Hypoxic-ischemic Injury Research Articles

FGF21 modulates hippocampal cold-shock proteins and CA2-subregion proteins in neonatal mice with hypoxia-ischemia.

Fibroblast growth factor 21 (FGF21) is a neuroprotectant with cognitive enhancing effects but with poorly characterized mechanism(s) of action, particularly in females. Prior studies suggest that FGF21 may regulate cold-shock proteins (CSPs) and CA2-marker proteins in the hippocampus but empirical evidence is lacking. We assessed in normothermic postnatal day (PND) 10 female mice, if hypoxic-ischemic (HI) brain injury (25 min 8% O2/92% N2) altered endogenous levels of FGF21 in serum or in the hippocampus, or its receptor β-klotho. We also tested if systemic administration of FGF21 (1.5 mg/kg) modulated hippocampal CSPs or CA2 proteins. Finally, we measured if FGF21 therapy altered markers of acute hippocampal injury. HI increased endogenous serum FGF21 (24 h), hippocampal tissue FGF21 (4d), and decreased hippocampal β-klotho levels (4d). Exogenous FGF21 therapy modulated hippocampal CSP levels, and dynamically altered hippocampal CA2 marker expression (24 h and 4d). Finally, FGF21 ameliorated neuronal damage markers at 24 h but did not affect GFAP (astrogliosis) or Iba1 (microgliosis) levels at 4d. FGF21 therapy modulates CSP and CA2 protein levels in the injured hippocampus. These proteins serve different biological functions, but our findings suggest that FGF21 administration modulates them in a homeostatic manner after HI. Hypoxic-ischemic (HI) injury in female post-natal day (PND) 10 mice decreases hippocampal RNA binding motif 3 (RBM3) levels in the normothermic newborn brain. HI injury in normothermic newborn female mice alters serum and hippocampal fibroblast growth factor 21 (FGF21) levels 24 h post-injury. HI injury in normothermic newborn female mice alters hippocampal levels of N-terminal EF-hand calcium binding protein 2 (NECAB2) in a time-dependent manner. Exogenous FGF21 therapy ameliorates the HI-mediated loss of hippocampal cold-induced RNA-binding protein (CIRBP). Exogenous FGF21 therapy modulates hippocampal levels of CA2-marker proteins after HI.

Diffusion Tensor Imaging to Predict Neurodevelopmental Impairment in Infants after Hypoxic-Ischemic Injury.

Magnetic resonance imaging (MRI) is the standard of care for evaluation of brain injury after hypoxic-ischemic encephalopathy (HIE) in term newborns. This study utilizes diffusion tensor imaging (DTI) to (1) identify infants at highest risk of development of cerebral palsy (CP) following HIE and to (2) identify regions of the brain critical to normal fidgety general movements (GMs) at 3 to 4 months of postterm. Absence of these normal, physiological movements is highly predictive of CP. Term infants treated with hypothermia for HIE from January 2017 to December 2021 were consented for participation and had brain MRI with DTI after rewarming. The Prechtl's General Movements Assessment was performed at 12 to 16 weeks of age. Structural MRIs were reviewed for abnormalities, and DTI data were processed with the FMRIB Software Library. Infants underwent the Bayley Scales of Infant and Toddler Development III test at 24 months. Forty-five infant families were consented; three infants died prior to MRI and were excluded, and a fourth infant was excluded due to diagnosis of a neuromuscular disorder. Twenty-one infants were excluded due to major movement artifact on diffusion images. Ultimately, 17 infants with normal fidgety GMs were compared with 3 infants with absent fidgety GMs with similar maternal and infant characteristics. Infants with absent fidgety GMs had decreased fractional anisotropy of several important white matter tracts, including the posterior limb of the internal capsule, optic radiations, and corpus callosum (p < 0.05). All three infants with absent fidgety GMs and two with normal GMs went on to be diagnosed with CP. This study identifies white matter tracts of the brain critical to development of normal fidgety GMs in infants at 3 to 4 months of postterm using advanced MRI techniques. These findings identify those at highest risk for CP among infants with moderate/severe HIE prior to hospital discharge. · HIE has devastating impacts on families and infants.. · Diffusion MRI identifies infants at highest risk for developing neurodevelopmental impairment.. · Normal general movements of infancy are generated by key white matter tracts..

Diffusion kurtosis imaging and diffusion weighted imaging comparison in diagnosis of early hypoxic–ischemic brain edema

BackgroundHypoxic–ischemic encephalopathy (HIE) refers to cerebral hypoxic–ischemic injury caused by asphyxia during perinatal period, which is one of the important causes of neonatal death and sequelae. Early and accurate diagnosis of HIE is of great significance for the prognostic evaluation of patients. The purpose of this study is to explore the efficacy of diffusion-kurtosis imaging (DKI) and diffusion-weighted imaging (DWI) in the diagnosis of early HIE.MethodsTwenty Yorkshire newborn piglets (3–5 days) were randomly divided into control group and experimental group. DWI and DKI scanning were performed at timepoints of 3, 6, 9, 12, 16, and 24 h after hypoxic–ischemic exposure. At each timepoint, the parameter values obtained by each group scan were measured, and the lesion area of the apparent diffusion coefficient (ADC) map and mean diffusion coefficient (MDC) map were measured. (For better interpretation of this study, we replaced the description of MD with MDC). Then, we completely removed the brain for pathological examination, and observed the state of cells and mitochondria in the ADC/MDC matching area (the actual area of the lesion), and the mismatch area (the area around the lesion).ResultsIn the experimental group, the ADC and MDC values decreased with time, but the MDC decreased more significantly and the change rate was higher. Both MDC and ADC values changed rapidly from 3 to 12 h and slowly from 12 to 24 h. The MDC and ADC images showed obvious lesions at 3 h for the first time. At this time, the area of ADC lesions was larger than that of MDC. As the lesions developed, the area of ADC maps was always larger than that of the MDC maps within 24 h. By observing the microstructure of the tissues by light microscopy, we found that the ADC and MDC matching area in the experimental group showed swelling of neurons, infiltration of inflammatory cells, and local necrotic lesions. Consistent with the observation under light microscope, pathological changes were observed in the matching ADC and MDC regions under electron microscopy as well, including collapse of mitochondrial membrane, fracture of partial mitochondrial ridge, and emergence of autophagosomes. In the mismatching region, the above pathological changes were not observed in the corresponding region of the ADC map.ConclusionsDKI’s characteristic parameter MDC is better than ADC (parameter of DWI) to reflect the real area of the lesion. Therefore, DKI is superior to DWI in diagnosing early HIE.

Effect of type 1 diabetes during pregnancy and lactation on neonatal hypoxia-ischemia injury and apoptotic gene expression.

Hypoxia-ischemia (HI) is one of the major disorders that causes a variety of abnormalities and infant mortality. Type 1 diabetes is one of the most common worldwide metabolic disorders, and its prevalence has become one of the public health concerns of the 21st century. This study aims to evaluate the effect of type 1 diabetes during pregnancy and lactation on vulnerability to neonatal HI in rats. Female Wistar rats (weighing 200 ± 220 g) were randomly assigned into two groups: Group 1 (rats that received 0.5mL/day of normal saline solution) and Group 2 (type 1 diabetes was induced in rats on the second day of pregnancy with a single dose of intraperitoneal injection of alloxan monohydrate [150 mg/kg]). After delivery, offspring were divided into four groups: (a) Control (Co), (b) Diabetic (DI), (c) Hypoxia-ischemia (HI), (d) HI + Diabetic (HI + DI). Seven days after HI induction, neurobehavioral tests were performed, and then cerebral edema, infarct volume, inflammatory factors, Bax-Bcl2 expression, and oxidative stress were measured. The BAX level in the DI + HI (p = 0.0355) group was significantly higher than the HI group. The Bcl-2 expression levels in the HI (p = 0.0027) and DI + HI (p < 0.0001) groups were significantly lower than the DI group. Total antioxidant capacity (TAC) levels in the DI + HI (p < 0.0001) group were significantly lower than HI and CO groups. TNF-α, CRP, and total oxidant status (TOS) levels in the DI + HI (p < 0.0001) group were significantly higher than the HI group. Infarct volume and cerebral edema in the DI + HI (p < 0.0001) group were significantly higher than the HI group. According to the results, type 1 diabetes during pregnancy and lactation increased the destructive effects of HI injury in pups. It also decreased the expression of the anti-apoptotic Bcl-2 and increased the expression BAX apoptosis factor gene in pups.

TO STUDY ON MRI BRAIN FINDINGS IN SEVERE PRE- ECLAMPSIA AND ECLAMPSIA IN PREGNANT WOMEN IN TERTIARY CARE CENTRE-A PROSPECTIVE OBSERVATIONAL STUDY

Background: To corroborate the clinical ndings of severe pre-eclampsia and eclampsia patients with magnetic resonance imaging ndings of brain. This is a 2-year prospective study was conducted in the VMGMC of departme Methods: nt of obstetrics and gynaecology, Solapur. A sample size of 50 patients with severe pre- eclampsia/ eclampsia were included. Each patient was studied comparing under different variables to MRI brain ndings. Comparison was done using appropriate statistical method to ascertain our ndings statistical signicance. MRI revealed Results: abnormal ndings in 52% (26) of the patients, of that most common nding were bilateral PRES (40%), followed by hypoxic ischemic injury (4%), metabolic encephalopathy (2%), infarct (4%) and subacute infarct (2%). Among patients with abnormal MRI ndings 4 of them belong to unregistered group and 22 of them are registered group, most of them are in younger age group of 21 to 25 years. Convulsions, eclampsia, consciousness level, systolic blood pressure, diastolic blood pressure, mean arterial pressure, haemoglobin level (p=0.05, p=0.012, p=0.001, p=0.002, p=0.019, p=0.007, p=0.027) respectively are in line with MRI ndings. Age group, residence, socio economic level, parity status, gestational age, urine albumin level, mode of delivery, MgSO4 (p=0.364, p=1.00, p=0.235, p=0.120, p=0.162, p=0.721, p=0.611, p=0.749) respectively not in line with the MRI ndings. Number of convulsions, type of eclam Conclusions: psia, consciousness level, systolic blood pressure, diastolic blood pressure, mean arterial pressure, haemoglobin level are statistically signicant with MRI ndings so, this ndings in pregnant patients should arise concern and helps in plan of action for better management. Age group, residence, socio economic status, parity, gestational age, urine albumin level, mode of delivery RFT, and MgSo4 were not statistically signicant for MRI ndings

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

We correlate ultrasound, MRI, and clinical findings in neonates with suspected hypoxic ischemic injury. 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. In this study, we compare cranial ultrasound to MRI for the evaluation of suspected HIE in preterm infants. 147 premature infant patients with paired ultrasound and MRI exams were retrospectively analyzed to compare imaging finding accuracy and clinical value. 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. 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.

Unique Patterns of Ischemic Stroke from Combined Cocaine and Heroin Use: A Case Series (P3-5.031)

<h3>Objective:</h3> To describe cases of multiple territory ischemic stroke in young individuals secondary to combined cocaine and heroin use. <h3>Background:</h3> Abuse of cocaine and heroin has been linked to ischemic stroke via various mechanisms. Cocaine use can lead to vasospasm, direct cerebral vessel damage, or other end-organ damage which can promote clot formation. Heroin use has been linked to hypoxic-ischemic injury, promoting cardioembolism, and rarely hypereosinophilia. The effects of a combination of these two substances on acute ischemic stroke are less frequently reported. <h3>Design/Methods:</h3> Retrospective case series of three individuals. <h3>Results:</h3> <h3>Case 1:</h3> A 37-year-old female with a history of polysubstance use disorder presented after being found down. She was disoriented, confabulating, had ataxia and dysarthria with a NIHSS of 15. MRI revealed symmetric ischemic changes within the bilateral hippocampi, bilateral cerebellar regions, and right occipital lobe. The patient endorsed use of synthetic heroin and cocaine prior to presentation. <h3>Case 2:</h3> A 46-year-old male presented after being found down in a hotel room with an empty syringe, later endorsing combined cocaine and heroin use. On exam, he was severely obtunded and required intubation, NIHSS was 27. MRI revealed symmetric ischemic changes in the bilateral globus pallidus, centrum semiovale, corona radiata, and scattered foci of restricted diffusion in both cerebral hemispheres. <h3>Case 3:</h3> A 46-year-old male with a history of type 2 diabetes mellitus and polysubstance use disorder presented with a 5-day history of altered mental status. Exam notable for apraxia, short term memory loss, and shuffling gait, but NIHSS was 0. Use of cocaine and heroin was identified. MRI revealed bilateral globus pallidus infarcts with petechial hemorrhage, and a right temporal lobe infarct. <h3>Conclusions:</h3> The combined use of cocaine and heroin can lead to multiple territory ischemic stroke plus striking symmetric globus pallidus and/or hippocampus ischemia. <b>Disclosure:</b> Dr. Hasan has nothing to disclose. Dr. Pinna has nothing to disclose. Dr. Lynch has nothing to disclose. Dr. Kim has nothing to disclose.

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 1.0-1.5kg and 3days 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 48-72h 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 0-6h and 6-12h post-HI. The expression of synaptic proteins, such as postsynaptic density protein 95 (PSD95) and synaptophysin, increased 6-12h and 12-24h 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.

Effect of Hypoxia-Ischemia on the Expression of Iron-Related Proteins in Neonatal Rat Brains.

Hypoxic-ischemic white matter injury (WMI) pathogenesis in preterm infants is not well established, and iron-related proteins in the brain may play an important role in imbalanced iron metabolism. We aimed to investigate the iron-related protein changes in neonatal rats after hypoxia-ischemia (HI), clarify the role of iron-related proteins in hypoxic-ischemic WMI, and potentially provide a new target for the clinical treatment of hypoxic-ischemic WMI in preterm infants. We adopted a WMI animal model of bilateral common carotid artery electrocoagulation combined with hypoxia in neonatal 3-day-old Sprague-Dawley rats. We observed basic myelin protein (MBP) and iron-related protein expression in the brain (ferritin, transferrin receptor [TfR], and membrane iron transporter 1 [FPN1]) via Western blot and double immunofluorescence staining. The expression of MBP in the WMI group was significantly downregulated on postoperative days (PODs) 14, 28, and 56. Ferritin levels were significantly increased on PODs 3, 7, 14, and 28 and were most significant on POD 28, returning to the sham group level on POD 56. FPN1 levels were significantly increased on PODs 7, 28, and 56 and were still higher than those in the sham group on POD 56. TfR expression was significantly upregulated on PODs 1, 7, and 28 and returned to the sham group level on POD 56. Immunofluorescence staining showed that ferritin, TfR, and FPN1 were expressed in neurons, blood vessels, and oligodendrocytes in the cortex and corpus callosum on POD 28. Compared with the sham group, the immune-positive markers of three proteins in the WMI group were significantly increased. The expression of iron-related proteins in the brain (ferritin, FPN1, and TfR) showed spatiotemporal dynamic changes and may play an important role in hypoxic-ischemic WMI.

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-printedmodels 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.

Evaluation of heterogeneity in effect of therapeutic hypothermia by sex among infants with neonatal encephalopathy.

Our objective was to examine heterogeneity in the effect of therapeutic hypothermia by sex in infants with moderate or severe neonatal encephalopathy. We conducted a post hoc analysis of the Induced Hypothermia trial, which included infants born at gestational ages ≥36 weeks, admitted at ≤6 postnatal hours with evidence of severe acidosis or perinatal complications and moderate or severe neonatal encephalopathy. Multivariate modified Poisson regression models were used to compare the treatment effect of whole-body hypothermia versus control, with an evaluation of interaction by sex, on the primary outcome of death or moderate or severe disability at 18-22 months of corrected age. A total of 101 infants (51 male, 50 female) were randomly assigned to hypothermia treatment and 104 infants (64 male, 40 female) to control. The primary outcome occurred in 45% of the hypothermia group and 63% of the control group (RR 0.73; 95% CI 0.56, 0.94). There was no significant difference (interaction P = 0.50) in the treatment effect of hypothermia on the primary outcome between females (RR 0.79; 95% CI 0.54, 1.17) compared to males (RR 0.63; 95% CI 0.44, 0.91). We found no evidence that sex influences the treatment effect of hypothermia in infants with moderate or severe neonatal encephalopathy. Preclinical evidence suggests a differential effect in response to cooling treatment of hypoxic-ischemic injury between males and females. We found no evidence of heterogeneity in the treatment effect of whole-body hypothermia by sex in this post hoc subgroup analysis of infants with moderate or severe neonatal encephalopathy from the National Institute of Child Health and Human Development Neonatal Research NetworkInduced Hypothermia trial.

Up-Regulation of miR-9-5p Inhibits Hypoxia-Ischemia Brain Damage Through the DDIT4-Mediated Autophagy Pathways in Neonatal Mice.

Hypoxia-ischemia (HI) remains the leading cause of cerebral palsy and long-term neurological sequelae in infants. Despite intensive research and many therapeutic approaches, there are limited neuroprotective strategies against HI insults. Herein, we reported that HI insult significantly down-regulated microRNA-9-5p (miR-9-5p) level in the ipsilateral cortex of neonatal mice. The biological function and expression patterns of protein in the ischemic hemispheres were evaluated by qRT-PCR, Western Blotting analysis, Immunofluorescence and Immunohistochemistry. Open field test and Y-maze test were applied to detect locomotor activity and exploratory behavior and working memory. Overexpression of miR-9-5p effectively alleviated brain injury and improved neurological behaviors following HI insult, accompanying with suppressed neuroinflammation and apoptosis. MiR-9-5p directly bound to the 3' untranslated region of DNA damage-inducible transcript 4 (DDIT4) and negatively regulated its expression. Furthermore, miR-9-5p mimics treatment down-regulated light chain 3 II/light chain 3 I (LC3 II/LC3 I) ratio and Beclin-1 expression and decreased LC3B accumulation in the ipsilateral cortex. Further analysis showed that DDIT4 knockdown conspicuously inhibited the HI-up-regulated LC3 II/ LC3 I ratio and Beclin-1 expression, associating with attenuated brain damage. The study indicates that miR-9-5p-mediated HI injury is regulated by DDIT4-mediated autophagy pathway and up-regulation of miR-9-5p level may provide a potential therapeutic effect on HI brain damage.

60-year-old male with rapidly progressive pneumocephalus caused by Clostridium septicum in the setting of an occult colonic adenocarcinoma

BackgroundDisseminated Clostridium septicum infection is an uncommon complication associated with malignancies, particular colonic adenocarcinoma. The organism appears to preferentially colonize large masses in rare individuals and subsequently seed the blood via mucosal ulceration. This has rarely been reported to lead to central nervous system infection and, in several cases, rapidly progressive pneumocephalus. In the few cases reported, this was a universally fatal condition. The current case adds to the reports of this extremely rare complication and provides a unique and complete clinicopathologic characterization with autopsy examination, microscopy, and molecular testing.Case PresentationA 60-year-old man with no known past medical history was discovered having seizure-like activity and stroke-like symptoms. Blood cultures turned positive after six hours. Imaging revealed a large, irregular cecal mass as well as 1.4 cm collection of air in the left parietal lobe that progressed to over 7 cm within 8 h. By the following morning, the patient had lost all neurologic reflexes and died. Post-mortem examination revealed brain tissue with multiple grossly evident cystic spaces and intraparenchymal hemorrhage, while microscopic exam showed diffuse hypoxic-ischemic injury and gram-positive rods. Clostridium septicum was identified on blood cultures and was confirmed in paraffin embedded tissue from the brain by 16 S ribosomal sequencing and from the colon by C. septicum specific PCR.ConclusionsC. septicum is an anaerobic, gram-positive rod that can become invasive and is strongly associated with gastrointestinal pathology including colonic adenocarcinomas. Central nervous system infection with rapidly progressive pneumocephalus is a rarely reported and universally fatal complication of disseminated C. septicum infection.

Chemogenetic inhibition of amygdala excitatory neurons impairs rhEPO-enhanced contextual fear memory after TBI

Erythropoietin (EPO) is a hypoxia-responsive cytokine that induces neuroprotective effect in hypoxic-ischaemic, traumatic, excitotoxic and inflammatory injuries. Recently, utilizing a clinically relevant murine model of TBI and delayed hypoxemia, we have found that ongoing recombinant human EPO (rhEPO) administration influenced neurogenesis, neuroprotection, synaptic density and, behavioral outcomes early after TBI, and the impact on long-lasting outcomes 6 months after injury. We also demonstrated that the 1-month behavioral improvement was associated with mitogen-activated protein kinase (MAPK)/cAMP response element-binding protein (CREB) signaling activation and increased of excitatory synaptic density in the amygdala. However, we did not uncover which type of cells were involved in fear memory response enhancement after rhEPO treatment in the setting of TBI with delayed hypoxemia. In this report, using chemogenetic tools in our controlled cortical impact (CCI) model, we were able to inactivate excitatory neurons and eliminate rhEPO-induced fear memory recall enhancement. In summary, these data demonstrate that rhEPO treatment initiated after TBI enhances contextual fear memory in the injured brain via activation of excitatory neurons in the amygdala.

Hypothermic Oxygenated Machine Perfusion Promotes Mitophagy Flux against Hypoxia-Ischemic Injury in Rat DCD Liver

Hypothermic oxygenated machine perfusion (HOPE) can enhance organ preservation and protect mitochondria from hypoxia-ischemic injury; however, an understanding of the underlying HOPE mechanism that protects mitochondria is somewhat lacking. We hypothesized that mitophagy may play an important role in HOPE mitochondria protection. Experimental rat liver grafts were exposed to 30 min of in situ warm ischemia. Then, grafts were procured, followed by cold storage for 3 or 4 h to mimic the conventional preservation and transportation time in donation after circulatory death (DCD) in clinical contexts. Next, the grafts underwent hypothermic machine perfusion (HMP) or HOPE for 1 h through portal vein only perfusion. The HOPE-treated group showed a better preservation capacity compared with cold storage and HMP, preventing hepatocyte damage, nuclear injury, and cell death. HOPE can increase mitophagy marker expression, promote mitophagy flux via the PINK1/Parkin pathway to maintain mitochondrial function, and reduce oxygen free radical generation, while the inhibition of autophagy by 3-methyladenine and chloroquine could reverse the protective effect. HOPE-treated DCD liver also demonstrated more changes in the expression of genes responsible for bile metabolism, mitochondrial dynamics, cell survival, and oxidative stress. Overall, HOPE attenuates hypoxia-ischemic injury in DCD liver by promoting mitophagy flux to maintain mitochondrial function and protect hepatocytes. Mitophagy could pave the way for a protective approach against hypoxia-ischemic injury in DCD liver.

Myricetin attenuates hypoxic-ischemic brain damage in neonatal rats via NRF2 signaling pathway.

Introduction: Hypoxic-ischemic encephalopathy (HIE) is a crucial cause of neonatal death and neurological sequelae, but currently there is no effective therapy drug for HIE. Both oxidative stress and apoptosis play critical roles in the pathological development of HIE. Myricetin, a naturally extracted flavonol compound, exerts remarkable effects against oxidative stress, apoptosis, and inflammation. However, the role and underlying molecular mechanism of myricetin on HIE remain unclear. Methods: In this study, we established the neonatal rats hypoxic-ischemic (HI) brain damage model in vivo and CoCl2 induced PC12 cell model in vitro to explore the neuroprotective effects of myricetin on HI injury, and illuminate the potential mechanism. Results: Our results showed that myricetin intervention could significantly reduce brain infarction volume, glia activation, apoptosis, and oxidative stress marker levels through activating NRF2 (Nuclear factor-E2-related factor 2) and increase the expressions of NRF2 downstream proteins NQO-1 and HO-1. In addition, the NRF2 inhibitor ML385 could significantly reverse the effects of myricetin. Conclusion: This study found that myricetin might alleviate oxidative stress and apoptosis through NRF2 signaling pathway to exert the protective role for HI injury, which suggested that myricetin might be a promising therapeutic agent for HIE.

The Spectrum of MRI and Electrographic Findings in Pediatric Patients With Seizures: A Retrospective Tertiary Care Center Study.

Background Seizures constitute a serious public health concern, especially in pediatric patients. They are among the most prevalent medical issues affecting children. Magnetic resonance imaging (MRI) is a widely used imaging modality to evaluate, assess, and follow up on brain abnormalities. Objectives The purpose of the study is to explore the clinical findings of pediatric patients with seizures and their associated findings on MRI examinations. Material and methods A retrospective cohort study was conducted between 2021 and 2022 at King Abdulaziz University Hospital (KAUH). A total of 171 pediatric patients (ages 1-14 years old) who had seizures and underwent brain MRI examinations were included in the study. The mean age of the group was two years. Results Focal seizures represented the majority of seizure types in 62 (60.2%)patients compared to 42 patients who presented with generalized seizures and 67 patients who presented with normal findings based on magnetic resonance imaging (MRI) analysis. The most common finding in imaging was the presence of developmental anomalies, which were found in 31 (18.5%) patients. This was followed by hypoxic-ischemic injury in 12 patients, vascular abnormalities in 10 patients, inherited metabolic disorders in nine patients, and infection-related findings in six patients. Conclusion MRI has an invaluable role in managing pediatric patients with seizures. Accurate diagnosis of patients is an essential step for delivering proper care to patients. MRI is considered the main imaging modality to establish a correct diagnosis and thereby improve prognosis, and electroencephalogram (EEG) should be taken into account during standard neurodiagnostic testing.

Neuroradiological findings in children with subdural hematoma and suspected abusive head trauma

AbstractAimAbusive head trauma (AHT) is often suspected in infants with subdural hematoma (SDH). Other neuroradiological findings have also been reported in assumed AHT, such as hypoxic–ischemic injury (HII), cortical vein thrombosis, and subarachnoid hemorrhage. The purpose of this study was to investigate neuroradiological and clinical findings in cases of suspected AHT.MethodsInfants with SDH suspected to be caused by AHT, referred to the Swedish National Board of Forensic Medicine during the period 1994–2018, were considered for inclusion.ResultsNinety‐six cases were included, with 68% males. The proportions of infants born prematurely, and twins, were higher than in the normal population. Signs of “benign enlargement of the subarachnoid space” (BESS) were found in 36% and were associated with chronic SDH and nonacute symptoms. HII was found in 16% and was associated with subarachnoid hemorrhage and high mortality, but not traumatic findings. Clinical signs of increased intracranial pressure were associated with retinal hemorrhages.ConclusionThis analysis indicates that infants with SDH investigated for AHT are a heterogeneous group with some cases associated with external signs of trauma and others with possibly nontraumatic etiologies. Infants with BESS are more likely to have chronic SDH and nonacute symptoms. Patients with HII often have serious/fatal outcomes, but are not associated with external signs of injury. The overrepresentation of males, premature infants, and twins is unexplained.

N-acetylserotonin inhibits oxidized mitochondrial DNA-induced neuroinflammation by activating the AMPK/PGC-1α/TFAM pathway in neonatal hypoxic-ischemic brain injury model

Hypoxic-ischemic encephalopathy (HIE) is a substantial cause of irreversible nerve injury in newborns. As the endogenous precursor of melatonin, N-acetylserotonin (NAS) can cross the blood–brain barrier and exert neuroprotective effects. Evidence shows that NAS exerts a neuroprotective role in ischemic brain injury by inhibiting the mitochondrial death pathway. This study investigates whether NAS can play a neuroprotective role in the HIE model and explores its underlying molecular mechanism. In vivo, postnatal day 7 (P7) Sprague-Dawley rats were used to construct the HIE rat model. Significant improvement in short-term neurobehavioral impairment, cerebral infarction volume decrease, and neuronal injury mitigation was observed with NAS treatment after hypoxic-ischemic (HI) injury. In addition, we validated that NAS suppressed NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation and NLRP3 inflammasome-related protein expression in the HIE model. Furthermore, we demonstrate that NAS reduced mitochondrial membrane potential loss, oxidative damage to mitochondrial DNA (mtDNA), cytosolic mtDNA copy number and activation of its downstream cyclic guanosine monophosphate adenylate synthase (cGAS)/ stimulator of interferon genes (STING) pathway. Additionally, we further verified the activation of NAS on the AMP-activated protein kinase (AMPK)/ peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)/ mitochondrial transcription factor A (TFAM) pathway and found that inhibition of AMPK could increase cytosolic mtDNA copy number and NLRP3 inflammasome-related protein expression while decreasing STING protein expression. Our study demonstrated that NAS inhibits oxidative mtDNA-induced neuroinflammation, which is partially associated with AMPK/PGC-1α/TFAM pathway activation in the HIE model.

Transcranial direct current stimulation for focal status epilepticus or lateralized periodic discharges in four patients in a critical care setting.

Transcranial direct current stimulation (tDCS) has been advocated for various neurological conditions, including epilepsy. A 1-4-mA cathodal current applied to the scalp over a seizure focus can reduce spikes and seizures. This series of four patients with focal status epilepticus is among the first case series to demonstrate benefit of tDCS in the critical care setting. Patients in the intensive care unit were referred for tDCS treatment when focal status epilepticus or clinically relevant lateralized periodic discharges did not resolve with conventional antiseizure medications and anesthetics. Battery-powered direct cathodal current at 2mA was delivered by an ActivaDose (Caputron) tDCS device via a saline-soaked sponge on the scalp over the seizure focus. Anode was on the contralateral forehead or shoulder. Treatment was for 30 min, repeated twice in a day, then again 1-4 times more over the next few days. Three females and one male, aged 34-68 years, were treated. Etiologies of status epilepticus were posterior reversible encephalopathy syndrome in association with immunosuppressants for a liver transplant, perinatal hypoxic-ischemic injury, a prior cardioembolic parietal stroke, and central nervous system lupus. tDCS led to significant reduction of interictal spikes (.78 to .38/s, p< .0001) in three cases and electrographic seizures (3.83/h to 0/h, p< .001) in two cases. Medication reductions were enabled in all cases subsequent to tDCS. The only side effect of tDCS was transient erythema under the sponge in one case. Two patients died of causes unrelated to tDCS, one was discharged to a nursing home, and one became fully responsive as seizures were controlled with tDCS. Spikes and electrographic seizure frequency significantly improved within 1 day of tDCS. Results are potentially confounded by multiple ongoing changes in medications and treatments. These results might encourage further investigation of tDCS in the critical care setting, but verification by controlled studies will be required.