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Jeanine L. Bussiere - One of the best experts on this subject based on the ideXlab platform.
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A comparison of effects on reproduction and Neonatal Development in cynomolgus monkeys given human soluble IL-4R and mice given murine soluble IL-4R.
Regulatory toxicology and pharmacology : RTP, 2009Co-Authors: Linda L. Carlock, Laine Cowan, Satoru Oneda, Alan M. Hoberman, Diane D. Wang, Roberta Hanna, Jeanine L. BussiereAbstract:Abstract The effects of treatment with a soluble IL-4 receptor (sIL-4R) on reproduction and Neonatal Development were assessed in pregnant cynomolgus monkeys and mice. When pregnant cynomolgus monkeys were administered a human sIL-4R intravenously twice a week during organogenesis (GD 20–51) at 0, 0.2 or 2.0 mg/kg, there was an increase in abortion/embryo–fetal death in the 0.2 (42.9%) and 2.0 (26.3%) mg/kg groups compared to controls (17.6%). All fetuses removed at cesarean sectioning on GD 100–102 were alive and no abnormalities were noted. There were three stillborn neonates (2.0 mg/kg group), which were determined to have died before birth. No neonates died after birth and no abnormalities were noted. Due to the unanticipated results in the monkey study, a mouse Developmental study with a murine surrogate molecule was conducted. When pregnant Crl:CD-1 ® (ICR)BR mice were administered murine sIL-4R intravenously once daily during the organogenesis period (GD 6–15) at 0, 25, 75, 250, or 625 μg/mouse (∼20 mg/kg), there were no test-article-related abnormalities in any parameters. Antibody Development to the drug did not influence toxicity in the monkey or mouse. In conclusion, evaluation of reproductive effects in mice administered murine soluble IL-4R was not predictive of reproductive effects noted in cynomolgus monkeys administered human soluble IL-4R.
Andrew J Quantock - One of the best experts on this subject based on the ideXlab platform.
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Neonatal Development of the corneal stroma in wild type and lumican null mice
Investigative Ophthalmology & Visual Science, 2006Co-Authors: Nicola Beecher, Shukti Chakravarti, Sarah Joyce, Keith Michael Andrew Meek, Andrew J QuantockAbstract:PURPOSE: Between days 8 and 14 of Neonatal Development, the corneal stroma of the mouse undergoes critical changes in tissue thickness, cell density, and light scattering. The authors investigate the stromal matrix structure in wild-type and lumican-deficient corneas in this Developmental phase. METHODS: Wild-type (n = 44) and lumican-deficient (n = 42) mouse corneas at Neonatal days 8, 10, 12, and 14 were investigated by synchrotron x-ray diffraction to establish the average collagen fibril spacing, average collagen fibril diameter, and level of fibrillar organization in the stromal matrix. RESULTS: Collagen interfibrillar spacing in the normal mouse cornea became more closely packed between days 8 and 14, though not significantly so. In lumican-null mice, interfibrillar spacing was significantly elevated at days 8, 10, and 12, but not day 14, compared with that in wild-type mice. At all stages investigated, collagen fibrils were, on average, marginally thinner than normal in lumican-null mutants, and the spatial distribution of the fibrils was less well organized. CONCLUSIONS: Transient thickening of the corneal stroma of the normal mouse at eye opening is probably not caused by widespread, homogeneous rearrangement of collagen fibrils but more likely by a temporary increase in cell or stromal "lake" volume. Lumican, structurally influential in adult mouse corneas, is also a key molecule in the Neonatal Development of the stromal matrix.
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Neonatal Development of the corneal stroma in wild-type and lumican-null mice.
Investigative ophthalmology & visual science, 2006Co-Authors: Nicola Beecher, Shukti Chakravarti, Sarah Joyce, Keith Michael Andrew Meek, Andrew J QuantockAbstract:PURPOSE: Between days 8 and 14 of Neonatal Development, the corneal stroma of the mouse undergoes critical changes in tissue thickness, cell density, and light scattering. The authors investigate the stromal matrix structure in wild-type and lumican-deficient corneas in this Developmental phase. METHODS: Wild-type (n = 44) and lumican-deficient (n = 42) mouse corneas at Neonatal days 8, 10, 12, and 14 were investigated by synchrotron x-ray diffraction to establish the average collagen fibril spacing, average collagen fibril diameter, and level of fibrillar organization in the stromal matrix. RESULTS: Collagen interfibrillar spacing in the normal mouse cornea became more closely packed between days 8 and 14, though not significantly so. In lumican-null mice, interfibrillar spacing was significantly elevated at days 8, 10, and 12, but not day 14, compared with that in wild-type mice. At all stages investigated, collagen fibrils were, on average, marginally thinner than normal in lumican-null mutants, and the spatial distribution of the fibrils was less well organized. CONCLUSIONS: Transient thickening of the corneal stroma of the normal mouse at eye opening is probably not caused by widespread, homogeneous rearrangement of collagen fibrils but more likely by a temporary increase in cell or stromal "lake" volume. Lumican, structurally influential in adult mouse corneas, is also a key molecule in the Neonatal Development of the stromal matrix.
Alan W. Flake - One of the best experts on this subject based on the ideXlab platform.
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Quantitative contrast-enhanced ultrasound of the brain on twin fetal lambs maintained by the extrauterine environment for Neonatal Development (EXTEND): initial experience
Pediatric Radiology, 2020Co-Authors: Anush Sridharan, Marcus G. Davey, Alan W. Flake, Kendall M. Lawrence, Juan S. Martin-saavedra, Ryne A. DidierAbstract:Background With the Development of an artificial environment to support the extremely premature infant, advanced imaging techniques tested in this extrauterine system might be beneficial to evaluate the fetal brain. Objective We evaluated the feasibility of (a) performing contrast-enhanced ultrasound (CEUS) and (b) quantifying normal and decreased brain perfusion in fetal lambs maintained on the extrauterine environment for Neonatal Development (EXTEND) system. Materials and methods Twin premature fetal lambs (102 days of gestational age) were transferred to the EXTEND system. Twin B was subjected to sub-physiological flows (152 mL/kg/min) and oxygen delivery (15.9 mL/kg/min), while Twin A was maintained at physiological levels. We administered Lumason contrast agent into the oxygenator circuit and performed serial CEUS examinations. We quantified perfusion parameters and generated parametric maps. We also recorded hemodynamic parameters, serum blood analysis, and measurements across the oxygenator. Postmortem MRIs were performed. Results No significant changes in hemodynamic variables were attributable to CEUS examinations. On gray-scale images, Twin B demonstrated ventriculomegaly and progressive parenchymal volume loss culminating in hydranencephaly. By CEUS, Twin B demonstrated decreased peak enhancement and decreased overall parenchymal perfusion when compared to Twin A by perfusion parameters and parametric maps. Changes in perfusion parameters were detected immediately following blood transfusion. Postmortem MRI confirmed ultrasonographic findings in Twin B. Conclusion In this preliminary experience, we show that CEUS of the brain is feasible in fetal lambs maintained on the EXTEND system and that changes in perfusion can be quantified, which is promising for the application of CEUS in this extrauterine system supporting the premature infant.
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Fetal echocardiographic assessment of cardiovascular impact of prolonged support on EXTrauterine Environment for Neonatal Development (EXTEND) system.
Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology, 2020Co-Authors: K. Ozawa, Marcus G. Davey, Alan W. Flake, Matthew A. Hornick, Ali Y. Mejaddam, Patrick E. Mcgovern, Zhiyun Tian, Jack RychikAbstract:Objective EXTrauterine Environment for Neonatal Development (EXTEND) is a system to support ongoing fetal growth and organ Development in an extrauterine environment, utilizing a pumpless low-resistance oxygenator circuit. The aim of this study was to evaluate hemodynamics and cardiac function in fetal sheep sustained on the EXTEND system. Methods This was a prospective study of fetal sheep supported for a minimum of 3 weeks on EXTEND. Hemodynamic parameters were assessed weekly and included heart rate, mean arterial pressure (MAP), Doppler-echocardiography-derived cardiac output (CO), pulsatility indices (PIs) of the fetal middle cerebral artery (MCA), umbilical artery (UA) and ductus venosus and cardiac function, as assessed by speckle-tracking-derived global longitudinal strain and strain rate in the right (RV) and left (LV) ventricles. Parameters were compared at 0 days and 1, 2 and 3 weeks following placement on EXTEND. Results Of 10 fetal sheep enrolled, seven survived for 3 weeks and were included in the analysis. Median gestational age at cannulation was 107 (range, 95-109) days. Heart rate decreased and MAP increased significantly, but within acceptable ranges, during the study period. The quantities and relative ratios of right and left CO remained stable within the anticipated physiological range throughout the study period. Vascular tracings and PIs appeared to be similar to those seen normally in the natural in-utero state, with MCA-PI being higher than UA-PI. UA tracings demonstrated maintained abundant diastolic flow despite the absence of placental circulation. In both the RV and LV, strain decreased significantly at 1 and 2 weeks relative to baseline but returned to baseline values by week 3. Conclusions The EXTEND mechanical support system replicates natural physiology and creates a stable and sustainable cardiovascular construct that supports growth over a 3-week period. However, there is a period of depressed contractility within the first week with subsequent improvement by week 3. This may reflect a period of physiological accommodation that warrants further investigation. This study lays the foundation for further exploration as the EXTEND system moves towards human application. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.
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Technical feasibility of umbilical cannulation in midgestation lambs supported by the EXTra‐uterine Environment for Neonatal Development (EXTEND)
Artificial organs, 2019Co-Authors: Matthew A. Hornick, Emily A. Partridge, Marcus G. Davey, Ali Y. Mejaddam, Patrick E. Mcgovern, Grace Hwang, Jiancheng Han, William H. Peranteau, Alan W. FlakeAbstract:EXTEND (EXTra-uterine Environment for Neonatal Development) is a novel system for supporting extremely premature infants that replicates in utero conditions by maintaining a sterile fluid environment and providing gas exchange via a pumpless arteriovenous oxygenator circuit connected to the umbilical vessels. Target gestational age (GA) for EXTEND support in human infants is 23-27 weeks, when immature lungs are most susceptible to injury in the setting of air ventilation. We previously demonstrated physiologic support of premature lambs cannulated at 105-117 days GA (lungs Developmentally analogous to the 23-27 week GA human infant) for up to 28 days on EXTEND. In the present study, we sought to determine the technical feasibility of umbilical vessel cannulation in 85-96 days GA lambs delivered to EXTEND at weights equivalent to the 23-27 week GA human infant (500-850 g). Five preterm lambs were cannulated at 85-96 days GA (term 145 days) and supported on EXTEND for 4-7 days. All lambs underwent umbilical artery and umbilical vein cannulation. Circuit flows and pressures were monitored continuously, and blood gases were obtained at regular intervals for assessment of oxygen parameters. Systemic pH and lactate were measured at least once daily. Mean body weight at cannulation was 641 ± 71 g (range 480-850 g). All lambs were cannulated successfully (cannula size varied from 8 to 12 Fr), and mean survival on EXTEND was 140 ± 7 hours. Mean circuit flow was 213 ± 15 mL/kg*min, mean pH was 7.37 ± 0.01, and mean lactate was 1.6 ± 0.2 mmol/L. During the initial 120 hours after EXTEND cannulation, there were no significant differences between 85-96 days GA lambs and 105-117 days GA lambs in weight-adjusted circuit flows, oxygen delivery, pH, or lactate levels. This study demonstrates successful umbilical cord cannulation and adequate circuit flows and oxygen delivery in midgestation lambs size-matched to the 23-27 week GA human fetus, which represents an important step in the translation of EXTEND to clinical practice.
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Contrast‐Enhanced Ultrasound in Extracorporeal Support: In Vitro Studies and Initial Experience and Safety Data in the Extreme Premature Fetal Lamb Maintained by the Extrauterine Environment for Neonatal Development
Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine, 2018Co-Authors: Ryne A. Didier, Marcus G. Davey, Kendall M. Lawrence, Anush Sridharan, Beverly G. Coleman, Alan W. FlakeAbstract:OBJECTIVES To evaluate the effects of ultrasound contrast agent (UCA) administration on hemodynamic parameters and support equipment in in vitro and in vivo models of extracorporeal support. METHODS In vitro, incrementally increasing bolus doses of a UCA were administered proximal to a membrane oxygenator, and ultrasound cine clips were obtained. The rates of microbubble destruction across the oxygenator and over time were calculated from time-intensity-curves. Measurements across the membrane oxygenator were recorded and compared by a repeated-measures analysis of variance. In vivo, 7 premature fetal lambs were transferred from placental support to the extrauterine environment for Neonatal Development. Contrast agent boluses were administered for contrast-enhanced ultrasound (CEUS) examinations. Hemodynamic parameters and serum laboratory values were evaluated before and after the examinations by paired t tests. For oxygenator staining, oxygenator membranes from the in vitro circuit, study animals (n = 4), and control animals (n = 4) were stained for the adherent UCA. RESULTS In vitro, with all doses (0.1-4 mL), there was no difference in measured parameters across the oxygenator (P ≥ .09). Contrast agent destruction (3%-14%) across the oxygenator was observed at the first pass with a progressive decline in contrast intensity over time. In vivo, there was no difference in hemodynamic parameters or serum laboratory values (P ≥ .08) with any CEUS examination (n = 17). For oxygenator staining, all oxygenator membranes were negative for UCA with lipid staining. CONCLUSIONS The UCA had no detectable effect on the oxygenator or measured parameters in in vitro and in vivo studies, thus providing additional safety data to support the use of CEUS in the setting of extracorporeal support.
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An EXTrauterine environment for Neonatal Development: EXTENDING fetal physiology beyond the womb.
Seminars in Fetal and Neonatal Medicine, 2017Co-Authors: Emily A. Partridge, Marcus G. Davey, Matthew A. Hornick, Alan W. FlakeAbstract:Extreme prematurity is a major cause of Neonatal mortality and morbidity, and remains an unsolved clinical challenge. The Development of an artificial womb, an extrauterine system recreating the intrauterine environment, would support ongoing growth and organ maturation of the extreme preterm fetus and would have the potential to substantially improve survival and reduce morbidity. Previous efforts toward the Development of such a system have demonstrated the ability to maintain the isolated fetus for short periods of support, but have failed to achieve the long-term stability required for clinical application. Here we describe our initial experiments demonstrating the stable support of fetal lambs Developmentally equivalent to the extreme premature infant for up to four weeks with stable hemodynamics, growth, and Development. The achievement of long-term physiologic support of the fetus in an extrauterine system has the potential to fundamentally change the management and clinical outcome of the extreme premature infant.
Arjen B. Brussaard - One of the best experts on this subject based on the ideXlab platform.
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Neonatal Development of the rat visual cortex: synaptic function of GABAa receptor α subunits
The Journal of physiology, 2002Co-Authors: Laurens W. J. Bosman, Thomas W. Rosahl, Arjen B. BrussaardAbstract:Each GABAA receptor consists of two α and three other subunits. The spatial and temporal distribution of different α subunit isomeres expressed by the CNS is highly regulated. Here we study changes in functional contribution of different α subunits during Neonatal Development in rat visual cortex. First, we characterized postsynaptic α subunit expression in layer II-III neurons, using subunit-specific pharmacology combined with electrophysiological recordings in acutely prepared brain slices. This showed clear Developmental downregulation of the effects of bretazenil (1 μm) and marked upregulation of the effect of 100 nm of zolpidem on the decay of spontaneous inhibitory postsynaptic currents (sIPSCs). Given the concentrations used we interpret this as downregulation of the synaptic α3 and upregulation of α1 subunit. Furthermore, the effect of furosemide, being indicative of the functional contribution of α4, was increased between postnatal days 6 and 21. Our second aim was to study the effects of plasticity in α subunit expression on decay properties of GABAergic IPSCs. We found that bretazenil-sensitive IPSCs have the longest decay time constant in juvenile neurons. In mature neurons, zolpidem- and furosemide-sensitive IPSCs have relatively fast decay kinetics, whereas bretazenil-sensitive IPSCs decay relatively slowly. Analysis of α1 deficient mice and α1 antisense oligonucleotide deletion in rat explants showed similar results to those obtained by zolpidem application. Thus, distinct α subunit contributions create heterogeneity in Developmental acceleration of IPSC decay in neocortex.
Linda L. Carlock - One of the best experts on this subject based on the ideXlab platform.
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A comparison of effects on reproduction and Neonatal Development in cynomolgus monkeys given human soluble IL-4R and mice given murine soluble IL-4R.
Regulatory toxicology and pharmacology : RTP, 2009Co-Authors: Linda L. Carlock, Laine Cowan, Satoru Oneda, Alan M. Hoberman, Diane D. Wang, Roberta Hanna, Jeanine L. BussiereAbstract:Abstract The effects of treatment with a soluble IL-4 receptor (sIL-4R) on reproduction and Neonatal Development were assessed in pregnant cynomolgus monkeys and mice. When pregnant cynomolgus monkeys were administered a human sIL-4R intravenously twice a week during organogenesis (GD 20–51) at 0, 0.2 or 2.0 mg/kg, there was an increase in abortion/embryo–fetal death in the 0.2 (42.9%) and 2.0 (26.3%) mg/kg groups compared to controls (17.6%). All fetuses removed at cesarean sectioning on GD 100–102 were alive and no abnormalities were noted. There were three stillborn neonates (2.0 mg/kg group), which were determined to have died before birth. No neonates died after birth and no abnormalities were noted. Due to the unanticipated results in the monkey study, a mouse Developmental study with a murine surrogate molecule was conducted. When pregnant Crl:CD-1 ® (ICR)BR mice were administered murine sIL-4R intravenously once daily during the organogenesis period (GD 6–15) at 0, 25, 75, 250, or 625 μg/mouse (∼20 mg/kg), there were no test-article-related abnormalities in any parameters. Antibody Development to the drug did not influence toxicity in the monkey or mouse. In conclusion, evaluation of reproductive effects in mice administered murine soluble IL-4R was not predictive of reproductive effects noted in cynomolgus monkeys administered human soluble IL-4R.
