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In the proposed systematic review, we seek to identify, compile, examine, and synthesize the findings of quantitative and mixed methods research in which both brain imaging techniques and assessments of achievement have been used to evaluate and understand the relationships among developmental programming , neurodevelopment and achievement in reading and mathematics. The principal aims of the present review are to provide an accurate, concise, and accessible overview of the major findings of literature in the field and at the same time address the following research questions: (1) What is the current state of the evidence concerning the relationships among developmental programming, neurodevelopment and achievement in reading and mathematics? (2) What trends can be observed in the extant literature? (3) What gaps exist in the in the extant literature? (4) What are appropriate directions for future research?

Diffusion-time- ( td) dependent diffusion MRI (dMRI) extends our ability to characterize brain microstructure by measuring dMRI signals at varying td. The use of oscillating gradient (OG) is essential for accessing short td but is technically challenging on clinical MRI systems. This study aims to investigate the clinical feasibility and value of td-dependent dMRI in neonatal hypoxic-ischemic encephalopathy (HIE). Eighteen HIE neonates and six normal term-born neonates were scanned on a 3 T scanner, with OG-dMRI at an oscillating frequency of 33 Hz (equivalent td ≈ 7.5 ms) and pulsed gradient (PG)-dMRI at a td of 82.8 ms and b-value of 700 s/mm2. The td-dependence, as quantified by the difference in apparent diffusivity coefficients between OG- and PG-dMRI (ΔADC), was observed in the normal neonatal brains, and the ΔADC was higher in the subcortical white matter than the deep grey matter. In HIE neonates with severe and moderate injury, ΔADC significantly increased in the basal ganglia (BG) compared to the controls (23.7% and 10.6%, respectively). In contrast, the conventional PG-ADC showed a 12.6% reduction only in the severe HIE group. White matter edema regions also demonstrated increased ΔADC, where PG-ADC did not show apparent changes. Our result demonstrated that td-dependent dMRI provided high sensitivity in detecting moderate-to-severe HIE.

Introduction: Among the hypertensive pathologies of pregnancy, preeclampsia remains the entity responsible for pregnancy complications. Objective: The aim of this work was to determine the frequency of hypertensive pathologies in the peripartum, to determine the maternal and neonatal morbidity factors associated with preeclampsia on the one hand, and on the other hand, to other forms of hypertension in the peripartal period. Patients and methods: This is a cross-sectional study of hypertensive pathologies in per partum over a period of 15 months which have been included any pregnant, parturient and hypertensive childbirth. The data was analyzed using SPSS software version 21.0. Data positioning and dispersion parameters were studied. The factor analysis was performed by determining the odds ratio with a 95% confidence interval and a significance level set at p ≤ 0.05. Results: 142 cases of hypertension were collected from a total of 2988 deliveries, i.e. a frequency of hypertension of 4.8%. The main form of high blood pressure (HBP) was the isolated HBP at 51.4%. 60.3% of primiparas were preeclamptic [OR 2.47 (CI 1.25 - 4.91)], 63.2% of preeclampsia did not follow prenatal consultations [OR 2.43 (CI 1.06 - 5.62)], 63.6% of preeclampsia had moderate and severe threat premature delivery [OR 4.57 (CI 2.11 - 9.99)], neonatal hypoxia in the fifth minute was found in 34.4% of newborns of preeclamptic mothers [OR 3.02 (CI 1.44 - 6.34)], hypotrophy was observed in 41.4% of the cases in the preeclamptic patients [OR 5.41 (IC 1, from 55 to 19.57)]. Conclusion: Preeclampsia is significantly associated with maternal and neonatal morbidity.

Background: Creatine kinase MB (CK-MB), which exists mainly in the cytoplasm of myocardial cells, is currently accepted as an indicator and has high sensitivity and specificity for the diagnosis of myocardial injury. Objective: This study was aimed to estimate serum creatine kinase MB (CK-MB) levels after asphyxia-induced myocardial injury in neonates. Patients and methods: 40 neonates were included in this study and divided into 20 cases with the diagnosis of perinatal hypoxia ischemia and 20 controls admitted to Neonatology Unit of Pediatric Department at Zagazig University. Serum CK-MB levels were estimated in all studied neonates. Results: In the present study serum CK-MB levels in cases were significantly higher than controls. A significant area under curve with cutoff >14.5 (units /L) with sensitivity 99%and specificity 97.5% for CK-MB. Encephalopathy cases were significantly associated with higher HR and CKMB. Cases with organ failure were significantly associated with higher HR and CKMB. Cases with metabolic acidosis were significantly associated with higher HR and CKMB. Conclusion: It could be concluded that cases with hypoxic ischemic encephalopathy (HIE) and those with multiple organ failure had a more pronounced elevation of serum CK-MB compared with cases of hypoxia-ischemia with no organ failure. Similarly, patients with HIE had significant elevation of cardiac enzymes. Collectively, these findings indicate more myocardial systolic dysfunction and damage in neonates with HIE and organ failure.

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.

We assessed the quality of life and the amount of parental stress in families with children treated with therapeutic hypothermia (TH) after hypoxic ischemic encephalopathy (HIE). Our sample included 19 children (10 with mild HIE, 6 with moderate HIE, and 3 children with severe HIE) and their parents. The children were 6 to 9 years old. Parents completed two questionnaires (PedsQL-FIM and PSI-III). As a developmental outcome indicator we measured the children’s intelligence with WISC-IIISI and WPPSI-IIISI. The quality of life in participating families was better and parental stress did not differ significantly from normative values. Families have adapted to the risk factors for lower quality of life caused by the child’s illness, which is consistent with the theory of positive adaptation (the dual ABC-X model). Poor quality of family life and increased parental stress in some (but not all) areas were found in families with children of an under average IQ in comparison with families with children of an average or above average IQ. This finding is consistent with previous studies involving families of children with HIE and some other chronic diseases. Developmental outcomes of children with HIE treated with TH are different with specific characteristics and needs of children and their families. Further investigation should be focused on the early period, as parents often expressed uncertainty and fear experienced after a diagnosis and acute treatment of the child. Health care professionals need to inform parents about sources of help in the local environment, as well as those available at the national level. It is important for parents to obtain information and education, as well as receive professional therapeutic help when necessary. In order to provide optimum support to families of chronically ill children, adequate health and social policy is essential.

Vaisiaus kraujagyslių pirmeiga (VKP) yra labai reta patologija, kurios nediagnozavus laiku, dėl didelės naujagimių hipoksijos ir nukraujavimo rizikos smarkiai sumažėja naujagimių išgyvenamumas. Prenatalinė VKP diagnozė ir tinkamai pasirinktas cezario pjūvio operacijos laikas yra būdas išvengti nepalankios nėštumo baigties. Šiuo metu nėra pakankamai aukšto lygio mokslinių įrodymų dėl virkštelės tvirtinimosi vietos nustatymo įtraukimo į standartinį ultragarsinio tyrimo protokolą. Straipsnyje pristatomas prenataliai nediagnozuotos VKP atvejis ir pateikiama literatūros apžvalga.

The connection between early brain injury and subsequent development of disorders is unknown. Neonatal hypoxia-ischemia (HI) alters circuits associated with subplate neurons (SPNs). SPNs are among the first maturing cortical neurons, project to thalamorecipient layer 4 (L4), and are required for the development of thalamocortical connections. Thus, early HI might influence L4 and such influence might persist. We investigated functional circuits to L4 neurons in neonatal rat HI models of different severities (mild and moderate) shortly after injury and at adolescence. We used laser-scanning photostimulation in slices of auditory cortex during P5–10 and P18–23. Mild injuries did not initially (P6/P7) alter the convergence of excitatory inputs from L2/3, but hyperconnectivity emerged by P8–10. Inputs from L4 showed initial hypoconnectivity which resolved by P8–10. Moderate injuries resulted in initial hypoconnectivity from both layers which resolved by P8–10 and led to persistent strengthening of connections. Inhibitory inputs to L4 cells showed similar changes. Functional changes were mirrored by reduced dendritic complexity. We also observed a persistent increase in similarity of L4 circuits, suggesting that HI interferes with developmental circuit refinement and diversification. Altogether, our results show that neonatal HI injuries lead to persistent changes in intracortical connections.

Electronic FHR monitoring is already widely used for antenatal fetal monitoring and labor observation. It is believed to be able to reduce the risk of intrauterine fetal hypoxia and decrease the probability of neonatal hypoxia and the neonatal mortality rate. In 2002, 85% of 3.4 million pregnant women in the United States received electronic FHR monitoring during labor. At present, continuous electronic FHR monitoring has become the most widely used obstetric monitoring technology.

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Perinatal Asphyxia (PA) is a leading cause of motor and neuropsychiatric disability associated with sustained oxidative stress, neuroinflammation, and cell death, affecting brain development. Based on a rat model of global PA, we investigated the neuroprotective effect of intranasally administered secretome, derived from human adipose mesenchymal stem cells (MSC-S), preconditioned with either deferoxamine (an hypoxia-mimetic) or TNF-&alpha, +IFN-&gamma, (pro-inflammatory cytokines). PA was generated by immersing fetus-containing uterine horns in a water bath at 37 &deg, C for 21 min. Thereafter, 16 &mu, L of MSC-S (containing 6 &mu, g of protein derived from 2 &times, 105 preconditioned-MSC), or vehicle, were intranasally administered 2 h after birth to asphyxia-exposed and control rats, evaluated at postnatal day (P) 7. Alternatively, pups received a dose of either preconditioned MSC-S or vehicle, both at 2 h and P7, and were evaluated at P14, P30, and P60. The preconditioned MSC-S treatment (i) reversed asphyxia-induced oxidative stress in the hippocampus (oxidized/reduced glutathione), (ii) increased antioxidative Nuclear Erythroid 2-Related Factor 2 (NRF2) translocation, (iii) increased NQO1 antioxidant protein, (iv) reduced neuroinflammation (decreasing nuclearNF-&kappa, B/p65 levels and microglial reactivity), (v) decreased cleaved-caspase-3 cell-death, (vi) improved righting reflex, negative geotaxis, cliff aversion, locomotor activity, anxiety, motor coordination, and recognition memory. Overall, the study demonstrates that intranasal administration of preconditioned MSC-S is a novel therapeutic strategy that prevents the long-term effects of perinatal asphyxia.

The past 25 years have seen a strong increase in the number of publications related to criticality in different areas of neuroscience. The potential of criticality to explain various brain properties, including optimal information processing, has made it an increasingly exciting area of investigation for neuroscientists. Recent reviews on this topic, sometimes termed brain criticality, make brief mention of clinical applications of these findings to several neurological disorders such as epilepsy, neurodegenerative disease, and neonatal hypoxia. Other clinicallyrelevant domains – including anesthesia, sleep medicine, developmental-behavioral pediatrics, and psychiatry – are seldom discussed in review papers of brain criticality. Thorough assessments of these application areas and their relevance for clinicians have also yet to be published. In this scoping review, studies of brain criticality involving human data of all ages are evaluated for their current and future clinical relevance. To make the results of these studies understandable to a more clinical audience, a review of the key concepts behind criticality (e.g., phase transitions, long-range temporal correlation, self-organized criticality, power laws, branching processes) precedes the discussion of human clinical studies. Open questions and forthcoming areas of investigation are also considered.

Objective: Herein, we aimed to investigate the long-term effects of neonatal hypoxia and the potential protective role of melatonin and memantine on the learning and memory. Methods: Seven-day-old rat underwent right carotid ligation, followed by hypoxia. Rat received Melatonin (MLT) (4 mg/kg), Memantine (MEM) (20 mg/kg), and MLT+MEM combination after hypoxia. We tested these rats for anxiety by elevated O-maze and for spatial learning and memory by Morris water maze (MWM) at postnatal day 45. Results: Hypoxia increased the level of anxiety compared to the control group (p=0.05) while treatment of MLT, MEM, and MLT+MEM ameliorated this effect. In addition, hypoxia produced significant decrease in spatial learning of the rats on the fourth day of training (P=0.05) and the percent time spent in the platform quadrant and the entrance frequencies to the platform quadrant compared to the control group (P=0.049 and P=0.023). Treatment of MLT, MEM, and MLT+MEM after hypoxia improved the performance of the rats at the third (P=0.686, P=0.876, P=0.977, respectively) and fourth day (P=0.738, P=0.553, P=0.789, respectively) of MWM training. The decrease in the percent time spent was ameliorated by the treatment of MLT (P=0.239), MEM (P=0.289), and MLT+MEM (P=0.567) compared to the control group. In addition, MLT treatment significantly increased the entrance frequency to the platform quadrant compared to the hypoxia group (P=0.020). Conclusion: Our data suggested that the MLT was more effective in the release of memory deficits from hypoxia-related damage. MLT might have a therapeutic value in improving hypoxic damage in the developing brain. WOS:000640976900004

Valentina Vio,1,2 Ana L Riveros,1 Andrea Tapia-Bustos,2 Carolyne Lespay-Rebolledo,2 Ronald Perez-Lobos,2 Luis Muñoz,3 Paola Pismante,3 Paola Morales,2,4 Eyleen Araya,5 Natalia Hassan,1,6 Mario Herrera-Marschitz,2 Marcelo J Kogan1,7 1Department of Pharmacological and Toxicology Chemistry, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile; 2Program of Molecular and Clinical Pharmacology, Medical Faculty, Universidad de Chile, Santiago, Chile; 3Chemical Meteorology Section, Comisión Chilena de Energía Nuclear, Santiago, Chile; 4Department of Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile; 5Departamento de Ciencias Quimicas, Facultad de Ciencias Exactas, Universidad Andres Bello, Santiago, Chile; 6Programa Institucional de Fomento a la Investigación, Desarrollo e Innovación, Universidad Tecnológica Metropolitana, Santiago,Chile; 7Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile Background: Perinatal asphyxia interferes with neonatal development, resulting in long-term deficits associated with systemic and neurological diseases. Despite the important role of poly (ADP-ribose) polymerase 1 (PARP-1) in the regulation of gene expression and DNA repair, overactivation of PARP-1 in asphyxia-exposed animals worsens the ATP-dependent energetic crisis. Inhibition of PARP-1 offers a therapeutic strategy for diminishing the effects of perinatal asphyxia. Methods: We designed a nanosystem that incorporates a specific siRNA for PARP-1 knockdown. The siRNA was complexed with gold nanorods (AuNR) conjugated to the peptide CLPFFD for brain targeting. Results: The siRNA was efficiently delivered into PC12 cells, resulting in gene silencing. The complex was administered intraperitoneally in vivo to asphyxia-exposed rat pups, and the ability of the AuNR-CLPFFD/siRNA complex to reach the brain was demonstrated. Conclusion: The combination of a nanosystem for delivery and a specific siRNA for gene silencing resulted in effective inhibition of PARP-1 in vivo. Keywords: neonatal hypoxia, siRNA delivery, PARP-1 knockdown, gold nanorods, in vivo administration, PC12, rats

The recently developed oscillating-gradient diffusion MRI (OG-dMRI) technique extends our ability to examine brain structures at different spatial scales. In this study, we investigated the sensitivity of OG-dMRI in detecting cellular and subcellular structural changes in a mouse model of neonatal hypoxia ischemia (HI). Neonatal mice received unilateral HI injury or sham injury at postnatal day 10, followed by in vivo T2-weighted and diffusion MRI of the brains at 3–6 h and 24 h after HI. Apparent diffusion coefficient (ADC) maps were acquired using conventional pulsed-gradient dMRI (PG-dMRI) and OG-dMRI with oscillating frequencies from 50 to 200 Hz. Pathology at cellular and subcellular levels was evaluated using neuronal, glial, and mitochondrial markers. We found significantly higher rates of ADC increase with oscillating frequencies (Δ fADC) in the ipsilateral edema region, compared to the contralateral side, starting as early as 3 h after HI. Even in injured regions that showed no apparent change in PG-ADC or pseudo-normalized PG-ADC measurements, Δ fADC remained significantly elevated. Histopathology showed swelling of sub-cellular structures in these regions with no apparent whole-cell level change. These results suggest that OG-dMRI is sensitive to subcellular structural changes in the brain after HI and is less susceptible to pseudo-normalization than PG-dMRI.

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.

Although the adverse effects of neonatal hypoxia associated with premature birth on the central nervous system are well known, the contribution of hypoxic damage to the peripheral nervous system (PNS) has not been addressed. We demonstrate that neonatal hypoxia results in hypomyelination and delayed axonal sorting in mice leading to electrophysiological and motor deficits that persist into adulthood. These findings support a potential role for PNS hypoxic damage in the motor impairment that results from premature birth and suggest that therapies designed to protect the PNS may provide clinical benefit.

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.

Valentina Vio,1,2 Ana L Riveros,1 Andrea Tapia-Bustos,2 Carolyne Lespay-Rebolledo,2 Ronald Perez-Lobos,2 Luis Muñoz,3 Paola Pismante,3 Paola Morales,2,4 Eyleen Araya,5 Natalia Hassan,1,6 Mario Herrera-Marschitz,2 Marcelo J Kogan1,7 1Department of Pharmacological and Toxicology Chemistry, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile; 2Program of Molecular and Clinical Pharmacology, Medical Faculty, Universidad de Chile, Santiago, Chile; 3Chemical Meteorology Section, Comisión Chilena de Energía Nuclear, Santiago, Chile; 4Department of Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile; 5Departamento de Ciencias Quimicas, Facultad de Ciencias Exactas, Universidad Andres Bello, Santiago, Chile; 6Programa Institucional de Fomento a la Investigación, Desarrollo e Innovación, Universidad Tecnológica Metropolitana, Santiago,Chile; 7Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile Background: Perinatal asphyxia interferes with neonatal development, resulting in long-term deficits associated with systemic and neurological diseases. Despite the important role of poly (ADP-ribose) polymerase 1 (PARP-1) in the regulation of gene expression and DNA repair, overactivation of PARP-1 in asphyxia-exposed animals worsens the ATP-dependent energetic crisis. Inhibition of PARP-1 offers a therapeutic strategy for diminishing the effects of perinatal asphyxia. Methods: We designed a nanosystem that incorporates a specific siRNA for PARP-1 knockdown. The siRNA was complexed with gold nanorods (AuNR) conjugated to the peptide CLPFFD for brain targeting. Results: The siRNA was efficiently delivered into PC12 cells, resulting in gene silencing. The complex was administered intraperitoneally in vivo to asphyxia-exposed rat pups, and the ability of the AuNR-CLPFFD/siRNA complex to reach the brain was demonstrated. Conclusion: The combination of a nanosystem for delivery and a specific siRNA for gene silencing resulted in effective inhibition of PARP-1 in vivo. Keywords: neonatal hypoxia, siRNA delivery, PARP-1 knockdown, gold nanorods, in vivo administration, PC12, rats

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: The objective of this pilot study was to start evaluating the efficacy and the safety (i.e., carboxyhemoglobin concentration of carbon monoxide (CO)) as a putative neuroprotective therapy in neonates. Study Design: Neonatal C57BL/6 mice were exposed to CO at a concentration of either 200 or 250 ppm for a period of 1 h. The pups were then sacrificed at 0, 10, 20, 60, 120, 180, and 240 min after exposure to either concentration of CO, and blood was collected for analysis of carboxyhemoglobin. Following the safety study, 7-day-old pups underwent a unilateral carotid ligation. After recovery, the pups were exposed to a humidified gas mixture of 8% oxygen and 92% nitrogen for 20 min in a hypoxia chamber. One hour after the hypoxia exposure, the pups were randomized to one of two groups: air (HI+A) or carbon monoxide (HI+CO). An inhaled dose of 250 ppm of CO was administered to the pups for 1 h per day for a period of 3 days. At 7 days post-injury, the pups were sacrificed and the brains analyzed for cortical and hippocampal volumes. Results: CO exposure at 200 and 250 ppm produced a peak carboxyhemoglobin concentration of 21.52 ± 1.18% and 27.55 ± 3.58%, respectively. The carboxyhemoglobin concentrations decreased rapidly, reaching control concentrations by 60 min post exposure. At 14 days of age (7 days post injury), the HI+CO (treated with 1 h per day of 250 ppm of CO for 3 days post injury) had significant preservation of the ratio of ipsilateral to contralateral cortex (median 1.07, 25% 0.97, 75% 1.23, n = 10) compared the HI+A group (p < 0.05). Conclusion: CO exposure of 250 ppm did not reach carboxyhemoglobin concentrations which would induce acute neurologic abnormalities and was effective in preserving cortical volumes following hypoxic-ischemic injury.

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.

RESUMO: Os objetivos deste estudo foram descrever a frequência cardíaca (FC) e os índices de variabilidade da frequência cardíaca (VFC) materna e fetal no terço final da gestação, bem como descrever a evolução do desenvolvimento do sistema nervoso autônomo durante o período fetal e neonatal. Foram avaliados 20 animais de cada categoria, cujos exames eletrocardiográficos, maternos e fetais, foram realizados aos 15 e sete dias pré-parto. Quanto ao eletrocardiograma neonatal, os momentos avaliados foram ao nascimento até as primeiras 48 horas de vida, e posteriormente, uma vez por semana até os 35 dias de idade. Ocorreram diferenças significativas na frequência cardíaca fetal (FCF) no período avaliado, porém os índices de VFC fetais não se alteraram. Não foram encontradas diferenças significativas nos índices de VFC materna. A média da FCF diminuiu significativamente dos 15 para sete dias do pré-parto (95,6±11,4 bpm; 83,1±12,6, respectivamente), entretanto os índices de VFC fetal não diminuíram. Os resultados obtidos da VFC fetal e neonatal deste estudo, quando comparados aos maternos, indicaram predomínio parassimpático durante a fase fetal e, simpático durante a neonatal, até a terceira e/ou quarta semanas de idade, momento no qual se inicia o equilíbrio entre os dois sistemas. ABSTRACT: The aim of this study were to describe the heart rate (HR) and indexes of maternal and fetal heart rate variability (HRV) in final period of pregnancy, as well as to describe the evolution of the development of autonomic nervous system during fetal and neonatal period. There were 20 animals in each category, whose maternal and fetal electrocardiographic examinations were performed at 15 and 7 days antepartum. Neonatal ECG it was evaluated at birth until the first 48 hours of life, and then once a week up to 35 days. There were significant differences in fetal heart rate (FHR) during this period, but the fetal HRV indexes have not changed. There were no significant differences in the rates of maternal HRV. The mean of fetal HR decreased significantly from 15 to seven antepartum days (95.6±11.4 bpm; 83.1±12.6, respectively), though the fetal HRV indexes have not decreased. The results of fetal and neonatal HRV in the present study, when compared to maternal indicate the parasympathetic dominance during fetal and neonatal sympathetic phase during to the third and/or fourth weeks of age, at which point begins the modulation of the two systems.

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.

Finding risk factors in pregnancy related to neonatal hypoxia is a challenging task due to the informal nature and a wide scatter of the data. In this work, we propose a methodology for sequential estimation of interestingness of association rules with two sets of criteria. The rules suggest that a strong relationship exists between the specific sets of attributes and the diagnosis. We set up a profile of the pregnant woman with a high likelihood of hypoxia of the newborn that would be beneficial to medical professionals.

Objective: To describe the value of HBO in the acute management of neonatal hypoxia (hypoxic–ischemic encephalopathy) and necrotizing enterocolitis.

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.

BACKGROUND Hypoxic preconditioning (HPc) protects the neonatal brain in the setting of hypoxia-ischemia (HI). The mechanisms of protection may depend on activation of hypoxia inducible factor (HIF-1α). The present study sought to clarify the role of HIF-1α after HPc and HI. METHODS To induce HPc, HIF-1α knockout and wildtype mice were exposed to hypoxia at postnatal day 6. At day 7, the mice underwent HI. Brain injury was determined by histology. HIF-1α, downstream targets, and markers of cell death were measured by Western blot. RESULTS HPc protected the wildtype brain compared to wildtype without HPc, but did not protect the HIF-1α knockout brain. In wildtype, HIF-1α increased after hypoxia and after HI, but not with HPc. The HIF-1α knockout showed no change in HIF-1α after hypoxia, HI, or HPc/HI. After HI, spectrin 145/150 was higher in HIF-1α knockout, but after HPc/HI, it was higher in wildtype. LAMP2 was higher in wildtype early after HI, but not later. After HPc/HI, LAMP2 was higher in HIF-1α knockout. CONCLUSION These results indicate that HIF-1α is necessary for HPc protection in the neonatal brain, and may affect cell death after HI. Different death and repair mechanisms depend on the timing of HPc.

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.

Purpose To investigate if frequency-dependent contrasts using oscillating gradient diffusion MRI (dMRI) can detect hypoxia–ischemia (HI) -induced neurodegeneration in the neonatal mouse hippocampus. Methods Pulsed- and oscillating-gradient dMR images (at 50, 100, and 150 Hz) were acquired from postmortem fixed brains of mice exposed to neonatal HI using the Rice-Vanucci model. MRI data were acquired at 1, 4, and 8 days following HI, and compared with histological data from the same mice for in situ histological validation of the MRI findings. Results The rate of change of apparent diffusion coefficient with gradient frequency (ΔfADC) revealed unique layer-specific contrasts in the neonatal mouse hippocampus. ΔfADC measurements were found to show a significant decrease in response to neonatal HI injury, in the pyramidal (Py) and granule (GrDG) cell layers compared with contralateral regions. The areas of reduced intensity in the ΔfADC maps corresponded to regional neurodegeneration seen with H&E and Fluoro-Jade C stainings, indicating that alterations in ΔfADC contrasts are sensitive to early microstructural changes due to HI-induced neurodegeneration in the studied regions. Conclusion The findings show that the frequency-dependence of ADC measurements with oscillating-gradient dMRI can provide a sensitive contrast to detect HI-induced neurodegeneration in neuronal layers of the neonatal mouse hippocampus. Magn Reson Med 72:829–840, 2014. © 2013 Wiley Periodicals, Inc.

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.