ) and in vitro studies do not reflect true metabolism in utero . Here we propose an MRI method to non‐invasively quantify in utero placental and fetal oxygen delivery ( ) and in healthy humans and sheep. Women ( n = 20) and Merino sheep ( n = 10 23 sets of measurements) with singleton pregnancies underwent an MRI in late gestation (36 ± 2 weeks and 128 ± 9 days, respectively mean ± SD). Blood flow (phase‐contrast) and oxygen content (T1 and T2 relaxometry) were measured in the major uterine‐ and umbilical‐placental vessels, allowing calculation of uteroplacental and fetal and . Maternal (ml min −1 kg −1 fetus) to the gravid uterus was similar in humans and sheep (human = 54 ± 15, sheep = 53 ± 21, P = 0.854), while fetal (human = 25 ± 4, sheep = 22 ± 5, P = 0.049) was slightly lower in sheep. Uteroplacental and fetal (ml min −1 kg −1 fetus uteroplacental: human = 4.1 ± 1.5, sheep = 3.5 ± 1.9, P = 0.281 fetus: human = 6.8 ± 1.3, sheep = 7.2 ± 1.7, P = 0.426) were similar between species. Late gestational uteroplacental:fetal ratio did not change with age (human, P = 0.256 sheep, P = 0.121). Human umbilical blood flow (ml min −1 kg −1 fetus) decreased with advancing age ( P = 0.008), while fetal was preserved through an increase in oxygen extraction ( P = 0.046). By contrast, sheep fetal was preserved through stable umbilical flow (ml min −1 kg −1 P = 0.443) and oxygen extraction ( P = 0.582). MRI derived measurements of uteroplacental and fetal between humans and sheep were similar and in keeping with prior data obtained using invasive techniques. Taken together, these data confirm the reliability of our approach, which offers a novel clinical ‘placental function test’.
Publisher: American Physiological Society
Date: 12-2019
DOI: 10.1152/AJPREGU.00273.2017
Abstract: Phase-contrast cine MRI (PC-MRI) is the gold-standard noninvasive technique for measuring vessel blood flow and has previously been applied in the human fetal circulation. We aimed to assess the feasibility of using PC-MRI to define the distribution of the fetal circulation in sheep. Fetuses were catheterized at 119–120 days of gestation (term, 150 days) and underwent MRI at ∼123 days of gestation under isoflurane anesthesia, ventilated at a [Formula: see text] of 1.0. PC-MRI was performed using a fetal arterial blood pressure catheter signal for cardiac triggering. Blood flows were measured in the major fetal vessels, including the main pulmonary artery, ascending and descending aorta, superior vena cava, ductus arteriosus, left and right pulmonary arteries, umbilical vein, ductus venosus, and common carotid artery and were indexed to estimated fetal weight. The combined ventricular output, pulmonary blood flow, and flow across the foramen ovale were calculated from vessel flows. Intraobserver and interobserver agreement and reproducibility was assessed. Blood flow measurements were successfully obtained in 61 out of 74 vessels (82.4%) interrogated in 9 fetuses. There was good intraobserver [ R = 0.998, P 0.0001 intraclass correlation (ICC) = 0.997] and interobserver agreement ( R = 0.996, P 0.0001 ICC = 0.996). Repeated MRI measurements showed good reproducibility ( R = 0.989, P = 0.0002 ICC = 0.990). We conclude that PC-MRI using fetal catheters for gating triggers is feasible in the major vessels of late gestation fetal sheep. This approach may provide a useful new tool for assessing the circulatory characteristics of fetal sheep models of human disease, including fetal growth restriction and congenital heart disease.
Publisher: Elsevier BV
Date: 08-2016
Publisher: Frontiers Media SA
Date: 05-03-2019
Publisher: Frontiers Media SA
Date: 10-06-2020
Publisher: Wiley
Date: 16-03-2021
DOI: 10.1113/EP089237
Publisher: Wiley
Date: 19-07-2019
DOI: 10.1113/JP277629
Publisher: Wiley
Date: 29-05-2020
DOI: 10.1113/JP279725
No related grants have been discovered for Jack Darby.