2024 |
Pavy CL, Shaw JC, Moloney RA, Palliser HK, Hirst JJ, 'Potential for a cerebellar role in moderate-late preterm associated behavioural disorders.', Front Pediatr, 12 1336137 (2024) [C1]
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Nova |
2023 |
Moloney RA, Pavy CL, Kahl RGS, Palliser HK, Hirst JJ, Shaw JC, 'Dual isolation of primary neurons and oligodendrocytes from guinea pig frontal cortex.', Front Cell Neurosci, 17 1298685 (2023) [C1]
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Nova |
2023 |
Crombie GK, Palliser HK, Shaw JC, Hanley BA, Moloney RA, Hirst JJ, 'Prenatal Stress Induces Translational Disruption Associated with Myelination Deficits.', Developmental neuroscience, 45 290-308 (2023) [C1]
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Nova |
2022 |
Crombie GK, Palliser HK, Shaw JC, Hodgson DM, Walker DW, Hirst JJ, 'Evaluating changes in GABAergic and glutamatergic pathways in early life following prenatal stress and postnatal neurosteroid supplementation', PSYCHONEUROENDOCRINOLOGY, 139 (2022) [C1]
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Nova |
2022 |
Shaw JC, Dyson RM, Palliser HK, Sixtus RP, Barnes H, Pavy CL, et al., 'Examining Neurosteroid-Analogue Therapy in the Preterm Neonate For Promoting Hippocampal Neurodevelopment', FRONTIERS IN PHYSIOLOGY, 13 (2022) [C1]
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Nova |
2022 |
Shaw JC, Dyson RM, Palliser HK, Crombie GK, Berry MJ, Hirst JJ, 'Adaptations in the Hippocampus during the Fetal to Neonatal Transition in Guinea Pigs', Reproductive Medicine, 3 85-100 [C1]
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2021 |
Crombie GK, Palliser HK, Shaw JC, Hodgson DM, Walker DW, Hirst JJ, 'Effects of prenatal stress on behavioural and neurodevelopmental outcomes are altered by maternal separation in the neonatal period', PSYCHONEUROENDOCRINOLOGY, 124 (2021) [C1]
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Nova |
2021 |
Crombie GK, Palliser HK, Shaw JC, Hodgson DM, Walker DW, Hirst JJ, 'Neurosteroid-based intervention using Ganaxolone and Emapunil for improving stress-induced myelination deficits and neurobehavioural disorders', PSYCHONEUROENDOCRINOLOGY, 133 (2021) [C1]
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Nova |
2021 |
Shaw JC, Crombie GK, Palliser HK, Hirst JJ, 'Impaired Oligodendrocyte Development Following Preterm Birth: Promoting GABAergic Action to Improve Outcomes', FRONTIERS IN PEDIATRICS, 9 (2021) [C1]
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Nova |
2019 |
Shaw JC, Crombie GK, Zakar T, Palliser HK, Hirst JJ, 'Perinatal compromise contributes to programming of GABAergic and glutamatergic systems leading to long-term effects on offspring behaviour', JOURNAL OF NEUROENDOCRINOLOGY, 32 (2019) [C1]
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Nova |
2019 |
Shaw JC, Berry MJ, Dyson RM, Crombie GK, Hirst JJ, Palliser HK, 'Reduced Neurosteroid Exposure Following Preterm Birth and Its' Contribution to Neurological Impairment: A Novel Avenue for Preventative Therapies', Frontiers in Physiology, 10 (2019) [C1]
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Nova |
2019 |
Dyson RM, Palliser HK, Wilding N, Kelly MA, Chwatko G, Glowacki R, et al., 'Microvascular circulatory dysregulation driven in part by cystathionine gamma-lyase: A new paradigm for cardiovascular compromise in the preterm newborn', MICROCIRCULATION, 26 (2019) [C1]
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Nova |
2019 |
Shaw JC, Dyson RM, Palliser HK, Gray C, Berry MJ, Hirst JJ, 'Neurosteroid replacement therapy using the allopregnanolone-analogue ganaxolone following preterm birth in male guinea pigs', Pediatric Research, 85 86-96 (2019) [C1]
Background: Children born preterm, especially boys, are at increased risk of developing attention deficit hyperactivity disorder (ADHD) and learning difficulties. We propose that ... [more]
Background: Children born preterm, especially boys, are at increased risk of developing attention deficit hyperactivity disorder (ADHD) and learning difficulties. We propose that neurosteroid-replacement therapy with ganaxolone (GNX) following preterm birth may mitigate preterm-associated neurodevelopmental impairment. Methods: Time-mated sows were delivered preterm (d62) or at term (d69). Male preterm pups were randomized to ganaxolone (Prem-GNX; 2.5 mg/kg subcutaneously twice daily until term equivalence), or preterm control (Prem-CON). Surviving male juvenile pups underwent behavioural testing at d25-corrected postnatal age (CPNA). Brain tissue was collected at CPNA28 and mature myelinating oligodendrocytes of the hippocampus and subcortical white matter were quantified by immunostaining of myelin basic protein (MBP). Results: Ganaxolone treatment returned the hyperactive behavioural phenotype of preterm-born juvenile males to a term-born phenotype. Deficits in MBP immunostaining of the preterm hippocampus and subcortical white matter were also ameliorated in animals receiving ganaxolone. However, during the treatment period weight gain was poor, and pups were sedated, ultimately increasing the neonatal mortality rate. Conclusion: Ganaxolone improved neurobehavioural outcomes in males suggesting that neonatal treatment may be an option for reducing preterm-associated neurodevelopmental impairment. However, dosing studies are required to reduce the burden of unwanted side effects.
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Nova |
2018 |
Hirst JJ, Palliser HK, Shaw JC, Crombie G, Walker DW, Zakar T, 'Birth and Neonatal Transition in the Guinea Pig: Experimental Approaches to Prevent Preterm Birth and Protect the Premature Fetus', FRONTIERS IN PHYSIOLOGY, 9 (2018) [C1]
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Nova |
2018 |
Shaw JC, Palliser HK, Dyson RM, Berry MJ, Hirst JJ, 'Disruptions to the cerebellar GABAergic system in juvenile guinea pigs following preterm birth', International Journal of Developmental Neuroscience, 65 1-10 (2018) [C1]
Background Children that are born preterm are at an increased risk of developing cognitive problems and behavioural disorders, such as attention deficit hyperactivity disorder (AD... [more]
Background Children that are born preterm are at an increased risk of developing cognitive problems and behavioural disorders, such as attention deficit hyperactivity disorder (ADHD). There is increasing interest in the role of the cerebellum in these processes and the potential involvement of GABAergic pathways in neurodevelopmental disorders. We propose that preterm birth, and the associated loss of the trophic intrauterine environment, alters the development of the cerebellum, contributing to ongoing neurobehavioral disorders. Methods Guinea pigs were delivered preterm (GA62) or spontaneously at term (GA69), and tissues collected at corrected postnatal day (PND) 28. Neurodevelopmental and GABAergic markers myelin basic protein (MBP), neuronal nuclei (NeuN), calbindin (Purkinje cells), and GAD67 (GABA synthesis enzyme) were analysed in cerebellar lobules IX and X by immunohistochemistry. Protein expression of GAD67 and GAT1 (GABA transporter enzyme) were quantified by western blot, whilst neurosteroid-sensitive GABAA receptor subunits were measured by RT-PCR. Results MBP immunostaining was increased in lobule IX of preterm males, and reduced in lobule X of preterm females when compared to their term counterparts. GAD67 staining was decreased in lobule IX and X of the preterm males, but only in lobule X of the preterm females compared to term cohorts for each sex. Internal granule cell layer width of lobule X was decreased in preterm cohorts of both sexes compared to terms. There were no differences between gestational age groups for NeuN staining, GAD67 and GAT1 protein expression as measured by western blotting, or GABAA receptor subunits as measured by RT-PCR between preterm and term for either sex. Conclusions The present findings suggest that components of the cerebellar GABAergic system of the ex-preterm cerebellum are disrupted. The higher expression of myelin in the preterm males may be due to a deficit in axonal pruning, whereas females have a deficit in myelination at 28 corrected days of age. Together these ongoing alterations may contribute to the neurodevelopmental and behavioural disorders observed in those born preterm.
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Nova |
2018 |
Shaw JC, Palliser HK, Palazzi K, Hirst JJ, 'Administration of Progesterone Throughout Pregnancy Increases Maternal Steroids Without Adverse Effect on Mature Oligodendrocyte Immunostaining in the Guinea Pig', Reproductive Sciences, 25 395-405 (2018) [C1]
Progesterone is administered to pregnant women at risk of premature labor, despite systematic reviews showing conflicting outcomes regarding its use, highlighting doubt over the e... [more]
Progesterone is administered to pregnant women at risk of premature labor, despite systematic reviews showing conflicting outcomes regarding its use, highlighting doubt over the effectiveness of the therapy. Progesterone can be rapidly metabolized into a number of steroids, but to date, there has been a lack of investigation into the fetal steroid profiles following administration and whether this impacts fetal neurodevelopment. The objective of this study was to determine the effect of progesterone treatment on allopregnanolone and cortisol levels in the fetus and on a marker of myelination in the fetal brain. We used a guinea pig model where pregnant dams were administered vehicle (ß-cyclodextrin) or progesterone orally throughout pregnancy (GA29-61). Maternal and fetal fluids and tissues were collected at both preterm (GA61) and term (GA68) ages. Maternal and fetal progesterone and cortisol were analyzed by enzyme immunoassay and allopregnanolone by radioimmunoassay. Measurement of myelination of fetal brains (hippocampus, cingulum, and subcortical white matter) at preterm and term ages was performed by immunohistochemistry staining for myelin basic protein. We found that dams receiving progesterone had significantly elevated progesterone and cortisol concentrations, but there was no effect on allopregnanolone. Interestingly, the increased cortisol concentrations were not reflected in the fetuses, and there was no effect of progesterone treatment on myelination. Therefore, we conclude that in our guinea pig model, maternal administration of progesterone has no effect on cortisol levels or markers of mature oligodendrocytes in the fetus and suggest this is potentially due to the protective cortisol barrier in the placenta.
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Nova |
2018 |
Morrison JL, Botting KJ, Darby JRT, David AL, Dyson RM, Gatford KL, et al., 'Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic', Journal of Physiology, 596 5535-5569 (2018) [C1]
Over 30¿years ago Professor David Barker first proposed the theory that events in early life could explain an individual's risk of non-communicable disease in later life: the... [more]
Over 30¿years ago Professor David Barker first proposed the theory that events in early life could explain an individual's risk of non-communicable disease in later life: the developmental origins of health and disease (DOHaD) hypothesis. During the 1990s the validity of the DOHaD hypothesis was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health. A variety of animal models have been used to develop and evaluate interventions, each with strengths and limitations. It is becoming apparent that effective translational research requires that the animal paradigm selected mirrors the tempo of human fetal growth and development as closely as possible so that the effect of a perinatal insult and/or therapeutic intervention can be fully assessed. The guinea pig is one such animal model that over the past two decades has demonstrated itself to be a very useful platform for these important reproductive studies. This review highlights similarities in the in utero development between humans and guinea pigs, the strengths and limitations of the guinea pig as an experimental model of DOHaD and the guinea pig's potential to enhance clinical therapeutic innovation to improve human health. (Figure presented.).
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Nova |
2017 |
Cumberland AL, Palliser HK, Crombie GK, Walker DW, Hirst JJ, 'Increased anxiety-like phenotype in female guinea pigs following reduced neurosteroid exposure in utero', International Journal of Developmental Neuroscience, 58 50-58 (2017) [C1]
Neurosteroids are essential for aiding proper fetal neurodevelopment. Pregnancy compromises such as preterm birth, prenatal stress and intrauterine growth restriction are associat... [more]
Neurosteroids are essential for aiding proper fetal neurodevelopment. Pregnancy compromises such as preterm birth, prenatal stress and intrauterine growth restriction are associated with an increased risk of developing behavioural and mood disorders, particularly during adolescence. These pathologies involve the premature loss or alteration of trophic steroid hormones reaching the fetus leading to impaired neurodevelopment. While the specific programming mechanisms are yet to be fully elucidated, in adult life, dysfunctions of allopregnanolone action are prevalent in individuals with depression, post-traumatic stress disorder and anxiety disorders. The objective of this study was to assess if changes in concentrations of the neurosteroid, allopregnanolone, may be a fetal programming factor in priming the brain towards a negative behavioural phenotype during the childhood to adolescent period using a guinea pig model. Pregnant guinea pigs received either vehicle (45% (2-hydroxypropyl)-ß-cyclodextrin) or the 5a-reductase inhibitor, finasteride (25¿mg/kg maternal weight) from gestational age 60 until spontaneous delivery (~71¿days gestation). Male and female offspring from vehicle and finasteride treated dams were tested at postnatal day 20 (juvenile-equivalence) in an open field arena, and hippocampus and amygdala subsequently assessed for neurological changes in markers of development and GABA production pathways 24¿h later. Females with reduced allopregnanolone exposure in utero displayed increased neophobic-like responses to a change in their environment compared to female controls. There were no differences in the neurodevelopmental markers assessed; MAP2, NeuN, MBP, GFAP or GAD67 between intrauterine finasteride or vehicle exposure, in either the hippocampus or amygdala whereas GAT1 staining was decreased. This study indicates that an intrauterine reduction in the supply of allopregnanolone programs vulnerability of female offspring to anxiety-like disorders in juvenility without impacting long term allopregnanolone concentrations.
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Nova |
2017 |
Cumberland AL, Palliser HK, Rani P, Walker DW, Hirst JJ, 'Effects of combined IUGR and prenatal stress on the development of the hippocampus in a fetal guinea pig model.', J Dev Orig Health Dis, 8 584-596 (2017) [C1]
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Nova |
2017 |
Bennett GA, Palliser HK, Shaw JC, Palazzi KL, Walker DW, Hirst JJ, 'Maternal stress in pregnancy affects myelination and neurosteroid regulatory pathways in the guinea pig cerebellum', Stress, 20 580-588 (2017) [C1]
Prenatal stress predisposes offspring to behavioral pathologies. These may be attributed to effects on cerebellar neurosteroids and GABAergic inhibitory signaling, which can be li... [more]
Prenatal stress predisposes offspring to behavioral pathologies. These may be attributed to effects on cerebellar neurosteroids and GABAergic inhibitory signaling, which can be linked to hyperactivity disorders. The aims were to determine the effect of prenatal stress on markers of cerebellar development, a key enzyme in neurosteroid synthesis and the expression of GABAA receptor (GABAAR) subunits involved in neurosteroid signaling. We used a model of prenatal stress (strobe light exposure, 2 h on gestational day 50, 55, 60 and 65) in guinea pigs, in which we have characterized anxiety and neophobic behavioral outcomes. The cerebellum and plasma were collected from control and prenatally stressed offspring at term (control fetus: n = 9 male, n = 7 female; stressed fetus: n = 7 male, n = 8 female) and postnatal day (PND) 21 (control: n = 8 male, n = 8 female; stressed: n = 9 male, n = 6 female). We found that term female offspring exposed to prenatal stress showed decreased expression of mature oligodendrocytes (~40% reduction) and these deficits improved to control levels by PND21. Reactive astrocyte expression was lower (~40% reduction) following prenatal stress. GABAAR subunit (d and a6) expression and circulating allopregnanolone concentrations were not affected by prenatal stress. Prenatal stress increased expression (~150¿250% increase) of 5a-reductase type-1 mRNA in the cerebellum, which may be a neuroprotective response to promote GABAergic inhibition and aid in repair. These observations indicate that prenatal stress exposure has marked effects on the development of the cerebellum. These findings suggest cerebellar changes after prenatal stress may contribute to adverse behavioral outcomes after exposure to these stresses.
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Nova |
2017 |
Cumberland AL, Palliser HK, Walker DW, Hirst JJ, 'Cerebellar Changes in Guinea Pig Offspring Following Suppression of Neurosteroid Synthesis During Late Gestation', Cerebellum, 16 306-313 (2017) [C1]
Elevated gestational concentrations of allopregnanolone are essential for the development and neuroprotection of the foetal brain. Preterm birth deprives the foetus of these high ... [more]
Elevated gestational concentrations of allopregnanolone are essential for the development and neuroprotection of the foetal brain. Preterm birth deprives the foetus of these high levels of allopregnanolone, which may contribute to the associated adverse effects on cerebellar development. Preterm birth alters expression of GABAA receptor subunit composition, which may further limit neurosteroid action. The objective of this study was to determine the effects of suppression of allopregnanolone levels on the markers of development and functional outcome. Pregnant guinea pigs were treated with finasteride at a dose (25¿mg/kg maternal weight) shown to suppress allopregnanolone between 60¿days of gestation until delivery (term ~71¿days). The cerebella from neonates, whose mothers were treated with finasteride or vehicle during pregnancy, were collected at postnatal age 8. Pups that received finasteride displayed significantly greater glial fibrillary acid protein area coverage and reduced GABAA receptor a6-subunit messenger RNA within the cerebellum than pups that were exposed to vehicle. These findings indicate that loss of neurosteroid action on the foetal brain in late gestation produces prolonged astrocyte activation and reductions in GABAA receptor a6-subunit expression. These changes may contribute to the long-term changes in function associated with preterm birth.
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Nova |
2016 |
Saif Z, Dyson RM, Palliser HK, Wright IMR, Lu N, Clifton VL, 'Identification of Eight Different Isoforms of the Glucocorticoid Receptor in Guinea Pig Placenta: Relationship to Preterm Delivery, Sex and Betamethasone Exposure', PLOS ONE, 11 (2016) [C1]
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Nova |
2016 |
Bennett GA, Palliser HK, Walker D, Hirst J, 'Severity and timing: How prenatal stress exposure affects glial developmental, emotional behavioural and plasma neurosteroid responses in guinea pig offspring', Psychoneuroendocrinology, 70 47-57 (2016) [C1]
Prenatal stress has been associated with a variety of developmental changes in offspring, notably those associated with brain development and subsequent risk for neuropathologies ... [more]
Prenatal stress has been associated with a variety of developmental changes in offspring, notably those associated with brain development and subsequent risk for neuropathologies later in life. Recently, the importance of the timing and the severity of the stressor during pregnancy has been emphasized with neurosteroids including allopregnanolone implicated in the regulation of stress and also for endogenous neuroprotection in offspring.Prenatal stress was induced using strobe light exposure in pregnant guinea pigs (term 71 days) in three defined stress exposure groups (Gestational Age (GA)35-65, GA50-65 and GA60-65). Stress was induced for 2 h (9-11 am) every 5 days via strobe light exposure. A fetal cohort were euthanased at term with fetal brains and plasma collected. Anxiety-like behaviour was evaluated at 18 days of age in a separate cohort of offspring with brains and plasma collected at 21 days of age. Markers for mature oligodendrocytes and reactive astrocytes were measured in the CA1 region of the hippocampus and the subcortical white matter. The neurosteroid allopregnanolone was measured by radioimmunoassay in offspring plasma.In the CA1 region of the hippocampus, fetuses from all stress groups showed reduced expression of mature oligodendrocytes and reactive astrocytes. By juvenility, all male stress exposure groups had recovered to levels of unaffected controls with the exception of the GA35-65 stress group. In juvenile females, mature oligodendrocyte marker expression was reduced in all stress groups and reactive astrocyte expression was reduced in the GA35-65 and GA60-65 stress groups by juvenility. Increased reactive astrocyte expression was also apparent in the subcortical white matter in both sexes both at term and at juvenility. Prenatally stressed offspring spent less time exploring in the object exploration test and also entered the inner zone of the open field less than controls at 18 days of age. Circulating allopregnanolone concentrations were significantly reduced in GA35-65 and GA 60-65 stress exposed fetuses with those in the GA35-65 stress group remaining reduced by juvenility.This study has shown the effects of differing levels of prenatal stress severity and timing on glial development, emotional behaviour and plasma allopregnanolone concentrations in offspring.
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Nova |
2016 |
Hirst JJ, Cumberland AL, Shaw JC, Bennett GA, Kelleher MA, Walker DW, Palliser HK, 'Loss of neurosteroid-mediated protection following stress during fetal life', Journal of Steroid Biochemistry and Molecular Biology, 160 181-188 (2016) [C1]
Elevated levels of neurosteroids during late gestation protect the fetal brain from hypoxia/ischaemia and promote neurodevelopment. Suppression of allopregnanolone production duri... [more]
Elevated levels of neurosteroids during late gestation protect the fetal brain from hypoxia/ischaemia and promote neurodevelopment. Suppression of allopregnanolone production during pregnancy leads to the onset of seizure-like activity and potentiates hypoxia-induced brain injury. Markers of myelination are reduced and astrocyte activation is increased. The placenta has a key role in maintaining allopregnanolone concentrations in the fetal circulation and brain during gestation and levels decline markedly after both normal and preterm birth. This leads to the preterm neonate developing in a neurosteroid deficient environment between delivery and term equivalence. The expression of 5a-reductases is also lower in the fetus prior to term. These deficiencies in neurosteroid exposure may contribute to the increase in incidence of the adverse patterns of behaviour seen in children that are born preterm. Repeated exposure to glucocorticoid stimulation suppresses 5a-reductase expression and allopregnanolone levels in the fetus and results in reduced myelination. Both fetal growth restriction and prenatal maternal stress lead to increased cortisol concentrations in the maternal and fetal circulation. Prenatal stress results in reduced expression of key GABAA receptor subunits that normally heighten neurosteroid sensitivity. These stressors also result in altered placental allopregnanolone metabolism pathways. These findings suggest that reduced neurosteroid production and action in the perinatal period may contribute to some of the adverse neurodevelopmental and behavioural outcomes that result from these pregnancy compromises. Studies examining perinatal steroid supplementation therapy with non-metabolisable neurosteroid analogues to improve these outcomes are warranted.
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Nova |
2016 |
Shaw JC, Palliser HK, Dyson RM, Hirst JJ, Berry MJ, 'Long-term effects of preterm birth on behavior and neurosteroid sensitivity in the Guinea pig', Pediatric Research, 80 275-283 (2016) [C1]
Background: Ex-preterm children and adolescents are at risk of developing late-onset neurodevelopmental and behavioral disorders. The mechanisms by which this happens are poorly u... [more]
Background: Ex-preterm children and adolescents are at risk of developing late-onset neurodevelopmental and behavioral disorders. The mechanisms by which this happens are poorly understood and relevant animal models are required. Methods: Ex-preterm (delivered at 62 d gestation) and term (spontaneously delivered) juvenile Guinea pigs underwent behavioral testing at 25 d corrected postnatal age, with tissues collected at 28 d. Neurodevelopmental markers (myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP)) were analyzed in the hippocampus and subcortical white matter by immunohistochemistry. Gamma-aminobutyric acid A (GABA A) receptor subunit mRNA levels were quantified by reverse transcription polymerase chain reaction (RT-PCR), and salivary cortisol measured by enzyme-linked immunosorbent assay. Results: Preterm males travelled greater distances, were mobile for longer, spent more time investigating objects, and approached or interacted with familiar animals more than controls. Myelination and reactive astrocyte coverage was lower in the hippocampus and the subcortical white matter in preterm males. Hippocampal levels of the a5 subunit were also lower in the preterm male brain. Baseline salivary cortisol was higher for preterm males compared to controls. Conclusion: We conclude that juvenile ex-preterm male Guinea pigs exhibit a hyperactive phenotype and feature impaired neurodevelopment, making this a suitable model for future therapeutic studies.
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Nova |
2015 |
Bennett GA, Palliser HK, Shaw JC, Walker D, Hirst JJ, 'Prenatal stress alters hippocampal neuroglia and increases anxiety in childhood', Developmental Neuroscience, 37 533-545 (2015) [C1]
Prenatal stress has been associated with detrimental outcomes of pregnancy, including altered brain development leading to behavioural pathologies. The neurosteroid allopregnanolo... [more]
Prenatal stress has been associated with detrimental outcomes of pregnancy, including altered brain development leading to behavioural pathologies. The neurosteroid allopregnanolone has been implicated in mediating some of these adverse outcomes following prenatal stress due to its potent inhibitory and anxiolytic effects on the brain. The aims of the current study were to characterise key markers for brain development as well as behavioural parameters, adrenocortical responses to handling and possible neurosteroid influences towards outcomes in Guinea pig offspring in childhood. Pregnant Guinea pig dams were exposed to strobe light for 2 h (9-11 a.m.) on gestational days 50, 55, 60, and 65 and were left to deliver spontaneously at term and care for their litter. Behavioural testing (open-field test, object exploration test) of the offspring was performed at postnatal day 18 (with salivary cortisol and DHEA measured), and brains were collected at post-mortem on day 21. Markers of brain development myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) were assessed via immunohistochemistry, and the neurosteroid allopregnanolone and its rate-limiting enzymes 5a-reductase types 1 and 2 (5aR1/2) were measured in neonatal brains by radioimmunoassay, reverse transcriptase polymerase chain reaction (RT-PCR), and Western blot, respectively. Brain-derived neurotrophic factor protein was measured as a marker of synaptic plasticity, and GABAA receptor subunit expression was also assessed using RT-PCR. Neonates born from mothers stressed during late pregnancy showed a reduction in both MBP (p < 0.01) and GFAP (p < 0.05) expression in the CA1 region of the hippocampus at 21 days of age. Pups of prenatally stressed pregnancies also showed higher levels of anxiety and neophobic behaviours at the equivalent of childhood (p < 0.05). There were no significant changes observed in allopregnanolone levels, 5aR1/2 expression, or GABAA receptor subunit expression in prenatally stressed neonates compared to controls. This study shows alterations in markers of myelination and reactive astrocytes in the hippocampus of offspring exposed to prenatal stress. These changes are also observed in offspring that show increased anxiety behaviours at the equivalent of childhood, which indicates ongoing structural and functional postnatal changes after prenatal stress exposure.
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Nova |
2015 |
Shaw JC, Palliser HK, Walker DW, Hirst JJ, 'Preterm birth affects GABA
Modulation of gamma-aminobutyric acid A (GABAA) receptor signalling by the neurosteroid allopregnanolone has a major role in late gestation neurodevelopment. The objective of this... [more]
Modulation of gamma-aminobutyric acid A (GABAA) receptor signalling by the neurosteroid allopregnanolone has a major role in late gestation neurodevelopment. The objective of this study was to characterize the mRNA levels of GABAA receptor subunits (a4, a5, a6 and d) that are key to neurosteroid binding in the brain, following preterm birth. Myelination, measured by the myelin basic protein immunostaining, was used to assess maturity of the preterm brains. Foetal guinea pig brains were obtained at 62 days' gestational age (GA, preterm) or at term (69 days). Neonates were delivered by caesarean section, at 62 days GA and term, and maintained until tissue collection at 24 h of age. Subunit mRNA levels were quantified by RT-PCR in the hippocampus and cerebellum of foetal and neonatal brains. Levels of the a6 and d subunits were markedly lower in the cerebellum of preterm guinea pigs compared with term animals. Importantly, there was an increase in mRNA levels of these subunits during the foetal-to-neonatal transition at term, which was not seen following preterm birth. Myelination was lower in preterm neonatal brains, consistent with marked immaturity. Salivary cortisol concentrations, measured by EIA, were also higher for the preterm neonates, suggesting greater stress. We conclude that there is an adaptive increase in the levels of mRNA of the key GABAA receptor subunits involved in neurosteroid action after term birth, which may compensate for declining allopregnanolone levels. The lower levels of these subunits in preterm neonates may heighten the adverse effect of the premature decline in neurosteroid exposure.
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Nova |
2015 |
Dyson RM, Palliser HK, Latter JL, Kelly MA, Chwatko G, Glowacki R, Wright IMR, 'Interactions of the gasotransmitters contribute to microvascular tone (Dys)regulation in the preterm neonate', PLoS ONE, 10 (2015) [C1]
Background & Aims: Hydrogen sulphide (H2S), nitric oxide (NO), and carbon monoxide (CO) are involved in transitional microvascular tone dysregulation in the preterm infant; ho... [more]
Background & Aims: Hydrogen sulphide (H2S), nitric oxide (NO), and carbon monoxide (CO) are involved in transitional microvascular tone dysregulation in the preterm infant; however there is conflicting evidence on the interaction of these gasotransmitters, and their overall contribution to the microcirculation in newborns is not known. The aim of this study was to measure the levels of all 3 gasotransmitters, characterise their interrelationships and elucidate their combined effects on microvascular blood flow. Methods: 90 preterm neonates were studied at 24h postnatal age. Microvascular studies were performed by laser Doppler. Arterial COHb levels (a measure of CO) were determined through co-oximetry. NO was measured as nitrate and nitrite in urine. H2S was measured as thiosulphate by liquid chromatography. Relationships between levels of the gasotransmitters and microvascular blood flow were assessed through partial correlation controlling for the influence of gestational age. Structural equation modelling was used to examine the combination of these effects on microvascular blood flow and derive a theoretical model of their interactions. Results: No relationship was observed between NO and CO (p = 0.18, r = 0.18). A positive relationship between NO and H2S (p = 0.008, r = 0.28) and an inverse relationship between CO and H2S (p = 0.01, r = -0.33) exists. Structural equation modelling was used to examine the combination of these effects on microvascular blood flow. The model with the best fit is presented. Conclusions: The relationships between NO and H2S, and CO and H2S may be of importance in the preterm newborn, particularly as NO levels in males are associated with higher H2S levels and higher microvascular blood flow and CO in females appears to convey protection against vascular dysregulation. Here we present a theoretical model of these interactions and their overall effects on microvascular flow in the preterm newborn, upon which future mechanistic studies may be based.
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Nova |
2015 |
Palliser HK, Kelleher MA, Tolcos M, Walker DW, Hirst JJ, 'Effect of postnatal progesterone therapy following preterm birth on neurosteroid concentrations and cerebellar myelination in guinea pigs', Journal of Developmental Origins of Health and Disease, 6 350-361 (2015) [C1]
Allopregnanolone protects the fetal brain and promotes normal development including myelination. Preterm birth results in the early separation of the infant from the placenta and ... [more]
Allopregnanolone protects the fetal brain and promotes normal development including myelination. Preterm birth results in the early separation of the infant from the placenta and consequently a decline in blood and brain allopregnanolone concentrations. Progesterone therapy may increase allopregnanolone and lead to improved oligodendrocyte maturation. The objectives of this study were to examine the efficacy of progesterone replacement in augmenting allopregnanolone concentrations during the postnatal period and to assess the effect on cerebellar myelination - a region with significant postnatal development. Preterm guinea pig neonates delivered at 62 days of gestation by caesarean section received daily s.c. injections of vehicle (2-Hydroxypropyl-ß-cyclodextrin) or progesterone (16 mg/kg) for 8 days until term-equivalent age (TEA). Term delivered controls (PND1) received vehicle. Neonatal condition/wellbeing was scored, and salivary progesterone was sampled over the postnatal period. Brain and plasma allopregnanolone concentrations were measured by radioimmunoassay; cortisol and progesterone concentrations were determined by enzyme immunoassay; and myelin basic protein (MBP), proteolipid protein (PLP), oligodendroctye transcription factor 2 (OLIG2) and platelet-derived growth factor receptor-a (PDGFRa) were quantified by immunohistochemistry and western blot. Brain allopregnanolone concentrations were increased in progesterone-treated neonates. Plasma progesterone and cortisol concentrations were elevated in progesterone-treated male neonates. Progesterone treatment decreased MBP and PLP in lobule X of the cerebellum and total cerebellar OLIG2 and PDGFRa in males but not females at TEA compared with term animals. We conclude that progesterone treatment increases brain allopregnanolone concentrations, but also increases cortisol levels in males, which may disrupt developmental processes. Consideration should be given to the use of non-metabolizable neurosteroid agonists.
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Nova |
2014 |
Dyson RM, Palliser HK, Latter JL, Chwatko G, Glowacki R, Wright IMR, 'A Role for H
Excessive vasodilatation during the perinatal period is associated with cardiorespiratory instability in preterm neonates. Little evidence of the mechanisms controlling microvascu... [more]
Excessive vasodilatation during the perinatal period is associated with cardiorespiratory instability in preterm neonates. Little evidence of the mechanisms controlling microvascular tone during circulatory transition exists. We hypothesised that hydrogen sulphide (H2S), an important regulator of microvascular reactivity and central cardiac function in adults and animal models, may contribute to the vasodilatation observed in preterm newborns. Term and preterm neonates (24-43 weeks gestational age) were studied. Peripheral microvascular blood flow was assessed by laser Doppler. Thiosulphate, a urinary metabolite of H2S, was determined by high performance liquid chromatography as a measure of 24 hr total body H2S turnover for the first 3 days of postnatal life. H2S turnover was greatest in very preterm infants and decreased with increasing gestational age (p = 0.0001). H2S turnover was stable across the first 72 hrs of life in older neonates. In very preterm neonates, H2S turnover increased significantly from day 1 to 3 (p = 0.0001); and males had higher H2S turnover than females (p = 0.04). A significant relationship between microvascular blood flow and H2S turnover was observed on day 2 of postnatal life (p = 0.0004). H2S may play a role in maintaining microvascular tone in the perinatal period. Neonates at the greatest risk of microvascular dysfunction characterised by inappropriate peripheral vasodilatation - very preterm male neonates - are also the neonates with highest levels of total body H2S turnover suggesting that overproduction of this gasotransmitter may contribute to microvascular dysfunction in preterms. Potentially, H2S is a target to selectively control microvascular tone in the circulation of newborns. © 2014 Dyson et al.
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2014 |
Dyson RM, Palliser HK, Lakkundi A, de Waal K, Latter JL, Clifton VL, Wright IMR, 'Early microvascular changes in the preterm neonate: a comparative study of the human and guinea pig.', Physiol Rep, 2 (2014) [C1]
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2014 |
Hirst JJ, Kelleher MA, Walker DW, Palliser HK, 'Neuroactive steroids in pregnancy: Key regulatory and protective roles in the foetal brain', Journal of Steroid Biochemistry and Molecular Biology, 139 144-153 (2014) [C1]
Neuroactive steroid concentrations are remarkably high in the foetal brain during late gestation. These concentrations are maintained by placental progesterone synthesis and the i... [more]
Neuroactive steroid concentrations are remarkably high in the foetal brain during late gestation. These concentrations are maintained by placental progesterone synthesis and the interaction of enzymes in the placenta and foetal brain. 5a-Pregnane-3a-ol-20-one (allopregnanolone) is a key neuroactive steroid during foetal life, although other 3a-hydroxy- pregnanes may make an additional contribution to neuroactive steroid action. Allopregnanolone modulates GABAergic inhibition to maintain a suppressive action on the foetal brain during late gestation. This action suppresses foetal behaviour and maintains the appropriate balance of foetal sleep-like behaviours, which in turn are important to normal neurodevelopment. Neuroactive steroid-induced suppression of excitability has a key role in protecting the foetal brain from acute hypoxia/ischaemia insults. Hypoxia-induced brain injury is markedly increased if neuroactive steroid levels are suppressed and there is increased seizure activity. There is also a rapid increase in allopregnanolone synthesis and hence levels in response to acute stress that acts as an endogenous protective mechanism. Allopregnanolone has a trophic role in regulating development, maintaining normal levels of apoptosis and increasing myelination during late gestation in the brain. In contrast, chronic foetal stressors, including intrauterine growth restriction, do not increase neuroactive steroid levels in the brain and exposure to repeated synthetic corticosteroids reduce neuroactive steroid levels. The reduced availability of neuroactive steroids may contribute to the adverse effects of chronic stressors on the foetal and newborn brain. Preterm birth also deprives the foetus of neuroactive steroid mediated protection and may increase vulnerability to brain injury and suboptimal development. These finding suggest replacement therapies should be explored. This article is part of a Special Issue entitled 'Pregnancy and steroids © 2013 Elsevier Ltd. All rights reserved.
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2014 |
Welsh TN, Hirst JJ, Palliser H, Zakar T, 'Progesterone Receptor Expression Declines in the Guinea Pig Uterus during Functional Progesterone Withdrawal and in Response to Prostaglandins', PLOS ONE, 9 (2014) [C1]
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2014 |
Palliser HK, Kelleher MA, Welsh TN, Zakar T, Hirst JJ, 'Mechanisms Leading to Increased Risk of Preterm Birth in Growth-Restricted Guinea Pig Pregnancies', REPRODUCTIVE SCIENCES, 21 269-276 (2014) [C1]
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2014 |
Cumberland AL, Palliser HK, Hirst JJ, 'Increased placental neurosteroidogenic gene expression precedes poor outcome in the preterm guinea pig', Journal of Developmental Origins of Health and Disease, 5 74-78 (2014) [C1]
Placental 5a-reductase (5aR) is influenced by in utero compromises and has a role in regulating neuroactive steroid concentrations in the fetus. The objective of this study was to... [more]
Placental 5a-reductase (5aR) is influenced by in utero compromises and has a role in regulating neuroactive steroid concentrations in the fetus. The objective of this study was to determine if changes in placental 5aR were associated with neonatal outcome after birth. Guinea pigs were delivered by cesarean section at term (GA69, n=22) or preterm (GA62, n=36) and the placenta collected. Preterm neonates were maintained for 24 h unless their condition deteriorated before this time. Enzyme mRNA expression of 5aR type-1 and 5aR type-2 were determined using real-time PCR. All preterm neonates had significantly higher 5aR2 expression in their placenta compared with placentae from term neonates (P<0.0001). Expression was also markedly higher in the placentae from neonates that did not survive until 24 h, compared with surviving preterm neonates (P=0.04). These findings suggest differences of in utero neurosteroidogenic capacity between surviving and non-surviving preterm guinea pig neonates. The increased 5aR2 mRNA expression in the placenta of non-survivors suggests an induction of the neurosteroid pathway due to prior exposure to an in utero compromise, with such exposure possibly a predisposing factor that contributed to their poor ex utero outcome. © 2014 Cambridge University Press.
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2013 |
Bennett GA, Palliser HK, Saxby B, Walker DW, Hirst JJ, 'Effects of Prenatal Stress on Fetal Neurodevelopment and Responses to Maternal Neurosteroid Treatment in Guinea Pigs', DEVELOPMENTAL NEUROSCIENCE, 35 416-426 (2013) [C1]
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2013 |
Kelleher MA, Hirst JJ, Palliser HK, 'Changes in neuroactive steroid concentrations after preterm delivery in the guinea pig', Reproductive Sciences, 20 1365-1375 (2013) [C1]
Background: Preterm birth is a major cause of neurodevelopmental disorders. Allopregnanolone, a key metabolite of progesterone, has neuroprotective and developmental effects in th... [more]
Background: Preterm birth is a major cause of neurodevelopmental disorders. Allopregnanolone, a key metabolite of progesterone, has neuroprotective and developmental effects in the brain. The objectives of this study were to measure the neuroactive steroid concentrations following preterm delivery in a neonatal guinea pig model and assess the potential for postnatal progesterone replacement therapy to affect neuroactive steroid brain and plasma concentrations in preterm neonates. Methods: Preterm (62-63 days) and term (69 days) guinea pig pups were delivered by cesarean section and tissue was collected at 24 hours. Plasma progesterone, cortisol, allopregnanolone, and brain allopregnanolone concentrations were measured by immunoassay. Brain 5a-reductase (5aR) expression was determined by Western blot. Neurodevelopmental maturity of preterm neonates was assessed by immunohistochemistry staining for myelination, glial cells, and neurons. Results: Brain allopregnanolone concentrations were significantly reduced after birth in both preterm and term neonates. Postnatal progesterone treatment in preterm neonates increased brain and plasma allopregnanolone concentrations. Preterm neonates had reduced myelination, low birth weight, and high mortality compared to term neonates. Brain 5aR expression was also significantly reduced in neonates compared to fetal expression. Conclusions: Delivery results in a loss of neuroactive steroid concentrations resulting in a premature reduction in brain allopregnanolone in preterm neonates. Postnatal progesterone therapy reestablished neuroactive steroid levels in preterm brains, a finding that has implications for postnatal growth following preterm birth that occurs at a time of neurodevelopmental immaturity. © 2013 The Author(s).
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2012 |
Palliser HK, Yates DM, Hirst JJ, 'Progesterone receptor isoform expression in response to in utero growth restriction in the fetal guinea pig brain', Neuroendocrinology, 96 60-67 (2012) [C1]
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2012 |
Dyson RM, Palliser HK, Kelleher MA, Hirst JJ, Wright IM, 'The guinea pig as an animal model for studying perinatal changes in microvascular function', Pediatric Research, 71 20-24 (2012) [C1]
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2012 |
Welsh T, Paul J, Palliser H, Hirst J, Mesiano S, Zakar T, 'PGDH Expression Decreases at Term before Labor Onset in Guinea Pig Fetal Membranes', REPRODUCTIVE SCIENCES, 19 192A-192A (2012) [C3]
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2012 |
Welsh TN, Paul JW, Palliser HK, Tabatabaeehatambakhsh SH, Hirst JJ, Mesiano S, Zakar T, '15-hydroxyprostaglandin dehydrogenase expression and localization in guinea pig gestational tissues during late pregnancy and parturition', Reproductive Sciences, 19 1099-1109 (2012) [C1]
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2011 |
Kelleher MA, Palliser HK, Walker DW, Hirst JJ, 'Sex-dependent effect of a low neurosteroid environment and intrauterine growth restriction on foetal guinea pig brain development', Journal of Endocrinology, 208 301-309 (2011) [C1]
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2010 |
Palliser HK, Zakar T, Symonds IM, Hirst JJ, 'Progesterone receptor isoform expression in the guinea pig myometrium from normal and growth restricted pregnancies', Reproductive Sciences, 17 776-782 (2010) [C1]
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2010 |
Dellios NL, Lappas M, Young IR, Palliser HK, Hirst JJ, Oliva K, et al., 'Increased expression of alpha-enolase in cervico-vaginal fluid during labour', European Journal of Obstetrics Gynecology and Reproductive Biology, 153 16-22 (2010) [C1]
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2010 |
McKendry AA, Palliser HK, Yates DM, Walker DW, Hirst JJ, 'The effect of betamethasone treatment on neuroactive steroid synthesis in a foetal guinea pig model of growth restriction', Journal of Neuroendocrinology, 22 166-174 (2010) [C1]
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2009 |
Hirst JJ, Walker DW, Yawno T, Palliser HK, 'Stress in pregnancy: A role for neuroactive steroids in protecting the fetal and neonatal brain', Developmental Neuroscience, 31 363-377 (2009) [C1]
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2009 |
Vu TT, Hirst JJ, Stark MJ, Wright IM, Palliser HK, Hodyl NA, Clifton VL, 'Changes in human placental 5 alpha-reductase isoenzyme expression with advancing gestation: Effects of fetal sex and glucocorticoid exposure', Reproduction Fertility and Development, 21 599-607 (2009) [C1]
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2008 |
Hirst JJ, Palliser HK, Roach DM, Yawno T, Walker DW, 'Neurosteroids in the fetus and neonate: Potential protective role in compromised pregnancies', Neurochemistry International, 52 602-610 (2008) [C1]
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2007 |
Young R, Rice GE, Palliser HK, Ayhan M, Dellios NL, Hirst JJ, 'Identification of bactenecin-1 in cervicovaginal fluid by two-dimensional electrophoresis in an ovine model of preterm labour', Proteomics, 7 281-288 (2007) [C1]
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2007 |
Smith R, Van Helden DF, Hirst JJ, Zakar T, Read MA, Chan EC, et al., 'Pathological interactions with the timing of birth and uterine activation', Australian & New Zealand Journal of Obstetrics & Gynaecology, 47 430-437 (2007) [C1]
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2006 |
Palliser HK, Dellios N, Escalona R, Ooi G, Rice GE, Hirst J, Young IR, 'Labor-Associated Regulation of Prostaglandin E and F Synthesis and Action in the Ovine Amnion and Cervix', Reproductive Sciences, 13 19-24 (2006) [C1]
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2005 |
Hirst JJ, Parkington HC, Young IR, Palliser HK, Peri KG, Olsen DM, 'Delay of preterm birth in sheep by THG113.31, a prostaglandin F2[a] receptor antagonist', American Journal of Obstetrics and Gynecology, 193 256-266 (2005) [C1]
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2005 |
Palliser HK, Hirst J, Ooi GT, Rice GE, Escalona RM, Dellios NL, et al., 'Prostaglandin E and F receptor expression and myometrial sensitivity at labour onset in sheep', Biology of Reproduction, 72 937-943 (2005) [C1]
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2004 |
Palliser HK, Dellios N, Escalona R, Ooi G, Rice GE, Hirst J, Young IR, 'Changes in the Expression of prostaglandin E and F synthases at induced and spontaneous labour onset in the sheep', Journal of Endocrinology, 180 469-477 (2004) [C1]
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