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Objective: To determine the incidence of new onset type 1 diabetes in children aged 0–14 years from 1977 to 2019 in Auckland, New Zealand. Research design and methods: A cohort study of children with type 1 diabetes aged 0–14 years (n = 1688; 50.4% male) managed by the regional diabetes service between 1977 and 2019. Incidence rates were estimated using census data. Results: The incidence of type 1 diabetes increased by 2.9%/year from 1977 to 2006 (95% confidence interval [CI] 2.13% – 3.48%). Although there was no significant change from 2006 to 2019 (−0.3%/year, 95% CI ‐1.62% – 1.08%), there was a dramatic fall from 1976 to 2018 in the proportion of New Zealand Europeans, from 69.9 to 33.9%. New Zealand Europeans had the highest incidence (23.3/100,000, 95% CI 20.6–26.1) compared to Māori (8.3/100,000, 95% CI 6.3–10.2), Pasifika (8.6/100,000, 95% CI 6.9–10.4) and other (6.4/100,000, 95% CI 4.7–8.0). All groups showed an overall increase in incidence over time, Māori 4.4%/year, Pasifika 3.7%, compared to New Zealand European 2.7%, and other 2.1%. Incidence increased consistently in 5–9 and 10–14 year olds (2.0% and 2.2%/year, respectively). By contrast, whereas 0–4 year olds showed an increase of 4.6%/year from 1977 to 2003 (p < 0.01), there was no change from 2003 to 2019 (p = 0.2). Conclusion: There has been a plateau in the incidence of type 1 diabetes in children 0–4 years of age in the Auckland region since 2003, but not older children. The apparent plateau in the overall incidence of new onset type 1 diabetes in children 0–14 years since 2006 was mediated by substantial changes in the ethnic makeup of the Auckland region. [ABSTRACT FROM AUTHOR]

Keywords: brain injury; creatine; hypoxia-ischaemia; oxidative stress EN brain injury creatine hypoxia-ischaemia oxidative stress 3013 3014 2 07/04/22 20220701 NES 220701 Neonatal hypoxic-ischaemic encephalopathy (HIE) attributable to a lack of oxygen and reduced blood flow around the time of birth remains a major global problem, with more than a million associated deaths and 400,000 babies with brain injury every year, contributing to 2.4% of the total global burden of disease. Furthermore, the extent of brain injury with prophylactic creatine treatment has not yet been assessed extensively in this or any other large animal translational model of perinatal hypoxia-ischaemia. The reader should consider that in the present study, creatine treatment did not attenuate histological evidence of oxidative stress in the brain at 3 days after hypoxia-ischaemia. [Extracted from the article]

Despite the successful clinical translation of therapeutic hypothermia for perinatal encephalopathy into routine care, treatment is only partially effective. It is likely that this reflects the formidable challenges of initiating treatment for neonatal encephalopathy within a few hours after birth. In randomized controlled trials, cooling has been typically initiated at a mean of 4 to 5 h after birth. This is clearly not optimal, given accumulating evidence that cooling is significantly more effective when it can be initiated before 3 h. In this review, we propose that given the consistent evidence that milder hypoxic-ischemic injury is associated with slower evolution of damage, any future clinical trials of delayed treatment starting more than 6 h after an insult should target infants with milder encephalopathy. We then critically examine the evidence that erythropoietin is one of the most promising preclinical candidates either for co-treatment with the mild therapeutic hypothermia or to support neuroregeneration after the therapeutic window for acute neuroprotection. [ABSTRACT FROM AUTHOR]

Background 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. Methods 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-isoxazolepropionate (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. Results 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. Conclusions 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. [ABSTRACT FROM AUTHOR]

Aims Oxidative stress is an early event in the cascade leading in neuronal damage after hypoxic-ischemic ( HI) brain injury. In the present study, we examined the dose response and window of opportunity for neuroprotection after HI injury with Allene Oxide Synthase ( AOS), an anti-oxidative enzyme of the member of cytochrome P450 family. Methods Adult male rats received intra-cerebro-ventricular infusions of either saline (vehicle) or AOS (1 μg or 10 μg or 100 μg per rat, intracerebroventricular n = 16 all groups) either 45 min or 3 h after unilateral HI brain injury. Brains were collected 5 days later. The extent of brain damage, neuronal survival, apoptosis, and glial reactions were assessed in the striatum, hippocampus, and cortex. Results Allene Oxide Synthase was associated with reduced neuronal damage scores when given 45 min, but not 3 h, after HI injury ( P < 0.0001) in all brain regions. AOS treatment (10 μg) improved neuronal survival in the striatum, cortex, and hippocampus ( P < 0.05, P < 0.001) and reduced the microglia reaction ( P < 0.05) and numbers of caspase-3-positive cells in the hippocampus ( P < 0.01). Conclusions Early blockade of oxidative stress after HI injury reduces inflammatory response, neuronal necrosis, and apoptosis. The neuroprotective effects of AOS were time of administration-dependent suggesting a relatively restricted window of opportunity for acute brain injury. [ABSTRACT FROM AUTHOR]

Aim: To assess participation with a structured transition programme for adolescents with diabetes. Methods: Data from a regional cohort aged less than 16 years of age with type 1 (T1) and type 2 diabetes (T2D) in Auckland, New Zealand (2006–2016). Participation was defined as opting into a structured transition programme. Results: Five hundrend and twelve adolescents who were to be transferred to adult care (476 type 1 (T1D) and 36 type 2 (T2D)), overall participation rate of 83%, 86% (408/476) with T1D compared to 47% (17/36) with T2D. Within the cohort of T1D, participation rates for Māori and Pacific were lower (74% and 77%, respectively) than New Zealand Europeans (88%, p = 0.020 and p = 0.039, respectively). Lower socio‐economic status was associated with reduced participation (77%) compared to higher socio‐economic status (90%, p = 0.002). Of the 476 T1D who participated, 408 (96%) subsequently attended at least one adult service clinic ("capture"). 42% attended an adult clinic within the planned 3 months, 87% at 6 months and retention in adult clinics over 5 years of follow‐up was 78%. By contrast, the 68 young people with T1D who did not participate in the structured transition had a capture rate of 78% (p < 0.001) and retention of 63% (p = 0.036). Conclusions: In adolescents with diabetes, a formal transition from a paediatric service was associated with high rates of adult capture and subsequent retention in adult care over a 5‐year follow‐up period. Low socio‐economic status, Māori or Pacific ethnicity and T2D were associated with reduced participation in the structured transition programme. [ABSTRACT FROM AUTHOR]

Aim: To examine the clinical impact of insulin-pump therapy for children with type 1 diabetes mellitus (T1DM) in a regional paediatric service, Auckland, New Zealand. Methods: Retrospective analysis of children with T1DM from the Starship paediatric diabetes database who started on insulin-pump therapy from 2002 to 2008 compared with the whole T1DM population and with an equal number of non-pump patients matched by age, sex, ethnicity and duration of diabetes. Results: From 621 subjects with 6680 clinic visits, 75 children were treated with insulin-pump therapy for more than 12 months. Transitioning to insulin-pump treatment was associated with an improvement in HbA1c compared with baseline (−0.3%/year, P < 0.001) for up to 3 years. In contrast, despite similar deprivation scores, non-pump controls showed a continuing trend to higher HbA1C values (+0.2%/year, P < 0.01). The risk of severe hypoglycaemia fell after pump start (from 27 (0-223) to 5 (0-0.91) events/100 patient years) with no change in non-pump controls; the rate of diabetic ketoacidosis remained low in both groups. Conclusions: In a pump-naïve regional paediatric population, insulin-pump therapy for T1DM was safe and effective, and associated with sustained improvements in HbA1c and lower risk of hypoglycaemia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The discovery that mild, induced hypothermia can improve neurological recovery after global moderate to severe hypoxia-ischemia has been a dramatic validation of the strong foundation of preclinical studies that informed current protocols. The major challenge is to find ways to further improve outcomes. As discussed in this review, the findings from large clinical trials of extended cooling are highly concordant with recent animal studies. These findings support the use of precise, carefully selected animal models to refine our strategies to protect babies with moderate to severe encephalopathy before instigating further large trials. [ABSTRACT FROM AUTHOR]

The article examines the scientific advances that led to a resurgence of interest in hypothermia. It studies clinical evidence that hypothermia is efficacious, and considers whether hypothermia should be considered for routine clinical practice. The article also discusses the potential issues relating to the alternate approaches to using cooling.

Exposure to severe hypoxia leads to delayed cerebral and peripheral hypoperfusion. There is evidence in the very immature brain that transient abnormal glutaminergic receptor activity can occur during this phase of recovery. We therefore examined the role of N-methyl-d-aspartate (NMDA) receptor activity in mediating secondary hypoperfusion in preterm fetal sheep at 70% of gestation. Fetuses received either sham asphyxia or asphyxia and were studied for 12 h recovery. The specific, non-competitive NMDA receptor antagonist dizocilpine maleate (2 mg kg−1 bolus plus 0.07 mg kg h−1i.v.) or saline (vehicle) was infused from 15 min after asphyxia until 4 h. In the asphyxia–vehicle group abnormal epileptiform EEG transients were observed during the first 4 h of reperfusion, the peak of which corresponded approximately to the nadir in peripheral and cerebral hypoperfusion. Dizocilpine significantly suppressed this activity (2.7 ± 1.3 versus 11.2 ± 2.7 counts min−1 at peak frequency, P < 0.05) and markedly delayed and attenuated the rise in vascular resistance in both peripheral and cerebral vascular beds observed after asphyxia, effectively preventing the initial deep period of hypoperfusion in carotid blood flow and femoral blood flow ( P < 0.01). However, while continued infusion did attenuate subsequent transient tachycardia, it did not prevent the development of a secondary phase of persistent but less profound hypoperfusion. In conclusion, the present studies suggest that in the immature brain the initial phase of delayed cerebral and peripheral hypoperfusion following exposure to severe hypoxia is mediated by NMDA receptor activity. The timing of this effect in the cerebral circulation corresponds closely to abnormal EEG activity, suggesting a pathological glutaminergic activation that we speculate is related to evolving brain injury. [ABSTRACT FROM AUTHOR]

It has been hypothesized that the hypothalamic-pituitary-adrenal (HPA) axis is immature in the preterm fetus and that this compromises their ability to adapt to hypoxic stress; however, there are few direct data. We therefore examined the effects of asphyxia on HPA responses in chronically instrumented preterm fetal sheep (104 days of gestation; term is 147 days), allocated to a sham control group ( n= 7) or 25 min of complete umbilical cord occlusion ( n= 8), followed by recovery for 72 h. During umbilical cord occlusion there was a rapid rise in ACTH levels (230.4 ± 63.5 versus 14.1 ± 1.8 ng ml−1 in sham controls, 16-fold) and cortisol levels (7.4 ± 4.9 versus 0.2 ± 0.1 ng ml−1, 31-fold), with further increases after release of cord occlusion. ACTH levels were normalized by 24 h, while plasma cortisol levels returned to sham control values 72 h after asphyxia. Fetal arterial blood pressure was elevated in the first 36 h, with a marked increase in femoral vascular resistance, and correlated positively with cortisol levels after asphyxia ( P= 0.05). In conclusion, the preterm fetus shows a brisk, substantial HPA response to severe hypoxia. [ABSTRACT FROM AUTHOR]

The possibility of a therapeutic role for cerebral hypothermia during or after resuscitation from perinatal asphyxia has been a long-standing focus of research. However, early studies had limited and contradictory results. It is now known that severe hypoxia-ischemia may not cause immediate cell death, but may precipitate a complex biochemical cascade leading to the delayed development of neuronal loss. These phases include a latent phase after reperfusion, with initial recovery of cerebral energy metabolism but EEG suppression, followed by a secondary phase characterized by accumulation of cytotoxins, seizures, cytotoxic edema, and failure of cerebral oxidative metabolism from 6 to 15 h post insult. Although many of the secondary processes can be injurious, they appear to be primarily epiphenomena of the 'execution' phase of cell death. This conceptual framework allows a better understanding of the experimental parameters that determine effective hypothermic neuroprotection, including the timing of initiation of cooling, its duration and the depth of cooling attained. Moderate cerebral hypothermia initiated in the latent phase, between one and as late as 6 h after reperfusion, and continued for a sufficient duration in relation to the severity of the cerebral injury, has been consistently associated with potent, long-lasting neuroprotection in both adult and perinatal species. The results of the first large multicentre randomized trial of head cooling for neonatal encephalopathy and previous phase I and II studies now strongly suggest that prolonged cerebral hypothermia is both generally safe -- at least in an intensive care setting -- and can improve intact survival up to 18 months of age. Both long-term follow-up studies and further large studies of whole body cooling are in progress. [ABSTRACT FROM AUTHOR]

Objectives: Persistent reductions in insulin-like growth factor I (IGF-I) levels in the preterm infant are strongly associated with increased risk of retinopathy and other complications, and may result from exposure to severe hypoxia. The effects of a potential new treatment for hypoxic-ischemic encephalopathy, cerebral hypothermia, on the responses of the IGF axis to hypoxia are unknown. The aim of this study was to examine the effects of prenatal asphyxia and cerebral hypothermia on changes in IGF-I and -II, IGF-binding protein 1 (IGFBP-1), and insulin levels. Methods: Fetal sheep at 0.7 of gestation underwent either sham asphyxia and sham cooling (n = 7), asphyxia induced by 25 minutes of complete umbilical cord occlusion alone (n = 8), or asphyxia and head cooling (n = 8, extradural temperature 29.5 ± 2.6C [vs 39.4 ± 0.3C; P < .05]). Fetuses were studied for 3 days post-insult, during which time fetal blood samples were taken for endocrine measurements. Results: There were no IGF axis changes during occlusion. Plasma IGF-I levels significantly decreased between 6 hours and 48 hours after asphyxia and IGF-II levels by 10 hours, in both asphyxia groups. IGFBP-1 rose from 4 hours, reaching a peak at 10 hours and returning to control values by 48 hours in the normothermia group, and by 24 hours in the hypothermia group. Insulin levels decreased between 2 hours and 10 hours after asphyxia in both asphyxia groups, and subsequently normalized. Conclusions: This study demonstrates for the first time that transient asphyxia in the preterm sheep fetus is associated with a significant decrease in IGF-II as well as IGF-I during recovery, and that these responses are not altered by mild systemic hypothermia. [Copyright &y& Elsevier]

George, Sherly, Alistair J. Gunn, Jenny A. Westgate, Christine Brabyn, Jian Guan, and Laura Bennet. Fetal heart rate variability and brain stem injury after asphyxia in preterm fetal sheep. Am J Physiol Regul Integr Comp Physiol 287: R925-R933, 2004. First published June 10, 2004; 10.1152/ajpregu.00263.2004.—This study was undertaken to determine the mechanisms mediating changes in fetal heart rate variability (FHRV) during and after exposure to asphyxia in the premature fetus. Preterm fetal sheep at 0.6 of gestation (91 ± 1 days, term is 147 days) were exposed to either sham occlusion (n = 10) or to complete umbilical cord occlusion for either 20 (n = 7) or 30 min (n = 10). Cord occlusion led to a transient increase in FHRV with abrupt body movements that resolved after 5 min. In the 30 min group there was a marked increase in FHRV in the final 10 min of occlusion related to abnormal atrial activity. After reperfusion, FHRV in both study groups was initially suppressed and progressively increased to baseline levels over the first 4 h of recovery. In the 20 min group this improvement was associated with return of normal EEG activity and movements. In contrast, in the 30 min group the EEG was abnormal with epileptiform activity superimposed on a suppressed background, which was associated with abnormal fetal movements. As the epileptiform activity resolved, FHRV fell and became suppressed for the remainder of the study. Histological assessment after 72 h demonstrated severe brain stem injury in the 30 min group but not in the 20 min group. In conclusion, during early recovery from asphyxia, epileptiform activity and associated abnormal fetal movements related to evolving neural injury can cause a confounding transient increase in FHRV, which mimics the normal pattern of recovery. However, chronic suppression of FHRV was a strong predictor of severe brain stem injury. [ABSTRACT FROM AUTHOR]

Focuses on a study which examined the hypothesis that the development of hydrops fetalis after asphyxia in the gestation sheep fetus would be associated with activation of the fetal renin-angiotensin system. Methods; Results; Discussion.

Studies nonimmune hydrops fetalis and activation of the renin-angiotensin system after asphyxia in preterm fetal sheep. Blood composition and cardiovascular measurements; Time sequence of changes in plasma renin concentration; Effects of asphyxia caused by occlusion of the umbilical cord on renal renin concentration.

• Postnatal inflammation causes evolving deficits in cortical neuronal dendritic maturation. • EEG was effective for identifying the early onset of cortical neuronal dysmaturation. • DTI and NODDI only detect established neuronal changes after postnatal inflammation. • EEG and MRI are complementary tools for assessing postnatal cortical dysmaturation. Exposure to postnatal systemic inflammation is associated with increased risk of brain injury in preterm infants, leading to impaired maturation of the cerebral cortex and adverse neurodevelopmental outcomes. However, the optimal method for identifying cortical dysmaturation is unclear. Herein, we compared the utility of electroencephalography (EEG), diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI) at different recovery times after systemic inflammation in newborn rats. Sprague Dawley rat pups of both sexes received single-daily lipopolysaccharide (LPS; 0.3 mg/kg i.p.; n = 51) or saline (n = 55) injections on postnatal days (P)1, 2, and 3. A subset of these animals were implanted with EEG electrodes. Cortical EEG was recorded for 30 min from unanesthetized, unrestrained pups at P7, P14, and P21, and in separate groups, brain tissues were collected at these ages for ex-vivo MRI analysis (9.4 T) and Golgi–Cox staining (to assess neuronal morphology) in the motor cortex. Postnatal inflammation was associated with reduced cortical pyramidal neuron arborization from P7, P14, and P21. These changes were associated with dysmature EEG features (e.g., persistence of delta waveforms, higher EEG amplitude, reduced spectral edge frequency) at P7 and P14, and higher EEG power in the theta and alpha ranges at P21. By contrast, there were no changes in cortical DTI or NODDI in LPS rats at P7 or P14, while there was an increase in cortical fractional anisotropy (FA) and decrease in orientation dispersion index (ODI) at P21. EEG may be useful for identifying the early evolution of impaired cortical development after early life postnatal systemic inflammation, while DTI and NODDI seem to be more suited to assessing established cortical changes. [ABSTRACT FROM AUTHOR]

Antenatal hypoxia-ischaemia (HI) in preterm fetal sheep can trigger delayed evolution of severe, cystic white matter injury (WMI), in a similar timecourse to WMI in preterm infants. We therefore examined how severe hypoxia-ischaemia affects recovery of electroencephalographic (EEG) activity. Chronically instrumented preterm fetal sheep (0.7 gestation) received 25 min of complete umbilical cord occlusion (UCO, n = 9) or sham occlusion (controls, n = 9), and recovered for 21 days. HI was associated with a shift to lower frequency EEG activity for the first 5 days with persisting loss of EEG power in the delta and theta bands, and initial loss of power in the alpha and beta bands in the first 14 days of recovery. In the final 3 days of recovery, there was a marked rhythmic shift towards higher frequency EEG activity after UCO. The UCO group spent less time in high-voltage sleep, and in the early evening (7:02 pm ± 47 min) abruptly stopped cycling between sleep states, with a shift to a high frequency state for 2 h 48 min ± 40 min, with tonic electromyographic activity. These findings demonstrate persisting EEG and sleep state dysmaturation after severe hypoxia-ischaemia. Loss of fetal or neonatal sleep state cycling in the early evening may be a useful biomarker for evolving cystic WMI. [ABSTRACT FROM AUTHOR]

Provides information on a study which determined whether prolonged head cooling before postischemic seizures in fetal sheep is neuroprotective. Methodology; Results.

Presents information on a study that determined the practicality and safety of head cooling with mild or minimal systematic hypothermia. Background on hypoxic-ischemic injury in newborn infants; Methodology; Results of the study; Discussion of the study; Conclusions.

Tests the galactopoietic response to recombinant human growth hormone in mothers of premature infants with inadequate lactation. Subjects; Milk production; Assays; Study groups; Statistical analysis.

([1]) report one of the key limitations: similarly to the historical experience (Silverman & Sinclair, [4]), a cohort of 14 infants with encephalopathy cared for in a sub-Saharan African hospital developed poorly controlled spontaneous hypothermia after birth. Healthy rat pups have rectal temperatures that are typically 1-2°C less than 37°C, inferring that the neonatal rats will have received milder but ongoing passive hypothermia I after i the 5 h period of active hypothermia (Wood I et al i . Given these considerations, as much as we would like to recommend actively managed hypothermia for neonatal encephalopathy in all situations, on balance, allowing mild spontaneous hypothermia is likely to provide some net benefit for neonatal encephalopathy in a low resource setting, provided that deeper hypothermia is avoided. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the article "Cooling for Neonatal Hypoxic Ischemic Encephalopathy: Do We Have the Answer?" published in a 2007 issue of "Pediatrics" and a response to it are presented.

Premature babies are at high risk of serious neurodevelopmental disabilities, which in many cases are related to perinatal hypoxic–ischemic encephalopathy (HIE). Studies of neuroprotection in animal models consistently suggest that treatment must be started as early as possible in the first 6 h after hypoxia–ischemia (HI), the so-called latent phase before secondary deterioration, to improve outcomes. We have shown in preterm sheep that EEG biomarkers of injury, in the form of high-frequency micro-scale spike transients, develop and evolve in this critical latent phase after severe asphyxia. Real-time automatic identification of such events is important for the early and accurate detection of HI injury, so that the right treatment can be implemented at the right time. We have previously reported successful strategies for accurate identification of EEG patterns after HI. In this study, we report an alternative high-performance approach based on the fusion of spectral Fourier analysis and Type-I fuzzy classifiers (FFT-Type-I-FLC). We assessed its performance in over 2520 min of latent phase EEG recordings from seven asphyxiated in utero preterm fetal sheep exposed to a range of different occlusion periods. The FFT-Type-I-FLC classifier demonstrated 98.9 ± 1.0% accuracy for identification of high-frequency spike transients in the gamma frequency band (namely 80–120 Hz) post-HI. The spectral-based approach (FFT-Type-I-FLC classifier) has similar accuracy to our previous reverse biorthogonal wavelets rbio2.8 basis function and type-1 fuzzy classifier (rbio-WT-Type-1-FLC), providing competitive performance (within the margin of error: 0.89%), but it is computationally simpler and would be readily adapted to identify other potentially relevant EEG waveforms. [ABSTRACT FROM AUTHOR]

Perinatal infection or inflammation are associated with adverse neurodevelopmental effects and cardiovascular impairments in preterm infants. Most preclinical studies have examined the effects of gram-negative bacterial inflammation on the developing brain, although gram-positive bacterial infections are a major contributor to adverse outcomes. Killed Su-strain group 3 A streptococcus pyogenes (Picibanil, OK-432) is being used for pleurodesis in fetal hydrothorax/chylothorax. We therefore examined the neural and cardiovascular effects of clinically relevant intra-plural infusions of Picibanil. Chronically instrumented preterm (0.7 gestation) fetal sheep received an intra-pleural injection of low-dose (0.1 mg, n = 8) or high-dose (1 mg, n = 8) Picibanil or saline-vehicle (n = 8). Fetal brains were collected for histology one-week after injection. Picibanil exposure was associated with sustained diffuse white matter inflammation and loss of immature and mature oligodendrocytes and subcortical neurons, and associated loss of EEG power. These neural effects were not dose-dependent. Picibanil was also associated with acute changes in heart rate and attenuation of the maturational increase in mean arterial pressure. Even a single exposure to a low-dose gram-positive bacterial-mediated inflammation during the antenatal period is associated with prolonged changes in vascular and neural function. [ABSTRACT FROM AUTHOR]

However, while waiting for these methods to be validated, there is already convincing evidence that increased FHRV on routine, visually assessed intrapartum FHR tracing is an important index of fetal compromise, without distracting clinicians with the unproven future benefits of subsidiary methods. Abbreviations FHR fetal heart rate FHRV fetal heart rate variability NICE National Institute for Health and Care Excellence DATA AVAILABILITY STATEMENT Data sharing is not applicable to this article as no new data were created or analysed in this manuscript. Dr Frasch fundamentally argues that FHRV should not be described or interpreted as "decreased" or "increased", as this 'goes against the evidence of what variability represents - a complex dynamic multi-dimensional pattern, such that a single-order description in terms of "ups" and "downs" discards most of its predictive information.'[1] Unfortunately, Dr Frasch fails to clarify what predictive features in this meta-level FHRV the frontline clinician should draw from to support their decisions, for example, whether to perform intrauterine resuscitation methods or caesarean delivery. [Extracted from the article]

Brain maturity and many clinical treatments such as therapeutic hypothermia (TH) can significantly influence the morphology of neonatal EEG seizures after hypoxia–ischemia (HI), and so there is a need for generalized automatic seizure identification. This study validates efficacy of advanced deep-learning pattern classifiers based on a convolutional neural network (CNN) for seizure detection after HI in fetal sheep and determines the effects of maturation and brain cooling on their accuracy. The cohorts included HI–normothermia term (n = 7), HI–hypothermia term (n = 14), sham–normothermia term (n = 5), and HI–normothermia preterm (n = 14) groups, with a total of >17,300 h of recordings. Algorithms were trained and tested using leave-one-out cross-validation and k-fold cross-validation approaches. The accuracy of the term-trained seizure detectors was consistently excellent for HI–normothermia preterm data (accuracy = 99.5%, area under curve (AUC) = 99.2%). Conversely, when the HI–normothermia preterm data were used in training, the performance on HI–normothermia term and HI–hypothermia term data fell (accuracy = 98.6%, AUC = 96.5% and accuracy = 96.9%, AUC = 89.6%, respectively). Findings suggest that HI–normothermia preterm seizures do not contain all the spectral features seen at term. Nevertheless, an average 5-fold cross-validated accuracy of 99.7% (AUC = 99.4%) was achieved from all seizure detectors. This significant advancement highlights the reliability of the proposed deep-learning algorithms in identifying clinically translatable post-HI stereotypic seizures in 256Hz recordings, regardless of maturity and with minimal impact from hypothermia. [ABSTRACT FROM AUTHOR]

Hypoxic-ischemic (HI) studies in preterms lack reliable prognostic biomarkers for diagnostic tests of HI encephalopathy (HIE). Our group's observations from in utero fetal sheep models suggest that potential biomarkers of HIE in the form of developing HI micro-scale epileptiform transients emerge along suppressed EEG/ECoG background during a latent phase of 6–7 h post-insult. However, having to observe for the whole of the latent phase disqualifies any chance of clinical intervention. A precise automatic identification of these transients can help for a well-timed diagnosis of the HIE and to stop the spread of the injury before it becomes irreversible. This paper reports fusion of Reverse-Biorthogonal Wavelets with Type-1 Fuzzy classifiers, for the accurate real-time automatic identification and quantification of high-frequency HI spike transients in the latent phase, tested over seven in utero preterm sheep. Considerable high performance of 99.78 ± 0.10% was obtained from the Rbio-Wavelet Type-1 Fuzzy classifier for automatic identification of HI spikes tested over 42 h of high-resolution recordings (sampling-freq:1024 Hz). Data from post-insult automatic time-localization of high-frequency HI spikes reveals a promising trend in the average rate of the HI spikes, even in the animals with shorter occlusion periods, which highlights considerable higher number of transients within the first 2 h post-insult. [ABSTRACT FROM AUTHOR]

Seizures are common in preterm newborns and are associated with poor neurodevelopmental outcomes. Current anticonvulsants have poor efficacy, and many have been associated with upregulation of apoptosis in the developing brain. Apigenin, a natural bioactive flavonoid, is a potent inhibitor of hyaluronidase and reduces seizures in adult animal models. However, its impact on perinatal seizures is unclear. In the present study, we examined the effect of apigenin and S3, a synthetic, selective hyaluronidase inhibitor, on seizures after cerebral ischemia in preterm fetal sheep at 0.7 gestation (98–99 days, term ~147 days). Fetuses received sham ischemia (n = 9) or ischemia induced by bilateral carotid occlusion for 25 min. Immediately after ischemia, fetuses received either a continuous infusion of vehicle (0.036% dimethyl sulfoxide, n = 8) or apigenin (50 µM, n = 6). In a pilot study, we also tested infusion of S3 (2 µM, n = 3). Fetuses were monitored continuously for 72 h after ischemia. Infusion of apigenin or S3 were both associated with reduced numbers of animals with seizures, total seizure time, and mean seizure burden. S3 was also associated with a reduction in the total number of seizures over the 72 h recovery period. In animals that developed seizures, apigenin was associated with earlier cessation of seizures. However, apigenin or S3 treatment did not alter recovery of electroencephalographic power or spectral edge frequency. These data support that targeting brain hyaluronidase activity with apigenin or S3 may be an effective strategy to reduce perinatal seizures following ischemia. Further studies are required to determine their effects on neurohistological outcomes. [ABSTRACT FROM AUTHOR]

Presents a reply by Alistair J. Gunn, Peter D. Gluckman, John S. Wyatt, Marianne Thoresen, and A. David Edwards to letters to the editor about their article, "Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicenter randomized trial," in the February 19, 2005 issue.

Focuses on a research study which reported on the how fetal anemia can lead to augmented contractile response to hypoxic stress in adulthood. Occurrence of a doubling of maximal coronary artery conductance after the same paradigm illustrated in the study; Possibility that sustained adaptation of autonomic control is a more likely mechanism of action.

Assesses the changes in postischemic cerebral temperature initiated after cardiac arrest in children. Occurrence of spontaneous hyperthermia; Association of hyperthermia after cardiac arrest.

Deals with hypothermic centralization in pediatrics. Physiological effect of hypothermia; Effect of hypothermic centralization of blood flow; Major responses to hypothermia; use of therapeutic hypothermia.

Background: Perinatal infection/inflammation is associated with a high risk for neurological injury and neurodevelopmental impairment after birth. Despite a growing preclinical evidence base, anti-inflammatory interventions have not been established in clinical practice, partly because of the range of potential targets. We therefore systematically reviewed preclinical studies of immunomodulation to improve neurological outcomes in the perinatal brain and assessed their therapeutic potential. Methods: We reviewed relevant studies published from January 2012 to July 2023 using PubMed, Medline (OvidSP) and EMBASE databases. Studies were assessed for risk of bias using the SYRCLE risk of bias assessment tool (PROSPERO; registration number CRD42023395690). Results: Forty preclinical publications using 12 models of perinatal neuroinflammation were identified and divided into 59 individual studies. Twenty-seven anti-inflammatory agents in 19 categories were investigated. Forty-five (76%) of 59 studies reported neuroprotection, from all 19 categories of therapeutics. Notably, 10/10 (100%) studies investigating anti-interleukin (IL)-1 therapies reported improved outcome, whereas half of the studies using corticosteroids (5/10; 50%) reported no improvement or worse outcomes with treatment. Most studies (49/59, 83%) did not control core body temperature (a known potential confounder), and 25 of 59 studies (42%) did not report the sex of subjects. Many studies did not clearly state whether they controlled for potential study bias. Conclusion: Anti-inflammatory therapies are promising candidates for treatment or even prevention of perinatal brain injury. Our analysis highlights key knowledge gaps and opportunities to improve preclinical study design that must be addressed to support clinical translation. [ABSTRACT FROM AUTHOR]

Key points Hypoxia‐ischaemia (HI) before birth is a key risk factor for stillbirth and severe neurodevelopmental disability in survivors, including cerebral palsy, although there are no reliable biomarkers to detect at risk fetuses that may have suffered a transient period of severe HI. We investigated time and frequency domain measures of fetal heart rate variability (FHRV) for 3 weeks after HI in preterm fetal sheep at 0.7 gestation (equivalent to preterm humans) until 0.8 gestation (equivalent to term humans). We have previously shown that this is associated with delayed development of severe white and grey matter injury, including cystic white matter injury (WMI) resembling that observed in human preterm infants. HI was associated with suppression of time and frequency domain measures of FHRV and reduced their circadian rhythmicity during the first 3 days of recovery. By contrast, circadian rhythms of multiple measures of FHRV were exaggerated over the final 2 weeks of recovery, mediated by a greater reduction in FHRV during the morning nadir, but no change in the evening peak. These data suggest that the time of day at which FHRV measurements are taken affects their diagnostic utility. We further propose that circadian changes in FHRV may be a low‐cost, easily applied biomarker of antenatal HI and evolving brain injury. Hypoxia‐ischaemia (HI) before birth is a key risk factor for stillbirth and probably for disability in survivors, although there are no reliable biomarkers for antenatal brain injury. In preterm fetal sheep, acute HI that is known to lead to delayed development of severe white and grey matter injury over 3 weeks, was associated with early suppression of multiple time and frequency domain measures of fetal heart rate variability (FHRV) and loss of their circadian rhythms during the first 3 days after HI. Over the final 2 weeks of recovery after HI, exaggerated circadian rhythms of frequency domain FHRV measures were observed. The morning nadirs were lower with no change in the evening peak of FHRV. Circadian changes in FHRV may be a low‐cost, easily applied biomarker of antenatal HI and evolving brain injury. [ABSTRACT FROM AUTHOR]

Our objective is to develop a model for the prediction of minimum fetal blood pressure (FBP) during fetal heart rate (FHR) decelerations. Experimental data from umbilical occlusions in near-term fetal sheep (2698 occlusions from 57 near-term lambs) were used to train a convolutional neural network. This model was then used to estimate FBP for decelerations extracted from the final 90 min of 53,445 human FHR signals collected using cardiotocography. Minimum sheep FBP was predicted with a mean absolute error of 6.7 mmHg (25th, 50th, 75th percentiles of 2.3 , 5.2 , 9.7 mmHg), mean absolute percentage errors of 17.3 % ( 5.5 %, 12.5 %, 23.9 %) and a coefficient of determination R 2 = 0.36 . While the model was unable to clearly predict severe compromise at birth in humans, there is positive evidence that such a model could predict human FBP with further development. The neural network is capable of predicting FBP for many of the sheep decelerations accurately but performed far from satisfactory at identifying FHR segments that correspond to the highest or lowest minimum FBP. These results indicate that with further work and a larger, more variable training dataset, the model could achieve higher accuracy. [ABSTRACT FROM AUTHOR]

Exposure to hypoxic-ischaemia (HI) is consistently followed by a delayed fall in cerebral perfusion. In preterm fetal sheep this is associated with impaired cerebral oxygenation, consistent with mismatch between perfusion and metabolism. In the present study we tested the hypothesis that alpha-adrenergic inhibition after HI would improve cerebral perfusion, and so attenuate mismatch and reduce neural injury. Chronically instrumented preterm (0.7 gestation) fetal sheep received sham-HI (n = 10) or HI induced by complete umbilical cord occlusion for 25 minutes. From 15 minutes to 8 hours after HI, fetuses received either an intravenous infusion of a non-selective alpha-adrenergic antagonist, phentolamine (10 mg bolus, 10 mg/h infusion, n = 10), or saline (n = 10). Fetal brains were processed for histology 72 hours post-HI. Phentolamine infusion was associated with increased epileptiform transient activity and a greater fall in cerebral oxygenation in the early post-HI recovery phase. Histologically, phentolamine was associated with greater loss of oligodendrocytes and hippocampal neurons. In summary, contrary to our hypothesis, alpha-adrenergic inhibition increased epileptiform transient activity with an exaggerated fall in cerebral oxygenation, and increased neural injury, suggesting that alpha-adrenergic receptor activation after HI is an important endogenous neuroprotective mechanism. [ABSTRACT FROM AUTHOR]

Background: Antenatal infection/inflammation is associated with disturbances in neuronal connectivity, impaired cortical growth and poor neurodevelopmental outcomes. The pathophysiological substrate that underpins these changes is poorly understood. We tested the hypothesis that progressive inflammation in late gestation fetal sheep would alter cortical neuronal microstructure and neural function assessed using electroencephalogram band power analysis. Methods: Fetal sheep (0.85 of gestation) were surgically instrumented for continuous electroencephalogram (EEG) recording and randomly assigned to repeated saline (control; n = 9) or LPS (0 h = 300 ng, 24 h = 600 ng, 48 h = 1200 ng; n = 8) infusions to induce inflammation. Sheep were euthanised 4 days after the first LPS infusion for assessment of inflammatory gene expression, histopathology and neuronal dendritic morphology in the somatosensory cortex. Results: LPS infusions increased delta power between 8 and 50 h, with reduced beta power from 18 to 96 h (P < 0.05 vs. control). Basal dendritic length, numbers of dendritic terminals, dendritic arborisation and numbers of dendritic spines were reduced in LPS-exposed fetuses (P < 0.05 vs. control) within the somatosensory cortex. Numbers of microglia and interleukin (IL)-1β immunoreactivity were increased in LPS-exposed fetuses compared with controls (P < 0.05). There were no differences in total numbers of cortical NeuN + neurons or cortical area between the groups. Conclusions: Exposure to antenatal infection/inflammation was associated with impaired dendritic arborisation, spine number and loss of high-frequency EEG activity, despite normal numbers of neurons, that may contribute to disturbed cortical development and connectivity. [ABSTRACT FROM AUTHOR]

Maternal magnesium sulphate (MgSO4) treatment is widely recommended before preterm birth for neuroprotection. However, this is controversial because there is limited evidence that MgSO4 provides long‐term neuroprotection. Preterm fetal sheep (104 days gestation; term is 147 days) were assigned randomly to receive sham occlusion with saline infusion (n = 6) or i.v. infusion with MgSO4 (n = 7) or vehicle (saline, n = 6) from 24 h before hypoxia–ischaemia induced by umbilical cord occlusion until 24 h after occlusion. Sheep were killed after 21 days of recovery, for fetal brain histology. Functionally, MgSO4 did not improve long‐term EEG recovery. Histologically, in the premotor cortex and striatum, MgSO4 infusion attenuated post‐occlusion astrocytosis (GFAP+) and microgliosis but did not affect numbers of amoeboid microglia or improve neuronal survival. In the periventricular and intragyral white matter, MgSO4 was associated with fewer total (Olig‐2+) oligodendrocytes compared with vehicle + occlusion. Numbers of mature (CC1+) oligodendrocytes were reduced to a similar extent in both occlusion groups compared with sham occlusion. In contrast, MgSO4 was associated with an intermediate improvement in myelin density in the intragyral and periventricular white matter tracts. In conclusion, a clinically comparable dose of MgSO4 was associated with moderate improvements in white and grey matter gliosis and myelin density but did not improve EEG maturation or neuronal or oligodendrocyte survival. Key points: Magnesium sulphate is widely recommended before preterm birth for neuroprotection; however, there is limited evidence that magnesium sulphate provides long‐term neuroprotection.In preterm fetal sheep exposed to hypoxia–ischaemia (HI), MgSO4 was associated with attenuated astrocytosis and microgliosis in the premotor cortex and striatum but did not improve neuronal survival after recovery to term‐equivalent age, 21 days after HI.Magnesium sulphate was associated with loss of total oligodendrocytes in the periventricular and intragyral white matter tracts, whereas mature, myelinating oligodendrocytes were reduced to a similar extent in both occlusion groups. In the same regions, MgSO4 was associated with an intermediate improvement in myelin density.Functionally, MgSO4 did not improve long‐term recovery of EEG power, frequency or sleep stage cycling.A clinically comparable dose of MgSO4 was associated with moderate improvements in white and grey matter gliosis and myelin density but did not improve EEG maturation or neuronal or oligodendrocyte survival. [ABSTRACT FROM AUTHOR]

Background: 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.Methods: 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.Results: 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.Conclusions: 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. [ABSTRACT FROM AUTHOR]

Currently, there are no developed methods to detect sharp wave transients that exist in the latent phase after hypoxia-ischemia (HI) in the electroencephalogram (EEG) in order to determine if these micro-scale transients are potential biomarkers of HI. A major issue with sharp waves in the HI-EEG is that they possess a large variability in their sharp wave profile making it difficult to build a compact 'footprint of uncertainty' (FOU) required for ideal performance of a Type-2 fuzzy logic system (FLS) classifier. In this paper, we develop a novel computational EEG analysis method to robustly detect sharp waves using over 30h of post occlusion HI-EEG from an equivalent, in utero, preterm fetal sheep model cohort. We demonstrate that initial wavelet transform (WT) of the sharp waves stabilizes the variation in their profile and thus permits a highly compact FOU to be built, hence, optimizing the performance of a Type-2 FLS. We demonstrate that this method leads to higher overall performance of for the clinical sampled EEG and for the high resolution sampled EEG that is improved upon over conventional standard wavelet and , respectively, and fuzzy approaches and , respectively, when performed in isolation. [ABSTRACT FROM AUTHOR]

Cystic white matter injury is highly associated with severe neurodevelopmental disability and cerebral palsy in preterm infants, yet its pathogenesis remains poorly understood and there is no established treatment. In the present study, we tested the hypothesis that slowly evolving cystic white matter injury after hypoxia-ischaemia is mediated by programmed necrosis initiated by tumour necrosis factor. Tumour necrosis factor blockade was begun 3 days after hypoxia-ischaemia to target the tertiary phase of injury, when most secondary cell death is thought to be complete. Chronically instrumented preterm foetal sheep (0.7 gestation) received 25 min of hypoxia-ischaemia induced by complete umbilical cord occlusion or sham-umbilical cord occlusion (controls, n = 10), followed by intracerebroventricular infusion of the soluble TNF inhibitor, Etanercept, at 3, 8 and 13 days after umbilical cord occlusion (n = 9) or vehicle (n = 9). Foetal brains were processed for histology at 21 days after umbilical cord occlusion. Umbilical cord occlusion with vehicle was associated with a spectrum of macroscopic white matter degeneration, including white matter atrophy, ventriculomegaly and overt temporal lobe cystic white matter injury. Oligodendrocyte maturational arrest and impaired labelling of myelin proteins, characteristic of diffuse white matter injury, was observed in the parietal lobe and surrounding the cystic lesions in the temporal lobe. Etanercept markedly attenuated cystic white matter injury on the side of the intracerebroventricular infusion, with partial contralateral protection. Further, Etanercept improved oligodendrocyte maturation and labelling of myelin proteins in the temporal and parietal lobes. The present study shows that cystic white matter injury reflects late-onset tertiary cell death mediated by delayed neuroinflammation through the tumour necrosis factor pathway. Delayed tumour necrosis factor blockade markedly attenuated cystic white matter injury and restored oligodendrocyte maturation and deficits in myelin protein expression. These data suggest that delayed tumour necrosis factor blockade may represent a viable therapeutic strategy to reduce the risk of cystic and diffuse white matter injury and potentially cerebral palsy after preterm birth, with a surprisingly wide therapeutic window. [ABSTRACT FROM AUTHOR]

Therapeutic hypothermia significantly improves outcomes after neonatal hypoxic-ischemic (HI) encephalopathy but is only partially protective. There is evidence that cortical inhibitory interneuron circuits are particularly vulnerable to HI and that loss of interneurons may be an important contributor to long-term neurological dysfunction in these infants. In the present study, we examined the hypothesis that the duration of hypothermia has differential effects on interneuron survival after HI. Near-term fetal sheep received sham ischemia or cerebral ischemia for 30 min, followed by cerebral hypothermia from 3 h after ischemia end and continued up to 48 h, 72 h, or 120 h recovery. Sheep were euthanized after 7 days for histology. Hypothermia up to 48 h recovery resulted in moderate neuroprotection of glutamate decarboxylase (GAD)+ and parvalbumin+ interneurons but did not improve survival of calbindin+ cells. Hypothermia up to 72 h recovery was associated with significantly increased survival of all three interneuron phenotypes compared with sham controls. By contrast, while hypothermia up to 120 h recovery did not further improve (or impair) GAD+ or parvalbumin+ neuronal survival compared with hypothermia up to 72 h, it was associated with decreased survival of calbindin+ interneurons. Finally, protection of parvalbumin+ and GAD+ interneurons, but not calbindin+ interneurons, with hypothermia was associated with improved recovery of electroencephalographic (EEG) power and frequency by day 7 after HI. The present study demonstrates differential effects of increasing the duration of hypothermia on interneuron survival after HI in near-term fetal sheep. These findings may contribute to the apparent preclinical and clinical lack of benefit of very prolonged hypothermia. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Whole-Body Hypothermia for Neonates With Hypoxic-Ischemic Encephalopathy" in the October 13, 2005 issue.