HIF-1α participates in secondary brain injury through regulating neuroinflammation.

A deeper understanding of the underlying biological mechanisms of secondary brain injury induced by traumatic brain injury (TBI) will greatly advance the development of effective treatments for patients with TBI. Hypoxia-inducible factor-1 alpha (HIF-1α) is a central regulator of cellular response to hypoxia. In addition, growing evidence shows that HIF-1α plays the important role in TBI-induced changes in biological processes; however, detailed functional mechanisms are not completely known. The aim of the present work was to further explore HIF-1α-mediated events after TBI. To this end, next-generation sequencing, coupled with cellular and molecular analysis, was adopted to interrogate vulnerable events in a rat controlled cortical impact model of TBI. The results demonstrated that TBI induced accumulation of HIF-1α at the peri-injury site at 24 h post-injury, which was associated with neuronal loss. Moreover, gene set enrichment analysis unveiled that neuroinflammation, especially an innate inflammatory response, was significantly evoked by TBI, which could be attenuated by the inhibition of HIF-1α. Furthermore, the inhibition of HIF-1α could mitigate the activation of microglia and astrocytes. Taken together, all these data implied that HIF-1α might contribute to secondary brain injury through regulating neuroinflammation.

Effects of Sevoflurane and Propofol on Neurological Recovery of Traumatic Brain Injury Patients in the Early Postoperative Stage: A Retrospective Cohort Study.

Objective To investigate the effects of propofol and sevoflurane on neurological recovery of traumatic brain injury (TBI) patients in the early postoperative stage.Methods We retrospectively analyzed the clinical data of TBI patients who underwent craniotomy or decompressive craniectomy. Generalized additive mixed model (GAMM) was used to analyze effects of propofol and sevoflurane on Glasgow Coma Scale (GCS) on postoperative days 1, 3, and 7. Multivariate regression analysis was used to analyze effects of the two anesthetics on Glasgow Outcome Scale (GOS) at discharge.Results A total of 340 TBI patients were enrolled in this study. There were 110 TBI patients who underwent craniotomy including 75 in the propofol group and 35 in the sevoflurane group, and 134 patients who underwent decompressive craniectomy including 63 in the propofol group and 71 in the sevoflurane group. It showed no significant difference in GCS at admission between the propofol and the sevoflurane groups among craniotomy patients (ß = 0.75, 95%CI: -0.55 to 2.05, P = 0.260). However, elevation in GCS from baseline was 1.73 points (95%CI: -2.81 to -0.66, P = 0.002) less in the sevoflurane group than that in the propofol group on postoperative day 1, 2.03 points (95%CI: -3.14 to -0.91, P < 0.001) less on day 3, and 1.31 points (95%CI: -2.43 to -0.19, P = 0.022) less on day 7. The risk of unfavorable GOS (GOS 1, 2, and 3) at discharge was higher in the sevoflurane group (OR = 4.93, 95%CI: 1.05 to 23.03, P = 0.043). No significant difference was observed among two-group decompressive craniectomy patients in GCS and GOS.Conclusions Compared to propofol, sevoflurane was associated with worse neurological recovery during the hospital stay in TBI patients undergoing craniotomy. This difference was not detected in TBI patients undergoing decompressive craniectomy.

Tandem Mass Tag-based proteomics analysis reveals the vital role of inflammation in traumatic brain injury in a mouse model.

Proteomics is a powerful tool that can be used to elucidate the underlying mechanisms of diseases and identify new biomarkers. Therefore, it may also be helpful for understanding the detailed pathological mechanism of traumatic brain injury (TBI). In this study, we performed Tandem Mass Tag-based quantitative analysis of cortical proteome profiles in a mouse model of TBI. Our results showed that there were 302 differentially expressed proteins in TBI mice compared with normal mice 7 days after injury. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that these differentially expressed proteins were predominantly involved in inflammatory responses, including complement and coagulation cascades, as well as chemokine signaling pathways. Subsequent transcription factor analysis revealed that the inflammation-related transcription factors NF-κB1, RelA, IRF1, STAT1, and Spi1 play pivotal roles in the secondary injury that occurs after TBI, which further corroborates the functional enrichment for inflammatory factors. Our results suggest that inflammation-related proteins and inflammatory responses are promising targets for the treatment of TBI.

Neutrophil-derived interleukin-17A participates in neuroinflammation induced by traumatic brain injury.

After brain injury, infiltration and abnormal activation of neutrophils damages brain tissue and worsens inflammation, but the mediators that connect activated neutrophils with neuroinflammation have not yet been fully clarified. To identify regulators of neutrophil-mediated neuroinflammation after traumatic brain injury, a mouse model of traumatic brain injury was established by controlled cortical impact. At 7 days post-injury (sub-acute phase), genome-wide transcriptomic data showed that interleukin 17A-associated signaling pathways were markedly upregulated, suggesting that interleukin 17A may be involved in neuroinflammation. Double immunofluorescence staining showed that interleukin 17A was largely secreted by neutrophils rather than by glial cells and neurons. Furthermore, nuclear factor-kappaB and Stat3, both of which are important effectors in interleukin 17A-mediated proinflammatory responses, were significantly activated. Collectively, our findings suggest that neutrophil-derived interleukin 17A participates in neutrophil-mediated neuroinflammation during the subacute phase of traumatic brain injury. Therefore, interleukin 17A may be a promising therapeutic target for traumatic brain injury.

Contralateral synaptic changes following severe unilateral brain injury.

The brain is highly integrated and thus unilateral injury can impact the contralateral hemisphere. However, further research is needed to clarify the changes in the response of the contralateral homotopic area to ipsilateral injury. We hypothesized that severe unilateral brain injury would be accompanied by contralateral synaptic changes that are related to functional recovery. To test this, we divided rats into sham and experimental groups. In the experimental group, we performed right motor cortex resection. These rats were further divided into three subgroups according to post-injury time: 7 days, 14 days, and 30 days post-injury. Rats in each group were evaluated using a beam walking test to quantify the recovery of motor function, and all rats received an injection of adeno-associated virus-containing green fluorescent protein (GFP). Finally, we conducted morphological and histological analyses to identify synaptic changes. Over time, the behavior of the rats that underwent right motor cortex resection recovered. Furthermore, in contrast to the sham group, the experimental groups exhibited an increase in the spine density and expression of synaptic proteins in layer V of the contralateral motor cortex, which was consistent with the GFP-labeled neurons. Moreover, more immature spines were observed 7 days post-injury. Notably, spine morphology matured from 7 to 30 days, and the increase in Synapsin-1 intensity in layer V peaked 14 days after the resection, whereas PSD-95 intensity continued to increase until day 30. Our findings suggested that following motor function recovery from unilateral brain injury, spine morphology and synaptic proteins change dynamically in the contralateral hemisphere.

Genome-wide interrogation of transfer RNA-derived small RNAs in a mouse model of traumatic brain injury.

Transfer RNA (tRNA)-derived small RNAs (tsRNAs) are a recently established family of regulatory small non-coding RNAs that modulate diverse biological processes. Growing evidence indicates that tsRNAs are involved in neurological disorders and play a role in the pathogenesis of neurodegenerative disease. However, whether tsRNAs are involved in traumatic brain injury-induced secondary injury remains poorly understood. In this study, a mouse controlled cortical impact model of traumatic brain injury was established, and integrated tsRNA and messenger RNA (mRNA) transcriptome sequencing were used. The results revealed that 103 tsRNAs were differentially expressed in the mouse model of traumatic brain injury at 72 hours, of which 56 tsRNAs were upregulated and 47 tsRNAs were downregulated. Based on microRNA-like seed matching and Pearson correlation analysis, 57 differentially expressed tsRNA-mRNA interaction pairs were identified, including 29 tsRNAs and 26 mRNAs. Moreover, Gene Ontology annotation of target genes revealed that the significantly enriched terms were primarily associated with inflammation and synaptic function. Collectively, our findings suggest that tsRNAs may be associated with traumatic brain injury-induced secondary brain injury, and are thus a potential therapeutic target for traumatic brain injury. The study was approved by the Beijing Neurosurgical Institute Animal Care and Use Committee (approval No. 20190411) on April 11, 2019.

The Dual Dose-Dependent Effects of Corticosterone on Hippocampal Cell Apoptosis After Traumatic Brain Injury Depend on the Activation Ratio of Mineralocorticoid Receptors to Glucocorticoid Receptors.

In our recent studies, we reported that mineralocorticoid receptor (MR) had the opposite effects of glucocorticoid receptor (GR) on neural cell survival after traumatic brain injury (TBI). However, whether short-term use of high-dose natural glucocorticoids, which are mixed agonists of both MR and GR, leads to neurotoxic effects by inducing excessive GR activation is unclear, as is the threshold GR activation level and the possible signaling pathways remain unclear. In this study, we examined the dual dose-dependent effects of corticosterone (CORT) on spatial memory, hippocampal cell survival and receptor-mediated downstream signaling pathways after TBI. We found that different doses of CORT exhibited dual effects on hippocampal cell survival and rat spatial memory. Low doses of CORT (0.3 and 3 mg/kg) significantly increased MR activation, upregulated Akt/CREB/Bad phosphorylation and Bcl-2 concentration, reduced the number of apoptotic neural cells, and subsequently improved rat spatial memory. In contrast, a high dose of CORT (30 mg/kg) exerted the opposite effects by overactivating GR, upregulating P53/Bax levels, and inhibiting Erk/CREB activity. The results suggest that the neuroprotective and neurotoxic effects of endogenous GC depend on a threshold level and that a higher dose of GC, even for short-term use, should be avoided after TBI.

Protein profiling identified mitochondrial dysfunction and synaptic abnormalities after dexamethasone intervention in rats with traumatic brain injury.

Dexamethasone has been widely used after various neurosurgical procedures due to its anti-inflammatory property and the abilities to restore vascular permeability, inhibit free radicals, and reduce cerebrospinal fluid production. According to the latest guidelines for the treatment of traumatic brain injury in the United States, high-dose glucocorticoids cause neurological damage. To investigate the reason why high-dose glucocorticoids after traumatic brain injury exhibit harmful effect, rat controlled cortical impact models of traumatic brain injury were established. At 1 hour and 2 days after surgery, rat models were intraperitoneally administered dexamethasone 10 mg/kg. The results revealed that 31 proteins were significantly upregulated and 12 proteins were significantly downregulated in rat models of traumatic brain injury after dexamethasone treatment. The Ingenuity Pathway Analysis results showed that differentially expressed proteins were enriched in the mitochondrial dysfunction pathway and synaptogenesis signaling pathway. Western blot analysis and immunohistochemistry results showed that Ndufv2, Maob and Gria3 expression and positive cell count in the dexamethasone-treated group were significantly greater than those in the model group. These findings suggest that dexamethasone may promote a compensatory increase in complex I subunits (Ndufs2 and Ndufv2), increase the expression of mitochondrial enzyme Maob, and upregulate synaptic-transmission-related protein Gria3. These changes may be caused by nerve injury after traumatic brain injury treatment by dexamethasone. The study was approved by Institutional Ethics Committee of Beijing Neurosurgical Institute (approval No. 201802001) on June 6, 2018.

Astaxanthin provides neuroprotection in an experimental model of traumatic brain injury via the Nrf2/HO-1 pathway.

BACKGROUND: Astaxanthin (ATX) is a carotenoid pigment with effective antioxidant, anti-inflammatory, antitumor and immunomodulatory actions. ATX has been proposed to exert neuroprotective effects and attenuate oxidative stress in mice after traumatic brain injury (TBI). The nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase 1 (HO-1) signaling pathway is stimulated after TBI and activates a compensatory mechanism against TBI. Nevertheless, the effect of ATX on the pathophysiology of TBI in mice is limited. Our present study evaluated the neuroprotection afforded by ATX and the possible role of the Nrf2/HO-1 pathway in experimental TBI. MATERIALS AND METHODS: Mice were casually separated into 3 groups: the sham, TBI + vehicle, and TBI + ATX (100 mg/kg, intraperitoneally administered) groups. Neurobehaviors of the mice were assessed using the neurological severity scores (NSSs), the forced swimming test (FST) and the rotarod test. Levels of the Nrf2, HO-1, NAD(P)H: quinine oxidoreductase-1 (NQO1), cleaved caspase3 (C-caspase3), and superoxide dismutase1 (SOD1) proteins and levels of the Nrf2 and HO-1 mRNAs were assessed. In addition, Nrf2 nuclear import and apoptosis were measured after TBI. RESULTS: The ATX treatment significantly improved the neurological status, promoted Nrf2 activation, and upregulated the expression of the Nrf2 and HO-1 mRNAs and the levels of the Nrf2, HO-1, and NQO1 proteins after TBI. The level of the SOD1 protein was decreased after TBI and increased after ATX treatment; however, the difference was not significant. ATX markedly reduced the level of the C-caspase3 protein and the number of TUNEL-positive cells, indicating that it exerted an antiapoptotic effect. Immunofluorescence staining confirmed that ATX promoted Nrf2 nuclear import. CONCLUSIONS: Based on our study, ATX possibly affords neuroprotection by activating the Nrf2/HO-1 signaling pathway in mice after TBI.

Prognostic Analysis of Emergency Decompressive Craniectomy for Patients with Severe Traumatic Brain Injury with Bilateral Fixed Dilated Pupils.

OBJECTIVE: For patients with severe traumatic brain injury (sTBI) with bilateral fixed dilated pupils (BFDP), the value of aggressively decompressive craniectomy (DC) treatment is still controversial. The objective of this study was to analyze and validate the outcome of DC in patients with sTBI with BFDP. METHODS: We retrospectively collected data from 44 patients with sTBI with BFDP who underwent DC treatment from July 2011 to June 2018. Outcomes used as indicators were mortality and favorable outcome. The analysis was based on the Glasgow Outcome Scale score recorded at discharge, 6, and 12 months after trauma. RESULTS: The overall survival was 36.4% (16/44) at discharge and 25.0% (11/44) at 6 and 12 months, and the favorable outcome (Glasgow Outcome Scale score = 4-5) at discharge, 6, and 12 months after injury was 9.1% (4/44), 13.6% (6/44), and 20.5% (9/44), respectively. Sex (P = 0.046), preoperative Glasgow Coma Scale (GCS) score (P = 0.031), injury-surgery intervals (P = 0.022), and tracheotomy (P = 0.017) were independent associations to 6 and 12 months follow-up survival, whereas only preoperative GCS score (odds ratio, 6.088; confidence interval, 1.172-31.612; P = 0.032) and injury-surgery intervals (odds ratio, 0.241; confidence interval, 0.065-0.893; P = 0.033) were independent associations with 12 months follow-up favorable outcome. CONCLUSIONS: BFDP indicates a grave prognostic sign after sTBI, but the higher preoperative GCS score and shorter injury-surgery intervals in patients who underwent DC treatment might independently predict favorable outcome for patients with sTBI with BFDP, and patients might benefit more than expected if the DC treatment were applied more aggressively and positively.

Glucose metabolism: A link between traumatic brain injury and Alzheimer's disease.

Traumatic brain injury (TBI), a growing public health problem, is a leading cause of death and disability worldwide, although its prevention measures and clinical cares are substantially improved. Increasing evidence shows that TBI may increase the risk of mood disorders and neurodegenerative diseases, including Alzheimer's disease (AD). However, the complex relationship between TBI and AD remains elusive. Metabolic dysfunction has been the common pathology in both TBI and AD. On the one hand, TBI perturbs the glucose metabolism of the brain, and causes energy crisis and subsequent hyperglycolysis. On the other hand, glucose deprivation promotes amyloidogenesis via ß-site APP cleaving enzyme-1 dependent mechanism, and triggers tau pathology and synaptic function. Recent findings suggest that TBI might facilitate Alzheimer's pathogenesis by altering metabolism, which provides clues to metabolic link between TBI and AD. In this review, we will explore how TBI-induced metabolic changes contribute to the development of AD.

Corticosterone Replacement Alleviates Hippocampal Neuronal Apoptosis and Spatial Memory Impairment Induced by Dexamethasone via Promoting Brain Corticosteroid Receptor Rebalance after Traumatic Brain Injury.

The balance of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) is indispensable for maintaining the normal function and structure of the hippocampus. However, changes in GR/MR and their effect on the survival of hippocampal neurons after traumatic brain injury (TBI) are still unclear. Previous studies have indicated that high-dose glucocorticoids (GC) aggravate hippocampal neuronal damage after TBI. We hypothesize that the imbalance of GR/MR expression and activation caused by injury and irrational use of dexamethasone (DEX) aggravates post-traumatic hippocampal apoptosis and spatial memory dysfunction, but that restoration by refilling MR and inhibiting GR promotes the survival of neurons. Using rat controlled cortical impact model, we examined the plasma corticosterone (CORT), corticosteroid receptor expression, apoptosis, and cell loss in the hippocampus, and, accordingly, the spatial memory after TBI and GC treatment within 7 days. Plasma CORT, MR, and GR expression level were significantly reduced at 2 days after TBI. Accordingly, the number of apoptotic cells also peaked at 2 days. Compared with the TBI control group, DEX treatment (5 mg/kg) significantly reduced plasma CORT, upregulated GR expression, and increased the number of apoptotic cells and cell loss, whereas CORT replacement (0.3 mg/kg) upregulated MR expression, inhibited apoptosis, and improved spatial memory. The deleterious and protective effects of DEX and CORT were counteracted by spironolactone and mifepristone respectively. The results suggest that inhibition of GR by RU486 or the refilling of MR by CORT protects hippocampal neurons and alleviates spatial memory impairment via promoting GR/MR rebalancing after TBI.

An Exhaustive Drainage Strategy in Burr-hole Craniostomy for Chronic Subdural Hematoma.

OBJECTIVE: To introduce an effective strategy to treat patients with chronic subdural hematoma (CSDH) that can achieve a low recurrence rate and good outcome. METHODS: Surgical patients with CSDH from August 2011 to May 2017 in our hospital were collected retrospectively. An exhaustive drainage strategy to treat CSDH with burr-hole craniostomy was conducted. All patients were drained, and catheter was removed when natural drainage ceased or when drainage was complete using urokinase. Clinical characteristics were reviewed and analyzed. Following this strategy, predictors of recurrence requiring reoperation and outcome were analyzed. RESULTS: In total, 1126 patients with CSDH who were treated with burr-hole craniostomy were included. Using the exhaustive drainage strategy, recurrence rate was only 1.9% (21/1117) with follow-up rate of 99.2%. 97.0% (1092/1117) of patients gained good outcome (modified Rankin scale scores 0-3) at 6 months after discharge. Postoperative hematoma volume (P = 0.001, B = 0.028, Exp (B) = 1.028, 95% CI 1.011-1.046), diabetes (P = 0.022, B = 1.082, Exp (B) = 2.950, 95% CI 1.169-7.440), bilateral hematoma (P = 0.011, B = 1.213, Exp (B) = 3.363, 95% CI 1.323-8.547), and complications (P = 0.013, B = 1.483, Exp (B) = 4.408, 95% CI 1.365-14.235) significantly increased the probability of recurrence. In contrast, use of urokinase (P = 0.007, B = -1.435, Exp (B) = 0.238, 95% CI 0.085-0.671) reduced recurrence. Finally, age (P = 0.026, B = 0.056, Exp (B) = 1.057, 95% CI 1.007-1.110), complications (P < 0.001, B = 1.710, Exp (B) = 5.529, 95% CI 2.104-14.531), and Bender grade (P < 0.001, B = 1.165, Exp (B) = 3.205, 95% CI 1.325-7.750) were significant predictors of outcome. CONCLUSIONS: The exhaustive drainage strategy is safe and effective for reducing recurrence rate and achieving good outcome in patients with CSDH. This procedure merits recommendation in clinical practice.

A comparative study of chronic subdural hematoma in three age ranges: Below 40 years, 41-79 years, and 80 years and older.

OBJECTIVE: To investigate clinical characteristics and outcomes of chronic subdural hematomas (CSDHs) in different age ranges. PATIENTS AND METHODS: A retrospective collection of data from CSDH patients ≤40 years, 41-79 years, and ≥80 years of age between August 2011 and May 2017 was performed. The differences and similarities of clinical data and outcomes among three groups were analyzed. RESULTS: A total of 1118 CSDH patients were included. We found that 64.5% patients had arachnoid cyst/ventriculoperitoneal shunt in patients ≤40 years, 4.3% in the 41-79 years group, and 3.2% in the ≥80 years group (P < 0.001). Headache was the most frequent symptom in the ≤40 years group (88.2%) and the 41-79 years group (60.9%), while the most frequent symptom in the ≥ 80 years group was limb weakness (80.4%). The history of head trauma was not significantly different between the three groups. After burr hole drainage craniostomy, the disappearance or alleviation of symptoms, duration of catheter drainage, and length of hospital stay were not significantly different, while the recurrence rate was also not significantly different between the three groups. Post-operation complications are an independent risk factor contributing to the death of patients of 41-79 years (P < 0.001, B = 3.140, Exp (B) = 23.103, 95% CI = 5.142-103.809) and of ≥ 80 years (P = 0.001, B=2.831, Exp (B) = 16.970, 95% CI = 3.365-85.567). The history of antithrombotic drug was an independent risk factor of complications in patients of 41-79 years (P = 0.042, B =1.341, Exp (B) =3.823, 95% CI = 1.048-13.942) and patients of ≥ 80 years (P = 0.026, B=1.399, Exp (B) = 4.052, 95% CI = 1.178-13.933), while complications were also an independent risk factor contributing to the outcome in patients of 41-79 years (P < 0.001, B =2.254, Exp (B) =0.314, 95% CI = 0.089-1.103) and patients of ≥ 80 years (P = 0.006, B=2.074, Exp (B) = 7.953, 95% CI = 1.791-35.313). In the ≤40 years group, all patients had a good outcome (MRS score 0-3), while 98.2% (851/867) of the cases in the 41-79 years group and 94.3% (149/158) of the cases in the ≥ 80 years group saw a good outcome (P = 0.001). CONCLUSIONS: Our results clearly display the common and different clinical data of CSDH in all age ranges, which is crucial to improve the management and treatment of patients with CSDH.

The Clinical Characteristics, Treatment, and Outcomes of Chronic Subdural Hematoma in Young Patients.

OBJECTIVE: To investigate the clinical characteristics, treatment, and outcomes of chronic subdural hematomas (CSDH) in young patients. METHODS: We retrospectively reviewed young patients under 40 years of age who received diagnoses of and were surgically treated for CSDH between August 2011 and May 2017. Clinical data, computed tomographic findings, surgical outcomes, and recurrence were collected for further analysis. RESULTS: A total of 101 patients (92 male; 91.1%) were analyzed. Ages ranged from 1 to 40 years (27.3 ± 10.5), and 59 (58.4%) patients had a history of recent head trauma. The most frequent symptoms were headache (86.1%) and dizziness (26.7%). A total of 60 (59.4%) patients had arachnoid cyst (AC), and 8 (7.9%) patients had ventriculoperitoneal (V-P) shunt. After burr hole drainage craniotomy, all patients experienced good outcomes, and 1 patient experienced recurrence requiring reoperation. Sixty-eight patients with AC/V-P shunts had a higher incidence of head trauma (P = 0.014), younger age at onset (P < 0.001), and lower incidence of dizziness (P = 0.013) than did those without AC/V-P shunts. Surgical recurrence rates and outcomes did not differ significantly between patients with and without AC/V-P shunts. CONCLUSIONS: Headache is the most common symptom, and AC/V-P shunts are risk factors of CSDH in young patients. AC/V-P shunt-associated CSDH is associated with younger morbidity. Head trauma is a risk factor for AC/V-P shunt-associated CSDH, but is not significance in patients without AC/V-P shunts. Catheter drainage through a burr hole may be the first-choice surgical procedure in treatment of CSDH in young patients, including AC/V-P shunt-associated CSDH.

Prognostic Predictors of Early Outcomes and Discharge Status of Patients Undergoing Decompressive Craniectomy After Severe Traumatic Brain Injury.

OBJECTIVE: Although several prognostic factors for traumatic brain injury (TBI) have been evaluated, a useful predictive scoring model for the outcomes has not been developed for patients with severe TBI who undergo decompressive craniectomy (DC). The aim of the present study was to determine independent predictors and develop a multivariate logistic regression equation to predict the early outcome and discharge status for patients with severe TBI who have undergone DC. METHODS: A total of 13 different variables were evaluated. The data from all 278 patients with severe TBI who had undergone DC in the present study were retrospectively evaluated from July 2011 to June 2017. Using univariate, multiple logistic regression and prognostic regression scoring equations it was possible to draw receiver operating characteristic curves to predict the early outcomes and discharge status after TBI. RESULTS: We found that younger age (P = 0.012), no significant medical history (P = 0.044), diameter of both pupils <4 mm (P = 0.032), higher admission Glasgow coma scale score (P = 0.004), no tracheotomy (P < 0.001), and DC for severe TBI were associated with a favorable early outcome and discharge status. Using receiver operating characteristic curves to predict the probability of a favorable outcome, the sensitivity was 80.0% and the specificity was 79.5%. CONCLUSIONS: Our preliminary findings have shown that 5 variables can be used as independent predictors in assessing the early outcome and discharge status for patients with severe TBI after DC.

Mitochondrial Division Inhibitor 1 Prevents Early-Stage Induction of Mitophagy and Accelerated Cell Death in a Rat Model of Moderate Controlled Cortical Impact Brain Injury.

BACKGROUND: Increasing evidence has implicated dysfunctional mitochondria in the pathophysiology of neurodegenerative disorders. Selective degradation of dysfunctional mitochondria has been termed mitophagy and constitutes a pivotal component of mitochondrial quality control to maintain cellular homeostasis. Mitochondrial fission plays a prominent role in controlling mitochondrial shape and function. However, it is unclear whether mitochondrial fission in the context of eliminating damaged mitochondria is involved in traumatic brain injury (TBI). We examined the role of mitochondrial division inhibitor 1 (Mdivi1), a small-molecule inhibitor of dynamin-related protein (Drp1), in general autophagy and mitophagy after controlled cortical impact (CCI). METHODS: Mitophagy and the role of Drp1 in this process after CCI were examined using Western blotting, electron microscopy, double immunofluorescence staining, neurological severity scores, and hematoxylin and eosin staining. Statistical analysis was performed using 1-way analysis of variance, followed by the least significant difference test or the Games-Howell test. RESULTS: The rats exposed to CCI exhibited induction of mitophagy and fragmentation of mitochondria. When fission was blocked with Mdivi1, the mitochondria became excessively long and interconnected. Inhibition of Drp1 blocked the induction of mitophagy specifically, which aggravated neurological manifestations and neuronal apoptosis. Mdivi1 activated caspase-3 and caspase-9, implying that selective degradation of damaged mitochondria by autophagy markedly decreased cell apoptosis induced by TBI and, thus, promoted cell survival. CONCLUSIONS: The findings from the present study support the hypothesis that Drp1-dependent mitochondrial fission contributes to mitophagy in TBI, and further understanding of the regulatory mechanisms of Drp1 will provide opportunities to develop novel strategies against TBI.

Decompressive craniectomy protects against hippocampal edema and behavioral deficits at an early stage of a moderately controlled cortical impact brain injury model in adult male rats.

A decompressive craniectomy (DC) has been shown to be a life-saving therapeutic treatment for traumatic brain injury (TBI) patients, which also might result in post-operative behavioral dysfunction. However, there is still no definite conclusion about whether the behavioral dysfunction already existed at an early stage after the DC operation or is just a long-term post-operation complication. Therefore, the aim of the present study was to analyze whether DC treatment was beneficial to behavioral function at an early stage post TBI. In this study, we established a controlled cortical impact injury rat model to evaluate the therapeutic effect of DC treatment on behavioral deficits at 1 d, 2 d, 3 d and 7 d after TBI. Our results showed that rats suffered significant behavioral and mood deficits after TBI compared to the control group, while decompressive craniectomy treatment could normalize MMP-9 expression levels and reduce hippocampal edema formation, stabilize the expression of Synapsin I, which was a potential indicator of maintaining the hippocampal synaptic function, thus counteracting behavioral but not mood decay in rats subjected to TBI. In conclusion, decompressive craniectomy, excepting for its life-saving effect, could also play a potential beneficial neuroprotective role on behavioral but not mood deficits at an early stage of moderate traumatic brain injury in rats.

Clinical Features, Treatment, and Prognostic Factors of 56 Intracranial and Intraspinal Clear Cell Meningiomas.

OBJECTIVE: Intracranial and intraspinal clear cell meningiomas (CCMs) are rarely reported because of their extremely low incidence, and the current understanding of CCM is poor. The purpose of this study was to analyze the incidence and the clinical, radiologic, pathologic, and prognostic features of intracranial and intraspinal CCMs. METHODS: Among 14,310 cases of intracranial and intraspinal meningiomas that were surgically treated between 2006 and 2016 at Beijing Tian Tan Hospital, 56 were chosen for analysis and retrospectively reviewed. To determine which parameters were associated with longer progression-free survival (PFS) and overall survival (OS), statistical analysis was performed. RESULTS: CCMs accounted for approximately 0.39% of all intracranial and intraspinal meningiomas. Patients with CCM had a mean age of 32.3 years and there was a female predilection (20 males and 36 females). Gross total resection was achieved in 35 cases, and subtotal resection was achieved in 21 cases. All patients were followed up for 10-206 months after surgery. Twenty-six patients experienced tumor recurrence, and the median PFS was 48.0 months. The 1-year, 3-year, and 5-year PFS was 87.5%, 59.8%, and 41.8%, respectively. Twelve patients died of tumor recurrence, and the median OS was not available. The 1-year, 3-year, and 5-year OS was 98.2%, 91.3%, and 65.8%, respectively. Univariate analysis showed that total tumor removal was significantly associated with a better prognosis. Multivariate analysis confirmed only Simpson grade III and IV resection as an independent risk factor for shorter PFS. Radiotherapy mildly improved PFS after both gross total resection and subtotal resection, showing no significant difference because of the small sample size and short follow-up duration. CONCLUSIONS: CCM is a rare subtype of World Health Organization grade II meningioma. CCM typically involves young patients and shows a female predilection and high recurrence rate. When possible, total resection is the primary and most suitable treatment for CCM. For patients with primary tumors, radiotherapy is recommended after the initial operation regardless of the extent of resection. For patients with disease recurrence, secondary surgery combined with radiotherapy might serve as an effective treatment.