ORCID Profile
0000-0003-0656-7035
Current Organisation
The University of Auckland
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Wiley
Date: 17-10-2008
DOI: 10.1111/J.1440-1681.2008.05013.X
Abstract: 1. Adenosine A(1) receptor activation is critical for endogenous neuroprotection from hypoxia-ischaemia, raising the possibility that treatment with A(1) receptor agonists may be an effective physiological protection strategy for vulnerable preterm infants. However, the A(1) receptor can mediate unwanted systemic effects, including vasoconstriction of the afferent glomerular arteriole. There is limited information on whether this occurs at doses that improve cerebral perfusion in the immature brain. 2. Therefore, in the present study, we examined whether infusion of the selective A(1) receptor agonist adenosine amine congener (ADAC) is associated with reduced renal perfusion in chronically instrumented preterm (0.7 gestation) fetal sheep. In the present study, ADAC was given in successive doses of 2.5, 5.0 and 15.0 microg, 45 min apart. 3. Treatment with ADAC was associated with a marked reduction in renal vascular conductance (and blood flow), whereas carotid conductance was increased and there was no significant effect on femoral conductance. In contrast with the stable effects of increasing ADAC dose on vascular conductance, there was a significant dose-related fall in fetal heart rate and blood pressure. 4. In conclusion, these short-term data support the concern that A(1) receptor agonist infusion can selectively impair renal perfusion, even at low doses.
Publisher: Wiley
Date: 19-02-2015
DOI: 10.1016/J.IJDEVNEU.2015.02.006
Abstract: Preterm born infants have high rates of brain injury, leading to motor and neurocognitive problems in later life. Infection and resulting inflammation of the fetus and newborn are highly associated with these disabilities. However, there are no established neuroprotective therapies. Microglial activation and expression of many cytokines play a key role in normal brain function and development, as well as being deleterious. Thus, treatment must achieve a delicate balance between possible beneficial and harmful effects. In this review, we discuss potential neuroprotective strategies targeting systemic infection or the resulting systemic and central inflammatory responses. We highlight the central importance of timing of treatment and the critical lack of studies of delayed treatment of infection/inflammation.
Publisher: Oxford University Press (OUP)
Date: 26-10-2020
DOI: 10.1002/SCTM.20-0314
Abstract: There is increasing evidence that administration of many types of stem cells, including human amnion epithelial cells (hAECs), can reduce hypoxic-ischemic injury, including in the perinatal brain. However, the therapeutic window for single dose treatment is not known. We compared the effects of early and delayed intracerebroventricular administration of hAECs in fetal sheep at 0.7 gestation on brain injury induced by 25 minutes of complete umbilical cord occlusion (UCO) or sham occlusion. Fetuses received either 1 × 106 hAECs or vehicle alone, as an infusion over 1 hour, either 2 or 24 hours after UCO. Fetuses were killed for brain histology at 7 days post-UCO. hAEC infusion at both 2 and 24 hours had dramatic anti-inflammatory and anti-gliotic effects, including significantly attenuating the increase in microglia after UCO in the white and gray matter and the number of astrocytes in the white matter. Both protocols partially improved myelination, but had no effect on total or immature/mature numbers of oligodendrocytes. Neuronal survival in the hippoc us was increased by hAEC infusion at either 2 or 24 hours, whereas only hAECs at 24 hours were associated with improved neuronal survival in the striatum and thalamus. Neither protocol improved recovery of electroencephalographic (EEG) power. These data suggest that a single infusion of hAECs is anti-inflammatory, anti-gliotic, and neuroprotective in preterm fetal sheep when given up to 24 hours after hypoxia-ischemia, but was associated with limited white matter protection after 7 days recovery and no improvement in the recovery of EEG power.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2013
DOI: 10.1038/PR.2013.188
Abstract: Cerebral palsy is one of the most devastating consequences of brain injury around the time of birth, and nearly a third of cases are now associated with premature birth. Compared with term babies, preterm babies have an increased incidence of complications that may increase the risk of disability, such as intraventricular hemorrhage, periventricular leukomalacia, sepsis, and necrotizing enterocolitis. The response to injury is highly dependent on brain maturity, and although cellular vulnerability is well documented, there is now evidence that premyelinating axons are also particularly sensitive to ischemic injury. In this review, we will explore recent evidence highlighting a central role for glia in mediating increased risk of disability in premature infants, including excessive activation of microglia and opening of astrocytic gap junction hemichannels in spreading injury after brain ischemia, in part likely involving release of adenosine triphosphate (ATP) and overactivation of purinergic receptors, particularly in white matter. We propose the hypothesis that inflammation-induced opening of connexin hemichannels is a key regulating event that initiates a vicious circle of excessive ATP release, which in turn propagates activation of purinergic receptors on microglia and astrocytes. This suggests that developing effective neuroprotective strategies for preterm infants requires a detailed understanding of glial responses.
Publisher: Wiley
Date: 02-2014
Publisher: Public Library of Science (PLoS)
Date: 15-06-2012
Publisher: American Physiological Society
Date: 02-2013
DOI: 10.1152/AJPREGU.00388.2012
Abstract: Acute, high-dose exposure to endotoxin lipopolysaccharide (LPS) in preterm fetal sheep can trigger periventricular white matter lesions (PVL), in association with severe hypotension/hypoxemia and significant mortality. Intriguingly, however, chronic or repeated exposure to LPS can induce tachyphylaxis. We therefore tested the hypothesis that progressive, acute on chronic fetal infection would be associated with white matter injury with little fetal mortality. Chronically instrumented preterm (0.7 gestational age) fetal sheep were exposed to a continuous low-dose LPS infusion (100 ng over 24 h, followed by 250 ng/24 h for 96 h) or saline. Boluses of 1 μg LPS or saline were given at 48, 72, and 96 h sheep were killed at day 10. Six of 11 fetal sheep exposed to saline infusion + LPS boluses died 4–7 h after the first bolus. In contrast, there was no fetal mortality after saline infusions alone ( n = 9), low-dose LPS infusion + saline boluses ( n = 5), or low-dose LPS + LPS boluses ( n = 9). Low-dose LPS infusion + LPS boluses was associated with greater microglial induction than low-dose LPS + saline boluses but a similar area of periventricular white matter inflammation. One fetus developed severe focal white matter necrosis after LPS infusion + boluses. The acute cardiovascular compromise associated with high-dose, acute exposure to LPS is markedly attenuated by previous low-dose infusions, with limited apparent exacerbation of periventricular white matter injury compared with low-dose infusion alone.
Publisher: Wiley
Date: 10-12-2010
DOI: 10.1113/EXPPHYSIOL.2010.055236
Abstract: Sympathetic nerve activity (SNA) has two main properties, the presence of co-ordinated bursts of activity, indicative of many nerve fibres firing at a similar time, and entrainment of the bursts to the cardiac cycle, due to inhibitory input from baroreceptors to a network of cell groups within the CNS. Although this patterning is used as a 'gold standard' for the identification of successful nerve recordings, the maturation of these basic features of SNA from fetal life to adulthood has not been investigated. Using a telemetry-based nerve lifier, renal SNA (RSNA) was recorded in preterm (99 ± 1 days gestation term 147 days) and near-term fetal sheep (119 ± 0 days gestation), without anaesthesia or paralysis, and contrasted with RSNA recorded in adult sheep. All three age groups showed a classic bursting pattern of RSNA and co-ordination of bursts with the cardiac cycle. However, the delay between diastole and the next peak in RSNA was longest in preterm fetuses (319 ± 1 ms), compared with near-term fetuses (250 ± 13 ms), and shortest in the adult sheep (174 ± 38 ms). This was independent of the maturational decrease in heart rate. The near-term fetuses showed a marked but sleep-state-dependent increase in resting RSNA compared with preterm fetuses. Although entrainment with the pressure pulse suggests that the intricate circuitry within the CNS is developed in the preterm fetus, the decrease in the length of the delay suggests continuing maturation of this key feature of RSNA in the last third of gestation and after birth.
Publisher: American Physiological Society
Date: 07-2007
DOI: 10.1152/AJPREGU.00891.2006
Abstract: Extensive studies in the adult have demonstrated that the sympathetic nervous system plays a central role in cardiovascular control. The maturation of the sympathetic nervous system before birth is poorly understood. In the present study, we directly recorded renal sympathetic nerve activity (renal SNA) in five preterm fetal sheep (99 ± 1 days gestation term is 147 days). Recordings were performed in utero using a telemetry-based technique to alleviate movement artifact without anesthesia or paralysis. The preterm fetuses exhibited a coordinated discharge pattern in renal SNA, indicating many in idual neurons active at approximately the same time. This is consistent with that observed previously in adult animals, although the frequency of the bursts was relatively low (0.5 ± 0.1 Hz). The discharges in renal SNA were entrained to the cardiac cycle (average delay between diastolic pressure and maximum renal SNA 319 ± 1 ms). The entrainment of the sympathetic discharges to the cardiac cycle indicates phasic baroreceptor input and that the underlying circuits controlling SNA within the central nervous system are active in premature fetuses.
Publisher: Wiley
Date: 16-03-2006
DOI: 10.1111/J.1440-1681.2006.04364.X
Abstract: 1. Poor perfusion of the kidneys and gut, and associated functional impairment, are major problems in the first days of life in very preterm infants. These complications can be associated with a substantial mortality and further problems such as reduced kidney growth and chronic renal problems in later childhood. 2. There is very little information, and consequently considerable debate, about how or even whether to improve perfusion of the vital organs of this most vulnerable group of babies. Current treatments simply do not consistently improve babies' perfusion generally or kidney and gut perfusion and function in particular. 3. In this review we critically examine clinical and experimental evidence that suggests that exposure to low oxygen levels before and during birth may be a significant contributor to impaired systemic perfusion, and highlight areas requiring further research. 4. This knowledge is essential to develop and refine ways of improving perfusion of the kidneys and other vital organs in premature babies.
Publisher: American Physiological Society
Date: 15-05-2013
DOI: 10.1152/AJPREGU.00005.2013
Abstract: There is increasing evidence that exposure to infection can sensitize the fetus to subsequent hypoxic injury. However, it is unclear whether this involves compromise of the fetal cardiovascular adaptation to acute asphyxia. Chronically instrumented 103-day-old (0.7 gestational age, term is 147 days) fetal sheep in utero were randomized to receive either gram-negative lipopolysaccharide (LPS) as a continuous low-dose infusion for 120 h plus boluses of 1 μg LPS at 48, 72, and 96 h with asphyxia at 102 h (i.e., 6 h after the final LPS bolus) induced by umbilical cord occlusion for 15 min (LPS treated, n = 8), or the same volume of saline plus occlusion (saline treated, n = 7). Fetuses were killed 5 days after occlusion. LPS was associated with a more rapid fall in fetal heart rate at the onset of occlusion ( P 0.05) and with minimally lower values during occlusion ( P 0.05). The LPS-treated fetuses had lower fetal mean arterial blood pressure (BP) and greater carotid artery blood flow (CaBF) before occlusion ( P 0.05) but showed an increase in BP and fall in CaBF to similar values as saline controls during occlusion. There were no differences between the groups in femoral blood flow before or during occlusion. Contrary to our initial hypothesis, acute on chronic exposure to LPS was associated with more rapid cardiovascular adaptation to umbilical cord occlusion.
Publisher: Wiley
Date: 03-08-2020
DOI: 10.1113/JP279573
Publisher: Public Library of Science (PLoS)
Date: 18-10-2013
Publisher: American Physiological Society
Date: 03-2009
DOI: 10.1152/AJPREGU.90624.2008
Abstract: The arterial baroreflex is a fundamental reflex that buffers rapid changes in arterial blood pressure (BP) via regulation of the heart rate and sympathetic nerve activity to the vasculature. In adults a sigmoidal relationship between BP and both heart rate and sympathetic nerve activity is well documented. Its role in blood pressure control before birth is unclear. Preterm babies have a high incidence of low BP, especially in the first few days of life, which could be related, in part, to immaturity of the baroreflex. In the present study, we investigated the baroreflex control of fetal heart rate and renal sympathetic nerve activity (RSNA) in preterm fetal sheep in utero (102 ± 1 days of gestation term 140 days). Phenylephrine was associated with a significant increase in BP from 38 ± 2 to 58 ± 3 mmHg and a decrease in heart rate (HR) from 177 ± 4 to 116 ± 8 beats per minute (bpm). Sodium nitroprusside was associated with a significant fall in BP from 38 ± 2 to 26 ± 1 mmHg and an increase in HR from 182 ± 4 to 274 ± 8 bpm. However, the time between the 50% changes in BP and HR was significantly greater after hypotension than hypertension (31 ± 8 s vs. 14 ± 5 s, P 0.05). No significant changes in RSNA occurred with either stimulus. This suggests that there are different maturational tempos for the components of the central autonomic response to altered blood pressure.
Publisher: S. Karger AG
Date: 2015
DOI: 10.1159/000370309
Abstract: One of the central, unanswered questions in perinatology is why preterm infants continue to have such poor long-term neurodevelopmental, cognitive and learning outcomes, even though severe brain injury is now rare. There is now strong clinical evidence that one factor underlying disability may be infection, as well as nonspecific inflammation, during fetal and early postnatal life. In this review, we examine the experimental evidence linking both acute and chronic infection/inflammation with perinatal brain injury and consider key experimental determinants, including the microglia response, relative brain and immune maturity and the pattern of exposure to infection. We highlight the importance of the origin and derivation of the bacterial cell wall component lipopolysaccharide. Such experimental paradigms are essential to determine the precise time course of the inflammatory reaction and to design targeted neuroprotective strategies to protect the perinatal brain from infection and inflammation.
Publisher: Wiley
Date: 20-04-2012
DOI: 10.1002/ANA.22670
Abstract: Perinatal hypoxic-ischemic brain injury remains a major cause of cerebral palsy. Although therapeutic hypothermia is now established to improve recovery from hypoxia-ischemia (HI) at term, many infants continue to survive with disability, and hypothermia has not yet been tested in preterm infants. There is increasing evidence from in vitro and in vivo preclinical studies that stem rogenitor cells may have multiple beneficial effects on outcome after hypoxic-ischemic injury. Stem rogenitor cells have shown great promise in animal studies in decreasing neurological impairment however, the mechanisms of action of stem cells, and the optimal type, dose, and method of administration remain surprisingly unclear, and some studies have found no benefit. Although cell-based interventions after completion of the majority of secondary cell death appear to have potential to improve functional outcome for neonates after HI, further rigorous testing in translational animal models is required before randomized controlled trials should be considered.
Publisher: Springer Science and Business Media LLC
Date: 16-05-2014
Publisher: American Physiological Society
Date: 07-2012
DOI: 10.1152/AJPREGU.00063.2012
Abstract: The sympathetic nervous system (SNS) is an important mediator of fetal adaptation to life-threatening in utero challenges, such as asphyxia. Although the SNS is active well before term, SNS responses mature significantly over the last third of gestation, and its functional contribution to adaptation to asphyxia over this critical period of life remains unclear. Therefore, we examined the hypotheses that increased renal sympathetic nerve activity (RSNA) is the primary mediator of decreased renal vascular conductance (RVC) during complete umbilical cord occlusion in preterm fetal sheep (101 ± 1 days term 147 days) and that near-term fetuses (119 ± 0 days) would have a more rapid initial vasomotor response, with a greater increase in RSNA. Causality of the relationship of RSNA and RVC was investigated using surgical (preterm) and chemical (near-term) denervation. All fetal sheep showed a significant increase in RSNA with occlusion, which was more sustained but not significantly greater near-term. The initial fall in RVC was more rapid in near-term than preterm fetal sheep and preceded the large increase in RSNA. These data suggest that although RSNA can increase as early as 0.7 gestation, it is not the primary determinant of RVC. This finding was supported by denervation studies. Interestingly, chemical denervation in near-term fetal sheep was associated with an initial fall in blood pressure, suggesting that by 0.8 gestation sympathetic innervation of nonrenal vascular beds is critical to maintain arterial blood pressure during the rapid initial adaptation to asphyxia.
Publisher: Elsevier BV
Date: 04-2012
Publisher: American Physiological Society
Date: 15-08-2014
DOI: 10.1152/AJPREGU.00110.2014
Abstract: Perinatal exposure to infection is highly associated with adverse outcomes. Experimentally, acute, severe exposure to gram-negative bacterial lipopolysaccharide (LPS) is associated with increased fetal heart rate variability (FHRV). It is unknown whether FHRV is affected by subclinical infection with or without acute exacerbations. We therefore tested the hypothesis that FHRV would be associated with hypotension after acute on chronic exposure to LPS. Chronically instrumented fetal sheep at 0.7 gestation were exposed to a continuous low-dose LPS infusion ( n = 12, 100 ng/kg over 24 h, followed by 250 ng·kg −1 ·24 h −1 for a further 96 h) or the same volume of saline ( n = 10). Boluses of either 1 μg LPS or saline were given at 48, 72, and 96 h. Low-dose infusion was not associated with hemodynamic or FHRV changes. The first LPS bolus was associated with tachycardia and suppression of nuchal electromyographic activity in all fetuses. Seven of twelve fetuses developed hypotension (a fall in mean arterial blood pressure ≥5 mmHg). FHRV was transiently increased only at the onset of hypotension, in association with increased cytokine induction and electroencephalogram suppression. FHRV then fell before the nadir of hypotension, with transient suppression of short-term FHRV. After the second LPS bolus, the hypotension group showed a biphasic pattern of a transient increase in FHRV followed by more prolonged suppression. These findings suggest that infection-related hypotension in the preterm fetus mediates the transient increase in FHRV and that repeated exposure to LPS leads to progressive loss of FHRV.
Publisher: American Physiological Society
Date: 09-2007
DOI: 10.1152/AJPREGU.00342.2007
Abstract: Clinically and experimentally male fetuses are at significantly greater risk of dying or suffering injury at birth, particularly after premature delivery. We undertook a retrospective cohort analysis of 60 female and 65 male singleton preterm fetal sheep (103–104 days, 0.7 gestation) with mean arterial blood pressure (MAP), heart rate, and carotid and femoral blood flow recordings during 25 min of umbilical cord occlusion in utero. Occlusions were stopped early if fetal MAP fell below 8 mmHg or if there was asystole for s. Fetuses that were able to complete the full 25-min period of occlusion showed no differences between sexes for any cardiovascular responses. Similar numbers of occlusions were stopped early in males (mean: 21 min, n = 16) and females (mean: 23 min, n = 16) however, they showed different responses. Short-occlusion males ( n = 16) showed a slower initial fall in femoral vascular conductance, followed by greater bradycardia, hypotension, and associated organ hypoperfusion compared with full-occlusion fetuses. In contrast, short-occlusion females ( n = 16) showed a significantly more rapid early increase in femoral vascular conductance than the full-occlusion fetuses, followed by worsening of bradycardia and hypotension that was intermediate to the full-occlusion fetuses and short-occlusion males. Among all fetuses, MAP at 15 min of occlusion, corresponding with the time of the maximal rate of fall, was correlated with postmortem weight in males ( R 2 = 0.07) but not females. In conclusion, male and female fetuses showed remarkably similar chemoreflex and hemodynamic responses to severe asphyxia, but some males did show impaired hemodynamic adaptation within the normal weight range.
Publisher: Wiley
Date: 06-12-2012
DOI: 10.1113/EXPPHYSIOL.2012.069989
Abstract: Dopamine is commonly used for blood pressure support in the neonate, but has limited empirical evidence to support its use. We tested the hypothesis that after near-terminal asphyxia in utero, dopamine infusions would prevent secondary hypotension. Fetal sheep (122-129 days of gestation term is 147 days) received umbilical cord occlusion for 15 min or sham occlusion (n = 5). If the mean arterial blood pressure fell below 90% of baseline within 6 h after occlusion, fetuses were randomized to either dopamine infusion starting at 4 μg kg(-1) min(-1) and titrated according to mean arterial blood pressure up to a maximum of 40 μg kg(-1) min(-1) (n = 5) or to the same volume of normal saline (n = 5). Dopamine infusion, initiated at a median of 180 min after occlusion (range 96-280 min), was associated with a marked but transient increase in mean arterial blood pressure and fall in femoral blood flow compared with saline. Terminal hypotension developed later in four of the five fetuses that received maximal dopamine infusions than in five of five receiving saline infusion [517 (range 240-715) versus 106 min (range 23-497) after the start of infusions, P < 0.05]. In conclusion, dopamine infusion delayed but did not prevent terminal hypotension after severe asphyxia.
Publisher: Elsevier BV
Date: 09-2002
Abstract: Current treatment of acute stroke remains unsatisfactory. This review presents experimental and clinical data which suggest that mild induced hypothermia could be a potent and practicable neuroprotective treatment of acute ischaemic stroke and intracerebral haemorrhage. Hypothermia, if proven to be safe, effective and widely practicable in patients with acute stroke, could have an enormous positive impact on reducing the burden of stroke worldwide. Critical issues that will need to be considered in a well designed randomised controlled trial of induced hypothermia in acute stroke patients are discussed.
Publisher: Wiley
Date: 21-06-2011
DOI: 10.1113/EXPPHYSIOL.2011.058354
Abstract: Late preterm infants, born between 34 and 36 weeks gestation, have significantly higher morbidity than neonates born at full term, which may be partly related to reduced sensitivity of the arterial baroreflex. The present study assessed baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) in near-term fetal sheep at 123 ± 1 days gestation. At this age, although fetuses are not fully mature in some respects (term is 147 days), sleep-state cycling is established [between high-voltage, low-frequency (HV) and low-voltage, high-frequency (LV) sleep], and neural myelination is similar to the term human infant. Fetal sheep were instrumented to record blood pressure (BP), HR (n = 15) and RSNA (n = 5). Blood pressure was manipulated using vasoactive drugs, phenylephrine and sodium nitroprusside. In both HV and LV sleep, phenylephrine was associated with increased arterial BP and decreased HR. In HV sleep, phenylephrine was associated with a fall in RSNA, from 124 ± 14 to 58 ± 11% (P < 0.05), but no significant change in RSNA in LV sleep. In contrast, the fall in BP after sodium nitroprusside was associated with a significant increase in HR during LV but not HV sleep, and there was no significant effect of hypotension on RSNA. These data demonstrate that in near-term fetal sheep baroreflex activity is only partly active and is highly modulated by sleep state. Critically, there was no RSNA response to marked hypotension this finding has implications for the ability of the late preterm fetus to adapt to low BP.
Publisher: Informa Healthcare
Date: 05-02-2015
DOI: 10.1517/14728222.2015.1010514
Abstract: Exogenous IGF-1 protects the brain from ischemic injury and improves function. However, its clinical application to neurological disorders is limited by its large molecular size, poor central uptake and mitogenic potential. In this review, the authors have discussed the efficacy, pharmacokinetics and mechanisms of IGF-1 derivatives on protecting acute brain injury, preventing memory impairment and improving recovery from neurological degenerative conditions evaluated in various animal models. We have included natural metabolites of IGF-1, glycine-proline-glutamate (GPE), cleaved from N-terminal IGF-1 and cyclic glycine-proline (cGP) as well as the structural analogues of GPE and cGP, glycine-2-methyl-proline-glutamate and cyclo-l-glycyl-l-2-allylproline, respectively. In addition, the regulatory role for cGP in bioavailability of IGF-1 has also been discussed. These small neuropeptides provide effective neuroprotection by offering an improved pharmacokinetic profile and more practical route of administration compared with IGF-1 administration. Developing modified neuropeptides to overcome the limitations of their endogenous counterparts represents a novel strategy of pharmaceutical discovery for neurological disorders. The mechanism of action may involve a regulation of IGF-1 bioavailability.
Publisher: Wiley
Date: 09-1995
Publisher: Elsevier BV
Date: 10-2010
Publisher: American Physiological Society
Date: 08-2012
DOI: 10.1152/AJPREGU.00216.2012
Abstract: Exposure to chorioamnionitis is strongly associated with neurodevelopmental disability after premature birth however, it remains unclear whether subclinical infection affects functional EEG maturation. Chronically instrumented 103–104-day-old (0.7 gestational age: term 147 days) fetal sheep in utero were randomized to receive either gram-negative LPS by continuous low-dose infusion (100 ng iv over 24 h, followed by 250 ng/24 h for 4 days n = 6) or the same volume of normal saline ( n = 9). Arterial plasma cortisol, ACTH, and IL-6 were measured. The delta (0–3.9 Hz), theta (4–7.9 Hz), alpha (8–12.9 Hz), and beta (13–22 Hz) components of the EEG were determined by power spectral analysis. Brains were taken after 10 days for histopathology. There were no changes in blood gases, cardiovascular variables, or EEG power during LPS infusion, but a transient rise in plasma cortisol and IL-6 ( P 0.05). LPS infusion was associated with loss of the maturational increase to higher frequency activity, with reduced alpha and beta power, and greater delta power than saline controls from 6 to 10 days ( P 0.05). Histologically, LPS was associated with increased numbers of microglia and TNF-α-positive cells in the periventricular white matter and frontoparietal cortex, increased caspase-3-positive cells in white matter, but no loss of CNPase-positive oligodendrocytes, Nurr-1 subplate cells, or gyral complexity. These data suggest that low-dose endotoxin exposure can impair EEG maturation in preterm fetal sheep in association with neural inflammation but without hemodynamic disturbances or cortical injury.
Publisher: Springer Science and Business Media LLC
Date: 05-11-2015
DOI: 10.1038/SREP16201
Abstract: Subclinical (shallow) heart rate decelerations occur during neonatal sepsis, but there is limited information on their relationship with hypotension or whether they occur before birth. We examined whether subclinical decelerations, a fall in fetal heart rate (FHR) that remained above 100 bpm, were associated with hypotension in preterm fetal sheep exposed to lipopolysaccharide (LPS). Chronically-instrumented fetal sheep at 0.7 gestation received continuous low-dose LPS infusions (n = 15, 100 ng/kg over 24 h, followed by 250 ng/kg/24 h for 96 h) or saline (n = 8). Boluses of 1 μg LPS or saline were given at 48 and 72 h. FHR variability (FHRV) was calculated and s le asymmetry was used to assess the severity and frequency of decelerations. Low-dose LPS infusion did not affect FHR. After the first LPS bolus, 7 fetuses remained normotensive, while 8 developed hypotension (a fall in mean arterial blood pressure of ≥5 mmHg). Developing hypotension was associated with subclinical decelerations, with a corresponding increase in s le asymmetry and FHRV (p 0.05). The second LPS bolus was associated with similar but attenuated changes in FHR and blood pressure (p 0.05). In conclusion, subclinical decelerations are not consistently seen during prenatal exposure to LPS, but may be a useful marker of developing inflammation-related hypotension before birth.
Publisher: American Physiological Society
Date: 10-2009
DOI: 10.1152/AJPREGU.90979.2008
Abstract: The efferent mechanisms mediating the well-known diurnal cardiovascular rhythms in the late-gestation fetus are only partially understood. In the present study, we evaluated the contribution of the parasympathetic and sympathetic nervous systems (SNS) to these rhythms. Chronically instrumented fetal sheep at a mean (SE) of 122 ( 1 ) days gestation (term is 147 days) underwent either chemical sympathectomy with 6-hydroxydopamine the day after surgery ( n = 8), vagotomy at surgery ( n = 8), or were sham controls ( n = 8). Fetal heart rate (HR), fetal HR variability (HRV), mean arterial blood pressure (MAP), carotid blood flow (CaBF), electrocorticogram (ECoG) activity, and nuchal activity were measured continuously for 24 h. Changes between sleep states were determined in a 6-h interval. Control fetal sheep showed consistent diurnal rhythms in fetal HR, HRV, MAP, and CaBF, with maximal activity in the evening, but not in nuchal activity. Sympathectomy was associated with a significant reduction of both fetal HR and HRV, while vagotomy was associated with a fall in fetal HRV ( P 0.05) but no change in HR. Despite this, most animals in the two intervention groups still showed diurnal rhythms for fetal HR, HRV, MAP, and CaBF, although peak HR may have been delayed in the sympathectomy group (mean 02:22 vs. 23:54 h in controls, P = 0.06). There was no effect of either intervention on sleep state cycling, although state-related cardiovascular rhythms were significantly modulated. These data indicate that, neither the SNS nor vagal activity, in isolation at least, is essential for generating cardiovascular diurnal rhythms in the late-gestation fetus.
Publisher: S. Karger AG
Date: 2014
DOI: 10.1159/000362206
Abstract: There is an important unmet need to further improve the outcome of neonatal encephalopathy in term infants. Meta-analyses of large controlled trials now suggest that maternal magnesium sulfate (MgSO sub /sub ) therapy is associated with a reduced risk of cerebral palsy and gross motor dysfunction after premature birth, but that it has no effect on death or disability. Because of this inconsistency, it remains controversial whether MgSO sub /sub is clinically neuroprotective and, thus, it is unclear whether it would be appropriate to test MgSO sub /sub for treatment of encephalopathy in term infants. We therefore systematically reviewed the preclinical evidence for neuroprotection with MgSO sub /sub before or after hypoxic-ischemic encephalopathy (HIE) in term-equivalent perinatal and adult animals. The outcomes were highly inconsistent between studies. Although there were differences in dose and timing of administration, there was evidence that beneficial effects of MgSO sub /sub were associated with confounding mild hypothermia and, strikingly, the studies that included rigorous maintenance of environmental temperature or body temperature consistently suggested a lack of effect. On balance, these preclinical studies suggest that peripherally administered MgSO sub /sub is unlikely to be neuroprotective. Rigorous testing in translational animal models of perinatal HIE is needed before MgSO sub /sub should be considered in clinical trials for encephalopathy in term infants.
Publisher: Public Library of Science (PLoS)
Date: 05-05-2014
Publisher: Springer Science and Business Media LLC
Date: 12-2013
Abstract: White matter injury (WMI) is the major antecedent of cerebral palsy in premature infants, and is often associated with maternal infection and the fetal inflammatory response. The current study explores the therapeutic potential of glutamate receptor blockade or cyclooxygenase-2 (COX-2) inhibition for inflammatory WMI. Using fetal ovine derived mixed glia cultures exposed to tumour necrosis factor-α (TNF-α) or lipopolysaccharide (LPS), the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and N-methyl D-aspartate (NMDA) glutamate receptors and their contribution to inflammation mediated pre-oligodendrocyte (OL) death was evaluated. The functional significance of TNF-α and COX-2 signalling in glutamate release in association with TNF-α and LPS exposure was also assessed. AMPA and NMDA receptors were expressed in primary mixed glial cultures on developing OLs, the main cell-type present in fetal white matter at a period of high risk for WMI. We show that glutamate receptor expression and configuration are regulated by TNF-α and LPS exposure, but AMPA and NMDA blockade, either alone or in combination, did not reduce pre-OL death. Furthermore, we demonstrate that glutamate and prostaglandin E2 (PGE2) release following TNF-α or LPS are mediated by a TNF-α-COX-2 dependent mechanism. Overall, these findings suggest that glial-localised glutamate receptors likely play a limited role in OL demise associated with chronic inflammation, but supports the COX-2 pathway as a potential therapeutic target for infection/inflammatory-mediated WMI.
Publisher: Elsevier BV
Date: 12-1992
DOI: 10.1016/S0022-3476(05)80342-7
Abstract: To assess the role of growth hormone in fetal and infant growth, we analyzed the pretreatment data on 52 patients with a diagnosis of congenital growth hormone deficiency before 2 years of age, obtained from the Kabi Pharmacia International Growth Study. These infants had reduced birth-length standard deviation scores, an excess of birth weight relative to length, and progressive growth failure. We conclude that congenital growth hormone deficiency may cause impaired growth in utero and early infancy, and that growth hormone plays an important role in perinatal and infantile growth.
Publisher: American Physiological Society
Date: 10-2007
DOI: 10.1152/JAPPLPHYSIOL.00396.2007
Abstract: There is evidence that preterm fetuses have blunted chemoreflex-mediated responses to hypoxia. However, the preterm fetus has much lower aerobic requirements than at term, and so moderate hypoxia may not be sufficient to elicit maximal chemoreflex responses there are only limited quantitative data on the ontogeny of chemoreflex and hemodynamic responses to severe asphyxia. Chronically instrumented fetal sheep at 0.6 ( n = 12), 0.7 ( n = 12), and 0.85 ( n = 8) of gestational age (GA term = 147 days) were exposed to 30, 25, or 15 min of complete umbilical cord occlusion, respectively. At all ages, occlusion was associated with early onset of bradycardia, profoundly reduced femoral blood flow and conductance, and hypertension. The 0.6-GA fetuses showed a significantly slower and lesser fall in femoral blood flow and conductance compared with the 0.85-GA group, with a correspondingly reduced relative rise in mean arterial blood pressure. As occlusion continued, the initial adaptation was followed by loss of peripheral vasoconstriction and progressive development of hypotension in all groups. The 0.85-GA fetuses showed significantly more sustained reduction in femoral conductance but also more rapid onset of hypotension than either of the younger groups. Electroencephalographic (EEG) activity was suppressed during occlusion in all groups, but the degree of suppression was less at 0.6 GA than at term. In conclusion, the near-midgestation fetus shows attenuated initial (chemoreflex) peripheral vasomotor responses to severe asphyxia compared with more mature fetuses but more sustained hemodynamic adaptation and reduced suppression of EEG activity during continued occlusion of the umbilical cord.
Publisher: Wiley
Date: 09-10-2013
Publisher: MDPI AG
Date: 07-02-2021
DOI: 10.3390/IJMS22041671
Abstract: Preterm birth is associated with a high risk of morbidity and mortality including brain damage and cerebral palsy. The development of brain injury in the preterm infant may be influenced by many factors including perinatal asphyxia, infection/inflammation, chronic hypoxia and exposure to treatments such as mechanical ventilation and corticosteroids. There are currently very limited treatment options available. In clinical trials, magnesium sulfate has been associated with a small, significant reduction in the risk of cerebral palsy and gross motor dysfunction in early childhood but no effect on the combined outcome of death or disability, and longer-term follow up to date has not shown improved neurological outcomes in school-age children. Recombinant erythropoietin has shown neuroprotective potential in preclinical studies but two large randomized trials, in extremely preterm infants, of treatment started within 24 or 48 h of birth showed no effect on the risk of severe neurodevelopmental impairment or death at 2 years of age. Preclinical studies have highlighted a number of promising neuroprotective treatments, such as therapeutic hypothermia, melatonin, human amnion epithelial cells, umbilical cord blood and vitamin D supplementation, which may be useful at reducing brain damage in preterm infants. Moreover, refinements of clinical care of preterm infants have the potential to influence later neurological outcomes, including the administration of antenatal and postnatal corticosteroids and more accurate identification and targeted treatment of seizures.
Publisher: Wiley
Date: 29-10-2012
DOI: 10.1111/J.1440-1681.2012.05744.X
Abstract: Preterm newborns, particularly very low birth weight newborns, frequently experience intermittent hypotension and/or hypoperfusion. Organ perfusion is largely distinct from systemic hypotension, suggesting that changes in underlying vascular tone are the major determinants of perfusion. Preterm fetuses have a remarkable anaerobic tolerance and ability to survive major insults with no or limited injury, balanced by relative immaturity of key autonomic responses. Exposure to hypoxia-ischaemia and infection trigger complex changes in vascular tone that evolve over many days and there is evidence that these are centrally controlled and linked, in part, with underlying organ metabolism. Hypoperfusion frequently occurs after hypoxia-ischaemia without organ injury occurring. Hypoxia-ischaemia, infection and many clinical interventions, such as steroid therapy and ventilation, can interact to increase or decrease the risk of brain injury.
Publisher: S. Karger AG
Date: 2013
DOI: 10.1159/000354862
Abstract: To determine whether increased matrix metalloproteinase (MMP) proteolytic activity plays a pathological role in infection/inflammation-induced preterm brain injury, primary cultures of preterm (day 90 of gestation term 145 days) fetal ovine mixed glia were exposed to 24-96 h of lipopolysaccharide (LPS, 1 μg/ml) or tumour necrosis factor-α (TNF-α, 100 ng/ml). MMP-2 mRNA levels were significantly increased after TNF-α (96 h) and LPS exposure (48 and 96 h), and MMP-9 mRNA levels were significantly increased at 48 and 96 h after TNF-α. On zymography, the active form of secreted MMP-2 was significantly increased 24 h after LPS, but not TNF-α. Both active and latent forms of MMP-9 gelatinolytic activity were significantly increased by TNF-α (96 h) and LPS (72 and 96 h). On reverse zymography, inhibitory activity of TIMP-1 but not TIMP-2 was significantly increased by TNF-α and LPS. SB-3CT-mediated MMP-2 and MMP-9 inhibition transiently reduced LPS-induced oligodendrocyte cell death but had no effect during TNF-α exposure. Collectively, these observations suggest a limited, transient effect of MMPs on immature white matter damage associated with infection but not TNF-α-mediated inflammation.
Publisher: SAGE Publications
Date: 12-09-2017
Abstract: Perinatal hypoxic-ischemic (HI) brain injury remains highly associated with neurodevelopmental disability after preterm birth. There is increasing evidence that disability is linked with impaired white matter maturation, but there is no specific treatment. In this study, we evaluated whether, in preterm fetal sheep, delayed intranasal infusion of human amnion epithelial cells (hAECs) given 1, 3 and 10 days after severe HI, induced by umbilical cord occlusion for 25 min, can restore white matter maturation or reduce delayed cell loss. After 21 days recovery, asphyxia was associated with reduced electroencephalographic (EEG) maturation, brain weight and cortical area, impaired maturation of oligodendrocytes (OLs), no significant loss of total OLs but a marked reduction in immature/mature OLs and reduced myelination. Intranasal infusion of hAECs was associated with improved brain weight and restoration of immature/mature OLs and fractional area of myelin basic protein, with reduced microglia and astrogliosis. Cortical EEG frequency distribution was partially improved, with reduced loss of cortical area, and attenuated cleaved-caspase-3 expression and microgliosis. Neuronal survival in deep grey matter nuclei was improved, with reduced microglia, astrogliosis and cleaved-caspase-3-positive apoptosis. These findings suggest that delayed intranasal hAEC administration has potential to alleviate chronic dysmaturation after perinatal HI.
Publisher: Elsevier BV
Date: 09-2003
Publisher: Springer Science and Business Media LLC
Date: 15-02-2012
DOI: 10.1038/PR.2011.80
Abstract: This study examined whether spectral analysis of the electroencephalogram (EEG) can discriminate between mild and severe hypoxic-ischemic injury in the immature brain. Total EEG power was profoundly suppressed after umbilical cord occlusion and recovered to baseline by 5 h after 15-min of occlusion, in contrast with transient recovery in the 25-min (P < 0.05). Power spectra were not different between groups in the first 3 h α and β power were significantly higher in the 15-min group from 4 h, and Δ and θ power from 5 h (P < 0.05). The 25-min group showed severe neuronal loss in hippoc al regions and basal ganglia at 3 days, in contrast with no/minimal injury in the 15-min group. EEG power after asphyxia did not discriminate between mild and severe injury in the first 3 h in preterm fetal sheep. Severe subcortical neural injury was associated with persistent loss of high-frequency activity. Chronically instrumented fetal sheep at 0.7 gestation (101-104 days term is 147 days) received either 15-min (n = 13) or 25-min (n = 13) of complete umbilical cord occlusion. The Δ (0-3.9 Hz), θ (4-7.9 Hz), α (8-12.9 Hz), and β (13-22 Hz) components of the EEG were determined by power spectral analysis. Brains were taken at 3 days for histopathology.
Publisher: Elsevier BV
Date: 08-2008
DOI: 10.1016/J.NEUROPHARM.2008.05.009
Abstract: We have previously shown that brief alpha(2)-adrenergic receptor blockade increased neuronal injury after severe hypoxia in preterm fetal sheep. We now examine whether infusion of an alpha(2)-adrenergic receptor agonist, clonidine, is neuroprotective. Preterm fetal sheep (70% gestation) received either saline-vehicle or clonidine at either 10 microg/kg/h (low-dose) or 100 microg/kg/h (high-dose) from 15 min until 4 h after 25 min of umbilical cord occlusion. Both low- and high-dose clonidine infusions after sham-occlusion were associated with transient EEG suppression but no neuronal loss. Low-dose but not high-dose clonidine infusions after umbilical cord occlusion were associated with a significant overall increase in numbers of surviving neurons after three days' recovery. High-dose clonidine was associated with transient hyperglycemia and increased numbers of delayed electrographic seizures. These results provide further evidence that alpha(2)-adrenergic receptor activation shortly after perinatal hypoxia-ischemia can promote neural recovery, but highlight the complex dose-response of exogenous therapy.
Publisher: SAGE Publications
Date: 09-10-2013
Abstract: Melatonin is a naturally occurring indolamine with mild antioxidant properties that is neuroprotective in perinatal animals. There is limited information on its effects on preterm brain injury. In this study, 23 chronically instrumented fetal sheep received 25 minutes of complete umbilical cord occlusion at 101 to 104 days gestation (term is 147 days). Melatonin was administered to the ewe 15 minutes before occlusion (0.1 mg/kg bolus followed by 0.1 mg/kg per hour for 6 hours, n=8), or the equivalent volume of vehicle (2% ethanol, n=7), or saline ( n=8), or maternal saline plus sham occlusion ( n=8). Sheep were killed after 7 days recovery in utero. Fetal blood pressure, heart rate, nuchal activity, and temperature were similar between groups. Vehicle infusion was associated with improved neuronal survival in the caudate nucleus, but greater neuronal loss in the regions of the hippoc us, with reduced proliferation and increased ameboid microglia in the white matter ( P .05). Maternal melatonin infusion was associated with faster recovery of fetal EEG, prolonged reduction in carotid blood flow, similar neuronal survival to vehicle, improved numbers of mature oligodendrocytes, and reduced microglial activation in the white matter ( P .05). Prophylactic maternal melatonin treatment is partially protective but its effects may be partly confounded by ethanol used to dissolve melatonin.
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000333109
Abstract: Sick preterm and term newborns are highly vulnerable to neural injury, and thus there has been a major search for new, safe and efficacious neuroprotective interventions in recent decades. Preclinical studies are essential to select candidate drugs for clinical trials in humans. This article focuses on ‘negative’ preclinical studies, i.e. studies where significant differences cannot be detected. Such findings are critical to inform both clinical and preclinical investigators, but historically they have been difficult to publish. A significant amount of time and resources is lost when negative results or nonpromising therapeutics are replicated in separate laboratories because these negative results were not shared with the research community in an open and accessible format. In this article, we discuss approaches to strengthen conclusions from negative preclinical studies and, conversely, to reduce false-negative preclinical evaluations of potential therapeutic compounds. Without being exhaustive, we address three major issues in conducting and interpreting preclinical experiments, including: (a) the choice of animal models, (b) the experimental design, and (c) issues concerning statistical analyses of the experiments. This general introduction is followed by synopses of negative data obtained from studies of three potential therapeutics for perinatal brain injury: (1) the somatostatin analog octreotide, (2) an AMPA/kainate receptor antagonist, topiramate, and (3) a pyruvate derivative, ethyl pyruvate.
No related grants have been discovered for Alistair Gunn.