Timothy Moss - Academia.edu (original) (raw)

Papers by Timothy Moss

Research paper thumbnail of Improving pregnancy outcomes in humans through studies in sheep

American journal of physiology. Regulatory, integrative and comparative physiology, Jan 16, 2018

Experimental studies that are relevant to human pregnancy rely on the selection of appropriate an... more 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 into 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.

Research paper thumbnail of Delivery of positive end-expiratory pressure to preterm lambs using common resuscitation devices

Archives of disease in childhood. Fetal and neonatal edition, Jan 2, 2018

In neonatal resuscitation, a ventilation device providing positive end-expiratory pressure (PEEP)... more In neonatal resuscitation, a ventilation device providing positive end-expiratory pressure (PEEP) is recommended. There is limited information about PEEP delivery in vivo, using different models of self-inflating bag (SIB) at different inflation rates and PEEP settings. We compared PEEP delivery to intubated preterm lambs using four commonly available models of paired SIBs and PEEP valves, with a T-piece, with gas flow of 8 L/min. Peak inspiratory pressure inflations of 30 cmHO, combined with set PEEP of 5, 7 and 10 cmHO, were delivered at rates of 20, 40 and 60/min. These combinations were repeated without gas flow. We measured mean PEEP, maximum and minimum PEEP, and its difference (PEEP reduction). A total of 3288 inflations were analysed. The mean PEEP delivered by all SIBs was lower than set PEEP (P<0.001), although some differences were <0.5 cmHO. In 55% of combinations, the presence of gas flow resulted in increased PEEP delivery (range difference 0.3-2 cmHO). The mean ...

Research paper thumbnail of Effect of Human Amnion Epithelial Cells on the Acute Inflammatory Response in Fetal Sheep

Frontiers in physiology, 2017

Intra-amniotic (IA) lipopolysaccharide (LPS) injection in sheep induces inflammation in the fetus... more Intra-amniotic (IA) lipopolysaccharide (LPS) injection in sheep induces inflammation in the fetus. Human amnion epithelial cells (hAECs) moderate the effect of IA LPS on fetal development, but their influence on the acute inflammatory response to IA LPS is unknown. We aimed to determine the effects of hAECs on the acute fetal inflammatory response to IA LPS. After surgical instrumentation at 116 days' gestation (d) ewes were randomized to 1 of 4 groups at 123 d: IA LPS (10 mg) and intravenous (IV) saline (n = 8), IA LPS and IV hAECs (n = 6), IA saline and IV saline (n = 5) or IA saline and IV hAECs (n = 5). IV injections were administered immediately after IA injections. Serial fetal blood samples were collected. At 125 d, placental, fetal lung and liver samples were collected. IA LPS increased inflammatory cell recruitment in the placenta and lungs, increased IL-1β and IL-8 mRNA levels in the lungs and increased serum amyloid A3 (SAA3) and C-reactive protein (CRP) mRNA levels i...

Research paper thumbnail of Exacerbation of Ventilation-Induced Lung Injury and Inflammation in Preterm Lambs by High-Dose Nanoparticles

Scientific reports, Jan 31, 2017

Mechanical ventilation of preterm neonates causes lung inflammation and injury, with potential li... more Mechanical ventilation of preterm neonates causes lung inflammation and injury, with potential life-long consequences. Inert 50-nm polystyrene nanoparticles (PS50G) reduce allergic inflammation in the lungs of adult mice. We aimed to confirm the anti-inflammatory effects of PS50G in a sheep asthma model, and investigate the effects of prophylactic administration of PS50G on ventilation-induced lung injury (VILI) in preterm lambs. We assessed lung inflammatory cell infiltration, with and without PS50G, after airway allergen challenge in ewes sensitised to house dust mite. Preterm lambs (0.83 gestation) were delivered by caesarean section for immediate tissue collection (n = 5) or ventilation either with (n = 6) or without (n = 5) prophylactic intra-tracheal administration of PS50G nanoparticles (3% in 2 ml). Ventilation was continued for a total of 2 h before tissue collection for histological and biomolecular assessment of lung injury and inflammation. In ewes with experimental asth...

Research paper thumbnail of Human amnion epithelial cells modulate the inflammatory response to ventilation in preterm lambs

PloS one, 2017

Ventilation of preterm neonates causes pulmonary inflammation that can contribute to lung injury,... more Ventilation of preterm neonates causes pulmonary inflammation that can contribute to lung injury, propagate systemically and result in long-term disease. Modulation of this initial response may reduce lung injury and its sequelae. We aimed to determine the effect of human amnion epithelial cells (hAECs) on immune activation and lung injury in preterm neonatal lambs. Preterm lambs received intratracheal hAECs (90x106) or vehicle, prior to 2 h of mechanical ventilation. Within 5 min of ventilation onset, lambs also received intravenous hAECs (90x106) or vehicle. Lung histology, bronchoalveolar lavage (BAL) cell phenotypes, and cytokine profiles were examined after 2 h of ventilation, and in unventilated controls. Histological indices of lung injury were higher than control, in vehicle-treated ventilated lambs but not in hAEC-treated ventilated lambs. Ventilation-induced pulmonary leukocyte recruitment was greater in hAEC-treated lambs than in vehicle-treated lambs. Lung IL-1β and IL-6...

Research paper thumbnail of Diffusion Tensor Imaging Colour Mapping Threshold for Identification of Ventilation-Induced Brain Injury after Intrauterine Inflammation in Preterm Lambs

Frontiers in pediatrics, 2017

The aim of this study is to examine whether advanced magnetic resonance imaging (MRI) techniques ... more The aim of this study is to examine whether advanced magnetic resonance imaging (MRI) techniques can detect early brain injury caused by intrauterine inflammation and inappropriate initial respiratory support in preterm lambs. Neuropathology caused by intrauterine inflammation is exacerbated by mechanical ventilation at birth and is detectable with advanced MRI techniques. Pregnant ewes received intra-amniotic lipopolysaccharide (LPS) 7 days prior to delivery at ~125 days of gestation (85% of gestation), whereupon lambs were delivered and randomised to receive an injurious (LPS + INJ, n = 6) or protective (LPS + PROT, n = 6) ventilation strategy. MRI of the brain was conducted 90 min after preterm delivery, using structural, diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (MRS) techniques. A colour map threshold technique was utilised to compare distributions of low diffusivity voxels in the brains of LPS-exposed lambs with those not exposed to LPS (PROT, n = 7 P...

Research paper thumbnail of The Effects of Dexamethasone Treatment in Early Gestation on Hypothalamic-Pituitary-Adrenal Responses and Gene Expression at 7 Months of Postnatal Age in Sheep

Reproductive Sciences, Nov 18, 2011

We determined the effects of prenatal dexamethasone administration in early gestation on developm... more We determined the effects of prenatal dexamethasone administration in early gestation on development of the hypothalamic-pituitary-adrenal (HPA) axis up to 7 months of postnatal age with measurements of hormone levels and gene expression. Plasma adrenocorticotropic hormone and cortisol levels after corticotropin-releasing hormone (CRH)/arginine vasopressin challenge were lower in treatment females than in control females and treatment males. Calculation of cortisol to adrenocorticotropic hormone ratios indicated however that the adrenals of treatment females were more responsive to adrenocorticotropic hormone than control females or treatment males. Effects of treatment and sex dependence at 7 months of age were observed in levels of hypothalamic CRH messenger RNA (mRNA), hypothalamic arginine vasopressin mRNA, pituitary proopiomelanocortin mRNA, pituitary prohormone convertase 1 and prohormone convertase 2, glucocorticoid receptor and mineralocorticoid receptor in the hypothalamus and hippocampus, adrenal adrenocorticotropic hormone receptor, steroidogenic acute regulatory, 3β hydroxysteroid dehydrogenase, and 11β hydroxysteroid dehydrogenase type 2 mRNA. The results indicate that exposure to glucocorticoids in early pregnancy produces persisting and sex-dependent effects on the hypothalamic-pituitary-adrenal axis at 7 months of age.

Research paper thumbnail of Antenatal corticosteroids: the good, the bad and the unknown

Current Opinion in Obstetrics Gynecology, 2002

The purpose of this review was to summarize recently published clinical and animal-based studies ... more The purpose of this review was to summarize recently published clinical and animal-based studies of antenatal corticosteroids, describe current recommendations for practice, and suggest priority areas for future research. A single course of antenatal corticosteroids is known to improve newborn lung function after preterm birth and to reduce the risk of newborn death. Current evidence from animal and clinical studies suggests that additional numbers of courses do not further improve lung function and are associated with risks of adverse consequences. These risks principally include restricted intrauterine growth, altered brain development, postnatal insulin resistance and changes to the hypothalamic-pituitary-adrenal axis. The research challenges in this field are now centred on uncovering the mechanisms by which cortisol is involved in programming the fetus for its future metabolic life, and discovering ways in which the effectiveness and safety of antenatal glucocorticoids can be enhanced.

Research paper thumbnail of Antenatal corticosteriod treatment

Research paper thumbnail of Expression of glucocorticoid receptor, mineralocorticoid receptor, and 11b-hydroxysteroid dehydrogenase 1 and 2 in the fetal and postnatal ovine hippocampus: ontogeny and effects of prenatal glucocorticoid exposure

Research paper thumbnail of Experimental intrauterine infection in sheep

Amer J Obstet Gynecol, 2005

Research paper thumbnail of Surfactant and Physiologic Responses of Preterm Lambs to Continuous Positive Airway Pressure

American Journal of Respiratory and Critical Care Medicine, Dec 20, 2012

Although continuous positive airway pressure (CPAP) is used frequently for preterm infants, the r... more Although continuous positive airway pressure (CPAP) is used frequently for preterm infants, the relationships between the amount of surfactant and lung physiologic and injury responses to CPAP are unknown. Therefore, saturated phosphatidylcholine (Sat PC) was measured to quantify the surfactant necessary for preterm lambs to breathe successfully on a CPAP of 5 cm H(2)O (CPAP 5). Five of 21 lambs delivered at 130-136 days gestation failed to keep PCO(2) below 100 mm Hg by 2 hours. The lambs that failed had less than 1.9 micromol/kg Sat PC in bronchoalveolar fluid (approximately 3% the pool size at term), less surfactant secretion, and less large aggregate surfactant. Physiologic responses of other 132-day preterm lambs after 2 or 6 hours of CPAP 5, 8 cm H(2)O CPAP (CPAP 8), or mechanical ventilation were then characterized. At 6 hours, oxygenation and lung gas volumes were higher with CPAP 8 relative to the other groups and VE was decreased with CPAP 8 relative to CPAP 5. Lung dry/wet ratios were greater for the CPAP groups than for the mechanical ventilation group. A small amount of endogenous Sat PC is required for preterm lambs to breathe successfully with CPAP. CPAP 8 improves early newborn respiratory transition relative to CPAP 5.

Research paper thumbnail of Long term amniotic fluid ureaplasma colonization with low dose Ureaplasma parvum serovar 3 induces severe, chronic chorioamnionitis

Research paper thumbnail of Pathogenicity of periodontal pathogens during pregnancy

American Journal of Obstetrics and Gynecology, 2005

Research paper thumbnail of Betamethasone effects on chorioamnionitis induced by intra-amniotic endotoxin in sheep

American Journal of Obstetrics and Gynecology, Nov 30, 2003

OBJECTIVE: Intra-amniotic administration of endotoxin in sheep is a model of subclinical chorioam... more OBJECTIVE: Intra-amniotic administration of endotoxin in sheep is a model of subclinical chorioamnionitis. Intrauterine inflammation alters lung development to improve postnatal lung function and may predispose the infant to lung and brain injury. We describe the effects of intra-amniotic endotoxin on cytokines and white cell responses in the membranes and amniotic fluid and investigate the hypothesis that betamethasone treatment suppresses these responses. STUDY DESIGN: Pregnant ewes were allocated at random to receive either intra-amniotic saline solution (control animals), maternal intramuscular betamethasone, intra-amniotic endotoxin by ultrasound guidance (10 mg Escherichia coli 055:B5), or a combination of the betamethasone and endotoxin treatments. Lambs were delivered abdominally at 110 to125 days of gestation at time points that ranged from 2 hours to 15 days after treatment. RESULTS: When compared with saline solution-injected control animals, the intra-amniotic injection of endotoxin increased white cell counts in amniotic fluid. Levels of interleukin-8, but not interleukin-6, were significantly increased in amniotic fluid from 5 hours to 15 days after intra-amniotic endotoxin injection, and interleukin-8 levels were not decreased by concurrent treatment with betamethasone. After endotoxin treatment, interleukin-1b and interleukin-8 messenger RNA were expressed in chorion, and interleukin-6 messenger RNA expression was localized to chorionic blood vessel epithelium. The half-life of endotoxin in the amniotic fluid was 1.7 days, and levels remained measurable 15 days after injection. CONCLUSION: These findings confirm that the fetus can survive within amniotic fluid that contains endotoxin, white cells, and cytokines for periods of weeks or more. Betamethasone treatment can suppress the initial inflammation in the amnion-chorion, but interleukin-8 levels and inflammatory cells in amniotic fluid were not suppressed 5 and 15 days after betamethasone treatment, presumably because of the slow clearance of bioactive endotoxin from the amniotic fluid.

Research paper thumbnail of The effect of oxygen content during an initial sustained inflation on heart rate in asphyxiated near-term lambs

Archives of disease in childhood. Fetal and neonatal edition, 2015

At birth, an initial sustained inflation (SI) uniformly aerates the lungs, increases arterial oxy... more At birth, an initial sustained inflation (SI) uniformly aerates the lungs, increases arterial oxygenation and rapidly improves circulatory recovery in asphyxiated newborns. We hypothesised that lung aeration, in the absence of an increase in arterial oxygenation, can increase heart rate (HR) in asphyxiated near-term lambs. Lambs were delivered and instrumented at 139±2 days of gestation. Asphyxia was induced by umbilical cord clamping and then delaying the onset of ventilation until mean carotid arterial pressures (CAPs) had decreased <20 mm Hg. Lambs then received a single 30-s SI using nitrogen (N2; n=6), 5% oxygen (O2; n=6), 21% O2 (n=6) or 100% O2 (n=6) followed by ventilation in air for 30 min. HR, CAP and pulmonary blood flow (PBF) were continuously recorded. HR and PBF increased more quickly in lambs resuscitated with 100% and 21% O2 than with 5% O2 or N2. HR and PBF recovery in the 5% O2 group was delayed relative to all other oxygen SI groups. HR in 5%, 21% and 100% O2 g...

Research paper thumbnail of Modulation of fetal inflammatory response upon exposure to lipopolysaccharide by chorioamnion, lung, or gut in sheep

American Journal of Obstetrics and Gynecology, 2010

Research paper thumbnail of Effects of chronic intra-amniotic Ureaplasma parvum (serovar 3 and 6) colonization in the ovine fetus

School of Biomedical Sciences Faculty of Health Institute of Health and Biomedical Innovation, 2008

Research paper thumbnail of Fetal HPA activation, preterm birth and postnatal programming

Placental—Brain Interactions, 2000

Research paper thumbnail of Minimal lung and systemic responses to TNF-α in preterm sheep

American Journal of Physiology Lung Cellular and Molecular Physiology, Jul 1, 2003

Research paper thumbnail of Improving pregnancy outcomes in humans through studies in sheep

American journal of physiology. Regulatory, integrative and comparative physiology, Jan 16, 2018

Experimental studies that are relevant to human pregnancy rely on the selection of appropriate an... more 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 into 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.

Research paper thumbnail of Delivery of positive end-expiratory pressure to preterm lambs using common resuscitation devices

Archives of disease in childhood. Fetal and neonatal edition, Jan 2, 2018

In neonatal resuscitation, a ventilation device providing positive end-expiratory pressure (PEEP)... more In neonatal resuscitation, a ventilation device providing positive end-expiratory pressure (PEEP) is recommended. There is limited information about PEEP delivery in vivo, using different models of self-inflating bag (SIB) at different inflation rates and PEEP settings. We compared PEEP delivery to intubated preterm lambs using four commonly available models of paired SIBs and PEEP valves, with a T-piece, with gas flow of 8 L/min. Peak inspiratory pressure inflations of 30 cmHO, combined with set PEEP of 5, 7 and 10 cmHO, were delivered at rates of 20, 40 and 60/min. These combinations were repeated without gas flow. We measured mean PEEP, maximum and minimum PEEP, and its difference (PEEP reduction). A total of 3288 inflations were analysed. The mean PEEP delivered by all SIBs was lower than set PEEP (P<0.001), although some differences were <0.5 cmHO. In 55% of combinations, the presence of gas flow resulted in increased PEEP delivery (range difference 0.3-2 cmHO). The mean ...

Research paper thumbnail of Effect of Human Amnion Epithelial Cells on the Acute Inflammatory Response in Fetal Sheep

Frontiers in physiology, 2017

Intra-amniotic (IA) lipopolysaccharide (LPS) injection in sheep induces inflammation in the fetus... more Intra-amniotic (IA) lipopolysaccharide (LPS) injection in sheep induces inflammation in the fetus. Human amnion epithelial cells (hAECs) moderate the effect of IA LPS on fetal development, but their influence on the acute inflammatory response to IA LPS is unknown. We aimed to determine the effects of hAECs on the acute fetal inflammatory response to IA LPS. After surgical instrumentation at 116 days' gestation (d) ewes were randomized to 1 of 4 groups at 123 d: IA LPS (10 mg) and intravenous (IV) saline (n = 8), IA LPS and IV hAECs (n = 6), IA saline and IV saline (n = 5) or IA saline and IV hAECs (n = 5). IV injections were administered immediately after IA injections. Serial fetal blood samples were collected. At 125 d, placental, fetal lung and liver samples were collected. IA LPS increased inflammatory cell recruitment in the placenta and lungs, increased IL-1β and IL-8 mRNA levels in the lungs and increased serum amyloid A3 (SAA3) and C-reactive protein (CRP) mRNA levels i...

Research paper thumbnail of Exacerbation of Ventilation-Induced Lung Injury and Inflammation in Preterm Lambs by High-Dose Nanoparticles

Scientific reports, Jan 31, 2017

Mechanical ventilation of preterm neonates causes lung inflammation and injury, with potential li... more Mechanical ventilation of preterm neonates causes lung inflammation and injury, with potential life-long consequences. Inert 50-nm polystyrene nanoparticles (PS50G) reduce allergic inflammation in the lungs of adult mice. We aimed to confirm the anti-inflammatory effects of PS50G in a sheep asthma model, and investigate the effects of prophylactic administration of PS50G on ventilation-induced lung injury (VILI) in preterm lambs. We assessed lung inflammatory cell infiltration, with and without PS50G, after airway allergen challenge in ewes sensitised to house dust mite. Preterm lambs (0.83 gestation) were delivered by caesarean section for immediate tissue collection (n = 5) or ventilation either with (n = 6) or without (n = 5) prophylactic intra-tracheal administration of PS50G nanoparticles (3% in 2 ml). Ventilation was continued for a total of 2 h before tissue collection for histological and biomolecular assessment of lung injury and inflammation. In ewes with experimental asth...

Research paper thumbnail of Human amnion epithelial cells modulate the inflammatory response to ventilation in preterm lambs

PloS one, 2017

Ventilation of preterm neonates causes pulmonary inflammation that can contribute to lung injury,... more Ventilation of preterm neonates causes pulmonary inflammation that can contribute to lung injury, propagate systemically and result in long-term disease. Modulation of this initial response may reduce lung injury and its sequelae. We aimed to determine the effect of human amnion epithelial cells (hAECs) on immune activation and lung injury in preterm neonatal lambs. Preterm lambs received intratracheal hAECs (90x106) or vehicle, prior to 2 h of mechanical ventilation. Within 5 min of ventilation onset, lambs also received intravenous hAECs (90x106) or vehicle. Lung histology, bronchoalveolar lavage (BAL) cell phenotypes, and cytokine profiles were examined after 2 h of ventilation, and in unventilated controls. Histological indices of lung injury were higher than control, in vehicle-treated ventilated lambs but not in hAEC-treated ventilated lambs. Ventilation-induced pulmonary leukocyte recruitment was greater in hAEC-treated lambs than in vehicle-treated lambs. Lung IL-1β and IL-6...

Research paper thumbnail of Diffusion Tensor Imaging Colour Mapping Threshold for Identification of Ventilation-Induced Brain Injury after Intrauterine Inflammation in Preterm Lambs

Frontiers in pediatrics, 2017

The aim of this study is to examine whether advanced magnetic resonance imaging (MRI) techniques ... more The aim of this study is to examine whether advanced magnetic resonance imaging (MRI) techniques can detect early brain injury caused by intrauterine inflammation and inappropriate initial respiratory support in preterm lambs. Neuropathology caused by intrauterine inflammation is exacerbated by mechanical ventilation at birth and is detectable with advanced MRI techniques. Pregnant ewes received intra-amniotic lipopolysaccharide (LPS) 7 days prior to delivery at ~125 days of gestation (85% of gestation), whereupon lambs were delivered and randomised to receive an injurious (LPS + INJ, n = 6) or protective (LPS + PROT, n = 6) ventilation strategy. MRI of the brain was conducted 90 min after preterm delivery, using structural, diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (MRS) techniques. A colour map threshold technique was utilised to compare distributions of low diffusivity voxels in the brains of LPS-exposed lambs with those not exposed to LPS (PROT, n = 7 P...

Research paper thumbnail of The Effects of Dexamethasone Treatment in Early Gestation on Hypothalamic-Pituitary-Adrenal Responses and Gene Expression at 7 Months of Postnatal Age in Sheep

Reproductive Sciences, Nov 18, 2011

We determined the effects of prenatal dexamethasone administration in early gestation on developm... more We determined the effects of prenatal dexamethasone administration in early gestation on development of the hypothalamic-pituitary-adrenal (HPA) axis up to 7 months of postnatal age with measurements of hormone levels and gene expression. Plasma adrenocorticotropic hormone and cortisol levels after corticotropin-releasing hormone (CRH)/arginine vasopressin challenge were lower in treatment females than in control females and treatment males. Calculation of cortisol to adrenocorticotropic hormone ratios indicated however that the adrenals of treatment females were more responsive to adrenocorticotropic hormone than control females or treatment males. Effects of treatment and sex dependence at 7 months of age were observed in levels of hypothalamic CRH messenger RNA (mRNA), hypothalamic arginine vasopressin mRNA, pituitary proopiomelanocortin mRNA, pituitary prohormone convertase 1 and prohormone convertase 2, glucocorticoid receptor and mineralocorticoid receptor in the hypothalamus and hippocampus, adrenal adrenocorticotropic hormone receptor, steroidogenic acute regulatory, 3β hydroxysteroid dehydrogenase, and 11β hydroxysteroid dehydrogenase type 2 mRNA. The results indicate that exposure to glucocorticoids in early pregnancy produces persisting and sex-dependent effects on the hypothalamic-pituitary-adrenal axis at 7 months of age.

Research paper thumbnail of Antenatal corticosteroids: the good, the bad and the unknown

Current Opinion in Obstetrics Gynecology, 2002

The purpose of this review was to summarize recently published clinical and animal-based studies ... more The purpose of this review was to summarize recently published clinical and animal-based studies of antenatal corticosteroids, describe current recommendations for practice, and suggest priority areas for future research. A single course of antenatal corticosteroids is known to improve newborn lung function after preterm birth and to reduce the risk of newborn death. Current evidence from animal and clinical studies suggests that additional numbers of courses do not further improve lung function and are associated with risks of adverse consequences. These risks principally include restricted intrauterine growth, altered brain development, postnatal insulin resistance and changes to the hypothalamic-pituitary-adrenal axis. The research challenges in this field are now centred on uncovering the mechanisms by which cortisol is involved in programming the fetus for its future metabolic life, and discovering ways in which the effectiveness and safety of antenatal glucocorticoids can be enhanced.

Research paper thumbnail of Antenatal corticosteriod treatment

Research paper thumbnail of Expression of glucocorticoid receptor, mineralocorticoid receptor, and 11b-hydroxysteroid dehydrogenase 1 and 2 in the fetal and postnatal ovine hippocampus: ontogeny and effects of prenatal glucocorticoid exposure

Research paper thumbnail of Experimental intrauterine infection in sheep

Amer J Obstet Gynecol, 2005

Research paper thumbnail of Surfactant and Physiologic Responses of Preterm Lambs to Continuous Positive Airway Pressure

American Journal of Respiratory and Critical Care Medicine, Dec 20, 2012

Although continuous positive airway pressure (CPAP) is used frequently for preterm infants, the r... more Although continuous positive airway pressure (CPAP) is used frequently for preterm infants, the relationships between the amount of surfactant and lung physiologic and injury responses to CPAP are unknown. Therefore, saturated phosphatidylcholine (Sat PC) was measured to quantify the surfactant necessary for preterm lambs to breathe successfully on a CPAP of 5 cm H(2)O (CPAP 5). Five of 21 lambs delivered at 130-136 days gestation failed to keep PCO(2) below 100 mm Hg by 2 hours. The lambs that failed had less than 1.9 micromol/kg Sat PC in bronchoalveolar fluid (approximately 3% the pool size at term), less surfactant secretion, and less large aggregate surfactant. Physiologic responses of other 132-day preterm lambs after 2 or 6 hours of CPAP 5, 8 cm H(2)O CPAP (CPAP 8), or mechanical ventilation were then characterized. At 6 hours, oxygenation and lung gas volumes were higher with CPAP 8 relative to the other groups and VE was decreased with CPAP 8 relative to CPAP 5. Lung dry/wet ratios were greater for the CPAP groups than for the mechanical ventilation group. A small amount of endogenous Sat PC is required for preterm lambs to breathe successfully with CPAP. CPAP 8 improves early newborn respiratory transition relative to CPAP 5.

Research paper thumbnail of Long term amniotic fluid ureaplasma colonization with low dose Ureaplasma parvum serovar 3 induces severe, chronic chorioamnionitis

Research paper thumbnail of Pathogenicity of periodontal pathogens during pregnancy

American Journal of Obstetrics and Gynecology, 2005

Research paper thumbnail of Betamethasone effects on chorioamnionitis induced by intra-amniotic endotoxin in sheep

American Journal of Obstetrics and Gynecology, Nov 30, 2003

OBJECTIVE: Intra-amniotic administration of endotoxin in sheep is a model of subclinical chorioam... more OBJECTIVE: Intra-amniotic administration of endotoxin in sheep is a model of subclinical chorioamnionitis. Intrauterine inflammation alters lung development to improve postnatal lung function and may predispose the infant to lung and brain injury. We describe the effects of intra-amniotic endotoxin on cytokines and white cell responses in the membranes and amniotic fluid and investigate the hypothesis that betamethasone treatment suppresses these responses. STUDY DESIGN: Pregnant ewes were allocated at random to receive either intra-amniotic saline solution (control animals), maternal intramuscular betamethasone, intra-amniotic endotoxin by ultrasound guidance (10 mg Escherichia coli 055:B5), or a combination of the betamethasone and endotoxin treatments. Lambs were delivered abdominally at 110 to125 days of gestation at time points that ranged from 2 hours to 15 days after treatment. RESULTS: When compared with saline solution-injected control animals, the intra-amniotic injection of endotoxin increased white cell counts in amniotic fluid. Levels of interleukin-8, but not interleukin-6, were significantly increased in amniotic fluid from 5 hours to 15 days after intra-amniotic endotoxin injection, and interleukin-8 levels were not decreased by concurrent treatment with betamethasone. After endotoxin treatment, interleukin-1b and interleukin-8 messenger RNA were expressed in chorion, and interleukin-6 messenger RNA expression was localized to chorionic blood vessel epithelium. The half-life of endotoxin in the amniotic fluid was 1.7 days, and levels remained measurable 15 days after injection. CONCLUSION: These findings confirm that the fetus can survive within amniotic fluid that contains endotoxin, white cells, and cytokines for periods of weeks or more. Betamethasone treatment can suppress the initial inflammation in the amnion-chorion, but interleukin-8 levels and inflammatory cells in amniotic fluid were not suppressed 5 and 15 days after betamethasone treatment, presumably because of the slow clearance of bioactive endotoxin from the amniotic fluid.

Research paper thumbnail of The effect of oxygen content during an initial sustained inflation on heart rate in asphyxiated near-term lambs

Archives of disease in childhood. Fetal and neonatal edition, 2015

At birth, an initial sustained inflation (SI) uniformly aerates the lungs, increases arterial oxy... more At birth, an initial sustained inflation (SI) uniformly aerates the lungs, increases arterial oxygenation and rapidly improves circulatory recovery in asphyxiated newborns. We hypothesised that lung aeration, in the absence of an increase in arterial oxygenation, can increase heart rate (HR) in asphyxiated near-term lambs. Lambs were delivered and instrumented at 139±2 days of gestation. Asphyxia was induced by umbilical cord clamping and then delaying the onset of ventilation until mean carotid arterial pressures (CAPs) had decreased <20 mm Hg. Lambs then received a single 30-s SI using nitrogen (N2; n=6), 5% oxygen (O2; n=6), 21% O2 (n=6) or 100% O2 (n=6) followed by ventilation in air for 30 min. HR, CAP and pulmonary blood flow (PBF) were continuously recorded. HR and PBF increased more quickly in lambs resuscitated with 100% and 21% O2 than with 5% O2 or N2. HR and PBF recovery in the 5% O2 group was delayed relative to all other oxygen SI groups. HR in 5%, 21% and 100% O2 g...

Research paper thumbnail of Modulation of fetal inflammatory response upon exposure to lipopolysaccharide by chorioamnion, lung, or gut in sheep

American Journal of Obstetrics and Gynecology, 2010

Research paper thumbnail of Effects of chronic intra-amniotic Ureaplasma parvum (serovar 3 and 6) colonization in the ovine fetus

School of Biomedical Sciences Faculty of Health Institute of Health and Biomedical Innovation, 2008

Research paper thumbnail of Fetal HPA activation, preterm birth and postnatal programming

Placental—Brain Interactions, 2000

Research paper thumbnail of Minimal lung and systemic responses to TNF-α in preterm sheep

American Journal of Physiology Lung Cellular and Molecular Physiology, Jul 1, 2003