36 results on '"Tolcos M"'
Search Results
2. ACE inhibition salvages the visual loss caused by diabetes
- Author
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Bui, B. V., Armitage, J. A., Tolcos, M., Cooper, M. E., and Vingrys, A. J.
- Published
- 2003
- Full Text
- View/download PDF
3. Knowledge gaps and emerging research areas in intrauterine growth restriction-associated brain injury.
- Author
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Baud O., Shearer I.K., Walker D.W., Tolcos M., Gressens P., Fleiss B., Wong F., Brownfoot F., Baud O., Shearer I.K., Walker D.W., Tolcos M., Gressens P., Fleiss B., Wong F., and Brownfoot F.
- Abstract
Intrauterine growth restriction (IUGR) is a complex global healthcare issue. Concerted research and clinical efforts have improved our knowledge of the neurodevelopmental sequelae of IUGR which has raised the profile of this complex problem. Nevertheless, there is still a lack of therapies to prevent the substantial rates of fetal demise or the constellation of permanent neurological deficits that arise from IUGR. The purpose of this article is to highlight the clinical and translational gaps in our knowledge that hamper our collective efforts to improve the neurological sequelae of IUGR. Also, we draw attention to cutting-edge tools and techniques that can provide novel insights into this disorder, and technologies that offer the potential for better drug design and delivery. We cover topics including: how we can improve our use of crib-side monitoring options, what we still need to know about inflammation in IUGR, the necessity for more human post-mortem studies, lessons from improved integrated histology-imaging analyses regarding the cell-specific nature of magnetic resonance imaging (MRI) signals, options to improve risk stratification with genomic analysis, and treatments mediated by nanoparticle delivery which are designed to modify specific cell functions.Copyright © 2019 Fleiss, Wong, Brownfoot, Shearer, Baud, Walker, Gressens and Tolcos. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
- Published
- 2019
4. Impact of High-Dose Caffeine on the Preterm Ovine Cerebrum and Cerebellum
- Author
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Atik, A, De Matteo, R, Boomgardt, M, Rees, S, Harding, R, Cheong, J, Rana, S, Crossley, K, Tolcos, M, Atik, A, De Matteo, R, Boomgardt, M, Rees, S, Harding, R, Cheong, J, Rana, S, Crossley, K, and Tolcos, M
- Abstract
Caffeine is one of the few treatments available for infants with apnea of prematurity. As the recommended dosing regimen is not always sufficient to prevent apnea, higher doses may be prescribed. However, little is currently known about the impact of high-dose caffeine on the developing brain; thus, our aim was to investigate the consequences of a high-dose regimen on the immature ovine brain. High-dose caffeine (25 mg/kg caffeine base loading dose; 20 mg/kg daily maintenance dose; n = 9) or saline (n = 8) was administered to pregnant sheep from 105 to 118 days of gestation (DG; term = 147 days); this is broadly equivalent to 28-33 weeks of human gestation. At 119DG, the cerebral cortex, striatum, and cerebellum were assessed histologically and by immunohistochemistry. Compared with controls, caffeine-exposed fetuses showed (i) an increase in the density of Ctip2-positive layers V-VI projection neurons (p = 0.02), Tbr1-positive layers V-VI projection neurons (p < 0.0001), astrocytes (p = 0.03), and oligodendrocytes (p = 0.02) in the cerebral cortex, (ii) a decrease in the density of Cux1-positive layers II-IV projection neurons (p = 0.01) in the cerebral cortex, and (iii) a reduction in the area of Purkinje cell bodies in the cerebellum (p = 0.03). Comparing high-dose caffeine-exposed fetuses with controls, there was no difference (p > 0.05) in: (i) the volume of the cerebral cortex or striatum, (ii) the density of neurons (total and output projection neurons) in the striatum, (iii) dendritic spine density of layer V pyramidal cells, (iv) the density of cortical GABAergic interneurons, microglia, mature oligodendrocytes or proliferating cells, (v) total cerebellar area or dimensions of cerebellar layers, or (vi) the density of cerebellar white matter microglia, astrocytes, oligodendrocytes, or myelin. Daily exposure of the developing brain to high-dose caffeine affects some aspects of neuronal and glial development in the cerebral cortex and cerebellum in the short
- Published
- 2019
5. Knowledge Gaps and Emerging Research Areas in Intrauterine Growth Restriction-Associated Brain Injury
- Author
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Fleiss, B, Wong, F, Brownfoot, F, Shearer, IK, Baud, O, Walker, DW, Gressens, P, Tolcos, M, Fleiss, B, Wong, F, Brownfoot, F, Shearer, IK, Baud, O, Walker, DW, Gressens, P, and Tolcos, M
- Abstract
Intrauterine growth restriction (IUGR) is a complex global healthcare issue. Concerted research and clinical efforts have improved our knowledge of the neurodevelopmental sequelae of IUGR which has raised the profile of this complex problem. Nevertheless, there is still a lack of therapies to prevent the substantial rates of fetal demise or the constellation of permanent neurological deficits that arise from IUGR. The purpose of this article is to highlight the clinical and translational gaps in our knowledge that hamper our collective efforts to improve the neurological sequelae of IUGR. Also, we draw attention to cutting-edge tools and techniques that can provide novel insights into this disorder, and technologies that offer the potential for better drug design and delivery. We cover topics including: how we can improve our use of crib-side monitoring options, what we still need to know about inflammation in IUGR, the necessity for more human post-mortem studies, lessons from improved integrated histology-imaging analyses regarding the cell-specific nature of magnetic resonance imaging (MRI) signals, options to improve risk stratification with genomic analysis, and treatments mediated by nanoparticle delivery which are designed to modify specific cell functions.
- Published
- 2019
6. Cellular and morphological changes in the fetal sheep brain during gyrification-an immunohistochemical study.
- Author
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Boomgardt M., Walker D., Tolcos M., Britto J., Boomgardt M., Walker D., Tolcos M., and Britto J.
- Abstract
Background: In some species (incl. humans) the formation of cortical gyri and sulci is largely accomplished by the time of birth; however, the fundamental mechanisms driving this process are poorly understood. Using fetal sheep, we have used immunohistochemistry to identify structural and cellular changes that occur between 56 and 113 days gestation, a time that precedes and accompanies cortical folding in this species. The effects of permanent restriction of feto-placental blood flow were assessed to determine the impact of growth processes on normal development. Method(s): Fetal brains were collected at 56, 70, 78, 90 and 113 days gestation (term~147 days) to assess ontogeny. In 5 fetuses, feto-placental blood flow was restricted by single umbilical artery ligation (SUAL) (n = 5) at 65-70 days gestation and brains collected at 90 days; controls were sham surgery (n = 7). All tissue was examined by diffusion-tensor MRI, and subsequently paraffin-embedded to assess gross histology and cellular architecture with specfic markers for neurons, microglia, astrocytes, oligodendrocytes, interneurons and blood vessels. Result(s): The first primary sulci appear after 70 days gestation, and the secondary folds are present within a 20-day period. This rapid growth phase is associated reorientation of glial-fibre tracts and migration of projection neurons, interneurons and oligodendrocytes into the expanding gyri. The SUAL perturbation did not change absolute or relative brain weight, but reduced the rate of gyri expansion and resulted in shallow sulci. Conclusion(s): Gyral formation involves changes in cell positioning within the entire cortical depth and depends on spatially distinct growth/ specification factors.
- Published
- 2015
7. Intrauterine Growth Restriction: Effects on Neural Precursor Cell Proliferation and Angiogenesis in the Foetal Subventricular Zone
- Author
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Tolcos, M, Markwick, R, O'Dowd, R, Martin, V, Turnley, A, Rees, S, Tolcos, M, Markwick, R, O'Dowd, R, Martin, V, Turnley, A, and Rees, S
- Abstract
Exposure to adverse prenatal factors can result in abnormal brain development, contributing to the aetiology of several neurological disorders. Intrauterine insults could occur during neurogenesis and gliogenesis, disrupting these events. Here we investigate the effects of chronic placental insufficiency (CPI) on cell proliferation and the microenvironment in the subventricular zone (SVZ). At 30 days of gestation (DG; term ∼67 DG), CPI was induced in pregnant guinea pigs via unilateral uterine artery ligation to produce growth-restricted (GR) foetuses (n = 7); controls (n = 6) were from the unoperated horn. At 60 DG, foetal brains were stained immunohistochemically to identify proliferating cells (Ki67), immature neurons (polysialylated neuronal cell adhesion molecule), astrocytes (glial fibrillary acidic protein), microglia (ionised calcium-binding adaptor molecule-1, Iba-1) and the microvasculature (von Willebrand factor) in the SVZ. There was no overall difference (p > 0.05) in the total number of Ki67-immunoreactive (IR) cells, the percentage of SVZ occupied by blood vessels or the density of Iba-1-IR microglia in control versus GR foetuses. However, regression analysis across both groups revealed that both the number of Ki67-IR cells and the percentage of SVZ occupied by blood vessels in the ventral SVZ were negatively correlated (p < 0.05) with brain weight. Furthermore, in the SVZ (dorsal and ventral) the density of blood vessels positively correlated (p < 0.05) with the number of Ki67-IR cells. Double-labelling immunofluorescence suggested that the majority of proliferating cells were likely to be neural precursor cells. Thus, we have demonstrated an association between angiogenesis and neurogenesis in the foetal neurogenic niche and have identified a window of opportunity for the administration of trophic support to enhance a neuroregenerative response.
- Published
- 2015
8. Unraveling the Links Between the Initiation of Ventilation and Brain Injury in Preterm Infants
- Author
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Barton, SK, Tolcos, M, Miller, SL, Roehr, CC, Schmolzer, GM, Davis, PG, Moss, TJM, LaRosa, DA, Hooper, SB, Polglase, GR, Barton, SK, Tolcos, M, Miller, SL, Roehr, CC, Schmolzer, GM, Davis, PG, Moss, TJM, LaRosa, DA, Hooper, SB, and Polglase, GR
- Abstract
The initiation of ventilation in the delivery room is one of the most important but least controlled interventions a preterm infant will face. Tidal volumes (V T) used in the neonatal intensive care unit are carefully measured and adjusted. However, the V Ts that an infant receives during resuscitation are usually unmonitored and highly variable. Inappropriate V Ts delivered to preterm infants during respiratory support substantially increase the risk of injury and inflammation to the lungs and brain. These may cause cerebral blood flow instability and initiate a cerebral inflammatory cascade. The two pathways increase the risk of brain injury and potential life-long adverse neurodevelopmental outcomes. The employment of new technologies, including respiratory function monitors, can improve and guide the optimal delivery of V Ts and reduce confounders, such as leak. Better respiratory support in the delivery room has the potential to improve both respiratory and neurological outcomes in this vulnerable population.
- Published
- 2015
9. Mid-gestation intra-amniotic infection with Ureaplasma parvum is resolved within spiny mice (Acomys cahirinus) by term delivery: but caused chronic infection of fetal lungs and placentae
- Author
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Knox, C. L., Bryan, E. R., Pasco, R., Rodgers, K., Sweeney, E. L., Dickinson, H., Polglase, G. R., Tolcos, M., Walker, D. W., and Moss, T. J. M.
- Subjects
animal model ,Spiny mice ,immunohistochemistry ,fetal lung infection ,110309 Infectious Diseases ,060500 MICROBIOLOGY ,111400 PAEDIATRICS AND REPRODUCTIVE MEDICINE ,111401 Foetal Development and Medicine ,Ureaplasma species ,indirect fluorescent antibody (IFA) ,intra-amniotic infection ,chorioamnionitis - Abstract
Background: Ureaplasma species in amniotic fluid at the time of second-trimester amniocentesis increases the risk of preterm birth, but most affected pregnancies continue to term (Gerber et al. J Infect Dis 2003). We aimed to model intra-amniotic (IA) ureaplasma infection in spiny mice, a species with a relatively long gestation (39 days) that allows investigation of the disposition and possible clearance of ureaplasmas in the feto-placental compartment. Method: Pregnant spiny mice received IA injections of U. parvum serovar 6 (10µL, 1x104 colony-forming-units in PBS) or 10B media (10µL; control) at 20 days (d) of gestation (term=39d). At 37d fetuses (n=3 ureaplasma, n=4 control) were surgically delivered and tissues were collected for; bacterial culture, ureaplasma mba and urease gene expression by PCR, tissue WBC counts and indirect fluorescent antibody (IFA) staining using anti-ureaplasma serovar 6 (rabbit) antiserum. Maternal and fetal plasma IgG was measured by Western blot. Results: Ureaplasmas were not detected by culture or PCR in fetal or maternal tissues but were visualized by IFA within placental and fetal lung tissues, in association with inflammatory changes and elevated WBC counts (p
- Published
- 2013
10. Early Detection of Ventilation-Induced Brain Injury Using Magnetic Resonance Spectroscopy and Diffusion Tensor Imaging: An In Vivo Study in Preterm Lambs
- Author
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Zhan, W, Skiold, B, Wu, Q, Hooper, SB, Davis, PG, McIntyre, R, Tolcos, M, Pearson, J, Vreys, R, Egan, GF, Barton, SK, Cheong, JLY, Polglase, GR, Zhan, W, Skiold, B, Wu, Q, Hooper, SB, Davis, PG, McIntyre, R, Tolcos, M, Pearson, J, Vreys, R, Egan, GF, Barton, SK, Cheong, JLY, and Polglase, GR
- Abstract
BACKGROUND AND AIM: High tidal volume (VT) ventilation during resuscitation of preterm lambs results in brain injury evident histologically within hours after birth. We aimed to investigate whether magnetic resonance spectroscopy (MRS) and/or diffusion tensor imaging (DTI) can be used for early in vivo detection of ventilation-induced brain injury in preterm lambs. METHODS: Newborn lambs (0.85 gestation) were stabilized with a "protective ventilation" strategy (PROT, n = 7: prophylactic Curosurf, sustained inflation, VT 7 mL/kg, positive end expiratory pressure (PEEP) 5 cmH2O) or an initial 15 minutes of "injurious ventilation" (INJ, n = 10: VT 12 mL/kg, no PEEP, late Curosurf) followed by PROT ventilation for the remainder of the experiment. At 1 hour, lambs underwent structural magnetic resonance imaging (Siemens, 3 Tesla). For measures of mean/axial/radial diffusivity (MD, AD, RD) and fractional anisotropy (FA), 30 direction DTI was performed. Regions of interests encompassed the thalamus, internal capsule, periventricular white matter and the cerebellar vermis. MRS was performed using a localized single-voxel (15×15×20 mm3, echo time 270 ms) encompassing suptratentorial deep nuclear grey matter and central white matter. Peak-area ratios for lactate (Lac) relative to N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) were calculated. Groups were compared using 2-way RM-ANOVA, Mann-Whitney U-test and Spearman's correlations. RESULTS: No cerebral injury was seen on structural MR images. Lambs in the INJ group had higher mean FA and lower mean RD in the thalamus compared to PROT lambs, but not in the other regions of interest. Peak-area lactate ratios >1.0 was only seen in INJ lambs. A trend of higher mean peak-area ratios for Lac/Cr and Lac/Cho was seen, which correlated with lower pH in both groups. CONCLUSION: Acute changes in brain diffusion measures and metabolite peak-area ratios were observed after injurious ventilation. Early MRS/DTI is able to detect
- Published
- 2014
11. Creatine in the fetal brain: A regional investigation of acute global hypoxia and creatine supplementation in a translational fetal sheep model.
- Author
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Tran NT, Muccini AM, Hale N, Tolcos M, Snow RJ, Walker DW, and Ellery SJ
- Abstract
Background: Creatine supplementation during pregnancy is a promising prophylactic treatment for perinatal hypoxic brain injury. Previously, in near-term sheep we have shown that fetal creatine supplementation reduces cerebral metabolic and oxidative stress induced by acute global hypoxia. This study investigated the effects of acute hypoxia with or without fetal creatine supplementation on neuropathology in multiple brain regions., Methods: Near-term fetal sheep were administered continuous intravenous infusion of either creatine (6 mg kg
-1 h-1 ) or isovolumetric saline from 122 to 134 days gestational age (dGA; term is approx. 145 dGA). At 131 dGA, global hypoxia was induced by a 10 min umbilical cord occlusion (UCO). Fetuses were then recovered for 72 h at which time (134 dGA) cerebral tissue was collected for either RT-qPCR or immunohistochemistry analyses., Results: UCO resulted in mild injury to the cortical gray matter, thalamus and hippocampus, with increased cell death and astrogliosis and downregulation of genes involved in regulating injury responses, vasculature development and mitochondrial integrity. Creatine supplementation reduced astrogliosis within the corpus callosum but did not ameliorate any other gene expression or histopathological changes induced by hypoxia. Of importance, effects of creatine supplementation on gene expression irrespective of hypoxia, including increased expression of anti-apoptotic ( BCL-2 ) and pro-inflammatory (e.g., MPO, TNFa, IL-6, IL-1 β) genes, particularly in the gray matter, hippocampus, and striatum were identified. Creatine treatment also effected oligodendrocyte maturation and myelination in white matter regions., Conclusion: While supplementation did not rescue mild neuropathology caused by UCO, creatine did result in gene expression changes that may influence in utero cerebral development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tran, Muccini, Hale, Tolcos, Snow, Walker and Ellery.)- Published
- 2023
- Full Text
- View/download PDF
12. Editorial: Visibility matters - women in neonatology.
- Author
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McGillick EV, Gizzi C, Volpe M, Nakstad B, Kooi EMW, Wixey J, and Tolcos M
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2022
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13. Genetic and microstructural differences in the cortical plate of gyri and sulci during gyrification in fetal sheep.
- Author
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Quezada S, van de Looij Y, Hale N, Rana S, Sizonenko SV, Gilchrist C, Castillo-Melendez M, Tolcos M, and Walker DW
- Subjects
- Animals, Cerebral Cortex metabolism, Gene Expression Regulation, Developmental, Neurites physiology, Sheep, Cerebral Cortex anatomy & histology, Cerebral Cortex growth & development, Fetal Development genetics, Fetal Development physiology
- Abstract
Gyrification of the cerebral cortex is a developmentally important process, but the mechanisms that drive cortical folding are not fully known. Theories propose that changes within the cortical plate (CP) cause gyrification, yet differences between the CP below gyri and sulci have not been investigated. Here we report genetic and microstructural differences in the CP below gyri and sulci assessed before (at 70 days of gestational age [GA] 70), during (GA 90), and after (GA 110) gyrification in fetal sheep. The areal density of BDNF, CDK5, and NeuroD6 immunopositive cells were increased, and HDAC5 and MeCP2 mRNA levels were decreased in the CP below gyri compared with sulci during gyrification, but not before. Only the areal density of BDNF-immunopositive cells remained increased after gyrification. MAP2 immunoreactivity and neurite outgrowth were also increased in the CP below gyri compared with sulci at GA 90, and this was associated with microstructural changes assessed via diffusion tensor imaging and neurite orientation dispersion and density imaging at GA 98. Differential neurite outgrowth may therefore explain the localized changes in CP architecture that result in gyrification., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)
- Published
- 2020
- Full Text
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14. Midkine: The Who, What, Where, and When of a Promising Neurotrophic Therapy for Perinatal Brain Injury.
- Author
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Ross-Munro E, Kwa F, Kreiner J, Khore M, Miller SL, Tolcos M, Fleiss B, and Walker DW
- Abstract
Midkine (MK) is a small secreted heparin-binding protein highly expressed during embryonic/fetal development which, through interactions with multiple cell surface receptors promotes growth through effects on cell proliferation, migration, and differentiation. MK is upregulated in the adult central nervous system (CNS) after multiple types of experimental injury and has neuroprotective and neuroregenerative properties. The potential for MK as a therapy for developmental brain injury is largely unknown. This review discusses what is known of MK's expression and actions in the developing brain, areas for future research, and the potential for using MK as a therapeutic agent to ameliorate the effects of brain damage caused by insults such as birth-related hypoxia and inflammation., (Copyright © 2020 Ross-Munro, Kwa, Kreiner, Khore, Miller, Tolcos, Fleiss and Walker.)
- Published
- 2020
- Full Text
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15. The Subplate: A Potential Driver of Cortical Folding?
- Author
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Rana S, Shishegar R, Quezada S, Johnston L, Walker DW, and Tolcos M
- Subjects
- Animals, Gestational Age, Humans, Magnetic Resonance Imaging, Neural Pathways anatomy & histology, Neural Pathways growth & development, Thalamus anatomy & histology, Thalamus growth & development, Cerebral Cortex anatomy & histology, Cerebral Cortex growth & development, Neurons physiology
- Abstract
In many species of Mammalia, the surface of the brain develops from a smooth structure to one with many fissures and folds, allowing for vast expansion of the surface area of the cortex. The importance of understanding what drives cortical folding extends beyond mere curiosity, as conditions such as preterm birth, intrauterine growth restriction, and fetal alcohol syndrome are associated with impaired folding in the infant and child. Despite being a key feature of brain development, the mechanisms driving cortical folding remain largely unknown. In this review we discuss the possible role of the subplate, a developmentally transient compartment, in directing region-dependent development leading to sulcal and gyral formation. We discuss the development of the subplate in species with lissencephalic and gyrencephalic cortices, the characteristics of the cells found in the subplate, and the possible presence of molecular cues that guide axons into, and out of, the overlying and multilayered cortex before the appearance of definitive cortical folds. An understanding of what drives cortical folding is likely to help in understanding the origins of abnormal folding patterns in clinical pathologies., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2019
- Full Text
- View/download PDF
16. Impact of High-Dose Caffeine on the Preterm Ovine Cerebrum and Cerebellum.
- Author
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Atik A, De Matteo R, Boomgardt M, Rees S, Harding R, Cheong J, Rana S, Crossley K, and Tolcos M
- Abstract
Caffeine is one of the few treatments available for infants with apnea of prematurity. As the recommended dosing regimen is not always sufficient to prevent apnea, higher doses may be prescribed. However, little is currently known about the impact of high-dose caffeine on the developing brain; thus, our aim was to investigate the consequences of a high-dose regimen on the immature ovine brain. High-dose caffeine (25 mg/kg caffeine base loading dose; 20 mg/kg daily maintenance dose; n = 9) or saline ( n = 8) was administered to pregnant sheep from 105 to 118 days of gestation (DG; term = 147 days); this is broadly equivalent to 28-33 weeks of human gestation. At 119DG, the cerebral cortex, striatum, and cerebellum were assessed histologically and by immunohistochemistry. Compared with controls, caffeine-exposed fetuses showed (i) an increase in the density of Ctip2-positive layers V-VI projection neurons ( p = 0.02), Tbr1-positive layers V-VI projection neurons ( p < 0.0001), astrocytes ( p = 0.03), and oligodendrocytes ( p = 0.02) in the cerebral cortex, (ii) a decrease in the density of Cux1-positive layers II-IV projection neurons ( p = 0.01) in the cerebral cortex, and (iii) a reduction in the area of Purkinje cell bodies in the cerebellum ( p = 0.03). Comparing high-dose caffeine-exposed fetuses with controls, there was no difference ( p > 0.05) in: (i) the volume of the cerebral cortex or striatum, (ii) the density of neurons (total and output projection neurons) in the striatum, (iii) dendritic spine density of layer V pyramidal cells, (iv) the density of cortical GABAergic interneurons, microglia, mature oligodendrocytes or proliferating cells, (v) total cerebellar area or dimensions of cerebellar layers, or (vi) the density of cerebellar white matter microglia, astrocytes, oligodendrocytes, or myelin. Daily exposure of the developing brain to high-dose caffeine affects some aspects of neuronal and glial development in the cerebral cortex and cerebellum in the short-term; the long-term structural and functional consequences of these alterations need to be investigated.
- Published
- 2019
- Full Text
- View/download PDF
17. Knowledge Gaps and Emerging Research Areas in Intrauterine Growth Restriction-Associated Brain Injury.
- Author
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Fleiss B, Wong F, Brownfoot F, Shearer IK, Baud O, Walker DW, Gressens P, and Tolcos M
- Abstract
Intrauterine growth restriction (IUGR) is a complex global healthcare issue. Concerted research and clinical efforts have improved our knowledge of the neurodevelopmental sequelae of IUGR which has raised the profile of this complex problem. Nevertheless, there is still a lack of therapies to prevent the substantial rates of fetal demise or the constellation of permanent neurological deficits that arise from IUGR. The purpose of this article is to highlight the clinical and translational gaps in our knowledge that hamper our collective efforts to improve the neurological sequelae of IUGR. Also, we draw attention to cutting-edge tools and techniques that can provide novel insights into this disorder, and technologies that offer the potential for better drug design and delivery. We cover topics including: how we can improve our use of crib-side monitoring options, what we still need to know about inflammation in IUGR, the necessity for more human post-mortem studies, lessons from improved integrated histology-imaging analyses regarding the cell-specific nature of magnetic resonance imaging (MRI) signals, options to improve risk stratification with genomic analysis, and treatments mediated by nanoparticle delivery which are designed to modify specific cell functions.
- Published
- 2019
- Full Text
- View/download PDF
18. Dose-dependent exacerbation of ventilation-induced lung injury by erythropoietin in preterm newborn lambs.
- Author
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Allison BJ, LaRosa DA, Barton SK, Hooper S, Zahra V, Tolcos M, Chan KYY, Barbuto J, Inocencio IM, Moss TJ, and Polglase GR
- Subjects
- Animals, Animals, Newborn, Dose-Response Relationship, Drug, Erythropoietin administration & dosage, Erythropoietin blood, Inflammation etiology, Inflammation metabolism, Liver metabolism, Lung pathology, Sheep, Ventilator-Induced Lung Injury metabolism, Ventilator-Induced Lung Injury pathology, Erythropoietin adverse effects, Respiration, Artificial adverse effects, Ventilator-Induced Lung Injury chemically induced
- Abstract
Erythropoietin (EPO) is being trialled in preterm infants to reduce brain injury, but high doses increase lung injury in ventilated preterm lambs. We aimed to determine whether early administration of lower doses of EPO could reduce ventilation-induced lung injury and systemic inflammation in preterm lambs. Ventilation was initiated in anaesthetized preterm lambs [125 ± 1 (SD) days gestation] using an injurious strategy for the first 15 min. Lambs were subsequently ventilated with a protective strategy for a total of 2 h. Lambs were randomized to receive either intravenous saline (Vent; n = 7) or intravenous 300 ( n = 5), 1,000 (EPO
1000 ; n = 5), or 3,000 (EPO3000 ; n = 5) IU/kg of human recombinant EPO via an umbilical vein. Lung tissue was collected for molecular and histological assessment of inflammation and injury and compared with unventilated control lambs (UVC; n = 8). All ventilated groups had similar blood gas and ventilation parameters, but EPO1000 lambs had a lower fraction of inspired oxygen requirement and lower alveolar-arterial difference in oxygen. Vent and EPO lambs had increased lung interleukin (IL)-1β, IL-6, and IL-8 mRNA, early lung injury genes connective tissue growth factor, early growth response protein 1, and cysteine-rich 61, and liver serum amyloid A3 mRNA compared with UVCs; no difference was observed between Vent and EPO groups. Histological lung injury was increased in Vent and EPO groups compared with UVCs, but EPO3000 lambs had increased lung injury scores compared with VENT only. Early low-doses of EPO do not exacerbate ventilation-induced lung inflammation and injury and do not provide any short-term respiratory benefit. High doses (≥3,000 IU/kg) likely exacerbate lung inflammation and injury in ventilated preterm lambs. NEW & NOTEWORTHY Trials are ongoing to assess the efficacy of erythropoietin (EPO) to provide neuroprotection for preterm infants. However, high doses of EPO increase ventilation-induced lung injury (VILI) in preterm lambs. We investigated whether early lower doses of EPO may reduce VILI. We found that lower doses did not reduce, but did not increase, VILI, while high doses (≥3,000 IU/kg) increase VILI. Therefore, lower doses of EPO should be used in preterm infants, particularly those receiving respiratory support.- Published
- 2019
- Full Text
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19. Development of the cerebral cortex and the effect of the intrauterine environment.
- Author
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Quezada S, Castillo-Melendez M, Walker DW, and Tolcos M
- Subjects
- Animals, Humans, Cerebral Cortex growth & development, Fetal Development
- Abstract
The human brain is one of the most complex structures currently under study. Its external shape is highly convoluted, with folds and valleys over the entire surface of the cortex. Disruption of the normal pattern of folding is associated with a number of abnormal neurological outcomes, some serious for the individual. Most of our knowledge of the normal development and folding of the cerebral cortex (gyrification) focuses on the internal, biological (i.e. genetically driven) mechanisms of the brain that drive gyrification. However, the impact of an adverse intrauterine and maternal physiological environment on cortical folding during fetal development has been understudied. Accumulating evidence suggests that the state of the intrauterine and maternal environment can have a significant impact on gyrification of the fetal cerebral cortex. This review summarises our current knowledge of how development in a suboptimal intrauterine and maternal environment can affect the normal development of the folded cerebral cortex., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)
- Published
- 2018
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20. Antenatal prevention of cerebral palsy and childhood disability: is the impossible possible?
- Author
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Ellery SJ, Kelleher M, Grigsby P, Burd I, Derks JB, Hirst J, Miller SL, Sherman LS, Tolcos M, and Walker DW
- Subjects
- Animals, Child, Disabled Children, Fetal Development, Fetal Hypoxia, Humans, Infections, Inflammation, Premature Birth, Cerebral Palsy prevention & control
- Abstract
This review covers our current knowledge of the causes of perinatal brain injury leading to cerebral palsy-like outcomes, and argues that much of this brain damage is preventable. We review the experimental evidence that there are treatments that can be safely administered to women in late pregnancy that decrease the likelihood and extent of perinatal brain damage that occurs because of acute and severe hypoxia that arises during some births, and the additional impact of chronic fetal hypoxia, infection, inflammation, growth restriction and preterm birth. We discuss the types of interventions required to ameliorate or even prevent apoptotic and necrotic cell death, and the vulnerability of all the major cell types in the brain (neurons, astrocytes, oligodendrocytes, microglia, cerebral vasculature) to hypoxia/ischaemia, and whether a pan-protective treatment given to the mother before birth is a realistic prospect., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)
- Published
- 2018
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21. Exacerbation of Ventilation-Induced Lung Injury and Inflammation in Preterm Lambs by High-Dose Nanoparticles.
- Author
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Inocencio IM, Bischof RJ, Xiang SD, Zahra VA, Nguyen V, Lim T, LaRosa D, Barbuto J, Tolcos M, Plebanski M, Polglase GR, and Moss TJ
- Subjects
- Animals, Animals, Newborn, Antigens, Dermatophagoides immunology, Cattle, Disease Models, Animal, Disease Progression, Humans, Immunization, Nanoparticles administration & dosage, Nanoparticles chemistry, Polystyrenes administration & dosage, Polystyrenes chemistry, Pulmonary Ventilation, Pyroglyphidae immunology, Sheep, Asthma therapy, Eosinophils immunology, Lung immunology, Nanoparticles adverse effects, Pneumonia immunology, Polystyrenes adverse effects, Ventilator-Induced Lung Injury immunology
- Abstract
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 asthma, PS50G decreased eosinophilic infiltration of the lungs. Ventilated preterm lambs showed molecular and histological signs of lung injury and inflammation, which were exacerbated in lambs that received PSG50G. PS50G treatment decreased established inflammation in the lungs of asthmatic sheep. However, prophylactic administration of PSG50 exacerbated ventilation-induced lung injury and lung inflammation in preterm lambs.
- Published
- 2017
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22. Erythropoietin Protects Against Lipopolysaccharide-Induced Microgliosis and Abnormal Granule Cell Development in the Ovine Fetal Cerebellum.
- Author
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McDougall ARA, Hale N, Rees S, Harding R, De Matteo R, Hooper SB, and Tolcos M
- Abstract
Erythropoietin (EPO) ameliorates inflammation-induced injury in cerebral white matter (WM). However, effects of inflammation on the cerebellum and neuroprotective effects of EPO are unknown. Our aims were to determine: (i) whether lipopolysaccharide (LPS)-induced intrauterine inflammation causes injury to, and/or impairs development of the cerebellum; and (ii) whether recombinant human EPO (rhEPO) mitigates these changes. At 107 ± 1 days gestational age (DGA; ~0.7 of term), fetal sheep received LPS (~0.9 μg/kg; i.v.) or an equivalent volume of saline, followed 1 h later with 5000 IU/kg rhEPO (i.v.) or an equivalent volume of saline (i.v.). This generated the following experimental groups: control (saline + saline; n = 6), LPS (LPS + saline, n = 8) and LPS + rhEPO ( n = 8). At necropsy (116 ± 1 DGA; ~0.8 of term) the brain was perfusion-fixed and stained histologically (H&E) and immunostained to identify granule cells (Neuronal Nuclei, NeuN), granule cell proliferation (Ki67), Bergmann glia (glial fibrillary acidic protein, GFAP), astrogliosis (GFAP) and microgliosis (Iba-1). In comparison to controls, LPS fetuses had an increased density of Iba-1-positive microglia ( p < 0.005) in the lobular WM; rhEPO prevented this increase ( p < 0.05). The thickness of both the proliferative (Ki67-positive) and post-mitotic zones (Ki67-negative) of the EGL were increased in LPS-exposed fetuses compared to controls ( p < 0.05), but were not different between controls and LPS + rhEPO fetuses. LPS also increased ( p < 0.001) the density of granule cells (NeuN-positive) in the internal granule layer (IGL); rhEPO prevented the increase ( p < 0.01). There was no difference between groups in the areas of the vermis (total cross-section), molecular layer (ML), IGL or WM, the density of NeuN-positive granule cells in the ML, the linear density of Bergmann glial fibers, the areal density or somal area of the Purkinje cells, the areal coverage of GFAP-positive astrocytes in the lobular and deep WM, the density of Iba-1-positive microglia in the deep WM or the density of apopotic cells in the cerebellum. LPS-induced intrauterine inflammation caused microgliosis and abnormal development of granule cells. rhEPO ameliorated these changes, suggesting that it is neuroprotective against LPS-induced inflammatory effects in the cerebellum.
- Published
- 2017
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23. Human amnion epithelial cells rescue cell death via immunomodulation of microglia in a mouse model of perinatal brain injury.
- Author
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Leaw B, Zhu D, Tan J, Muljadi R, Saad MI, Mockler JC, Wallace EM, Lim R, and Tolcos M
- Subjects
- Amnion immunology, Animals, Antigens, CD genetics, Antigens, CD immunology, Antigens, Differentiation, Myelomonocytic genetics, Antigens, Differentiation, Myelomonocytic immunology, B7-2 Antigen genetics, B7-2 Antigen immunology, Biomarkers metabolism, Brain Injuries genetics, Brain Injuries immunology, Brain Injuries pathology, Calcium-Binding Proteins genetics, Calcium-Binding Proteins immunology, Culture Media, Conditioned pharmacology, Disease Models, Animal, Epithelial Cells cytology, Epithelial Cells immunology, Female, Gene Expression, Glial Fibrillary Acidic Protein genetics, Glial Fibrillary Acidic Protein immunology, Humans, Hyperoxia genetics, Hyperoxia immunology, Hyperoxia pathology, Immunomodulation, Lipopolysaccharides administration & dosage, Mice, Mice, Inbred C57BL, Microfilament Proteins genetics, Microfilament Proteins immunology, Microglia drug effects, Microglia pathology, Perinatal Care, Pregnancy, Primary Cell Culture, Amnion cytology, Brain Injuries therapy, Epithelial Cells transplantation, Hyperoxia therapy, Microglia immunology
- Abstract
Background: Human amnion epithelial cells (hAECs) are clonogenic and have been proposed to reduce inflammatory-induced tissue injury. Perturbation of the immune response is implicated in the pathogenesis of perinatal brain injury; modulating this response could thus be a novel therapy for treating or preventing such injury. The immunomodulatory properties of hAECs have been shown in other animal models, but a detailed investigation of the effects on brain immune cells following injury has not been undertaken. Here, we investigate the effects of hAECs on microglia, the first immune responders to injury within the brain., Methods: We generated a mouse model combining neonatal inflammation and perinatal hyperoxia, both of which are risk factors associated with perinatal brain injury. On embryonic day 16 we administered lipopolysaccharide (LPS), or saline (control), intra-amniotically to C57Bl/6 J mouse pups. On postnatal day (P)0, LPS pups were placed in hyperoxia (65% oxygen) and control pups in normoxia for 14 days. Pups were given either hAECs or saline intravenously on P4., Results: At P14, relative to controls, LPS and hyperoxia pups had reduced body weight, increased density of apoptotic cells (TUNEL) in the cortex, striatum and white matter, astrocytes (GFAP) in the white matter and activated microglia (CD68) in the cortex and striatum, but no change in total microglia density (Iba1). hAEC administration rescued the decreased body weight and reduced apoptosis and astrocyte areal coverage in the white matter, but increased the density of total and activated microglia. We then stimulated primary microglia (CD45
low CD11b+ ) with LPS for 24 h, followed by co-culture with hAEC conditioned medium for 48 h. hAEC conditioned medium increased microglial phagocytic activity, decreased microglia apoptosis and decreased M1 activation markers (CD86). Stimulating hAECs for 24 h with LPS did not alter release of cytokines known to modulate microglia activity., Conclusions: These data demonstrate that hAECs can directly immunomodulate brain microglia, probably via release of trophic factors. This observation offers promise that hAECs may afford therapeutic utility in the management of perinatal brain injury.- Published
- 2017
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24. Correction: Single Sustained Inflation followed by Ventilation Leads to Rapid Cardiorespiratory Recovery but Causes Cerebral Vascular Leakage in Asphyxiated Near-Term Lambs.
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Sobotka KS, Hooper SB, Crossley KJ, Ong T, Schmölzer GM, Barton SK, McDougall AR, Miller SL, Tolcos M, Klingenberg C, and Polglase GR
- Abstract
[This corrects the article DOI: 10.1371/journal.pone.0146574.].
- Published
- 2016
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25. Differential short-term regional effects of early high dose erythropoietin on white matter in preterm lambs after mechanical ventilation.
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Barton SK, McDougall AR, Melville JM, Moss TJ, Zahra VA, Lim T, Crossley KJ, Polglase GR, and Tolcos M
- Subjects
- Animals, Astrocytes metabolism, Astrocytes pathology, Erythropoietin administration & dosage, Erythropoietin pharmacology, Female, Hypoxia, Brain etiology, Interleukins genetics, Interleukins metabolism, Male, Neuroprotective Agents administration & dosage, Neuroprotective Agents pharmacology, Pregnancy, Pulmonary Ventilation, Sheep, Tight Junction Proteins genetics, Tight Junction Proteins metabolism, White Matter metabolism, White Matter pathology, Erythropoietin therapeutic use, Hypoxia, Brain drug therapy, Neuroprotective Agents therapeutic use, Respiration, Artificial adverse effects, White Matter drug effects
- Abstract
Inadvertently injurious ventilation of preterm neonates in the delivery room can cause cerebral white matter (WM) inflammation and injury. We investigated the impact of an early high dose of recombinant human erythropoietin (EPO) on ventilation-induced WM changes in preterm lambs. Injurious ventilation, targeting a V(T) of 15 ml kg(-1) with no positive end-expiratory pressure, was initiated for 15 min in preterm lambs (0.85 gestation). Conventional ventilation was continued for a further 105 min. Lambs received either 5000 IU kg(-1) of EPO (EPREX®; Vent+EPO; n = 6) or vehicle (Vent; n = 8) via an umbilical vein at 4 ± 2 min. Markers of WM injury and inflammation were assessed using quantitative real-time PCR (qPCR) and immunohistochemistry and compared to a group of unventilated controls (UVC; n = 4). In Vent+EPO lambs compared to Vent lambs: (i) interleukin (IL)-1β and IL-6 mRNA levels in the periventricular WM and IL-8 mRNA levels in the subcortical WM were higher (P < 0.05 for all); (ii) the density of microglia within the aggregations was not different in the periventricular WM and was lower in the subcortical WM (P = 0.001); (iii) the density of astrocytes was lower in the subcortical WM (P = 0.002); (iv) occludin and claudin-1 mRNA levels were higher in the periventricular WM (P < 0.02 for all) and (vi) the number of blood vessels with protein extravasation was lower (P < 0.05). Recombinant human EPO had variable regional effects within the WM when administered during injurious ventilation. The adverse short-term outcomes discourage the use of early high dose EPO administration in preterm ventilated babies., (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.)
- Published
- 2016
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26. Single Sustained Inflation followed by Ventilation Leads to Rapid Cardiorespiratory Recovery but Causes Cerebral Vascular Leakage in Asphyxiated Near-Term Lambs.
- Author
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Sobotka KS, Hooper SB, Crossley KJ, Ong T, Schmölzer GM, Barton SK, McDougall AR, Miller SL, Tolcos M, Klingenberg C, and Polglase GR
- Subjects
- Animals, Asphyxia Neonatorum physiopathology, Blood-Brain Barrier physiology, Carotid Arteries physiology, Respiration, Artificial methods, Sheep, Ventilation-Perfusion Ratio, Asphyxia Neonatorum therapy, Cerebrovascular Circulation, Intracranial Hemorrhages etiology, Respiration, Artificial adverse effects
- Abstract
Background: A sustained inflation (SI) rapidly restores cardiac function in asphyxic, bradycardic newborns but its effects on cerebral haemodynamics and brain injury are unknown. We determined the effect of different SI strategies on carotid blood flow (CaBF) and cerebral vascular integrity in asphyxiated near-term lambs., Methods: Lambs were instrumented and delivered at 139 ± 2 d gestation and asphyxia was induced by delaying ventilation onset. Lambs were randomised to receive 5 consecutive 3 s SI (multiple SI; n = 6), a single 30 s SI (single SI; n = 6) or conventional ventilation (no SI; n = 6). Ventilation continued for 30 min in all lambs while CaBF and respiratory function parameters were recorded. Brains were assessed for gross histopathology and vascular leakage., Results: CaBF increased more rapidly and to a greater extent during a single SI (p = 0.01), which then decreased below both other groups by 10 min, due to a higher cerebral oxygen delivery (p = 0.01). Blood brain barrier disruption was increased in single SI lambs as indicated by increased numbers of blood vessel profiles with plasma protein extravasation (p = 0.001) in the cerebral cortex. There were no differences in CaBF or cerebral oxygen delivery between the multiple SI and no SI lambs., Conclusions: Ventilation with an initial single 30 s SI improves circulatory recovery, but is associated with greater disruption of blood brain barrier function, which may exacerbate brain injury suffered by asphyxiated newborns. This injury may occur as a direct result of the initial SI or to the higher tidal volumes delivered during subsequent ventilation.
- Published
- 2016
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27. Unraveling the Links Between the Initiation of Ventilation and Brain Injury in Preterm Infants.
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Barton SK, Tolcos M, Miller SL, Roehr CC, Schmölzer GM, Davis PG, Moss TJ, LaRosa DA, Hooper SB, and Polglase GR
- Abstract
The initiation of ventilation in the delivery room is one of the most important but least controlled interventions a preterm infant will face. Tidal volumes (V T) used in the neonatal intensive care unit are carefully measured and adjusted. However, the V Ts that an infant receives during resuscitation are usually unmonitored and highly variable. Inappropriate V Ts delivered to preterm infants during respiratory support substantially increase the risk of injury and inflammation to the lungs and brain. These may cause cerebral blood flow instability and initiate a cerebral inflammatory cascade. The two pathways increase the risk of brain injury and potential life-long adverse neurodevelopmental outcomes. The employment of new technologies, including respiratory function monitors, can improve and guide the optimal delivery of V Ts and reduce confounders, such as leak. Better respiratory support in the delivery room has the potential to improve both respiratory and neurological outcomes in this vulnerable population.
- Published
- 2015
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28. Protective ventilation of preterm lambs exposed to acute chorioamnionitis does not reduce ventilation-induced lung or brain injury.
- Author
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Barton SK, Moss TJ, Hooper SB, Crossley KJ, Gill AW, Kluckow M, Zahra V, Wong FY, Pichler G, Galinsky R, Miller SL, Tolcos M, and Polglase GR
- Subjects
- Animals, Animals, Newborn, Brain metabolism, Brain physiopathology, Brain Injuries veterinary, Chorioamnionitis veterinary, Female, Gene Expression, Glial Fibrillary Acidic Protein metabolism, Hemodynamics physiology, Immunohistochemistry, Inflammation Mediators metabolism, Interleukin-1beta genetics, Interleukin-6 genetics, Interleukin-8 genetics, Lung Injury veterinary, Pregnancy, Premature Birth veterinary, Respiration, Artificial veterinary, Reverse Transcriptase Polymerase Chain Reaction, Sheep, Brain Injuries physiopathology, Chorioamnionitis physiopathology, Lung Injury physiopathology, Premature Birth physiopathology, Respiration, Artificial methods, Sheep Diseases physiopathology
- Abstract
Background: The onset of mechanical ventilation is a critical time for the initiation of cerebral white matter (WM) injury in preterm neonates, particularly if they are inadvertently exposed to high tidal volumes (VT) in the delivery room. Protective ventilation strategies at birth reduce ventilation-induced lung and brain inflammation and injury, however its efficacy in a compromised newborn is not known. Chorioamnionitis is a common antecedent of preterm birth, and increases the risk and severity of WM injury. We investigated the effects of high VT ventilation, after chorioamnionitis, on preterm lung and WM inflammation and injury, and whether a protective ventilation strategy could mitigate the response., Methods: Pregnant ewes (n = 18) received intra-amniotic lipopolysaccharide (LPS) 2 days before delivery, instrumentation and ventilation at 127±1 days gestation. Lambs were either immediately euthanased and used as unventilated controls (LPSUVC; n = 6), or were ventilated using an injurious high VT strategy (LPSINJ; n = 5) or a protective ventilation strategy (LPSPROT; n = 7) for a total of 90 min. Mean arterial pressure, heart rate and cerebral haemodynamics and oxygenation were measured continuously. Lungs and brains underwent molecular and histological assessment of inflammation and injury., Results: LPSINJ lambs had poorer oxygenation than LPSPROT lambs. Ventilation requirements and cardiopulmonary and systemic haemodynamics were not different between ventilation strategies. Compared to unventilated lambs, LPSINJ and LPSPROT lambs had increases in pro-inflammatory cytokine expression within the lungs and brain, and increased astrogliosis (p<0.02) and cell death (p<0.05) in the WM, which were equivalent in magnitude between groups., Conclusions: Ventilation after acute chorioamnionitis, irrespective of strategy used, increases haemodynamic instability and lung and cerebral inflammation and injury. Mechanical ventilation is a potential contributor to WM injury in infants exposed to chorioamnionitis.
- Published
- 2014
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29. Impact of daily high-dose caffeine exposure on developing white matter of the immature ovine brain.
- Author
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Atik A, Cheong J, Harding R, Rees S, De Matteo R, and Tolcos M
- Subjects
- Animals, Apoptosis, Axons metabolism, Caffeine blood, Female, Gliosis pathology, Myelin Basic Protein metabolism, Myelin Sheath metabolism, Nerve Tissue Proteins metabolism, Neurons cytology, Oligodendroglia cytology, Pregnancy, Pregnancy, Animal, Sheep, Time Factors, Brain drug effects, Brain embryology, Caffeine adverse effects, Maternal Exposure adverse effects
- Abstract
Background: Caffeine is widely used to treat apnea of prematurity, but the standard dosing regimen is not always sufficient to prevent apnea. Before higher doses of caffeine can be used, their effects on the immature brain need to be carefully evaluated. Our aim was to determine the impact of daily high-dose caffeine administration on the developing white matter of the immature ovine brain., Methods: High-dose caffeine (25 mg/kg caffeine base loading dose; 20 mg/kg daily maintenance dose; n = 9) or saline (n = 8) were administered to pregnant sheep from 0.7 to 0.8 of term, equivalent to approximately 27-34 wk in humans. At 0.8 of term, the white and gray matter were assessed histologically and immunohistochemically., Results: Daily caffeine administration led to peak caffeine concentration of 32 mg/l in fetal plasma at 1 h, followed by a gradual decline, with no effects on mean arterial pressure and heart rate. Initial caffeine exposure led to transient, mild alkalosis in the fetus but did not alter oxygenation. At necropsy, there was no effect of daily high-dose caffeine on brain weight, oligodendrocyte density, myelination, axonal integrity, microgliosis, astrogliosis, apoptosis, or neuronal density., Conclusion: Daily high-dose caffeine administration does not appear to adversely affect the developing white matter at the microstructural level.
- Published
- 2014
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30. Respiratory support for premature neonates in the delivery room: effects on cardiovascular function and the development of brain injury.
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Polglase GR, Miller SL, Barton SK, Kluckow M, Gill AW, Hooper SB, and Tolcos M
- Subjects
- Brain blood supply, Delivery Rooms, Humans, Infant, Newborn, Lung pathology, Regional Blood Flow, Brain physiopathology, Infant, Premature physiology, Inflammation physiopathology, Lung blood supply, Positive-Pressure Respiration adverse effects, Respiration, Ventricular Function, Left physiology
- Abstract
The transition to newborn life in preterm infants is complicated by immature cardiovascular and respiratory systems. Consequently, preterm infants often require respiratory support immediately after birth. Although aeration of the lung underpins the circulatory transition at birth, positive pressure ventilation can adversely affect cardiorespiratory function during this vulnerable period, reducing pulmonary blood flow and left ventricular output. Furthermore, pulmonary volutrauma is known to initiate pulmonary inflammatory responses, resulting in remote systemic involvement. This review focuses on the downstream consequences of positive pressure ventilation, in particular, interactions between cardiovascular output and the initiation of a systemic inflammatory cascade, on the immature brain. Recent studies have highlighted that positive pressure ventilation strategies are precursors of cerebral injury, probably mediated through cerebral blood flow instability. The presence of, or initiation of, an inflammatory cascade accentuates adverse cerebral blood flow, in addition to being a direct source of brain injury. Importantly, the degree of brain injury is dependent on the nature of the initial ventilation strategy used.
- Published
- 2014
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31. Prophylactic erythropoietin exacerbates ventilation-induced lung inflammation and injury in preterm lambs.
- Author
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Polglase GR, Barton SK, Melville JM, Zahra V, Wallace MJ, Siew ML, Tolcos M, and Moss TJ
- Subjects
- Animals, Animals, Newborn, Erythropoietin administration & dosage, Female, Humans, Lung Injury pathology, Pneumonia pathology, Pregnancy, Random Allocation, Sheep, Domestic, Erythropoietin adverse effects, Lung Injury chemically induced, Lung Injury etiology, Pneumonia chemically induced, Pneumonia etiology, Respiration, Artificial adverse effects
- Abstract
Ventilation-induced lung injury (VILI) of preterm neonates probably contributes to the pathogenesis of bronchopulmonary dysplasia (BPD). Erythropoietin (EPO) has been suggested as a therapy for BPD. The aim of this study was to determine whether prophylactic administration of EPO reduces VILI in preterm newborn lambs. Lambs at 126 days of gestation (term is 147 days) were delivered and ventilated with a high tidal volume strategy for 15 min to cause lung injury, then received gentle ventilation until 2 h of age. Lambs were randomized to receive intravenous EPO (5000 IU kg(-1): Vent+EPO; n = 6) or phosphate-buffered saline (Vent; n = 7) soon after birth: unventilated controls (UVC; n = 8) did not receive ventilation or any treatment. Physiological parameters were recorded throughout the experimental procedure. Samples of lung were collected for histological and molecular assessment of inflammation and injury. Samples of liver were collected to assess the systemic acute phase response. Vent+EPO lambs received higher F IO 2, P aO 2 and oxygenation during the first 10 min than Vent lambs. There were no differences in physiological indices beyond this time. Total lung injury score, airway wall thickness, inflammation and haemorrhage were higher in Vent+EPO lambs than in Vent lambs. Lung inflammation and early markers of lung and systemic injury were elevated in ventilated lambs relative to unventilated lambs; EPO administration further increased lung inflammation and markers of lung and systemic injury. Prophylactic EPO exacerbates VILI, which may increase the incidence and severity of long-term respiratory disease. More studies are required before EPO can be used for lung protection in preterm infants.
- Published
- 2014
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32. Early detection of ventilation-induced brain injury using magnetic resonance spectroscopy and diffusion tensor imaging: an in vivo study in preterm lambs.
- Author
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Skiöld B, Wu Q, Hooper SB, Davis PG, McIntyre R, Tolcos M, Pearson J, Vreys R, Egan GF, Barton SK, Cheong JL, and Polglase GR
- Subjects
- Animals, Animals, Newborn, Sheep, Domestic, Brain Injuries diagnosis, Brain Injuries etiology, Diffusion Tensor Imaging methods, Magnetic Resonance Imaging methods, Respiration, Artificial adverse effects
- Abstract
Background and Aim: High tidal volume (VT) ventilation during resuscitation of preterm lambs results in brain injury evident histologically within hours after birth. We aimed to investigate whether magnetic resonance spectroscopy (MRS) and/or diffusion tensor imaging (DTI) can be used for early in vivo detection of ventilation-induced brain injury in preterm lambs., Methods: Newborn lambs (0.85 gestation) were stabilized with a "protective ventilation" strategy (PROT, n = 7: prophylactic Curosurf, sustained inflation, VT 7 mL/kg, positive end expiratory pressure (PEEP) 5 cmH2O) or an initial 15 minutes of "injurious ventilation" (INJ, n = 10: VT 12 mL/kg, no PEEP, late Curosurf) followed by PROT ventilation for the remainder of the experiment. At 1 hour, lambs underwent structural magnetic resonance imaging (Siemens, 3 Tesla). For measures of mean/axial/radial diffusivity (MD, AD, RD) and fractional anisotropy (FA), 30 direction DTI was performed. Regions of interests encompassed the thalamus, internal capsule, periventricular white matter and the cerebellar vermis. MRS was performed using a localized single-voxel (15×15×20 mm3, echo time 270 ms) encompassing suptratentorial deep nuclear grey matter and central white matter. Peak-area ratios for lactate (Lac) relative to N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) were calculated. Groups were compared using 2-way RM-ANOVA, Mann-Whitney U-test and Spearman's correlations., Results: No cerebral injury was seen on structural MR images. Lambs in the INJ group had higher mean FA and lower mean RD in the thalamus compared to PROT lambs, but not in the other regions of interest. Peak-area lactate ratios >1.0 was only seen in INJ lambs. A trend of higher mean peak-area ratios for Lac/Cr and Lac/Cho was seen, which correlated with lower pH in both groups., Conclusion: Acute changes in brain diffusion measures and metabolite peak-area ratios were observed after injurious ventilation. Early MRS/DTI is able to detect the initiation of ventilation-induced brain injury.
- Published
- 2014
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33. Initiation of resuscitation with high tidal volumes causes cerebral hemodynamic disturbance, brain inflammation and injury in preterm lambs.
- Author
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Polglase GR, Miller SL, Barton SK, Baburamani AA, Wong FY, Aridas JD, Gill AW, Moss TJ, Tolcos M, Kluckow M, and Hooper SB
- Subjects
- Animals, Animals, Newborn, Brain blood supply, Brain pathology, Encephalitis pathology, Encephalitis physiopathology, Hemodynamics physiology, Lung pathology, Lung physiopathology, Oxidative Stress physiology, Premature Birth pathology, Sheep, Tidal Volume physiology, Brain physiopathology, Cerebrovascular Circulation physiology, Encephalitis etiology, Premature Birth physiopathology, Resuscitation adverse effects
- Abstract
Aims: Preterm infants can be inadvertently exposed to high tidal volumes (V(T)) in the delivery room, causing lung inflammation and injury, but little is known about their effects on the brain. The aim of this study was to compare an initial 15 min of high V(T) resuscitation strategy to a less injurious resuscitation strategy on cerebral haemodynamics, inflammation and injury., Methods: Preterm lambs at 126 d gestation were surgically instrumented prior to receiving resuscitation with either: 1) High V(T) targeting 10-12 mL/kg for the first 15 min (n = 6) or 2) a protective resuscitation strategy (Prot V(T)), consisting of prophylactic surfactant, a 20 s sustained inflation and a lower initial V(T) (7 mL/kg; n = 6). Both groups were subsequently ventilated with a V(T) 7 mL/kg. Blood gases, arterial pressures and carotid blood flows were recorded. Cerebral blood volume and oxygenation were assessed using near infrared spectroscopy. The brain was collected for biochemical and histologic assessment of inflammation, injury, vascular extravasation, hemorrhage and oxidative injury. Unventilated controls (UVC; n = 6) were used for comparison., Results: High V(T) lambs had worse oxygenation and required greater ventilatory support than Prot V(T) lambs. High V(T) resulted in cerebral haemodynamic instability during the initial 15 min, adverse cerebral tissue oxygenation index and cerebral vasoparalysis. While both resuscitation strategies increased lung and brain inflammation and oxidative stress, High V(T) resuscitation significantly amplified the effect (p = 0.014 and p<0.001). Vascular extravasation was evident in the brains of 60% of High V(T) lambs, but not in UVC or Prot V(T) lambs., Conclusion: High V(T) resulted in greater cerebral haemodynamic instability, increased brain inflammation, oxidative stress and vascular extravasation than a Prot V(T) strategy. The initiation of resuscitation targeting Prot V(T) may reduce the severity of brain injury in preterm neonates.
- Published
- 2012
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34. HGF regulates the development of cortical pyramidal dendrites.
- Author
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Gutierrez H, Dolcet X, Tolcos M, and Davies A
- Subjects
- Animals, Brain-Derived Neurotrophic Factor pharmacology, Cell Polarity, Cell Size, Cerebral Cortex metabolism, Culture Techniques, Dendrites drug effects, Gene Transfer Techniques, Green Fluorescent Proteins, Hepatocyte Growth Factor pharmacology, Humans, Luminescent Proteins genetics, Luminescent Proteins metabolism, Mice, Neurons drug effects, Neurons metabolism, Proto-Oncogene Proteins c-met genetics, Proto-Oncogene Proteins c-met metabolism, Recombinant Proteins metabolism, Time Factors, Cerebral Cortex cytology, Cerebral Cortex embryology, Dendrites physiology, Hepatocyte Growth Factor physiology, Neurons cytology
- Abstract
Although hepatocyte growth factor (HGF) and its receptor tyrosine kinase MET are widely expressed in the developing and mature central nervous system, little is known about the role of MET signaling in the brain. We have used particle-mediated gene transfer in cortical organotypic slice cultures established from early postnatal mice to study the effects of HGF on the development of dendritic arbors of pyramidal neurons. Compared with untreated control cultures, exogenous HGF promoted a highly significant increase in dendritic growth and branching of layer 2 pyramidal neurons, whereas inactivation of endogenous HGF with function-blocking, anti-HGF antibody caused a marked reduction in size and complexity of the dendritic arbors of these neurons. Furthermore, pyramidal neurons transfected with an MET dominant-negative mutant receptor likewise had much smaller and less complex dendritic arbors than did control transfected neurons. Our results indicate that HGF plays a role in regulating dendritic morphology in the developing cerebral cortex.
- Published
- 2004
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35. Connective tissue growth factor is up-regulated in the diabetic retina: amelioration by angiotensin-converting enzyme inhibition.
- Author
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Tikellis C, Cooper ME, Twigg SM, Burns WC, and Tolcos M
- Subjects
- Animals, Blotting, Western, Connective Tissue Growth Factor, Diabetic Retinopathy metabolism, Immediate-Early Proteins analysis, Immunohistochemistry, In Situ Hybridization, Intercellular Signaling Peptides and Proteins analysis, Male, Perindopril pharmacology, RNA, Messenger analysis, Rats, Rats, Sprague-Dawley, Retinal Ganglion Cells chemistry, Reverse Transcriptase Polymerase Chain Reaction, Tissue Distribution, Angiotensin-Converting Enzyme Inhibitors pharmacology, Diabetes Mellitus, Experimental metabolism, Gene Expression Regulation drug effects, Immediate-Early Proteins genetics, Intercellular Signaling Peptides and Proteins genetics, Retina chemistry
- Abstract
Connective tissue growth factor (CTGF) has been postulated to have prosclerotic and angiogenic properties. The aim of this present study was to characterize retinal CTGF expression in the absence and presence of diabetes and in the context of treatment with the angiotensin-converting enzyme (ACE) inhibitor, perindopril. Retinas were obtained from control, diabetic, and diabetic plus perindopril-treated (3 mg/d) rats. CTGF gene expression was quantitated by RT-PCR and localized by in situ hybridization. CTGF protein expression was analyzed by Western blotting and localized by immunohistochemistry. Diabetes was associated with a greater than 2-fold increase in CTGF mRNA levels, which was attenuated by perindopril treatment. CTGF immunoreactivity was increased almost 2-fold in diabetes and was ameliorated by the ACE inhibitor perindopril. By in situ hybridization and immunohistochemistry, the major site of CTGF gene expression in the retina of diabetic rats was the ganglion cell layer. Based on the known in vivo effects of CTGF, it is postulated that this growth factor plays a pivotal role in mediating diabetes-associated retinal pathology. Furthermore, the protective effects of ACE inhibitors on retinal pathology may partly be mediated via effects on retinal CTGF expression.
- Published
- 2004
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36. Attenuation of tubular apoptosis by blockade of the renin-angiotensin system in diabetic Ren-2 rats.
- Author
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Kelly DJ, Cox AJ, Tolcos M, Cooper ME, Wilkinson-Berka JL, and Gilbert RE
- Subjects
- Angiotensin-Converting Enzyme Inhibitors pharmacology, Animals, Animals, Genetically Modified, Antihypertensive Agents pharmacology, Apoptosis drug effects, Atrophy, Autoradiography, Diabetes Mellitus, Experimental pathology, Diabetes Mellitus, Experimental physiopathology, Epidermal Growth Factor analysis, Epidermal Growth Factor genetics, Female, Fibrosis, Gene Expression physiology, In Situ Hybridization, In Situ Nick-End Labeling, Kidney Tubules chemistry, Kidney Tubules pathology, Nephritis, Interstitial pathology, Nephritis, Interstitial physiopathology, Perindopril pharmacology, RNA, Messenger analysis, Rats, Renin-Angiotensin System drug effects, Tetrazoles pharmacology, Transforming Growth Factor beta genetics, Valine analogs & derivatives, Valine pharmacology, Valsartan, Apoptosis physiology, Diabetic Nephropathies pathology, Diabetic Nephropathies physiopathology, Renin-Angiotensin System physiology
- Abstract
Background: Tubular atrophy is a major feature of most renal diseases and is closely associated with loss of renal function. The present study sought to investigate tubular epithelial cell apoptosis in experimental diabetic nephropathy and to explore the role of pro-apoptotic [transforming growth factor-beta (TGF-beta) and anti-apoptotic growth factors [epidermal growth factor (EGF)]. The effects of renoprotective therapy with blockade of the renin-angiotensin system (RAS) also were examined., Methods: Six-week-old female Ren-2 rats were injected with streptozotocin (STZ) and maintained diabetic for 12 weeks. Further groups of diabetic rats were treated with the angiotensin-converting enzyme (ACE) inhibitor, perindopril, or the angiotensin II type 1 (AT1) receptor antagonist, valsartan, for 12 weeks., Results: Widespread apoptosis, identified immunohistochemically by single stranded DNA and TUNEL, was noted in the tubules of diabetic Ren-2 rats. These changes were associated with a 50% decrease in EGF expression and a twofold increase in TGF-beta1 mRNA. Treatment of diabetic Ren-2 rats with either valsartan (20 mg/kg/day) or perindopril (6 mg/kg/day) reduced apoptosis to control levels in association with supranormal levels of EGF mRNA (P < 0.01) and a reduction in TGF-beta1 gene expression (P < 0.05) to that of control rats., Conclusions: Tubular apoptosis is a prominent feature of diabetic Ren-2 rats that is attenuated by blockade of the RAS in association with modulation of pro- and anti-apoptotic growth factor expression.
- Published
- 2002
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