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Despite occurrence of neonatal hypoxia and peripheral nerve injuries in complicated birthing scenarios, the effect of hypoxia on the biomechanical responses of neonatal peripheral nerves is not studied. In this study, neonatal brachial plexus (BP) and tibial nerves, obtained from eight normal and eight hypoxic 3–5-day-old piglets, were tested in uniaxial tension until failure at a rate of 0.01 mm/s or 10 mm/s. Failure load, stress, and modulus of elasticity were reported to be significantly lower in hypoxic neonatal BP and tibial nerves than respective normal tissue at both 0.01 and 10 mm/s rates. Failure strain was significantly lower in the hypoxic neonatal BP nerves only at 10 mm/s rate when compared to normal BP nerve. This is the first available data that indicate weaker mechanical behavior of hypoxic neonatal peripheral nerves as compared to normal tissue and offer an understanding of the biomechanical responses of peripheral nerves of hypoxic neonatal piglets.

Neonatal hypoxia-ischemia (HI) is responsible for movement disorders in preterm infants. Non-pharmacological strategies, such as environmental enrichment (EE) during adulthood, have shown positive effects on promoting sensorimotor recovery after HI. However, little is known about the effects of perinatal EE on sensorimotor function following HI. In present study we investigated the hypothesis that enriched experiences during pregnancy and lactation would reduce motor impairments caused by a model of neonatal HI in rats. At postnatal day (PND) 3, Wistar pups of both sexes were subject to the modified Rice-Vannucci model. Motor function was evaluated from PND 60 to PND 64. HI caused a reduction in the forepaws strength and worsening of movement quality in the right forepaw. These effects were attenuated in animals receiving prenatal or lactational EE, which showed better performance when compared to the control group. Moreover, enriched experiences during lactation reversed HI-induced asymmetric use of the forepaws and the trend to increased paw errors in a walking test. Lower scores were found in the contralateral forepaw placement in HI animals, except when EE was provided at both stages of neurodevelopment . These results indicate that enriched experiences reduce motor impairments, i.e , measured in force, asymmetry and coordination domains, and that EE during lactation is more effective in promoting post-injury recovery. These data support that early therapeutic interventions might enhance functional reorganization at a period of high brain plasticity and that enriched-like experience might be encouraged in pediatric rehabilitation programs, in order to reduce long-term movement disorders after neonatal brain insults.

Perinatal asphyxia (PA) is a relevant cause of death at the time of labour, and when survival is stabilised, associated with short- and long-term developmental disabilities, requiring inordinate care by health systems and families. Its prevalence is high (1 to 10/1000 live births) worldwide. At present, there are few therapeutic options, apart from hypothermia, that regrettably provides only limited protection if applied shortly after the insult. PA implies a primary and a secondary insult. The primary insult relates to the lack of oxygen, and the secondary one to the oxidative stress triggered by re-oxygenation, formation of reactive oxygen (ROS) and reactive nitrogen (RNS) species, and overactivation of glutamate receptors and mitochondrial deficiencies. PA induces overactivation of a number of sentinel proteins, including hypoxia-induced factor-1α (HIF-1α) and the genome-protecting poly(ADP-ribose) polymerase-1 (PARP-1). Upon activation, PARP-1 consumes high amounts of ATP at a time when this metabolite is scarce, worsening in turn the energy crisis elicited by asphyxia. The energy crisis also impairs ATP-dependent transport, including glutamate re-uptake by astroglia. Nicotinamide, a PARP-1 inhibitor, protects against the metabolic cascade elicited by the primary stage, avoiding NAD+ exhaustion and the energetic crisis. Upon re-oxygenation, however, oxidative stress leads to nuclear translocation of the NF-κB subunit p65, overexpression of the pro-inflammatory cytokines IL-1β and TNF-α, and glutamate-excitotoxicity, due to impairment of glial-glutamate transport, extracellular glutamate overflow, and overactivation of NMDA receptors, mainly of the extrasynaptic type. This leads to calcium influx, mitochondrial impairment, and inactivation of antioxidant enzymes, increasing further the activity of pro-oxidant enzymes, thereby making the surviving neonate vulnerable to recurrent metabolic insults whenever oxidative stress is involved. Here, we discuss evidence showing that (i) inhibition of PARP-1 overactivation by nicotinamide and (ii) inhibition of extrasynaptic NMDA receptor overactivation by memantine can prevent the short- and long-term consequences of PA. These hypotheses have been evaluated in a rat preclinical model of PA, aiming to identify the metabolic cascades responsible for the long-term consequences induced by the insult, also assessing postnatal vulnerability to recurrent oxidative insults. Thus, we present and discuss evidence demonstrating that PA induces long-term changes in metabolic pathways related to energy and oxidative stress, priming vulnerability of cells with both the neuronal and the glial phenotype. The effects induced by PA are region dependent, the substantia nigra being particularly prone to cell death. The issue of short- and long-term consequences of PA provides a framework for addressing a fundamental issue referred to plasticity of the CNS, since the perinatal insult triggers a domino-like sequence of events making the developing individual vulnerable to recurrent adverse conditions, decreasing his/her coping repertoire because of a relevant insult occurring at birth.

Introduction: Perinatal asphyxia is one of the most common primary causes of mortality and morbidity among neonates. Perinatal asphyxia will result in neonatal hypoxia and tissue/organ injury. Objective: The aim of this study was to observe the Co-relation between Perinatal asphyxia with Hypoxic Ischemic Encephalopathy (PNA with HIE) and Blood sugar level. Methodology: This is a descriptive cross-sectional case study where a total of 182 neonates were admitted to the hospital with the problem of Perinatal asphyxia with Hypoxic Ischemic Encephalopathy and with some other associated problem. Result: Among the cases, 114 (62.6%) were Boys and 68 (37.45%) Girls. The mean age was 29.72 ± 78.42, Weight 2.77 ± .60, RBS 6.57 ± 7.38. Among the asphyxiated neonates blood sugar levels in arterial cord blood were significantly lower and had a negative (r=−0.195, P

Perinatal hypoxia ischemia (HI) is a significant cause of brain injury in surviving infants. Although hypothermia improves outcomes in some infants, additional therapies are needed since about 40% of infants still have a poor outcome. Acetyl-L-carnitine (ALCAR), an acetylated derivative of L-carnitine, protected against early changes in brain metabolites and mitochondrial function after HI on postnatal day (PND) 7 in a rat pup model of near-term HI injury. However, its efficacy in long-term structural and functional outcomes remains unexplored. We determined the efficacy of ALCAR therapy administered to rat pups after HI at PND 7, using both longitudinal in vivo magnetic resonance imaging and behavioral tests, in male and female rats. HI led to sex-specific behavioral impairment, with males exhibiting more global functional deficits than females. Interestingly, HI reduced the volume of the contralateral hemisphere in males only, suggesting that the brain injury is more diffuse in males than in females. Treatment with ALCAR improved both morphological and functional outcomes in both male and female rats. These results suggest that ALCAR may be a potential therapy for clinical use since the treatment attenuated the moderate injury produced under the experimental conditions used and improved the functional outcome in preclinical studies.

Neonatal asphyxia occurs due to reduction in oxygen supply to vital organs in the newborn. Rapid restoration of oxygen to the lungs after a long period of asphyxia can cause lung injury and decline of respiratory function, which result from the activity of molecules that induce vascular changes in the lung such as nitric oxide (NO) and vascular endothelial growth factors (VEGF). In this study, we evaluated the pulmonary and vascular morphometry of rats submitted to the model of neonatal asphyxia and mechanical ventilation, their expression of pulmonary VEGF, VEGF receptors (VEGFR-1/VEGFR-2), and endothelial NO synthase (eNOS). Neonate Sprague-Dawley rats (CEUA #043/2011) were divided into four groups (n=8 each): control (C), control submitted to ventilation (CV), hypoxia (H), and hypoxia submitted to ventilation (HV). The fetuses were harvested at 21.5 days of gestation. The morphometric variables measured were body weight (BW), total lung weight (TLW), left lung weight (LLW), and TLW/BW ratio. Pulmonary vascular measurements, VEGFR-1, VEGFR-2, VEGF, and eNOS immunohistochemistry were performed. The morphometric analysis showed decreased TLW and TLW/BW ratio in HV compared to C and H (P

Objective: Optimal management of twin deliveries is controversial. We aimed to assess potential risk factors correlated to the development of hypoxia in the second twin after vaginal delivery of the first twin. Study design: This is a retrospective observational study including diamniotic twin pregnancies delivering at our Institution at 35 weeks of gestational age or more, weighing ≥1800 g. Hypoxia was defined as at least one of the following: Apgar score 10 minutes, neonatal acidosis (pH ≤7 and/or BE ≥12 mmol/L). Results: A number of 275 diamniotic twin pregnancies met the inclusion criteria and were divided within the following groups: (1) second twin not developing neonatal hypoxia (n = 265); and (2) second twin developing neonatal hypoxia (n = 10). The rate of second twins with neonatal hypoxia during the study period was 3.6% (10/275). Abnormal cardiotocography during the intertwin delivery interval, defined as ACOG category III, was significantly correlated to second twin hypoxia. Of interest, there was no significant difference in the intertwin delivery interval between the study groups. In addition, breech presentation of the second twin did not show to be a risk factor for neonatal hypoxia. None of the second twins developing neonatal hypoxia was reported to have encephalopathy (follow up of at least 24 months). At multivariate analysis, only abnormal cardiotocography was an independent risk factor for second twin hypoxia (OR 17.8, 95% CI 4.1–77.2). Conclusions: In our study, neonatal hypoxia was significantly correlated to abnormal cardiotocography, while intertwin delivery interval was not correlated to the development of this adverse neonatal outcome Objective: Optimal management of twin deliveries is controversial. We aimed to assess potential risk factors correlated to the development of hypoxia in the second twin after vaginal delivery of the first twin. Study design: This is a retrospective observational study including diamniotic twin pregnancies delivering at our Institution at 35 weeks of gestational age or more, weighing ≥1800 g. Hypoxia was defined as at least one of the following: Apgar score 10 minutes, neonatal acidosis (pH ≤7 and/or BE ≥12 mmol/L). Results: A number of 275 diamniotic twin pregnancies met the inclusion criteria and were divided within the following groups: (1) second twin not developing neonatal hypoxia (n = 265); and (2) second twin developing neonatal hypoxia (n = 10). The rate of second twins with neonatal hypoxia during the study period was 3.6% (10/275). Abnormal cardiotocography during the intertwin delivery interval, defined as ACOG category III, was significantly correlated to second twin hypoxia. Of interest, there was no significant difference in the intertwin delivery interval between the study groups. In addition, breech presentation of the second twin did not show to be a risk factor for neonatal hypoxia. None of the second twins developing neonatal hypoxia was reported to have encephalopathy (follow up of at least 24 months). At multivariate analysis, only abnormal cardiotocography was an independent risk factor for second twin hypoxia (OR 17.8, 95% CI 4.1–77.2). Conclusions: In our study, neonatal hypoxia was significantly correlated to abnormal cardiotocography, while intertwin delivery interval was not correlated to the development of this adverse neonatal outcome.

Se realizó un estudio retrospectivo parcial, longitudinal, comparativo, observacional evaluando a 2155 recién nacidos de un total de 18808, cuyo parto ocurrió entre enero de 1984 y diciembre de 1987 en el Hospital Nacional Cayetano Heredia. La incidencia de recién nacido pretérmino (RNPT) fue 4,92 % y la de bajo peso de (RNBP) 7,4%. De estos, 4,7% correspondieron a recién nacidos pretérmino de bajo peso (RNPBP). El riesgo de un nacimiento pretérmino de bajo peso, se ve influenciado por factores demográficos (paridad, grado de instrucción), antecedentes maternos (mala historia obstétrica, prematuros, toxemia e hipertensión) y complicaciones de la gestación actual. Entre las complicaciones médicas asociadas a la gestación destacaron la desnutrición, anemia e infecciones intercurrentes. Los recién nacidos pretérmino de bajo peso, se asocian significativamente a las gestaciones de mayor riesgo obstétrico, sin control prenatal a una elevada incidencia de hipoxia neonatal severa, así como a mayores tasas de morbilidad y mortalidad perinatal

While extensive studies report that neonatal hypoxia-ischemia (HI) induces long-term cognitive impairment via inflammatory responses in the brain, little is known about the role of early peripheral inflammation response in HI injury. Here we used a neonatal hypoxia rodent model by subjecting postnatal day 0 (P0d) rat pups to systemic hypoxia (3.5 h), a condition that is commonly seen in clinic neonates, Then, an initial dose of minocycline (45 mg/kg) was injected intraperitoneally (i.p.) 2 h after the hypoxia exposure ended, followed by half dosage (22.5 mg/kg) minocycline treatment for next 6 consecutive days daily. Saline was injected as vehicle control. To examine how early peripheral inflammation responded to hypoxia and whether this peripheral inflammation response was associated to cognitive deficits. We found that neonatal hypoxia significantly increased leukocytes not only in blood, but also increased the monocytes in central nervous system (CNS), indicated by presence of C-C chemokine receptor type 2 (CCR2+)/CD11b+CD45+ positive cells and CCR2 protein expression level. The early onset of peripheral inflammation response was followed by a late onset of brain inflammation that was demonstrated by level of cytokine IL-1β and ionized calcium binding adapter molecule 1(Iba-1; activated microglial cell marker). Interrupted blood-brain barrier (BBB), hypomyelination and learning and memory deficits were seen after hypoxia. Interestingly, the cognitive function was highly correlated with hypoxia-induced leukocyte response. Notably, administration of minocycline even after the onset of hypoxia significantly suppressed leukocyte-mediated inflammation as well as brain inflammation, demonstrating neuroprotection in systemic hypoxia-induced brain damage. Our data provided new insights that systemic hypoxia induces cognitive dysfunction, which involves the leukocyte-mediated peripheral inflammation response.

We compared the efficacy of three automated brain injury detection methods, namely symmetry-integrated region growing (SIRG), hierarchical region splitting (HRS) and modified watershed segmentation (MWS) in human and animal magnetic resonance imaging (MRI) datasets for the detection of hypoxic ischemic injuries (HIIs). Diffusion weighted imaging (DWI, 1.5T) data from neonatal arterial ischemic stroke (AIS) patients, as well as T2-weighted imaging (T2WI, 11.7T, 4.7T) at seven different time-points (1, 4, 7, 10, 17, 24 and 31 days post HII) in rat-pup model of hypoxic ischemic injury were used to assess the temporal efficacy of our computational approaches. Sensitivity, specificity, and similarity were used as performance metrics based on manual ('gold standard') injury detection to quantify comparisons. When compared to the manual gold standard, automated injury location results from SIRG performed the best in 62% of the data, while 29% for HRS and 9% for MWS. Injury severity detection revealed that SIRG performed the best in 67% cases while 33% for HRS. Prior information is required by HRS and MWS, but not by SIRG. However, SIRG is sensitive to parameter-tuning, while HRS and MWS are not. Among these methods, SIRG performs the best in detecting lesion volumes; HRS is the most robust, while MWS lags behind in both respects.

Hypoxia-ischemia (HI) is a model of cerebral ischemia used to model neonatal hypoxia and to study brain damage. Interpreting the results of experiments that use HI rests partly on the assumption that only the brain suffers major damage. In this study, we demonstrate that HI also has adverse consequences on the heart. Both infarction scoring and measurements of troponin I indicate cardiac damage subsequent to HI. These results indicate that the effects of HI on the heart may confound the interpretation of experiments that have used HI to study neuroprotection or other aspects of brain damage.

Despite its poor outcomes, therapeutic hypothermia (TH) is the current standard treatment for neonatal hypoxic-ischaemic encephalopathy (HIE). In this study, due to its antioxidant, anti-inflammatory, and antiapoptotic properties, the effectiveness of molecular hydrogen (H2) combined with TH was evaluated by means of neurological and histological assessments. Piglets were divided into three groups: hypoxic-ischaemic insult with normothermia (NT), insult with hypothermia (TH, 33.5 ± 0.5 °C), and insult with hypothermia with H2 ventilation (TH-H2, 2.1–2.7%). H2 ventilation and TH were administered for 24 h. After ventilator weaning, neurological assessment was performed every 6 h for 5 days. On day 5, the brains of the piglets were harvested for histopathological analysis. Regarding the neurological score, the piglets in the TH-H2 group consistently had the highest score from day 2 to 5 and showed a significantly higher neurological score from day 3 compared with the NT group. Most piglets in the TH-H2 group could walk at day 3 of recovery, whereas walking ability was delayed in the two other groups. The histological results revealed that TH-H2 tended to improve the status of cortical gray matter and subcortical white matter, with a considerable reduction in cell death. In this study, the combination of TH and H2 improved short-term neurological outcomes in neonatal hypoxic-ischaemic piglets.

It is believed that neonatal hypoxia–ischemia (HI) brain injury causes neuron loss and brain functional defects. However, the effect of HI brain injury on dendritic development of the remaining pyramidal cells of the hippocampus and the reaction of contralateral hippocampal neurons require further studies. The Morris water maze and Golgi–Cox staining were used to evaluate the learning and memory and dendritic morphology of pyramidal cells. The results of Golgi–Cox staining showed CA1 pyramidal neurons of HI injury models with fewer bifurcations and shorter dendrite length than the naive control group. The density of dendritic spines of hippocampal CA1 pyramidal neurons was significantly lower in the HI brain injury group than in controls. With respect to hippocampal function, the HI brain injury group presented cognitive deficits in the reference memory task and probe trail. In the HI group, the pyramidal cells of left hippocampus that did not experienced ischemia but did experience hypoxia had more complex dendrites and higher density of spine than the HI injury side and control. The functional implementation of injured hippocampus might depend mainly on the hypertrophy of contralateral hippocampus after HI brain injury. Corticosterone can partially prevent the hippocampal pyramidal cells from HI injury and reduce the difference of the bilateral hippocampus pyramidal cells, but there was no improvement in learning and memory. © 2013 Wiley Periodicals, Inc.

Neonatal hypoxia-ischemia (HI) affects 60% of low birth weight infants and up to 40% of preterm births. Cell death and brain injury after HI have been shown to cause long-lasting behavioral deficits. By using a battery of behavioral tests on second generation 3-week-old rodents, we found that neonatal HI is associated with behavioral outcomes in the progeny of HI-affected parents. Our results suggest an epigenetic transfer mechanism of some of the neurological symptoms associated with neonatal HI. Elucidating the transfer of brain injury to the next generation after HI calls attention to the risks associated with HI injury and the need for proper treatment to reverse these effects. Assessing the devastating extent of HI's reach serves as a cautionary tale to the risks associated with neonatal HI, and provides an incentive to create improved therapeutic measures to treat HI.

Background: Neonatal encephalopathy induced by perinatal asphyxia is a serious condition associated with high mortality and morbidity. Inflammation after the insult is thought to contribute to brain injury. This inflammatory response to hypoxia-ischemia (HI) may not only occur in the brain but also in peripheral organs. The aim of the present study was to investigate the effect of neonatal HI on the inflammatory response in the liver in comparison to inflammation in the brain. Methods: HI was induced in P7 Wistar rats by unilateral carotid artery occlusion and hypoxia. Cytokine and chemokine mRNA levels were determined in the brain and liver by quantitative PCR. Polarization of brain macrophages to the M1/M2-like phenotype and infiltration of neutrophils were characterized by immunohistochemistry. Results: 3 h after HI, an upregulation of the proinflammatory cytokines TNF-α and IL-1β and anti-inflammatory IL-10 was observed in the ipsilateral hemisphere of the brain compared to mRNA levels in sham-operated animals. Additionally, cerebral CINC-1 and MCP-1 mRNA expressions were increased. We also observed increased numbers of macrophages/microglia of the M1-like phenotype as well as a small increase in granulocyte influx in the ipsilateral hemisphere. Conversely, in the liver 3 h after HI, a downregulation of TNF-α, IL-1β, and MCP-1 and a trend towards an upregulation of IL-10 were observed compared to mRNA levels of sham-operated animals. However, hepatic CINC-1 expression was increased compared to levels in sham-operated animals. Following systemic hypoxia only, no significant changes in the expression of TNF-α, CINC-1 or MCP-1 were observed in the liver compared to sham-operated littermates, except for an upregulation in hepatic IL-1β expression 3 h after hypoxia. Twenty-four hours after insult, cerebral ipsilateral TNF-α, MCP-1 and CINC-1 mRNA expression was still increased, together with an increase in TGF-β expression. Moreover, an increase in macrophages/microglia of the M1-like phenotype was observed together with the appearance of macrophages/microglia of the M2-like phenotype around the cerebral lesion as well as an increase in granulocyte influx in comparison to 3 h after HI. In the liver, 24 h after HI, cytokine and chemokine responses were similar to mRNA levels in sham-operated animals except for a decrease in IL-10 and MCP-1. Conclusion: We describe for the first time that brain damage following neonatal HI induces an early downregulation of the proinflammatory response in the liver. HI induces an early proinflammatory response in the brain with a concomitant increase in influx of neutrophils and polarization of macrophages/microglia to the M1-like phenotype starting at 3 h and increasing up to 24 h after HI. The inflammatory state of the brain changes after 24 h, with an increase in the anti-inflammatory cytokine TGF-β together with the appearance of macrophages/microglia of the M2-like phenotype. The downregulation of proinflammatory cytokines in the liver is not due to systemic hypoxia only, but is induced by the cerebral damage.

Therapeutic hypothermia in term infants with neonatal asphyxial encephalopathy has been shown to have beneficial effects in relation to neurodevelopmental outcome and survival. This paper is a critical appraisal of two studies, which compares and contrasts the methodology and findings, and incorporates a synthesis of findings with reflection on clinical practice.

Acute hypoxia at postnatal day (P) 10 is an accepted model of human neonatal hypoxia which results, among other consequences, in increased hippocampal excitability. Hypoxic–ischemic injury, which mimics stroke, has been shown to result in changes in connexins (Cxs), however, changes in Cxs have not been studied in the P10 hypoxia model. The aim of this study was to investigate changes in the hippocampal expression of three different connexins at consecutive developmental stages after acute hypoxia at P10 (10 min and 30 min after reoxygenation, P11, P14, P17, P29, and P45) as compared to sham manipulated pups. After acute hypoxia at P10, Cx30 protein levels were increased at 30 min after reoxygenation, at P11 and at P14, and then returned to control levels. Cx36 protein levels transiently decreased at P11 after acute hypoxia then returned to control levels. Cx43 protein levels did not change at any of the time points. Although changes in mRNA expression were observed during development for Cx30 only, acute hypoxia did not result in changes in mRNA expression of all these Cxs when compared to age matched controls suggesting that acute hypoxia induced posttranslational changes in protein expression.

Although recent studies have documented compensatory generation of neurons in adult brains in response to various insults, a noninjurious short episode of hypoxia in rat neonates has been shown to trigger neurogenesis within the ensuing weeks, without apparent brain lesions. Very little is known of the long-term consequences. We therefore investigated the effects of such a conditioning-like hypoxia (100% N(2), 5 min) on the brain and the cognitive outcomes of rats at 40 to 100 days of age. Control and posthypoxic rats developed similar learning capacities over postnatal days 14 to 18, but hypoxia was associated with enhanced scores in a test used to evaluate memory retrieval between 40 and 100 days. A striking sexual dimorphism was observed, with an earlier functional gain observed in female (40 days) compared with male (100 days) rats; gains were associated with matching structural changes in areas involved in cognition, including the hippocampus and frontal cortex. Therefore, it is proposed that brief neonatal hypoxia may exert long-term beneficial effects through neurogenesis stimulation.

Neonatal hypoxic ischemic injury (HII) is a devastating brain disease for which hypothermia is currently the only approved treatment. As new therapeutic interventions emerge there is a significant need for noninvasive objective quantification of the spatiotemporal lesion dynamics combined with precise information about lesion constituents (ischemic core and penumbra). These metrics are important for deciding treatment parameters (type, time, site, and dose) and for monitoring injury-therapy interactions. Such information provided ‘on-line’ in a timely fashion to the clinician could revolutionize clinical management. Like other spatiotemporal biological processes, video bioinformatics can assist objective monitoring of injury–therapy interactions. We have been studying the efficacy of various potential treatments in translational (rodent) HII models using magnetic resonance imaging (MRI). We have developed a novel computational tool, hierarchical region splitting (HRS) to rapidly identify ischemic lesion metrics. HRS detects similar lesion volumes compared to manual detection methods and is fast, robust, and reliable compared to other computational methods. HRS also provides additional information about the location, size, and evolution of the core and penumbra, which are difficult to ascertain with manual methods. This chapter summarizes the ability of HRS to identify lesion dynamics and ischemic core-penumbra evolution following neonatal HII. In addition, we demonstrate that HRS provides information about lesion dynamics following different therapies (e.g., hypothermia, stem cell implantation). Our findings show that computational analysis of MR images using HRS provides novel quantitative approaches that can be applied to clinical and translational stroke research using data mining of standard experimental and clinical MRI data.

Hypoxia is the most common cause of neonatal seizures and can lead to epilepsy, but the epileptogenic mechanisms are not yet understood. We have previously shown that hypoxia-induced seizures in the neonatal rat result in acutely decreased amplitudes and frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) in hippocampal CA1 pyramidal neurons. In the current study, we asked whether such changes persist for several days following hypoxia-induced seizures. Similar to the acute findings, we observed decreased frequency and amplitudes of sIPSCs and decreased mIPSC amplitudes in CA1 pyramidal neurons at 3–5 days after hypoxia. However, in contrast to the acute findings, we observed no differences between hypoxia-treated and control groups in mIPSC frequency. Additionally, by 7 days after hypoxia, sIPSC amplitudes in the hypoxia group had recovered to control levels, but sIPSC frequency remained decreased. These data indicate that the persistently decreased sIPSC frequency result from decreased firing of presynaptic inhibitory interneurons, with only transient possible changes in postsynaptic responses to GABA release.

A participação de marcadores bioquímicos na avaliação de quadros de asfixia neonatal é cada vez mais relevante. A proteína S100B é de particular importância neste campo. O objetivo deste estudo foi procurar destacar a importância da proteína S100B na avaliação de recém-nascidos a termo com quadro de encefalopatia hipóxico-isquêmica, assim como correlacionar com outras substâncias que também participam do processo isquêmico. Foram analisados 21 casos de recém nascidos a termo que desenvolveram encefalopatia hipóxico-isquêmica no período de setembro de 2003 a outubro de 2004. Realizadas coletas no 1º e 4º dia de vida e dosadas, por método imunocitoquímico, a proteína S100B e o lactato. Observouse correlação positiva entre as duas substâncias, assim como quando comparadas entre si nas suas respectivas dosagens, obteve-se significância estatística. Biochemical markers have played an increasingly relevant role in the assessment of neonatal asphyxia. The S100B protein is particularly important in re s e a rch conducted in this field. The purpose of this study was to underline the importance of the S100B protein in the assessment of term newborn infants with hypoxic-ischemic encephalopathy, as well as to relate it to other substances also involved in the ischemic p rocess. An assessment was made from September 2003 to October 2004 of 21 term newborn infants who developed hypoxic-ischemic encephalopathy. Samples were collected on the 1st and 4th day of life and S100B p rotein and lactate concentrations were calculated using the immune cytochemical method. A positive relationship was found between the two substances. Additionally, a comparison between the two substances showed a statistically significant correlation.

WOS:000346149200005 PubMed: 25491683 Background. Neonatal hypoxic-ischemic (HI) injury has been considered to have acute and long term deleterious effects on many tissues, including the peripheral nerve. Objectives. In this study, the effects of a tumor necrosis factor-alpha (TNF-alpha) inhibitor (etanercept) on peripheral nerve damage and the ultrastructure of the sciatic nerve and gastrocnemius muscle in rats exposed to HI during the neonatal period were examined. Material and Methods. In this study, 45 seven-day-old rats were used and they were divided into three groups. The right carotid arteries of the rats in the saline and etanercept groups were ligated and put in a hypoxia chamber containing 8% oxygen for two hours. Just after hypoxia, the etanercept group was given 10 mg/kg etanercept, but the saline group had only saline intraperitoneally. The sham group rats' carotid arteries were not ligated or put in hypoxia. The amplitude, area and latency of sciatic nerve compound motor action potential (CMAP), which mainly reflects axonopathy and myelinopathy, were measured using standard techniques in the seventeenth week following the HI. Sciatic nerve and gastrocnemius muscle were evaluated with a transmission electron microscope, and grading for myelin sheath damage was done to all groups. Results. Neuropathy was seen in rats after HI. While treatment with etanercept showed a protective effect for the axons of sciatic nerve, demyelination could not be recovered with etanercept. Conclusions. This study is the first in literature to show a partial interruption of the signal through the peripheral nerve fibers caused by axonal and myelin dysfunction continuation in rats exposed to HI after birth, in the 17th week

Seizures after neonatal hypoxia are difficult to treat. A recent antiepileptic safety and dose-finding study examined phenobarbital plus bumetanide, but was stopped owing to apparent futility and increased risk of hearing loss. However, this decision could have been overcautious: 0.2 mg/kg bumetanide reduced seizure burden, and might not have increased hearing loss.

BACKGROUND The aim of this study is to determine carnitine levels in hypoxic-ischemiac neonates. METHODS Total and free carnitine levels were measured in 20 normal term neonates and 20 term neonates who were diagnosed as hypoxia-ischemia. RESULTS Both total carnitine levels (43.7 +/- 10.0 microg/dl vice 27.8 +/- 11.8 microg/dl, p

BackgroundHypoxic-ischemic (HI) injury to the developing brain remains a major cause of morbidity. Hypothermia is effective but does not provide complete neuroprotection, prompting a search for adjunctive therapies. Erythropoietin (Epo) has been shown to be beneficial in several models of neonatal HI. This study examines combination hypothermia and treatment with erythropoietin in neonatal rat HI.MethodsRats at postnatal day 7 were subjected to HI (Vannucci model) and randomized into four groups: no treatment, hypothermia alone, Epo alone, or hypothermia and Epo. Epo (1,000 U/kg) was administered in three doses: immediately following HI, and 24 h and 1 wk later. Hypothermia consisted of whole-body cooling for 8 h. At 2 and 6 wk following HI, sensorimotor function was assessed via cylinder-rearing test and brain damage by injury scoring. Sham-treated animals not subjected to HI were also studied.ResultsDifferences between experimental groups, except for Epo treatment on histopathological outcome in males, were not statistically significant, and combined therapy had no adverse effects.ConclusionNo significant benefit was observed from treatment with either hypothermia or combination therapy. Future studies may require older animals, a wider range of functional assays, and postinsult assessment of injury severity to identify only moderately damaged animals for targeted therapy.

The NaKCl cotransporter NKCC1 facilitates intraneuronal chloride accumulation in the developing brain. Bumetanide, a clinically available diuretic, inhibits this chloride transporter, and augments the antiepileptic effects of phenobarbital in neonatal rodents. In a neonatal cerebral hypoxia-ischemia (HI) model, elicited by right carotid ligation, followed by 90 min 8% O2 exposure in 7-day-old(P7) rats, phenobarbital(PB) increases the neuroprotective efficacy of hypothermia. We evaluated whether bumetanide influenced the neuroprotective efficacy of combination treatment with PB and hypothermia(HT). P7 rats underwent HI lesioning; 15 min later, all received PB (30 mg/kg). 10 min later, half received bumetanide (10 mg/kg, PB-HT+BUM) and half received saline (PB-HT+SAL). One hour after HI, all were cooled (30°C, 3h). Contralateral forepaw sensorimotor function and brain damage were evaluated 1 to 4 weeks later. Forepaw functional measures were close to normal in the PB-HT+BUM group, while deficits persisted in PB-HT+SAL controls; there were corresponding reductions in right cerebral hemisphere damage (at P35, % damage: PB-HT+BUM, 21±16 versus 38±20 in controls). These results provide evidence that NKCC1 inhibition amplifies phenobarbital bioactivity in the immature brain, and suggest that co-administration of phenobarbital and bumetanide may represent a clinically feasible therapy to augment the neuroprotective efficacy of therapeutic hypothermia in asphyxiated neonates.

OBJECTIVE. The findings of hypoxia in the term neonate are unique; neonatal brain imaging findings differ from those of older children. Evaluation of neonatal brain images for signs of hypoxic injury requires attention to a specific set of signs.CONCLUSION. Imaging findings in term neonates must be assessed according to different rules from those used in other age groups. Four major signs are proposed as a means of facilitating the diagnosis of hypoxia in the neonate.

Hypoxic-ischemic brain injury is often delayed and involves both apoptotic and immunoregulatory mechanisms. In this study, we used a neonatal model of hypoxia-ischemia to examine the effect of the mixed lineage kinase (MLK) inhibitor CEP-1347 on brain damage, apoptosis and inflammation. The tissue volume loss was reduced by 28% (p = 0.019) in CEP-1347-treated versus vehicle-treated rats and CEP-1347 significantly attenuated microgliosis at 7 days (p = 0.038). CEP-1347 decreased TUNEL-positive staining as well as cleaved caspase 3 immunoreactivity. CEP-1347 did not affect the expression of pro-inflammatory cytokines IL-1β, IL-6 and MCP-1, nor did it affect the expression of OX-42 (CR3) and OX-18 (MHC I) 24 h after the insult. In conclusion, the MLK inhibitor CEP-1347 has protective effects in a neonatal rat model of hypoxia-ischemia, which is mainly related to reduced apoptosis.

INTRODUCTION: As a consequence of obstetric complications hypoxia has been discussed as a possible factor in the pathophysiology of schizophrenia. The present study investigated the effects of weak chronic neonatal hypoxia in rats on different behavioural animal models of schizophrenia. METHODS: (1) After neonatal hypoxia, half of the pups were fostered by normally treated nurse animals to control for possible maternal effects. (2) The animals were tested on postnatal days (PD) 36, 86, 120 and 150 by applying three different behavioural tests: prepulse inhibition (PPI), social interaction and recognition, and motor activity in an open field. (3) Before the PD 150 test, half of the animals had been chronically treated with the antipsychotic drug clozapine (45 mg/kg/day). RESULTS: Rats exposed to hypoxia as neonates exhibited a deficit in locomotor activity on PD 86, 120, and 150, as well as a PPI deficit on PD 120 and 150 but not before. Chronic treatment with clozapine reverses the hypoxia induced PPI deficit, but not the decreased locomotor activity. In a second experiment, clozapine was chronically administered before PD 120 and blocked the development of the PPI deficit in the animals exposed to hypoxia. DISCUSSION: The time course of the hypoxia-induced PPI deficit and reversibility by clozapine supports the validity of our animal model and the hypothesis that hypoxia as an obstetric complication is an important factor in the pathophysiology of schizophrenia.

Materials and methods Seven days old male Swiss mice were distributed on three groups: hypoxia (H), maternal separation (MS) and no handling (NH). H group underwent to 10% oxygen during 6 hours/day for 6 days and MS group was maintained in normoxia, but separated from their dams such as H group. When mice completed 3 months old, they were tested on locomotor activity boxes or in plus-maze. The parameters measured were erythrocyte catalase, superoxide dismutase and glutathione peroxidase (GPx) and cerebral catalase. Data were analyzed by one-way ANOVA test and Bonferroni post-hoc test, when appropriated.

We have previously shown that neonatal mice deficient in endothelial nitric oxide synthase (eNOS−/−) are more susceptible to hypoxic inhibition of alveolar and vascular growth. Although eNOS is downregulated, the role of nitric oxide (NO) during recovery after neonatal lung injury is poorly understood. We hypothesized that lung vascular and alveolar growth would remain impaired in eNOS−/− mice during recovery in room air and that NO therapy would augment compensatory lung growth in the eNOS−/− mice during recovery. Mice (1 day old) from heterozygous (eNOS+/−) parents were placed in hypobaric hypoxia (FiO2= 0.16). After 10 days, pups were to recovered in room air (HR group) or inhaled NO (10 parts/million; HiNO group) until 3 wk of age, when lung tissue was collected. Morphometric analysis revealed that the eNOS−/− mice in the HR group had persistently abnormal lung structure compared with eNOS-sufficient (eNOS+/+) mice (increased mean linear intercept and reduced radial alveolar counts, nodal point density, and vessel density). Lung morphology of the eNOS+/− was not different from eNOS+/+. Inhaled NO after neonatal hypoxia stimulated compensatory lung growth in eNOS−/− mice that completely restored normal lung structure. eNOS+/− mice (HR group) had a 2.5-fold increase in lung vascular endothelial growth factor (VEGFR)-2 protein compared with eNOS+/+ ( P < 0.05). eNOS−/− mice (HiNO group) had a 66% increase in lung VEGFR-2 protein compared with eNOS−/− (HR group; P < 0.01). We conclude that deficiency of eNOS leads to a persistent failure of lung growth during recovery from neonatal hypoxia and that, after hypoxia, inhaled NO stimulates alveolar and vascular growth in eNOS−/− mice.

Background and aims The use of biomarkers is an important strategy for risk stratification for neonates admitted to the NICU after perinatal asphyxia. Total Tau (t-Tau), phosphorylatedTau (p-Tau) and Beta-Amyloid (1–42) (b-A) in CSF, are useful biomarkers in various neurological disorders, such as Alzheimer's. Few, if any, experiments have investigated the possible association between oxidative stress in the neonates and the levels of these proteins. ![Abstract PS-159 Table 1][1] Abstract PS-159 Table 1 ![Abstract PS-159 Table 2][1] Abstract PS-159 Table 2 Objective To study any correlations between the levels of t-Tau, p-Tau, b-A, S100B and NSE and oxidative stress in the newborn pig. Methods Fifty-four newborn piglets, age12–36 h, were included. One control group (n = 6) and 2 experimental groups (n = 24), exposed to global hypoxia (8% O2) until BE reached -15 mmol/l (moderate hypoxia) or -20 mmol/l (severe hypoxia) or BP fell below 20 mmHg. The pigs were observed for 9.5 h. CSF was collected 9.5 h after the intervention. Discussion To our knowledge this is the first study investigating the levels of Tau, p-Tau and b-Amyloid in a neonatal animal model after hypoxia-reoxygenation. The reduced level of CSF b-Amyloid may reflect the death of neurons after neonatal hypoxia. A strategy of measuring several biomarkers should be applied when assessing the prognosisafter perinatal asphyxia. Conclusion These findings show that b-amyloid and S100b are significantly changed in neonatal pigs subjected to hypoxia compared to controls, thus they may be valuable biomarkers after perinatal asphyxia. [1]: pending:yes

Increases in plasma lipids occur during hypoxia in suckling but not in weaned rats and may result from altered hepatic enzyme activity. We exposed rats to 7 days of hypoxia from birth to 7 days of age (suckling) or from 28 to 35 days of age (weaned at day 21). Hypoxia led to an increase in hepatic lipid content in the suckling rat only. Hepatic lipase was decreased to approximately 45% of control in 7-day-old rats exposed to hypoxia but not in hypoxic 35-day-old rats. Hypoxic suckling rats also had a 50% reduction in lactate dehydrogenase activity, whereas transaminase activity and CYP1A and CYP3A protein content were not different between hypoxic and normoxic groups. Additional rats were studied 7 and 14 days after recovery from hypoxic exposure from birth to 7 days of age; hepatic lipase activity had recovered to 85% by 7 days and to 100% by 14 days in the rats previously exposed to hypoxia. Administration of dexamethasone to neonatal rats to simulate the hyperglucocorticoid state found in hypoxic 7-day-old rats led to a moderate decrease ( approximately 75% of control) in hepatic lipases. Developmentally, in the normoxic state, hepatic lipases increased rapidly after birth and reached levels more than twofold that of the newborn by 7 days of age. Hypoxia delays the maturation of hepatic lipases. We suggest that the decrease in hepatic lipase activity contributes to hyperlipemia in the hypoxic newborn rats.

Background- Hypoxia during the first week of life can induce neuronal death in vulnerable brain regions usually associated with an impairment of cognitive function that can be detected later in life. The neurobiological changes mediated through neurotransmitters and other signaling molecules associated with neonatal hypoxia are an important aspect in establishing a proper neonatal care. Methods- The present study evaluated total GABA, GABAB receptor alterations, gene expression changes in GABAB receptor and glutamate decarboxylase in the cerebellum and brain stem of hypoxic neonatal rats and the resuscitation groups with glucose, oxygen and epinephrine. Radiolabelled GABA and baclofen were used for receptor studies of GABA and GABAB receptors respectively and Real Time PCR analysis using specific probes for GABAB receptor and GAD mRNA was done for gene expression studies. Results- The adaptive response of the body to hypoxic stress resulted in a reduction in total GABA and GABAB receptors along with decreased GABAB receptor and GAD gene expression in the cerebellum and brain stem. Hypoxic rats supplemented with glucose alone and with oxygen showed a reversal of the receptor alterations and changes in GAD. Resuscitation with oxygen alone and epinephrine was less effective in reversing the receptor alterations. Conclusions- Being a source of immediate energy, glucose can reduce the ATP-depletion-induced changes in GABA and oxygenation, which helps in encountering hypoxia. The present study suggests that reduction in the GABAB receptors functional regulation during hypoxia plays an important role in central nervous system damage. Resuscitation with glucose alone and glucose and oxygen to hypoxic neonatal rats helps in protecting the brain from severe hypoxic damage.

Noradrenergic (NA) neurons in the brainstem are assumed to be involved in arousal mechanisms (locus coeruleus or A6) and cardio-respiratory control(nucl. tr. solitarius or A2). We have earlier reported an acute depression of NA turnover in newborn rats exposed to hypoxia (Acta Physiol.Scand.1992.144:433) The aim was now to investigate the acute effect of perinatal asphyxia and the long-term effects of chronic hypoxia on NA-turnover in the rat brain.

Sligth hypoxic-ischemic perinatal event can originated scare problems in later netirodevelopment, The aim of this job is to show the effects of two levels of hypoxia in a maze test resolution. Three groups of newborn Wistar rats were placed in an exposure chamber. They were keep in their mothers' cages till weaning (day 21). Days 25 and 26 they were submitted to maze trials. After fasting from day 28 until 30th, they were submitted again to a new maze trial. The variable validating the anirrals' behaviour was the number of squares crossed in the maze resolution (SC). Results and statistical analisys (ANOVA) are as follows: V5 group obtained a best profile in the learning capacity than V10 group. Number of errors (SC) decreased dramatically in V5 as happend wiht SH group, while V10 remained the same level of the first trial. However we are not sure if these effects can be exclusively related to the absence of presumed handicap rats who died, or to any other genetic/environmental factor.

Forty-six neonates with hypoxemia were treated with tolazoline, a pulmonary vasodilator, within the first two days of life. Eight of ten (80%) infants without apparent lung disease responded with a mean increase in PaO2 of 116 torr within one hour of beginning tolazoline infusions. One of the responding infants and two nonresponders died. Thirty-six additional infants with a variety of pulmonary disorders had severe hypoxemia which was refractory to mechanical ventilation. Twenty-one (58%) responded with a mean increase in PaO2 of 130 torr within one hour after beginning tolazoline and 13 (62%) of these survived. Fifteen patients had little or no improvement in PaO2 following tolazoline and only three (20%) of these infants survived. Responders could not be distinguished from nonresponders by clinical or laboratory features prior to therapy with tolazoline. Fourteen infants experienced complications possibly related to tolazoline.

As a consequence of obstetric complications, neonatal hypoxia has been discussed as an environmental factor in the pathophysiology of schizophrenia. However, the biological consequences of hypoxia are unclear. The neurodevelopmental hypothesis of schizophrenia suggests that the onset of abnormal brain development and neuropathology occurs perinatally, whereas symptoms of the disease appear in early adulthood. In our animal model of chronic neonatal hypoxia, we have detected behavioral alterations resembling those known from schizophrenia. Disturbances in cell proliferation possibly contribute to the pathophysiology of this disease. In the present study, we used postnatal rats to investigate cell proliferation in several brain areas following neonatal hypoxia. Rats were repeatedly exposed to hypoxia (89 % N(2), 11 % O(2)) from postnatal day (PD) 4-8. We then evaluated cell proliferation on PD 13 and 39, respectively. These investigations were performed in the anterior cingulate cortex (ACC), caudate-putamen (CPU), dentate gyrus, and subventricular zone. Rats exposed to hypoxia exhibited increased cell proliferation in the ACC at PD 13, normalizing at PD 39. In other brain regions, no alterations have been detected. Additionally, hypoxia-treated rats showed decreased CPU volume at PD 13. The results of the present study on the one hand support the assumption of chronic hypoxia influencing transient cell proliferation in the ACC, and on the other hand reveal normalization during ageing.

Previous studies have shown that severe neonatal asphyxia and hypoxia lead to a redistribution of cerebral blood flow (CBF) with a preferential perfusion of the brain stem. The present study shows that this mechanism is operative also in moderately hypoxic newborn lambs (oxygen saturation 32.7-65.2) with a threshold of about 25% reduction in oxygen saturation. In hypoxia, the mean increase in total CBF, brain stem and telencephalic blood flow was 44%, 68% and 43%, respectively (five lambs). We found that naloxone reverses this redistribution, and that the effects of naloxone on telencephalic perfusion and cerebral metabolic rate of oxygen (CMRO2) were proportional. In hypoxia + naloxone (1 mg/kg), a further increase in total CBF, brain stem, and telencephalic blood flow of 30%, 7% and 31% was noted. We therefore suggest that the redistribution of CBF is an important opioid-mediated homeostatic mechanism, which diminishes the metabolic requirements of the newer part of the brain in hypoxia and allows a preferential perfusion of the vital structures of the brain stem.

The behavioral performance of rats subjected in the neonatal period to hypoxia-ischemia at either 37 degrees C or 21 degrees C was compared to that of sham-ligated animals. Performance on complex motor tests was significantly delayed only in the hypoxic-ischemic 37 degrees C rats. However, cognitive testing disclosed significant delay of spatial learning in animals subjected to hypoxia-ischemia at 21 degrees C and those with gross infarction at 37 degrees C. There was enhanced avoidance learning in the animals with gross infarction in the hypoxia-ischemia 37 degrees C group. Hypoxic-ischemic damage in the neonatal rat at 37 degrees C results in transient delay of complex motor skills, but longer lasting cognitive changes. Hypoxia-ischemia during hypothermia produces no motor deficits, although there may be similar alterations in learning.

Hypoxanthine levels were determined in both venous and arterial cord blood of 42 neonates. Two methods were compared, a PO2 electrode determination and an HPLC (high-pressure liquid chromatography) method. A good correlation was found between the two methods. However, the HPLC method was more sensitive, more reproducible and easier to perform. Hypoxanthine levels in the umbilical artery were found to be higher than in the vein. A significant negative correlation between pH and hypoxanthine level was established. The studies showed that plasma hypoxanthine levels by themselves did not provide an absolute diagnosis of intrauterine hypoxia.

Sinusoidal heart rate traces were detected in 8 patients, 6 of whom died; the 2 survivors showed evidence of gross cerebral damage. It is felt that the origin of the sinusoidal curve is probably central and reflects loss of central control of heart rate.