Astrocytic LRP1 enables mitochondria transfer to neurons and mitigates brain ischemic stroke by suppressing ARF1 lactylation.

Low-density lipoprotein receptor-related protein-1 (LRP1) is an endocytic/signaling cell-surface receptor that regulates diverse cellular functions, including cell survival, differentiation, and proliferation. LRP1 has been previously implicated in the pathogenesis of neurodegenerative disorders, but there are inconsistencies in its functions. Therefore, whether and how LRP1 maintains brain homeostasis remains to be clarified. Here, we report that astrocytic LRP1 promotes astrocyte-to-neuron mitochondria transfer by reducing lactate production and ADP-ribosylation factor 1 (ARF1) lactylation. In astrocytes, LRP1 suppressed glucose uptake, glycolysis, and lactate production, leading to reduced lactylation of ARF1. Suppression of astrocytic LRP1 reduced mitochondria transfer into damaged neurons and worsened ischemia-reperfusion injury in a mouse model of ischemic stroke. Furthermore, we examined lactate levels in human patients with stroke. Cerebrospinal fluid (CSF) lactate was elevated in stroke patients and inversely correlated with astrocytic mitochondria. These findings reveal a protective role of LRP1 in brain ischemic stroke by enabling mitochondria-mediated astrocyte-neuron crosstalk.

Microglia aggravate white matter injury via C3/C3aR pathway after experimental subarachnoid hemorrhage.

The activation of glial cells is intimately associated with the pathophysiology of neuroinflammation and white matter injury (WMI) during both acute and chronic phases following subarachnoid hemorrhage (SAH). The complement C3a receptor (C3aR) has a dual role in modulating inflammation and contributes to neurodevelopment, neuroplasticity, and neurodegeneration. However, its impact on WMI in the context of SAH remains unclear. In this study, 175 male C57BL/6J mice underwent SAH through endovascular perforation. Oxyhemoglobin (oxy-Hb) was employed to simulate SAH in vitro. A suite of techniques, including immunohistochemistry, transcriptomic sequencing, and a range of molecular biotechnologies, were utilized to evaluate the activation of the C3-C3aR pathway on microglial polarization and WMI. Results revealed that post-SAH abnormal activation of microglia was accompanied by upregulation of complement C3 and C3aR. The inhibition of C3aR decreased abnormal microglial activation, attenuated neuroinflammation, and ameliorated WMI and cognitive deficits following SAH. RNA-Seq indicated that C3aR inhibition downregulated several immune and inflammatory pathways and mitigated cellular injury by reducing p53-induced death domain protein 1 (Pidd1) and Protein kinase RNA-like ER kinase (Perk) expression, two factors mainly function in sensing and responding to cellular stress and endoplasmic reticulum (ER) stress. The deleterious effects of the C3-C3aR axis in the context of SAH may be related to endoplasmic reticulum (ER) stress-dependent cellular injury and inflammasome formation. Agonists of Perk can exacerbate the cellular injury and neuroinflammation, which was attenuated by C3aR inhibition after SAH. Additionally, intranasal administration of C3a during the subacute phase of SAH was found to decrease astrocyte reactivity and alleviate cognitive deficits post-SAH. This research deepens our understanding of the complex pathophysiology of WMI following SAH and underscores the therapeutic potential of C3a treatment in promoting white matter repair and enhancing functional recovery prognosis. These insights pave the way for future clinical application of C3a-based therapies, promising significant benefits in the treatment of SAH and its related complications.

Lightweight interactive feature inference network for single-image super-resolution.

The emergence of convolutional neural network (CNN) and transformer has recently facilitated significant advances in image super-resolution (SR) tasks. However, these networks commonly construct complex structures, having huge model parameters and high computational costs, to boost reconstruction performance. In addition, they do not consider the structural prior well, which is not conducive to high-quality image reconstruction. In this work, we devise a lightweight interactive feature inference network (IFIN), complementing the strengths of CNN and Transformer, for effective image SR reconstruction. Specifically, the interactive feature aggregation module (IFAM), implemented by structure-aware attention block (SAAB), Swin Transformer block (SWTB), and enhanced spatial adaptive block (ESAB), serves as the network backbone, progressively extracts more dedicated features to facilitate the reconstruction of high-frequency details in the image. SAAB adaptively recalibrates local salient structural information, and SWTB effectively captures rich global information. Further, ESAB synergetically complements local and global priors to ensure the consistent fusion of diverse features, achieving high-quality reconstruction of images. Comprehensive experiments reveal that our proposed networks attain state-of-the-art reconstruction accuracy on benchmark datasets while maintaining low computational demands. Our code and results are available at: https://github.com/wwaannggllii/IFIN .

Advanced diffusion tensor imaging in white matter injury after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is recognized as an especially severe stroke variant, notorious for its high mortality and long-term disability rates, in addition to a range of both immediate and enduring neurological impacts. Over half of the SAH survivors experience varying degrees of neurological disorders, with many enduring chronic neuropsychiatric conditions. Due to the limitations of traditional imaging techniques in depicting subtle changes within brain tissues post-hemorrhage, the accurate detection and diagnosis of white matter (WM) injuries are complicated. Against this backdrop, Diffusion Tensor Imaging (DTI) has emerged as a promising biomarker for structural imaging, renowned for its enhanced sensitivity in identifying axonal damage. This capability positions DTI as an invaluable tool for forming precise and expedient prognoses for SAH survivors. This study synthesizes an assessment of DTI for the diagnosis and prognosis of neurological dysfunctions in patients with SAH, emphasizing the notable changes observed in DTI metrics and their association with potential pathophysiological processes. Despite challenges associated with scanning technology differences and data processing, DTI demonstrates significant clinical potential for early diagnosis of cognitive impairments following SAH and monitoring therapeutic effects. Future research requires the development of highly standardized imaging paradigms to enhance diagnostic accuracy and devise targeted therapeutic strategies for SAH patients. In sum, DTI technology not only augments our understanding of the impact of SAH but also may offer new avenues for improving patient prognoses.

Endothelial mesenchymal transition promotes pannus formation in ankylosing spondylitis by activation of TGF-ß/SMAD signalling pathway.

OBJECTIVES: To explore the role of endothelial-mesenchymal transition (EndMT) mediated by the TGF-ß/SMAD signalling pathway in the pathogenesis of ankylosing spondylitis (AS). METHODS: Serum levels of TGF-ß1 were measured by enzyme-linked immunosorbent assay (ELISA) in 48 patients with AS and 15 healthy subjects. The expression levels of TGF-ß1, SMAD7, CTGF, CD34 and EndMT-related markers (α-SMA, vimentin, FSP-1, VE-cadherin) in the sacroiliac joint (SIJ) of three AS patients were detected by immunohistochemistry, and three non-spondyloarthritis (SpA) autopsy samples were used as controls. RESULTS: Serum TGF-ß1 level of AS patients was significantly higher than that of healthy controls (22971 ± 7667 pg/ml vs. 14837±4653 pg/ml, p<0.01). Compared with the non-SpA control group, the microvascular density (MVD) at the pannus formation site of SIJ in AS patients was significantly increased, accompanied by respectively increased expressions of TGF-ß1, CTGF, α-SMA, vimentin, and FSP-1 (all p<0.05), whereas respectively decreased expressions of VE-cadherin and SMAD7 (p<0.01). The expression level of FSP-1 was positively correlated with levels of TGF-ß1 and MVD, and negatively correlated with SMAD7. CONCLUSIONS: Our findings show that EndMT is involved in the promotion of pannus formation by TGF-ß/SMAD signalling pathway activation in AS.

Altered dynamic functional network connectivity in rheumatoid arthritis associated with peripheral inflammation and neuropsychiatric disorders.

OBJECTIVE: This study explored the dynamic functional connective (DFC) alterations in patients with rheumatoid arthritis (RA) and investigated the correlation between the neuropsychiatric symptoms, peripheral inflammation and DFC alterations. METHOD: Using resting-state functional MRI, we investigated the DFC based on spatial independent component analysis and sliding window method for 30 patients with RA and 30 healthy controls (HCs). The Spearman correlation was calculated between aberrant DFC alterations, Montreal Cognitive Assessment (MoCA), Hospital Anxiety and Depression Scale (HAD), C reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Diagnostic efficacy of indicators was assessed using receiver operating characteristic analysis (ROC). RESULTS: Three dynamic functional states were identified. Compared with HC, patients with RA showed reduced FC variabilities between sensorimotor network (SMN) and insula, SMN and orbitofrontal cortex, which were the crucial regions of sensory processing network. The above FC variabilities were correlated with the MoCA, HAD, CRP and ESR in patients with RA. Additionally, the CRP and ESR were negatively correlated to MoCA and positively related to HAD in patients with RA. The ROC analysis results showed that MoCA, HAD and FC variabilities of the sensory processing network could distinguish patients with RA from HC and also identify patients with RA with high ESR. CONCLUSION: Our findings demonstrated that abnormal DFC patterns in sensory processing networks in patients with RA were closely associated with peripheral inflammation and neuropsychiatric symptoms. This indicates that the dynamic temporal characteristics of the brain functional network may be potential neuroimaging biomarkers for revealing the pathological mechanism of RA.

Predictive Model for Prognosis of Sudden Sensorineural Hearing Loss by Nomogram.

Objective: To explore the prognostic factors of patients with sudden sensorineural hearing loss (SSNHL), analyze the possible influencing factors, and construct a nomogram for personalized evaluation of their prognosis. Methods: A retrospective study was conducted on 269 patients with SSNHL. The prognostic factors were analyzed by univariate analysis and multivariate logistic regression analysis. The nomogram was constructed based on the results of multivariate logistic regression analysis, and the model was verified by receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). Results: Among the 269 patients hospitalized, 136 cases were improved (44 cases were cured, 28 cases were markedly effective, 64 cases were effective) and 133 cases were ineffective. After univariate analysis, it was found that age, duration from onset to treatment, audiometric configuration, serum albumin (ALB), and neutrophil-to-lymphocyte ratio (NLR) were associated with hearing outcomes. Duration from onset to treatment and audiometric configuration were independent risk factors when the treatment outcome was divided into ineffective, effective, significant improvement, and complete recovery groups or divided into improvement and ineffective groups after multivariate logistic regression analysis. The factors according to univariate analysis and multivariate logistic regression analysis results were included in the nomogram to construct the prediction models. The area under the ROC curve of model discrimination was 0.752 [95% confidence interval (CI): 0.695-0.808] when the treatment outcome was divided into 2 groups. The calibration curve showed the consistency of the results, and the DCA prediction curve showed good clinical efficacy. The C-index was 0.756 (95% CI: 0.710-0.802) when the treatment outcome was divided into 4 groups. Conclusion: Age, duration from onset to treatment, audiometric configuration, ALB, and NLR are influencing factors for SSNHL. Duration from onset to treatment and audiometric configuration are independent risk factors for SSNHL. The nomogram presents the prognosis of patients with SSNHL in an intuitive, visual, and readable graph, providing clinicians with a personalized assessment.

Functional dysconnectivity and microstructural impairment of the cortico-thalamo-cortical network in women with rheumatoid arthritis: A multimodal MRI study.

Background: Cognitive deficits are common in rheumatoid arthritis (RA) patients, but the mechanisms remain unclear. We investigated the effective connectivity and structural alterations of the core brain regions in RA patients with cognitive impairment. Methods: Twenty-four female patients with RA and twenty-four healthy controls were enrolled. We analyzed abnormal brain activity patterns using functional MRI during the Iowa gambling task (IGT) and core regions effective connectivity using dynamic causal model (DCM). Structural alterations of white matter volume (WMV) and gray matter volume (GMV) were detected using voxel-based morphometry (VBM). Results: RA patients showed altered activation patterns of the cortico-thalamo-cortical network, increased coupling strength from the left ventromedial prefrontal gyrus to the anterior cingulate cortex (ACC), the ACC to the right thalamus, and decreased connectivity from the thalamus to left hippocampus. VBM structural analysis showed increased GMV in the bilateral orbital frontal gyrus, bilateral hippocampus and right putamen, and reduced GMV and WMV in the bilateral thalamus in RA patients. Right thalamic GMV and WMV were positively correlated with the right thalamus-to-hippocampus connective strength. Additionally, the bold signal, GMV and WMV of the right thalamus were positively correlated with cognitive performance (IGT score) in RA patients. Conclusion: Results suggest a structural and functional deficiency in the cortico-thalamo-cortical network, which is characterized by increased ACC-to-thalamus strength and reduced thalamus-to-hippocampus coupling in RA patients. The cognitive dysfunction may be the result of compensatory measures against imbalanced cortico-thalamic-cortical coupling.

Osteopontin modulates microglial activation states and attenuates inflammatory responses after subarachnoid hemorrhage in rats.

AIMS: Osteopontin (OPN) has demonstrated neuroprotective effects in various stroke models. Its role in neuroinflammation after brain injury remains to be elucidated. This study aims to clarify the effect of OPN on neuroinflammation, particularly on the functional states of microglia after subarachnoid hemorrhage (SAH). METHODS: 77 rats were randomly divided into the following groups: Sham, SAH 24 h, SAH + rOPN, SAH + Vehicle (PBS), SAH + OPN siRNA, and SAH + Scr siRNA, SAH + rOPN+Fib-14 and SAH + rOPN+DMSO. Modified Garcia and beam balance tests were used to evaluate neurobehavioral outcomes. Semi-quantitative immunofluorescence staining was performed to measure expression of myeloperoxidase (MPO) and microglia activation state markers CD16, CD206 after SAH and recombinant OPN treatment. The quantification of microglia activation and functional markers CD16, CD206, TNF-α and IL-10 were further evaluated using Western-blotting. RESULTS: Nasal administration of rOPN improved neurological dysfunction, attenuated neutrophil infiltration, and decreased expression of phenotypic and functional markers of pro-inflammatory microglia CD16 and TNF-α. It also promoted an anti-inflammatory microglial state, as evidenced by increased expression of CD206 and IL-10. Furthermore, after blocking the phosphorylation of FAK signaling, the effects of rOPN on microglial activation states were partially reversed. The downstream pathways of STAT3 and NF-κB also exhibited consistent changes, suggesting the involvement of the STAT3 and NF-κB pathways in OPN's modulation of microglial activation via integrin-FAK signaling. CONCLUSION: OPN attenuates inflammatory responses after SAH by promoting an anti-inflammatory microglial state, potentially mediated through the integrin-FAK-STAT3 and NF-κB signaling pathways.

Tumor Necrosis Factor-Alpha (+489 G/A) Polymorphism Can Predict the Response to Adalimumab in Chinese Han Patients With Ankylosing Spondylitis.

BACKGROUND: Studies investigating the association between single nucleotide polymorphisms (SNPs) of tumor necrosis factor-alpha (TNFα) and the efficacy of adalimumab (ADA) in ankylosing spondylitis (AS) therapy have reported conflicting results. We aimed to investigate the value of SNP typing of TNFα in predicting the efficacy of ADA in AS. MATERIALS AND METHODS: Eighty patients with active AS who received ADA treatment were followed up for 24 weeks. Six known SNPs of TNFα (+489G/A, -238G/A, -308G/A, -857C/T, -863C/A, and -1031C/T) were subjected to the SNaPshot SNP typing method, which has been proven to be a reliable, efficient, and cost-effective method for detecting SNPs. The relationship between each SNP genotype and the therapeutic efficacy of ADA was analyzed. RESULTS: At the end of the 24-week follow-up, 58.8% of the patients with AS achieved Assessment of SpondyloArthritis International Society (ASAS) partial remission (PR), 67.5% of the patients achieved the criteria of an ASAS40 response (40% improvement on indices), and 53.8% of the patients achieved Ankylosing Spondylitis Disease Activity Score (ASDAS) major improvement (MI). The univariate analysis showed that patients with AS carrying the TNFα +489 A allele were more likely to achieve ASAS-PR, ASAS40 response criteria, and ASDAS-MI after ADA treatment. In the multivariate regression analysis, the TNFα +489 A allele was an independent factor influencing the efficacy of ADA in treating AS (ASAS-PR odds ratio (OR) = 2.66, 95% confidence interval (CI) = 1.01-7.01; ASAS40 OR = 4.56, 95% CI = 1.39-15.00; ASDAS-MI OR = 3.31, 95% CI = 1.02-10.69). CONCLUSIONS: The patients carrying the TNFα +489 A allele may be more likely to experience better therapeutic efficacy and achieve the treatment target (ASAS-PR, ASAS40 response, or ASDAS-MI) after receiving ADA treatment. Detection of TNFα +489 G/A may predict the therapeutic efficacy of ADA, which can be used in clinical practice to tailor treatment for individual patients with AS. Further studies with larger sample sizes and longer follow-up periods with imaging evaluation are needed to verify our findings.

Comparison of clinical characteristics between adult-onset and juvenile-onset non-radiographic axial spondyloarthritis in Chinese patients: results from the COCAS cohort.

BACKGROUND: Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease predominantly affecting the axial skeleton. We aimed to describe the clinical characteristics of patients with non-radiographic axSpA (nr-axSpA) in China and compare the differences between adult- and juvenile-onset cases. METHODS: A cross-sectional study was conducted using data from 776 patients with nr-axSpA in the Clinical Characteristic and Outcome in Chinese Axial Spondyloarthritis (COCAS) study cohort. Patients were divided into two groups including the adult-onset group (n = 662) and the juvenile-onset group (n = 114) according to age at disease onset. Baseline demographics and clinical characteristics were compared between patients with adult-onset and juvenile-onset nr-axSpA. RESULTS: Overall, the male-to-female ratio was 1.26:1, the prevalence of HLA-B27 positivity was 72.2%, and the median age at disease onset of nr-axSpA was 22 years. Nearly 75% of nr-axSpA patients had peripheral arthritis in the disease course, and the prevalence of extra-articular manifestations was 10.4%. The juvenile-onset group contained a higher proportion of men (66.7% vs. 53.9%, P = 0.011) and a longer baseline disease duration (4.0 [4.0] vs. 1.6 [3.5], P < 0.001) than the adult-onset group. A family history of spondyloarthritis was more frequent in the juvenile-onset group than in the adult-onset group (23.7% vs. 15.4%, P = 0.028), but no significant difference in the prevalence of HLA-B27 positivity was observed between the two groups (P = 0.537). Regarding initial symptoms, peripheral arthritis occurred more often in patients with juvenile-onset nr-axSpA, whereas patients with adult-onset nr-axSpA presented more frequently with axial involvement. The prevalence of inflammatory back pain (IBP) was higher in the adult-onset group than in the juvenile-onset group (85.0% vs. 75.4%, P = 0.010), whereas the juvenile-onset group showed a higher prevalence of peripheral arthritis and enthesitis than the adult-onset group (67.5% vs. 48.5%, P < 0.001; 35.1% vs. 23.3%, P = 0.007, respectively). CONCLUSIONS: Compared with adult-onset nr-axSpA, juvenile-onset nr-axSpA was more common in men and those with a family history of spondyloarthritis. Juvenile-onset nr-axSpA presents with a "peripheral predominant" mode at disease onset and a higher frequency of peripheral arthritis and enthesitis during the disease course.

Enhanced activity of the left precuneus as a predictor of visuospatial dysfunction correlates with disease activity in rheumatoid arthritis.

OBJECTIVE: To identify the potential diagnostic biomarkers of rheumatoid arthritis (RA) and assess the relation between visuospatial dysfunction and disease activity in RA patients using mental rotation task (MRT)-based functional magnetic resonance imaging (fMRI). METHODS: A total of 27 RA patients (11 in remission, 16 in active) and 27 well-matched controls were enrolled. The visuospatial function of the subjects was measured by MRT. Brain activity data were collected using blood oxygen level dependent fMRI technique under MRT. Disease activity score 28 (DAS28) was used to evaluate the disease severity of RA patients. An analysis of the correlations between abnormal visuospatial-related brain regions, MRT performance, and DAS28 was conducted. RESULTS: RA patients performed worse on MRT than controls. Compared to the control group, RA patients showed enhanced activation in the left precuneus, left superior frontal gyrus and right cingulate gyrus during the rotation task, with left hemisphere dominance. RA patients in active showed enhanced activation in the left precuneus, left middle frontal gyrus and right cingulate gyrus compared to the patients in remission. The left precuneus activation was negatively correlated with MRT accuracy (r = -0.621, p = 0.01) and positively correlated with DAS28 (r = 0.710, p = 0.002), and MRT accuracy was negatively correlated with DAS28 in RA patients (r = -0.702, p = 0.002). CONCLUSION: Enhanced activation of the left precuneus in RA patients affects visuospatial function and is closely related to disease activity. These changes may provide a valuable diagnostic neuroimaging biomarker of RA.

Apolipoprotein E Polymorphism Impacts White Matter Injury Through Microglial Phagocytosis After Experimental Subarachnoid Hemorrhage.

Apolipoprotein E (apoE, protein; APOE, gene), divided into three alleles of E2, E3 and E4 in humans, is associated with the progression of white matter lesion load. However, mechanism evidence has not been reported regarding the APOE genotype in early white matter injury (WMI) under subarachnoid hemorrhage (SAH) conditions. In the present study, we investigated the effects of APOE gene polymorphisms, by constructing microglial APOE3 and APOE4-specific overexpression, on WMI and underlying mechanisms of microglia phagocytosis in a mice model of SAH. A total of 167 male C57BL/6J mice (weight 22-26 g) were used. SAH and bleeding environment were induced by endovascular perforation in vivo and oxyHb in vitro, respectively. Multi-technology approaches, including immunohistochemistry, high throughput sequencing, gene editing for adeno-associated viruses, and several molecular biotechnologies were used to validate the effects of APOE polymorphisms on microglial phagocytosis and WMI after SAH. Our results revealed that APOE4 significantly aggravated the WMI and decreased neurobehavioral function by impairing microglial phagocytosis after SAH. Indicators negatively associated with microglial phagocytosis increased like CD16, CD86 and the ratio of CD16/CD206, while the indicators positively associated with microglial phagocytosis decreased like Arg-1 and CD206. The increased ROS and aggravating mitochondrial damage demonstrated that the damaging effects of APOE4 in SAH may be associated with microglial oxidative stress-dependent mitochondrial damage. Inhibiting mitochondrial oxidative stress by Mitoquinone (mitoQ) can enhance the phagocytic function of microglia. In conclusion, anti-oxidative stress and phagocytosis protection may serve as promising treatments in the management of SAH.

Toll-like receptor 4-mediated microglial inflammation exacerbates early white matter injury following experimental subarachnoid hemorrhage.

Neuroinflammation has been reported to be associated with white matter injury (WMI) after subarachnoid hemorrhage (SAH). As the main resident immune cells of the brain, microglia can be activated into proinflammatory and anti-inflammatory phenotypes. Toll-like receptor 4 (TLR4), expressed on the surface of the microglia, plays a key role in microglial inflammation. However, the relationship between TLR4, microglial polarization, and WMI following SAH remains unclear. In this study, a total of 121 male adult C57BL/6 wild-type (WT) mice, 20 WT mice at postnatal day 1 (P1), and 41 male adult TLR4 gene knockout (TLR4-/-) mice were used to investigate the potential role of TLR4-induced microglial polarization in early WMI after SAH by radiological, histological, microstructural, transcriptional, and cytological evidence. The results indicated that microglial inflammation was associated with myelin loss and axon damage, shown as a decrease in myelin basic protein (MBP), as well as increase in degraded myelin basic protein (dMBP) and amyloid precursor protein (APP). Gene knockout of TLR4 revised microglial polarization toward the anti-inflammatory phenotype and protected the white matter at an early phase after SAH (24 h), as shown through reduction of toxic metabolites, preservation of myelin, reductions in APP accumulation, reductions in white matter T2 hyperintensity, and increases in FA values. Cocultures of microglia and oligodendrocytes, the cells responsible for myelin production and maintenance, were established to further elucidate the relationship between microglial polarization and WMI. In vitro, TLR4 inhibition decreased the expression of microglial MyD88 and phosphorylated NF-κB, thereby inhibiting M1 polarization and mitigating inflammation. Decrease in TLR4 in the microglia increased preservation of neighboring oligodendrocytes. In conclusion, microglial inflammation has dual effects on early WMI after experimental SAH. Future explorations on more clinically relevant methods for modulating neuroinflammation are warranted to combat stroke with both WMI and gray matter destruction.

Effect of Early External Ventricular Drainage on Perihemorrhagic Edema and Functional Outcome in Patients with Intraventricular Hemorrhage.

OBJECTIVE: External ventricular drainage (EVD) is the most common neurosurgical procedure that allows drainage of cerebrospinal fluid and intraventricular blood. A specific time threshold for insertion of an EVD catheter in patients with spontaneous intracerebral hemorrhage and intraventricular hemorrhage has not been established. This study aimed to evaluate the association of early EVD with functional outcome in patients with intracerebral hemorrhage and intraventricular hemorrhage. METHODS: Propensity score matching was used to account for baseline imbalances. Modified Rankin Scale score at 3 and 6 months, mortality rates at 3 and 6 months, postoperative complications, time course of edema evolution, and peak perihemorrhagic edema (PHE) were compared in patients who received early EVD versus routine EVD. RESULTS: The rate of favorable outcome at 3 months was higher in the early EVD group compared with the routine EVD group. There were no differences between groups in modified Rankin Scale score at 6 months or mortality rates at 3 and 6 months. Absolute peak PHE and relative PHE volumes were significantly less in the early EVD group compared with the routine EVD group. The incidence of postoperative infections was lower in the early EVD group compared with the routine EVD group. CONCLUSIONS: Early EVD was associated with improved functional outcome at 3 months, reduced PHE, and lower rate of infection in intracerebral hemorrhage and intraventricular hemorrhage. However, survival at 3 and 6 months and functional outcome at 6 months were not improved.

TRPM4 Drives Cerebral Edema by Switching to Alternative Splicing Isoform After Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) affects persons of all ages and is recognized as a major cause of death and disability worldwide; it also brings heavy life burden to patients and their families. The treatment of those with secondary injury after TBI is still scarce, however. Alternative splicing (AS) is a crucial post-transcriptional regulatory mechanism associated with various physiological processes, while the contribution of AS in treatment after TBI is poorly illuminated. In this study, we performed and analyzed the transcriptome and proteome datasets of brain tissue at multiple time points in a controlled cortical impact (CCI) mouse model. We found that AS, as an independent change against the transcriptional level, is a novel mechanism linked to cerebral edema after TBI. Bioinformatics analysis further indicated that the transformation of splicing isoforms after TBI was related to cerebral edema. Accordingly, we found that the fourth exon of transient receptor potential channel melastatin 4 (Trpm4) abrogated skipping at 72 h after TBI, resulting in a frameshift of the encoded amino acid and an increase in the proportion of spliced isoforms. Using magnetic resonance imaging (MRI), we have shown the numbers of 3nEx isoforms of Trpm4 may be positively correlated with volume of cerebral edema. Thus alternative splicing of Trpm4 becomes a noteworthy mechanism of potential influence on edema. In summary, alternative splicing of Trpm4 may drive cerebral edema after TBI. Trpm4 is a potential therapeutic targeting cerebral edema in patients with TBI.