GDF15 regulated by HDAC2 exerts suppressive effects on oxygen-glucose deprivation/reoxygenation-induced neuronal cell pyroptosis via the NLRP3 inflammasome.

Background: Pyroptosis, inflammation-related programed cell death mediated by NLRP3 inflammasome, is involved in the pathogenesis of cerebral hypoxic-ischemic injury. Our study aims to explore the biological role of growth differentiation factor (GDF)15 in oxygen-glucose deprivation/reoxygenation (OGD/R)-induced neuronal pyroptosis. Methods: HT22 neurons were subjected to OGD/R to simulate cerebral hypoxic-ischemic injury. Cells were transfected with plasmids to overexpress GDF15, or lentiviral-based shRNAs constructs to silence GDF15. ELISA assay was used to detect GDF15, IL-1ß, IL-18, and neuron specific enolase (NSE) levels. Cell pyroptosis was measured by flow cytometery. Chromatin immunoprecipitation assay was used to detect interaction of H3K27ac with GDF15 promoter. GDF15, NLRP3, Caspase-1 p20 and GSDMD-N expressions were measured by Western blotting. Results: Patients with malignant middle cerebral artery infarction showed decreased GDF15, but increased IL-1ß, IL-18, and NSE levels in serum compared to healthy controls. OGD/R treatment caused significant increases in the levels of IL-1ß, IL-18 and NSE, percentages of pyroptotic cells, and expressions of NLRP3, Caspase-1 p20, and GSDMD in HT22 cells, which were markedly reversed by GDF15 overexpression. However, GDF15 knockdown resulted in neuronal injury similar to those observed in OGD/R treatment. The GDF15 knockdown-induced effects were counteracted by treatment with NLRP3 inhibitor. OGD/R decreased the enrichment of H3K27ac in the promoter of GDF15 to down-regulate GDF15, but was compromised by co-treatment with HDAC2 inhibitor. Conclusion: Our data demonstrates that GDF15 attenuates OGD/R-induced pyroptosis through NLRP3 inflammasome. HDAC2 is involved in mediating OGD-induced GDF15 down-regulation via H3K27ac modification. GDF15 overexpression and HDAC2 inhibition hold potential as useful therapeutic strategies for neuroprotection.

Successful treatment of cortical visual impairment in children using anti-amblyopia treatment despite the absence of amblyopia: a case report.

BACKGROUND: Cortical visual impairment (CVI) is a verifiable visual dysfunction that cannot be attributed to disorders of the anterior visual pathways or any potentially co-occurring ocular impairment. Given the limited knowledge on the most effective interventions for visual impairment resulting from CVI, this case report provides valuable insights into an example of successful implementation of anti-amblyopia therapy in a patient with CVI. CASE PRESENTATION: This case report presents a 5-year-old girl with CVI secondary to hypoxic-ischemic injury, resulting in visual impairment, dyspraxia, and abnormal visual evoked potential testing. The girl did not suffer from amblyopia, there was no evidence of relevant refractive errors or strabismus, so visual pathway damage was the cause of her visual deficit. Nevertheless, the patient underwent anti-amblyopia therapy and showed significant improvement in visual acuity after 12 months of treatment. The improvement, resulting from visual stimulation, was due to a good functional recovery by a better usage of the damaged visual pathways. The therapy included prescribing corrective glasses and implementing secondary occlusion of the better eye for 4 months, which was protracted for another 4 months, leading to further improvements in visual acuity. CONCLUSIONS: The case report shows that addressing even minor refractive errors and implementing anti-amblyopia therapy can significantly improve vision in children with CVI, even without co-existing amblyopia. It also highlights the importance of early intervention and multidisciplinary rehabilitation in children with CVI, focusing on motor and cognitive skills. Additionally, it emphasizes the need for further research to establish evidence-based practice standards for improving vision in children with CVI.

Intraventricular haemorrhage in premature infants: the role of immature neuronal salt and water transport.

Intraventricular hemorrhage (IVH) is a common complication of premature birth. Survivors are often left with cerebral palsy, intellectual disability, and/or hydrocephalus. Animal models suggest that brain tissue shrinkage with subsequent vascular stretch and tear is an important step in the pathophysiology, but the cause of this shrinkage is unknown. Clinical risk factors for IVH are biomarkers of hypoxic-ischemic stress, which causes mature neurons to swell. However, immature neuronal volume might shift in the opposite direction under these conditions. This is because immature neurons express the chloride salt and water transporter NKCC1, which subserves regulatory volume increases in nonneural cells, whereas mature neurons express KCC2, which subserves regulatory volume decreases. When hypoxic ischemic conditions reduce active ion transport and increase the cytoplasmic membrane permeability, the effects of these transporters will be diminished. As a consequence, while mature neurons swell (cytotoxic edema) immature neurons might shrink. After hypoxic-ischemic stress, in vivo and in vitro multi-photon imaging of perinatal transgenic mice demonstrated shrinkage of viable immature neurons, bulk tissue shrinkage, and blood vessel displacement. Neuronal shrinkage was correlated with age-dependent membrane salt and water transporter expression using immunohistochemistry. Shrinkage of immature neurons was prevented by prior genetic or pharmacological inhibition of NKCC1 transport. These findings open new avenues of investigation for the detection of acute brain injury by neuroimaging, as well as prevention of neuronal shrinkage and the ensuing IVH, in premature infants.

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.

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.

Distinguishing multicystic from focal encephalomalacia on delayed MRI in children with term hypoxic ischemic injury.

BACKGROUND AND PURPOSE: To define cystic patterns resulting from term hypoxic ischemic injury (HII) on delayed Magnetic Resonance Imaging (MRI) and determine associated HII patterns and lesions that reflect the severity of injury, from a database of African children with cerebral palsy. METHODS: Retrospective review of 1175 children with cerebral palsy due to term HII diagnosed on late MRI, identifying those with cystic changes. These were classified as multicystic or (multi-) focal-cystic, and were evaluated for associated injuries-thalami, basal ganglia, hippocampi, cerebellum, and presence of ulegyria. RESULTS: Three hundred and eighty-eight of 1175 (33%) children had cystic encephalomalacia. Two hundred and seven of 388 (53.3%) had focal-cystic and 181/388 (46.6%) had multicystic injury. The focal-cystic group comprised 87.9% (182/207) with thalamic injury, 25.6% (53/207) with basal ganglia injury, and 15% (31/207) with cerebellar involvement. Basal-ganglia-thalamus (BGT) pattern was present in 43.9% (91/207) and ulegyria in 69.6% (144/207). In the multicystic group, 88.9% (161/181) had thalamic injury, 30.9% (56/181) had basal ganglia injury, and 21% (38/181) had cerebellar involvement. BGT pattern was observed in 29.8% (54/181) and ulegyria in 28.7%. (52/181). Significant associations (p<.05) were found between multicystic injury and caudate/globus pallidus involvement, and between focal-cystic pattern of injury and ulegyria. CONCLUSIONS: Cystic encephalomalacia was seen in almost one-third of patients with term HII imaged with delayed MRI, with a similar prevalence of focal-cystic and multicystic injury. Multicystic injury was associated with caudate and globus pallidi involvement, typical of the BGT pattern of HII, whereas the focal-cystic pattern was associated with ulegyria, typical of watershed injury.

Frequency of Cerebellar Abnormalities Associated With the Differing Magnetic Resonance Imaging Patterns of Term Hypoxic-Ischemic Injury in Children.

BACKGROUND: We aimed to determine the frequency of cerebellar injury using delayed magnetic resonance imaging (MRI) in children with cerebral palsy, diagnosed with term hypoxic-ischemic injury (HII), and to characterize this for the different MRI patterns of HII. METHODS: We retrospectively reviewed delayed MRI scans in children with cerebral palsy, of whom 1175 had term HII. The pattern of HII was classified into basal ganglia-thalamus (BGT) pattern, watershed (WS) pattern, combined BGT/WS, and multicystic HII. Cerebellar location (hemisphere versus vermis) and the MRI characteristics were documented overall and for each of the different patterns of HII, as well as the association with thalamic injury. RESULTS: Cerebellar injury was found in 252 of 1175 (21.4%) (median age 6 years [interquartile range: 3 to 9 years]). Of these, 49% (124 of 252) were associated with a BGT pattern, 13% (32 of 252) with a WS pattern, 28% (72 of 252) with a combined BGT/WS pattern, and 10% (24 of 252) with a multicystic pattern. The vermis was abnormal in 83% (209 of 252), and the hemispheres were abnormal in 34% (86 of 252) (with 17% [43 of 252] showing both vermis and hemispheric abnormality). CONCLUSIONS: Over a fifth of patients with cerebral palsy due to HII had a cerebellar abnormality on delayed MRI, most commonly involving the vermis (83%), and as part of a BGT pattern of injury in just under half of these likely reflecting the association of cerebellar vermis injury with profound insults.

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.

Long-term effect of indomethacin on a rat model of neonatal hypoxia ischemic encephalopathy through behavioral tests.

BACKGROUND: Many medical experts prescribe indomethacin because of its anti-inflammatory, analgesic, tocolytic, and duct closure effects. This article presents an evaluation of the enduring impact of indomethacin on neonatal rats with hypoxic-ischemic (HI) insults, employing behavioral tests as a method of assessment. METHODS: The experiment was conducted on male Wistar-Albino rats weighing 10 to 15 g, aged between seven and 10 days. The rats were divided into three groups using a random allocation method as follows: hypoxic ischemic encephalopathy (HIE) group, HIE treated with indomethacin group (INDO), and Sham group. A left common carotid artery ligation and hypoxia model was applied in both the HIE and INDO groups. The INDO group was treated with 4 mg/kg intraperitoneal indomethacin every 24 h for 3 days, while the Sham and HIE groups were given dimethylsulfoxide (DMSO). After 72 h, five rats from each group were sacrificed and brain tissue samples were stained with 2,3,5-Triphenyltetrazolium chloride (TCC) for infarct-volume measurement. Seven rats from each group were taken to the behavioral laboratory in the sixth postnatal week (PND42) and six from each group were sacrificed for the Evans blue (EB) experiment for blood-brain barrier (BBB) integrity evaluation. The open field (OF) test and Morris water maze (MWM) tests were performed. After behavioral tests, brain tissue were obtained and stained with TCC to assess the infarct volume. RESULTS: The significant increase in the time spent in the central area and the frequency of crossing to the center in the INDO group compared with the HIE group indicated that indomethacin decreased anxiety-like behavior (p < 0.001, p < 0.05). However, the MWM test revealed that indomethacin did not positively affect learning and memory performance (p > 0.05). Additionally, indomethacin significantly reduced infarct volume and neuropathological grading in adolescence (p < 0.05), although not statistically significant in the early period. Moreover, the EB experiment demonstrated that indomethacin effectively increased BBB integrity (p < 0.05). CONCLUSIONS: In this study, we have shown for the first time that indomethacin treatment can reduce levels of anxiety-like behavior and enhance levels of exploratory behavior in a neonatal rat model with HIE. It is necessary to determine whether nonsteroidal anti-inflammatory agents, such as indomethacin, should be used for adjuvant therapy in newborns with HIE.

Multifaceted functions of Drp1 in hypoxia/ischemia-induced mitochondrial quality imbalance: from regulatory mechanism to targeted therapeutic strategy.

Hypoxic-ischemic injury is a common pathological dysfunction in clinical settings. Mitochondria are sensitive organelles that are readily damaged following ischemia and hypoxia. Dynamin-related protein 1 (Drp1) regulates mitochondrial quality and cellular functions via its oligomeric changes and multiple modifications, which plays a role in mediating the induction of multiple organ damage during hypoxic-ischemic injury. However, there is active controversy and gaps in knowledge regarding the modification, protein interaction, and functions of Drp1, which both hinder and promote development of Drp1 as a novel therapeutic target. Here, we summarize recent findings on the oligomeric changes, modification types, and protein interactions of Drp1 in various hypoxic-ischemic diseases, as well as the Drp1-mediated regulation of mitochondrial quality and cell functions following ischemia and hypoxia. Additionally, potential clinical translation prospects for targeting Drp1 are discussed. This review provides new ideas and targets for proactive interventions on multiple organ damage induced by various hypoxic-ischemic diseases.

Temporal Evolution of Signal Alterations in the Deep Gray Nuclei in term Neonates With Hypoxic-Ischemic Brain Injury: A Comprehensive Review.

The deep gray nuclei are paired interconnected gray nuclei comprising the basal ganglia and thalami. Injury to the deep gray nuclei secondary to hypoxic-ischemic injury is associated with poor short- and long-term clinical outcomes. The signal changes following hypoxic-ischemic injury are dynamic and evolve over a period of time from injury to resolution. Radiologically relevant events following hypoxic-ischemic injury include the onset of anaerobic metabolism immediately following hypoxic-ischemic injury, increase in cytotoxic edema followed by its resolution, and the onset and progression of neuronal necrosis and gliosis. Appearance of lactate peak on proton spectroscopy is the initial radiologic evidence of hypoxic-ischemic injury. Diffusion-weighted imaging has the highest prognostic value and pseudo-normalizes following 1 week of hypoxic-ischemic injury. Recommended timing for magnetic resonance imaging (MRI) is between 4 and 7 days. MR imaging performed between 1 and 6 months underestimates the extent of injury because radiologic changes are subtle. This review provides a detailed timeline of radiologic abnormalities in the deep gray nuclei following hypoxic-ischemic injury.

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.

Astrocyte-neuron communication mediated by the Notch signaling pathway: focusing on glutamate transport and synaptic plasticity.

Maintaining glutamate homeostasis after hypoxic ischemia is important for synaptic function and neural cell activity, and regulation of glutamate transport between astrocyte and neuron is one of the important modalities for reducing glutamate accumulation. However, further research is needed to investigate the dynamic changes in and molecular mechanisms of glutamate transport and the effects of glutamate transport on synapses. The aim of this study was to investigate the regulatory mechanisms underlying Notch pathway mediation of glutamate transport and synaptic plasticity. In this study, Yorkshire neonatal pigs (male, age 3 days, weight 1.0-1.5 kg, n = 48) were randomly divided into control (sham surgery group) and five hypoxic ischemia subgroups, according to different recovery time, which were then further subdivided into subgroups treated with dimethyl sulfoxide or a Notch pathway inhibitor (N-[N-(3, 5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester). Once the model was established, immunohistochemistry, immunofluorescence staining, and western blot analyses of Notch pathway-related proteins, synaptophysin, and glutamate transporter were performed. Moreover, synapse microstructure was observed by transmission electron microscopy. At the early stage (6-12 hours after hypoxic ischemia) of hypoxic ischemic injury, expression of glutamate transporter excitatory amino acid transporter-2 and synaptophysin was downregulated, the number of synaptic vesicles was reduced, and synaptic swelling was observed; at 12-24 hours after hypoxic ischemia, the Notch pathway was activated, excitatory amino acid transporter-2 and synaptophysin expression was increased, and the number of synaptic vesicles was slightly increased. Excitatory amino acid transporter-2 and synaptophysin expression decreased after treatment with the Notch pathway inhibitor. This suggests that glutamate transport in astrocytes-neurons after hypoxic ischemic injury is regulated by the Notch pathway and affects vesicle release and synaptic plasticity through the expression of synaptophysin.

The Notch pathway regulates autophagy after hypoxic-ischemic injury and affects synaptic plasticity.

Following neonatal hypoxic-ischemia (HI) injury, it is crucial factor to reconstruct neural circuit and maintain neural network homeostasis for neurological recovery. A dynamic balance between the synthesis and degradation of synaptic protein is required for maintaining synaptic plasticity. Protein degradation is facilitated by autophagy. This study aimed to investigate the regulation of synaptic structural plasticity by the Notch pathway, by assessing changes in Notch pathway activation and their effects on synaptic proteins and autophagy after HI injury. The study involved 48 male newborn Yorkshire piglets, each weighing 1.0-1.5 kg and 3 days old. They were randomly assigned to two groups: the HI group and the Notch pathway inhibitor + HI group (n = 24 per group). Each group was further divided into six subgroups according to HI duration (n = 4 per group): a control subgroup, and 0-6, 6-12, 12-24, 24-48, and 48-72 h subgroups. The expression of Notch pathway-related proteins, including Notch1, Hes1, and Notch intracellular domains, increased following HI injury. The expression of autophagy proteins increased at 0-6 h and 6-12 h post-HI. The expression of synaptic proteins, such as postsynaptic density protein 95 (PSD95) and synaptophysin, increased 6-12 h and 12-24 h after HI, respectively. Notably, the increased expression of these proteins was reversed by a Notch pathway inhibitor. Transmission electron microscopy revealed the presence of autophagosome structures in synapses. These findings shed light on the underlying mechanisms of neurological recovery after HI injury and may provide insights into potential therapeutic targets for promoting neural circuit reconstruction and maintaining neural network homeostasis.

Intracranial Imaging of Preterm Infants with Suspected Hypoxic Ischemic Encephalopathy: Comparing MRI and Ultrasound.

AIMS: We correlate ultrasound, MRI, and clinical findings in neonates with suspected hypoxic ischemic injury. BACKGROUND: Recent advances in neuroimaging have led to improved detection of subtle insults associated with neurodevelopmental outcomes, beyond more historically described lesions such as large hemorrhages and hydrocephalus. OBJECTIVE: In this study, we compare cranial ultrasound to MRI for the evaluation of suspected HIE in preterm infants. METHODS: 147 premature infant patients with paired ultrasound and MRI exams were retrospectively analyzed to compare imaging finding accuracy and clinical value. RESULT: We confirm that ultrasound is highly sensitive and specific for hydrocephalus, ventricular prominence, and gross structural abnormalities. Ultrasound is not a substitute for MRI in cases of small hemorrhages or white matter injury, however, certain US findings were associated with Apgar score and MRI sequelae of HIE. CONCLUSION: Choosing between ultrasound and MRI for preterm neonates at risk for intracranial abnormalities based on their strengths can reduce cost and maximize clinical utility. MRI provides a highly sensitive identification of subtle brain injury, yet ultrasound is correlated with the peripartum clinical picture as measured by Apgar score.

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.

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.

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.

Role of the NF-kB/parkin/vegfr-1 pathway associated with hypoxic-ischemic insult in germinal matrix samples of newborn infants / O papel da via NF-kB/parkin/vegfr-1 associada à agressão hipóxico-isquêmica em amostras de matriz germinativa de pacientes recém-nascidos

Abstract Objective: Given the high proliferative activity of germinal matrix and its direct correlation with hypoxemia, it is necessary to investigate the possible molecular regulation pathways, to understand the existing clinical relationship between the hypoxic-ischemic insult and the biomarkers NF-kB, AKT-3, Parkin, TRK-C and VEGFR-1. Methods: A hundred and eighteen germinal matrix samples of the central nervous system of patients who died in the first 28 days of life were submitted to histological and immunohistochemistry analysis to identify the tissue immunoexpression of those biomarkers related to asphyxia, prematurity, and death events within 24h. Results: A significantly increased tissue immunoexpression of NF-kB, AKT-3 and Parkin was observed in the germinal matrix of preterm infants. In addition, significantly decreased tissue immunoexpression of VEGFR-1 and NF-kB was observed in patients who experienced asphyxia followed by death within 24 hours. Conclusions: The results suggest a direct involvement between the hypoxic-ischemic insult and NF-kB and VEGFR-1 markers since a decreased immunoexpression of these biomarkers was observed in asphyxiated patients. Furthermore, it is suggested that there was not enough time for VEGFR-1 to be transcribed, translated and expressed on the surface of the plasma membrane. This temporality can be observed in the relationship between NF-kB expression and the survival time of individuals who died within 24 hours, suggesting that this factor is essential for the production of VEGFR-1 and, therefore, to carry out the necessary remodeling effect to neovascularize the affected region.

RESUMO Objetivo: Dada a alta atividade proliferativa da matriz germinativa e sua correlação direta com a hipoxemia, é necessário investigar as possíveis vias de regulação molecular para entender a relação clínica existente entre o insulto hipóxico-isquêmico e os biomarcadores NF-kB, AKT -3, Parkina, TRK-C e VEGFR-1. Métodos: Cento e dezoito amostras de matriz germinativa do sistema nervoso central de pacientes que faleceram nos primeiros 28 dias de vida foram submetidas a análise histológica e imuno-histoquímica para identificar a imunoexpressão tecidual desses biomarcadores relacionados a eventos de asfixia, prematuridade e óbito em 24 horas. Resultados: Observou-se uma imunoexpressão tecidual significativamente aumentada de NF-kB, AKT-3 e Parkin na matriz germinativa de prematuros. Além disso, constatou-se uma imunoexpressão tecidual significativamente diminuída de VEGFR-1 e de NF-kB em pacientes que apresentaram asfixia seguida de morte em 24 horas. Conclusões: Os resultados sugerem o envolvimento direto entre o insulto hipóxico-isquêmico e os marcadores NF-kB e VEGFR-1, visto que se observou uma imunoexpressão diminuída destes biomarcadores nos pacientes asfixiados. Além disso, sugere-se que não houve tempo suficiente para que o VEGFR-1 fosse transcrito, traduzido e expresso na superfície da membrana plasmática. Essa temporalidade pode ser observada na relação entre a expressão de NF-kB e o tempo de vida dos indivíduos que morreram em 24 horas, o que sugere que esse fator é essencial para a produção do VEGFR-1 e, portanto, para realizar o efeito remodelador necessário para neovascularizar a região afetada.