TSG-6-Mediated Extracellular Matrix Modifications Regulate Hypoxic-Ischemic Brain Injury.

Proteoglycans containing link domains modify the extracellular matrix (ECM) to regulate cellular homeostasis and can also sensitize tissues/organs to injury and stress. Hypoxic-ischemic (H-I) injury disrupts cellular homeostasis by activating inflammation and attenuating regeneration and repair pathways. In the brain, the main component of the ECM is the glycosaminoglycan hyaluronic acid (HA), but whether HA modifications of the ECM regulate cellular homeostasis and response to H-I injury is not known. In this report, employing both male and female mice, we demonstrate that link-domain-containing proteoglycan, TNFα-stimulated gene-6 (TSG-6), is active in the brain from birth onward and differentially modifies ECM HA during discrete neurodevelopmental windows. ECM HA modification by TSG-6 enables it to serve as a developmental switch to regulate the activity of the Hippo pathway effector protein, yes-associated protein 1 (YAP1), in the maturing brain and in response to H-I injury. Mice that lack TSG-6 expression display dysregulated expression of YAP1 targets, excitatory amino acid transporter 1 (EAAT1; glutamate-aspartate transporter) and 2 (EAAT2; glutamate transporter-1). Dysregulation of YAP1 activation in TSG-6-/- mice coincides with age- and sex-dependent sensitization of the brain to H-I injury such that 1-week-old neonates display an anti-inflammatory response in contrast to an enhanced proinflammatory injury reaction in 3-month-old adult males but not females. Our findings thus support that a key regulator of age- and sex-dependent H-I injury response in the mouse brain is modulation of the Hippo-YAP1 pathway by TSG-6-dependent ECM modifications.

Brief apnea with hypoventilation reduces seizure duration and shifts seizure location for several hours in a model of severe traumatic brain injury.

OBJECTIVE: Seizures can be difficult to control in infants and toddlers. Seizures with periods of apnea and hypoventilation are common following severe traumatic brain injury (TBI). We previously observed that brief apnea with hypoventilation (A&H) in our severe TBI model acutely interrupted seizures. The current study is designed to determine the effect of A&H on subsequent seizures and whether A&H has potential therapeutic implications. METHODS: Piglets (1 week or 1 month old) received multifactorial injuries: cortical impact, mass effect, subdural hematoma, subarachnoid hemorrhage, and seizures induced with kainic acid. A&H (1 min apnea, 10 min hypoventilation) was induced either before or after seizure induction, or control piglets received subdural/subarachnoid hematoma and seizure without A&H. In an intensive care unit, piglets were sedated, intubated, and mechanically ventilated, and epidural electroencephalogram was recorded for an average of 18 h after seizure induction. RESULTS: In our severe TBI model, A&H after seizure reduced ipsilateral seizure burden by 80% compared to the same injuries without A&H. In the A&H before seizure induction group, more piglets had exclusively contralateral seizures, although most piglets in all groups had seizures that shifted location throughout the several hours of seizure. After 8-10 h, seizures transitioned to interictal epileptiform discharges regardless of A&H or timing of A&H. SIGNIFICANCE: Even brief A&H may alter traumatic seizures. In our preclinical model, we will address the possibility of hypercapnia with normoxia, with controlled intracranial pressure, as a therapeutic option for children with status epilepticus after hemorrhagic TBI.

Accuracy of non-medical and medical individuals in identifying cerebral cortical abnormality from three-dimensional printed models of magnetic resonance images in children with hypoxic ischemic injury.

Effective communication of imaging findings in term hypoxic ischemic injury to family members, non-radiologist colleagues and members of the legal profession can be extremely challenging through text-based radiology reports. Utilization of three-dimensional (D) printed models, where the actual findings of the brain can be communicated via tactile perception, is a potential solution which has not yet been tested in practice. We aimed to determine the sensitivity and specificity of different groups, comprising trained radiologists, non-radiologist physicians and non-physicians, in the detection of gross disease of the cerebral cortex from 3-D printed brain models derived from magnetic resonance imaging (MRI) scans of children. Ten MRI scans in children of varying ages with either watershed pattern hypoxic ischemic injury (cortical injury) or basal-ganglia-thalamus hypoxic ischemic injury pattern with limited perirolandic cortical abnormalities and 2 normal MRI scans were post processed and 3-D printed. In total, 71 participants reviewed the 12 models and were required to indicate only the brain models that they felt were abnormal (with a moderate to high degree of degree of confidence). The 71 participants included in the study were 38 laypeople (54%), 17 radiographic technologists (24%), 6 nurses (8%), 5 general radiologists (7%), 4 non-radiologist physicians- 3 pediatricians and 1 neurologist (6%) and 1 emergency medical services staff (1%). The sensitivity and specificity for detecting the abnormal brains of the 71 participants were calculated. Radiologists showed the highest sensitivity (72%) and specificity (70%). Non-radiologist physicians had a sensitivity of 67.5% and a specificity of 75%. Nurses had a sensitivity of 70% and a specificity of 41.7%. Laypeople (non-medical trained) had a sensitivity of 56.1% and a specificity of 55.3%. Radiologists' high sensitivity and specificity of 72% and 70%, respectively, validates the accuracy of the 3-D-printed models in reproducing abnormalities from MRI scans. The non-radiologist physicians also had a high sensitivity and specificity. Laypeople, without any prior training or guidance in looking at the models, had a sensitivity of 56.1% and a specificity of 55.3%. These results show the potential for use of the 3-D printed brains as an alternate form of communication for conveying the pathological findings of hypoxic ischemic injury of the brain to laypeople.

Gelsemine Exerts Neuroprotective Effects on Neonatal Mice with Hypoxic-Ischemic Brain Injury by Suppressing Inflammation and Oxidative Stress via Nrf2/HO-1 Pathway.

Given that the role of Gelsemine in neuroinflammation has been demonstrated, this research aimed to investigate the effect of Gelsemine on neonatal hypoxic-ischemic (HI) brain injury. An in vivo HI brain injury neonatal mouse model and an in vitro oxygen-glucose deprivation (OGD) cell model were established and pretreated with Gelsemine. The brain infarct volume, neuronal loss and apoptosis, as well as spatial learning and memory were examined by TTC staining, Nissl's staining, TUNEL staining and Morris water maze test. Immunohistochemical staining was applied to detect the microglia cells and astrocytes in the mouse brain tissue. The cell viability was analyzed by CCK-8 assay. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), TNF-α, IL-1ß, and IL-6 were determined via ELISA. The lactate dehydrogenase (LDH) release and reactive oxygen species (ROS) level in OGD-treated cells were detected by colorimetry and DCFH-DA staining. Nrf2, HO-1, and inflammation-related factors were analyzed by immunofluorescence, qRT-PCR, or western blot. Gelsemine reduced the infarct volume and neuronal loss and apoptosis, yet improved spatial learning and memory impairment of HI-injured mice. Gelsemine inhibited the elevated MDA, TNF-α, IL-1ß, IL-6, LDH and ROS levels, promoted the reduced SOD level and viability, and strengthened the up-regulation of HO-1 and Nrf2 in brain tissues and OGD-treated cells. However, Nrf2 silencing reversed the effects of Gelsemine on the Nrf2/HO-1 pathway, inflammation, and oxidative stress in OGD-treated cells. Gelsemine produces neuroprotective effects on neonatal mice with HI brain injury by suppressing inflammation and oxidative stress via Nrf2/HO-1 pathway.

Frequency of ulegyria on delayed MRI scans in children with term hypoxic-ischemic injury.

BACKGROUND: Ulegyria is an under-recognized and underreported potential sequela of hypoxic-ischemic injury (HII) in full-term neonates. Ulegyria is a unique form of parenchymal scarring that leads to a mushroom-shape of the affected gyri resulting from volume loss at the deep portions of the sulci during HII in this specific period in infantile neurodevelopment. Identifying ulegyria is important for ascribing cause and timing of HII on delayed magnetic resonance imaging (MRI) scans and because of its close association with pharmaco-resistant epilepsy. OBJECTIVE: The purpose of this study was to determine the frequency of ulegyria and characterize the anatomical distribution of watershed injury in a large database of patients who developed cerebral palsy with term HII pattern and underwent delayed MRI. MATERIALS AND METHODS: Patients with term HII patterns on MRI were analyzed for ulegyria. The frequency of ulegyria overall and for each pattern of HII distribution was determined as was the anatomical distribution of watershed injury. RESULTS: Of the 731 children with term HII and cortical injury, 484 (66%) had ulegyria. Ulegyria was most common in those cases with a combined watershed/basal ganglia-thalamic pattern (56%) and isolated watershed pattern (40%). Watershed injury in patients with ulegyria was most common at the posterior watershed (80.6%) and perisylvian watershed (76.7%). CONCLUSION: Ulegyria was present in nearly two-thirds of patients with term HII and cortical injury and should be sought to support the diagnosis of previous perinatal HII, especially in posterior and perisylvian watershed regions. The implications of ulegyria can be significant for clinical decision-making and for ascribing timing of injury to the perinatal period.

Caution: shortcomings of traditional segmentation methods from magnetic resonance imaging brain scans intended for 3-dimensional surface modelling in children with pathology.

This technical innovation assesses the adaptability of some common automated segmentation tools on abnormal pediatric magnetic resonance (MR) brain scans. We categorized 35 MR scans by pathologic features: (1) "normal"; (2) "atrophy"; (3) "cavity"; (4) "other." The following three tools, (1) Computational Anatomy Toolbox version 12 (CAT12); (2) Statistical Parametic Mapping version 12 (SPM12); and (3) MRTool, were tested on each scan-with default and adjusted settings. Success was determined by radiologist consensus on the surface accuracy. Automated segmentation failed in scans demonstrating severe surface brain pathology. Segmentation of the "cavity" group was ineffective, with success rates of 23.1% (CAT12), 69.2% (SPM12) and 46.2% (MRTool), even with refined settings and manual edits. Further investigation is required to improve this workflow and automated segmentation methodology for complex surface pathology.

Fidelity of 3D Printed Brains from MRI Scan in Children with Pathology (Prior Hypoxic Ischemic Injury).

Cortical injury on the surface of the brain in children with hypoxic ischemic injury (HII) can be difficult to demonstrate to non-radiologists and lay people using brain images alone. Three-dimensional (3D) printing is helpful to communicate the volume loss and pathology due to HII in children's brains. 3D printed models represent the brain to scale and can be held up against models of normal brains for appreciation of volume loss. If 3D printed brains are to be used for formal communication, e.g., with medical colleagues or in court, they should have high fidelity of reproduction of the actual size of patients' brains. Here, we evaluate the size fidelity of 3D printed models from MRI scans of the brain, in children with prior HII. Twelve 3D prints of the brain were created from MRI scans of children with HII and selected to represent a variety of cortical pathologies. Specific predetermined measures of the 3D prints were made and compared to measures in matched planes on MRI. Fronto-occipital length (FOL) and bi-temporal/bi-parietal diameters (BTD/BPD) demonstrated high interclass correlations (ICC). Correlations were moderate to weak for hemispheric height, temporal height, and pons-cerebellar thickness. The average standard error of measurement (SEM) was 0.48 cm. Our results demonstrate high correlations in overall measurements of each 3D printed model derived from brain MRI scans versus the original MRI, evidenced by high ICC values for FOL and BTD/BPD. Measures with low correlation values can be explained by variability in matching the plane of measurement to the MRI slice orientation.

The regulatory role of NAAG-mGluR3 signaling on cortical synaptic plasticity after hypoxic ischemia.

BACKGROUND: Synapses can adapt to changes in the intracerebral microenvironment by regulation of presynaptic neurotransmitter release and postsynaptic neurotransmitter receptor expression following hypoxic ischemia (HI) injury. The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) exerts a protective effect on neurons after HI and may be involved in maintaining the function of synaptic networks. In this study, we investigated the changes in the expression of NAAG, glutamic acid (Glu) and metabotropic glutamate receptors (mGluRs), as well as the dynamic regulation of neurotransmitters in the brain after HI, and assessed their effects on synaptic plasticity of the cerebral cortex. METHODS: Thirty-six Yorkshire newborn pigs (3-day-old, males, 1.0-1.5 kg) were selected and randomly divided into normal saline (NS) group (n = 18) and glutamate carboxypeptidase II inhibition group (n = 18), both groups were divided into control group, 0-6 h, 6-12 h, 12-24 h, 24-48 h and 48-72 h groups (all n = 3) according to different post-HI time. The content of Glu and NAAG after HI injury were detected by 1H-MRS scanning, immunofluorescence staining of mGluRs, synaptophysin (syph) along with postsynaptic density protein-95 (PSD95) and transmission electron microscopy were performed. ANOVA, Tukey and LSD test were used to compare the differences in metabolite and protein expression levels among subgroups. Correlation analysis was performed using Pearson analysis with a significance level of α = 0.05. RESULTS: We observed that the NAAG and mGluR3 expression levels in the brain increased and then decreased after HI and was significantly higher in the 12-24 h (P < 0.05, Tukey test). There was a significant positive correlation between Glu content and the expression of mGluR1/mGluR5 after HI with r = 0.521 (P = 0.027) and r = 0.477 (P = 0.045), respectively. NAAG content was significantly and positively correlated with the level of mGluR3 expression (r = 0.472, P = 0.048). When hydrolysis of NAAG was inhibited, the expression of synaptic protein PSD95 and syph decreased significantly. CONCLUSIONS: After 12-24 h of HI injury, there was a one-time elevation in NAAG levels, which was consistent with the corresponding mGluR3 receptor expression trend; the NAAG maintains cortical synaptic plasticity and neurotransmitter homeostasis by inhibiting presynaptic glutamate vesicle release, regulating postsynaptic density proteins and postsynaptic receptor expression after pathway activation. Video abstract.

Gray-scale ultrasound findings of hypoxic-ischemic injury in term infants.

Brain ultrasound has become a critical tool for bedside screening and monitoring of hypoxic-ischemic injury in infants. Transfontanellar ultrasound in infants allows delineation of anatomical structures of the brain and posterior fossa. The technique's low cost, lack of ionizing radiation and repeatability make it a popular alternative to magnetic resonance imaging. The published literature on interpreting hypoxic-ischemic injury on brain ultrasound is wide and varied, yet diagnostic challenges remain when detecting subtle or diffuse changes. This pictorial essay summarizes and illustrates the spectrum of sonographic findings of hypoxic-ischemic injuries in term infants.

Contrast-enhanced ultrasound of the pediatric brain.

Brain contrast-enhanced ultrasound (CEUS) is an emerging application that can complement gray-scale US and yield additional insights into cerebral flow dynamics. CEUS uses intravenous injection of ultrasound contrast agents (UCAs) to highlight tissue perfusion and thus more clearly delineate cerebral pathologies including stroke, hypoxic-ischemic injury and focal lesions such as tumors and vascular malformations. It can be applied not only in infants with open fontanelles but also in older children and adults via a transtemporal window or surgically created acoustic window. Advancements in CEUS technology and post-processing methods for quantitative analysis of UCA kinetics further elucidate cerebral microcirculation. In this review article we discuss the CEUS examination protocol for brain imaging in children, current clinical applications and future directions for research and clinical uses of brain CEUS.

Developmental dynamics of the periventricular parietal crossroads of growing cortical pathways in the fetal brain - In vivo fetal MRI with histological correlation.

The periventricular crossroads have been described as transient structures of the fetal brain where major systems of developing fibers intersect. The triangular parietal crossroad constitutes one major crossroad region. By combining in vivo and post-mortem fetal MRI with histological and immunohistochemical methods, we aimed to characterize these structures. Data from 529 in vivo and 66 post-mortem MRI examinations of fetal brains between gestational weeks (GW) 18-39 were retrospectively reviewed. In each fetus, the area adjacent to the trigone of the lateral ventricles at the exit of the posterior limb of the internal capsule (PLIC) was assessed with respect to signal intensity, size, and shape on T2-weighted images. In addition, by using in vivo diffusion tensor imaging (DTI), the main fiber pathways that intersect in these areas were identified. In order to explain the in vivo features of the parietal crossroads (signal intensity and developmental profile), we analyzed 23 post-mortem fetal human brains, between 16 and â€‹40 GW of age, processed by histological and immunohistochemical methods. The parietal crossroads were triangular-shaped areas with the base in the continuity of the PLIC, adjacent to the germinal matrix and the trigone of the lateral ventricles, with the tip pointing toward the subplate. These areas appeared hyperintense to the subplate, and corresponded to a convergence zone of the developing external capsule, the PLIC, and the fronto-occipital association fibers. They were best detected between GW 25-26, and, at term, they became isointense to the adjacent structures. The immunohistochemical results showed a distinct cellular, fibrillar, and extracellular matrix arrangement in the parietal crossroads, depending on the stage of development, which influenced the MRI features. The parietal crossroads are transient, but important structures in white matter maturation and their damage may be indicative of a poor prognosis for a fetus with regard to neurological development. In addition, impairment of this region may explain the complex neurodevelopmental deficits in preterm infants with periventricular hypoxic/ischemic or inflammatory lesions.

Magnetic resonance imaging features of four neonates with total brain injury.

PURPOSE: The most severe form of profound asphyxia in neonates is now known as "total brain injury," which forms part of the clinical spectrum of hypoxic-ischemic encephalopathy (HIE). Although the magnetic resonance (MR) imaging features of total brain injury remain to be determined, a widespread hyperintensity of the supratentorial brain, known as the "white cerebrum sign," has been reported in diffusion-weighted images (DWI). METHODS: We examined four neonates who developed severe profound asphyxia. RESULTS: In the first week of life, all neonates showed the white cerebrum sign on DWI. A follow-up of these cases over a period of 1 month revealed diffuse bilateral multicystic encephalomalacia (MCE) as well as shrinkage of the basal ganglia and thalami (BG/T). These MR findings were common to all neonates, and all the neonates had severe adverse clinical outcomes. CONCLUSION: Neonates, who exhibit the white cerebrum sign on MR imaging due to profound asphyxia, develop major disabilities, and MCE with shrinkage of the BG/T suggests miserable outcomes.

Physical exercise enhances adult cortical plasticity in a neonatal rat model of hypoxic-ischemic injury: Evidence from BOLD-fMRI and electrophysiological recordings.

Neuroplasticity is considered essential for recovery from brain injury in developing brains. Recent studies indicate that it is especially effective during early postnatal development and during the critical period. The current study used functional magnetic resonance imaging (fMRI) and local field potential (LFP) electrophysiological recordings in rats that experienced neonatal hypoxic-ischemic (HI) injury during the critical period to demonstrate that physical exercise (PE) can improve cortical plasticity even when performed during adulthood, after the critical period. We investigated to what extent the blood oxygen level-dependent (BOLD)-fMRI responses were increased in the contralesional spared cortex, and how these increases were related to the LFP electrophysiological measurements and the functional outcome. The balance of excitation and inhibition was assessed by measuring excitatory and inhibitory postsynaptic currents in stellate cells in the primary somatosensory (S1) cortex, which was compared with the BOLD-fMRI responses in the contralesional S1 cortex. The ratio of inhibitory postsynaptic current (IPSC) to excitatory postsynaptic current (EPSC) at the thalamocortical (TC) input to the spared S1 cortex was significantly increased by PE, which is consistent with the increased BOLD-fMRI responses and improved functional outcome. Our data clearly demonstrate in an experimental rat model of HI injury during the critical period that PE in adulthood enhances neuroplasticity and suggest that enhanced feed-forward inhibition at the TC input to the S1 cortex might underlie the PE-induced amelioration of the somatosensory deficits caused by the HI injury. In summary, the results of the current study indicate that PE, even if performed beyond the critical period or during adulthood, can be an effective therapy to treat neonatal brain injuries, providing a potential mechanism for the development of a potent rehabilitation strategy to alleviate HI-induced neurological impairments.

Novel Quantitative Contrast-Enhanced Ultrasound Detection of Hypoxic Ischemic Injury in Neonates and Infants: Pilot Study 1.

OBJECTIVES: To investigate whether quantitative contrast-enhanced ultrasound (CEUS) can accurately identify neonates and infants with hypoxic ischemic brain injury. METHODS: In this prospective cohort study, 8 neonates and infants with a suspicion of hypoxic ischemic injury were evaluated with CEUS. RESULTS: An interesting trend was observed in the central gray nuclei-to-cortex perfusion ratios. The ratios at the peak enhancement, wash-in area under the curve, perfusion index, and maximum wash-in slopes were lower in all of the affected cases compared to the normal group but not statistically significant given the small sample size (P = .0571). Additionally, when the central gray nuclei-to-cortex perfusion ratio was plotted for all time points along the time-intensity curve, it was observed that the affected cases showed a trend that was qualitatively different from that of the normal cases. In the affected cases, the ratio time-intensity curves either stayed below 1.0 for the entire enhancement period or reached 1.0 close to peak wash-in before falling just below 1.0 for the remaining period of enhancement. However, in the unaffected patients, there was a steep wash-in that crossed the 1.0 threshold and remained above 1.0 for most of the enhancement period. CONCLUSIONS: Bedside CEUS is an easily obtainable brain-imaging modality that has the potential to effectively identify infants and neonates with evolving brain injury. A larger prospective study evaluating the correlation between CEUS findings and the reference standard of diffusion- and perfusion-weighted magnetic resonance imaging is needed to establish it as a diagnostic tool.

A Case Study of Severe Hypercalcemia Secondary to Subcutaneous Fat Necrosis: A Diagnosis of Exclusion.

Subcutaneous fat necrosis (SCFN) is a rare complication, usually occurring in otherwise healthy full-term infants who have experienced some level of trauma that causes ischemic injury to adipose tissue. Tissue injury usually occurs in areas of the body that are exposed to excessive pressure as during delivery. Tissue injury has also been described secondary to therapeutic cooling. This case study presents an infant who received whole body cooling for hypoxic ischemic injury and later developed severe hypercalcemia at one month of age without the skin lesions consistent with SCFN. The differential diagnosis for hypercalcemia and how it relates to SCFN is presented, as well as clinical presentation, treatment, and prognosis.

Targeted Knockdown of Bone Morphogenetic Protein Signaling within Neural Progenitors Protects the Brain and Improves Motor Function following Postnatal Hypoxia-Ischemia.

Hypoxic-ischemic injury (HI) to the neonatal human brain results in myelin loss that, in some children, can manifest as cerebral palsy. Previously, we had found that neuronal overexpression of the bone morphogenic protein (BMP) inhibitor noggin during development increased oligodendroglia and improved motor function in an experimental model of HI utilizing unilateral common carotid artery ligation followed by hypoxia. As BMPs are known to negatively regulate oligodendroglial fate specification of neural stem cells and alter differentiation of committed oligodendroglia, BMP signaling is likely an important mechanism leading to myelin loss. Here, we showed that BMP signaling is upregulated within oligodendroglia of the neonatal brain. We tested the hypothesis that inhibition of BMP signaling specifically within neural progenitor cells (NPCs) is sufficient to protect oligodendroglia. We conditionally deleted the BMP receptor 2 subtype (BMPR2) in NG2-expressing cells after HI. We found that BMPR2 deletion globally protects the brain as assessed by MRI and protects motor function as assessed by digital gait analysis, and that conditional deletion of BMPR2 maintains oligodendrocyte marker expression by immunofluorescence and Western blot and prevents loss of oligodendroglia. Finally, BMPR2 deletion after HI results in an increase in noncompacted myelin. Thus, our data indicate that inhibition of BMP signaling specifically in NPCs may be a tractable strategy to protect the newborn brain from HI.

The contribution of TRPV1 channel to 20-HETE-Aggravated ischemic neuronal injury.

20-Hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P450 (CYP) 4A/4F-derived metabolite of arachidonic acid, directly contributes to ischemic neuronal injury. However, little is known about mediators of 20-HETE neurotoxicity after ischemia. Here, we focus on the role of transient receptor potential cation channel subfamily V member 1 (TRPV1) in 20-HETE-induced neurotoxicity. Our results showed that TRPV1 and CYP4A immunoreactivity were colocalized in neurons. TRPV1 inhibition attenuated 20-HETE mimetic 20-5,14-HEDGE-induced reactive oxygen species (ROS) production and neuronal injury in cultured neurons and protected ischemic neurons in vitro and in vivo. TRPV1 inhibition in combination with 20-HETE synthesis inhibitor HET0016 did not produce additional protective effects. Furthermore, TRPV1 genetic inhibition and NADPH oxidase inhibitor gp91ds-dat each attenuated ROS production to a similar extent. However, combined treatment did not achieve additional reduction. Therefore, we conclude that TRPV1 channels are involved in 20-HETE's ROS generation and neurotoxicity after ischemia.

Prognostic Value of EEG in Patients after Cardiac Arrest-An Updated Review.

PURPOSE OF REVIEW: This paper aims to review and summarize the key contributions of EEG to prognostication after cardiac arrest (CA). RECENT FINDINGS: While there are more EEG patterns predicting poor than good outcome, even EEG patterns previously considered to be "very malignant" may result in survival with a meaningful neurological outcome depending on their underlying etiology as well as the continuity and reactivity of the EEG background. Regardless of the potentially confounding factors, EEG patterns are highly specific with a relatively low false-positive rate. The development of more complex and comprehensive approaches to quantitative EEG analysis could help improve the prognostic value of EEG, but this approach has its own limitations. Seizures and status epilepticus in the setting of CA predict poor outcomes, but it is not clear whether treating them prevents additional brain damage and results in improved outcome. Either continuous EEG or frequent intermittent EEGs should be obtained within the first 12-24 h of return of spontaneous circulation in order to capture highly dynamic and prognostic patterns. Even though EEG has high predictive value for outcomes after cardiac arrest, it should not be the only prognostic tool. Rather, to improve prognostication, EEG should be used in combination with the neurological examination and other ancillary tests.

Oxymatrine attenuates brain hypoxic-ischemic injury from apoptosis and oxidative stress: role of p-Akt/GSK3ß/HO-1/Nrf-2 signaling pathway.

To investigate the potential neuroprotection of oxymatrine in hypoxic-ischemic injury in rat's brain and the associated underlying mechanisms, modified neurological severity scores (mNSS) for neurological functional deficits, 2,3,5-triphenyl-tetrazolium chloride (TTC) staining for infarct volume, TUNEL assay and flow cytometry analysis for apoptosis were assessed. The expressions of Akt, glycogen synthase kinase 3 beta (GSK3ß), phosphorylated Akt (p-Akt), phosphorylated GSK3ß (p-GSK3ß), nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) were measured by western blot. Our results showed that infarct volume and the apoptosis of NeuN-positive cells were significantly reduced in rats that administrated oxymatrine, with a corresponding improvement in neurological function after H/I. Upregulated p-Akt, p-GSK3ß, Nrf-2 and HO-1 expressions were observed in response to oxymatrine treatment. Moreover, the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 counteracted the protective effect of oxymatrine, evidenced by western blot and histological outcomes. To conclude, our results suggested that oxymatrine could exert efficacious neuroprotective effect against H/I injury by inhibiting apoptosis and oxidative stress, which might be related to the activation of Akt and GSK3ß and modulation of Nrf-2/HO-1 signaling pathway.

The combined exposure to intra-amniotic inflammation and neonatal respiratory distress syndrome increases the risk of intraventricular hemorrhage in preterm neonates.

OBJECTIVE: To evaluate the impact of combined exposure to intra-amniotic inflammation and neonatal respiratory distress syndrome (RDS) on the development of intraventricular hemorrhage (IVH) in preterm neonates. METHODS: This retrospective cohort study includes 207 consecutive preterm births (24.0-33.0 weeks of gestation). Intra-amniotic inflammation was defined as an amniotic fluid matrix metalloproteinase-8 concentration >23 ng/mL. According to McMenamin's classification, IVH was defined as grade II or higher when detected by neurosonography within the first weeks of life. RESULTS: (1) IVH was diagnosed in 6.8% (14/207) of neonates in the study population; (2) IVH was frequent among newborns exposed to intra-amniotic inflammation when followed by postnatal RDS [33% (6/18)]. The frequency of IVH was 7% (8/115) among neonates exposed to either of these conditions - intra-amniotic inflammation or RDS - and 0% (0/64) among those who were not exposed to these conditions; and (3) Neonates exposed to intra-amniotic inflammation and postnatal RDS had a significantly higher risk of IVH than those with only intra-amniotic inflammation [odds ratio (OR) 4.6, 95% confidence interval (CI) 1.1-19.3] and those with RDS alone (OR 5.6, 95% CI 1.0-30.9), after adjusting for gestational age. CONCLUSION: The combined exposure to intra-amniotic inflammation and postnatal RDS markedly increased the risk of IVH in preterm neonates.