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Background: Intracerebral hemorrhage (ICH) is a type of stroke which results in a high disability and mortality rate and has a poor prognosis. Tongqiao Huoxue Decoction (TQHXD) is a classical Chinese prescription. Clinical practice has proven that TQHXD can promote blood circulation and can effectively treat ICH and its sequelae. However, the current mechanism is still unclear., Methods: The chemical components and target genes of TQHXD were collected from the Traditional Chinese medicine (TCM) Systems Pharmacology and Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine analysis platforms, and the gene expression data of ICH tissues were downloaded from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed to obtain differentially co-expressed gene pairs and build a drug-target-disease network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the obtained target genes and shared genes. Finally, molecular docking was carried out to further clarify the utility of TQHXD for the treatment of ICH., Results: A total of 304 differentially expressed genes in ICH, 42 TQHXD active ingredients, and 279 predicted targets of its active compounds were obtained. Bioinformatics analysis showed that they were involved in angiogenesis, the regulation of wound healing, and other biological processes. Furthermore, their participation in fluid shear stress and the atherosclerosis signaling pathway indicated their close association with the pathological processes of ICH. Finally, molecular docking was carried out to further confirm the tightly binding structural sites of the effective components of TQHXD and key proteins., Conclusions: In summary, the results of this study suggest that the mechanism of action of TQHXD in the treatment of ICH involves multiple targets and signaling pathways related to its occurrence and development. This study not only provides a new theoretical basis for the treatment of ICH with traditional Chinese medicine, but also provides new ideas for the research and development of drugs for the treatment of ICH., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-1403/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

We studied how well the original intracerebral hemorrhage (ICH) score would predict mortality. All nine patients with an ICH score of 0 survived, whereas those having scores of 1, 2, 3, and 4 had 10, 53, 71, and 100 % mortality, respectively. Thirty-nine patients were found to have hematoma of <30 mL (56 % survived), whereas 11 patients were found to have volume of >30 mL (only 10 % survived). The ICH score and volume is a simple clinical grading scale that allows risk stratification on presentation with ICH. The use of a scale such as the ICH score could improve standardization of clinical treatment protocols. [ABSTRACT FROM AUTHOR]

Background: This study aimed to systematically compare the discrimination and calibration of 5 clinical scores for stroke-associated pneumonia (SAP) after intracerebral hemorrhage (ICH)., Methods: We derived a validation cohort from the Beijing Registration of Intracerebral Hemorrhage. SAP was then diagnosed according to the Center for Disease Control and Prevention's criteria for hospital-acquired pneumonia. The area under the receiver operating characteristic curve (AUROC) and Hosmer-Lemeshow goodness-of-fit test were used to assess model discrimination and calibration., Results: A total of 1964 patients were enrolled in the study. The mean age was 56.8±14.4 years, and 67.6% were male. The median National Institutes of Health Stroke Scale (NIHSS) score at admission was 11 [interquartile range (IQR), 3-21], while the median length of stay (LOS) was 16 days (IQR, 8-22 days). A total of 575 (29.2%) patients were diagnosed with in-hospital SAP after ICH. The AUROC of the 5 clinical scores ranged from 0.732 to 0.800. In comparing these scores, we found that the ICH-associated pneumonia score-B (ICH-APS-B 0.800; 95% CI: 0.780-0.820; P<0.001) showed a statistically better discrimination than did the other risk models (all P<0.001). Furthermore, all clinical scores performed better in patients with an LOS >72 h. The ICH-APS-B (0.827; 95% CI: 0.806-0.848; P<0.001) still showed statistically better discrimination than did the other risk models in patients with an LOS longer than 72 hours. The Hosmer-Lemeshow test also revealed that the ICH-APS-B. had the largest Cox and Snell R2 result for in-hospital SAP after ICH., Conclusions: Among the 5 models for predicting SAP after ICH, the ICH-APS-B showed the best predictive performance, suggests it may be a useful tool for implementing the personalized care of patients and conducting clinical trials of SAP after ICH., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-21-4046/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Phillyrin, a natural plant extract, has significant antioxidant and anti-apoptotic effects. However, its effect on intracerebral hemorrhage (ICH) remains unclear. In this study, we investigated a potential role for phillyrin in the regulation of the oxidative stress and apoptosis induced by ICH. A model of ICH was induced by collagenase IV (0.2 U in 1 μl sterile normal saline) in male C57BL/6J (B6) mice and different doses of phillyrin (5, 15, or 30 mg/kg) were intraperitoneally (i.p.) injected at 30 min, 6 h, and 22 h after modeling. We found that phillyrin significantly reduced neural function and lesion volume, improved injury of white and grey matter around the lesion, decreased apoptosis and oxidative stress, increased the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase 1(HO-1), NADPH quinone oxidoreductase 1 (NQO1) and Superoxide Dismutase-1(SOD-1) in vitro and in vivo , and protected neurons from the stimulation of hemin by promoting Nrf2 nuclear translocation. Treatment with ML385 (Nrf2 inhibitor) completely reversed the protective effects of phillyrin in vivo after ICH injury. Based on our findings, we conclude that phillyrin treatment alleviates ICH injury-induced apoptosis and oxidative stress via activation of the Nrf2 signaling pathway, highlighting a potential role for phillyrin as an ICH therapeutic. [ABSTRACT FROM AUTHOR]

Background: The cerebrospinal fluid circulation of patients with intracerebral hemorrhage (ICH) can be blocked by blood clots, resulting in acute hydrocephalus. However, current research on chronic hydrocephalus (CH) is lacking., Methods: A total of 253 patients with ICH combined with coma treated at The Third People's Hospital of Gansu Province after emergency hematoma removal from January 2018 to January 2020 were included. Patients were divided into the CH group (n=48) and the control group (n=205) depending on whether hydrocephalus occurred or not within 3-12 months after operation. The main clinical characteristics of the two groups were compared, and the risk factors for CH were analyzed. Counting data of the two groups were expressed as "n (%)", and multivariate logistic regression analysis was used to explore the risk factors for CH., Results: Compared with the control group, the proportion of patients with modified Graeb score ≥5 points in the CH group increased significantly (52.08% vs. 21.95%, P=0.000). The proportion of patients with preoperative cerebral hernia increased significantly (37.5% vs. 19.51%, P=0.008). The proportion of patients with preoperative obstructive hydrocephalus increased (43.75% vs. 24.39%, P=0.007). The proportion of patients with postoperative subdural effusion increased (41.67% vs. 13.66%, P=0.000). Multivariate logistic regression analysis showed that a modified Graeb score ≥5 points and postoperative subdural effusion were risk factors for the formation of CH in patients with ICH complicated by coma after emergency hematoma removal (P<0.05). The modified Graeb score has diagnostic value for the formation of CH in patients with ICH combined with coma after emergency hematoma removal, and the area under the curve was 0.653 [P=0.001, 95% confidence interval (CI): 0.561-0.744]. There was no significant difference in preoperative neurological deficit score between the control group and the CH group (19.75±3.03 vs. 19.86±3.01, P=0.113). Compared with the control group, the neurological deficit score at 12 months after operation in the CH group was significantly higher (12.73±2.99 vs. 10.64±2.82, P=0.000)., Conclusions: A modified Graeb score >5 points and postoperative subdural effusion are risk factors for the formation of CH in patients with ICH combined with coma after emergency hematoma removal. The formation of CH affects postoperative neurological rehabilitation., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-128/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Background: Intracerebral hemorrhage (ICH) is a severe cerebrovascular disease with high morbidity and mortality rates. Oxidative stress and inflammation are important pathological mechanisms of secondary brain injury (SBI) after ICH. Brain and muscle Arnt-like protein 1 (BMAL1), which forms the core component of the circadian clock, was previously shown to be involved in many diseases and to participate in oxidative stress and inflammatory responses. However, the role of BMAL1 in SBI following ICH is unknown. In addition, treatments targeting miR-155 and its downstream signaling pathway may exert a beneficial effect on SBI after ICH, while miR-155 may regulate Bmal1 mRNA stability and translation. Nevertheless, researchers have not clearly determined whetheantagomir-155 upregulates BMAL1 expression and subsequently attenuates ICH-induced brain injury in rats., Methods: After establishing an ICH rat model by injecting autologous blood, the time course of changes in levels of the BMAL1 protein after ICH was analyzed. Subsequently, this study was designed to investigate the potential role and mechanisms of BMAL1 in SBI following ICH using lentiviral overexpression and antagomir-155 treatments., Results: BMAL1 protein levels were significantly decreased in the ICH group compared to the sham group. Genetic overexpression of BMAL1 alleviated oxidative stress, inflammation, brain edema, blood-brain barrier injury, neuronal death, and neurological dysfunction induced by ICH. On the other hand, we observed that inhibiting miRNA-155 using antagomir-155 promoted the expression of BMAL1 and further activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway to attenuate brain injury after ICH., Conclusions: These results reveal that BMAL1 serves as a neuroprotective agent in ICH and upregulation of BMAL1 attenuates ICH-induced SBI. Therefore, BMAL1 may be a promising therapeutic target for SBI following ICH., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-1863). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Given the ongoing global SARS-CoV-2-vaccination efforts, clinical awareness needs to be raised regarding the possibility of an increased incidence of SARS-CoV-2-vaccine-related immune-mediated thrombocytopenia in patients with intracerebral hemorrhage (ICH) secondary to cerebral sinus and vein thrombosis (CVT) requiring (emergency) neurosurgical treatment in the context of vaccine-induced immune thrombotic thrombocytopenia (VITT). Only recently, an association of vaccinations and cerebral sinus and vein thrombosis has been described. In a number of cases, neurosurgical treatment is warranted for these patients and special considerations are warranted when addressing the perioperative coagulation. We, herein, describe the past management of patients with VITT and established a literature-guided algorithm for the treatment of patients when addressing the impaired coagulation in these patients. Increasing insights addressing the pathophysiology of SARS-CoV-2-vaccine-related immune-mediated thrombocytopenia guide physicians in developing an interdisciplinary algorithm taking into account the special considerations of this disease. [ABSTRACT FROM AUTHOR]

Dentin matrix protein 1 (DMP1) is an extracellular matrix phosphoprotein that is known to facilitate mineralization of collagen in bone and promote osteoblast/odontoblast differentiation. Blood-brain barrier (BBB) disruption is the major pathogenesis in secondary brain injury after intracerebral hemorrhage (ICH). This study aimed to investigate the expression pattern of DMP1 in the mouse brain and explore the role of DMP1 in BBB disruption and brain injury in a mouse model of ICH. Mice were subjected to autologous blood injection-induced ICH. Immunofluorescence staining, western blot analysis, neurobehavioral tests, brain water content measurements, Evans blue permeability assay, and transmission electron microscopy were performed. Small interfering RNA targeting DMP1 (DMP1 siRNA) was administered at 72 h prior to ICH. Results showed that DMP1 is expressed extensively in the mouse brain, and is upregulated in the ICH model. Administration of DMP1 siRNA effectively ameliorated BBB disruption, attenuated brain edema, and improved neurological function after ICH. Moreover, the expression of zonula occludens-1 (ZO-1) and occludin were upregulated, and matrix metalloproteinase-9 (MMP-9) was downregulated in the ICH model. DMP1 siRNA administration reversed the expression of ZO-1, occludin, and MMP-9. These results demonstrated that DMP1 upregulation plays an essential role in inducing BBB disruption and brain injury after ICH. The inhibition of DMP1 could be a potential therapeutic strategy for ICH treatment. [ABSTRACT FROM AUTHOR]

• The expressions of RIP3, p-MLKL, AIF and CaMKII increased in a time-dependent manner after ICH. • AIF leaks through the mPTP channel and forms a complex with RIP3 in the cytoplasm. • RIP3-AIF nucleus translocation is primary step of necroptosis. • Inhibition of RIP3/AIF/CaMKII signaling improved neurological functions after ICH. Necroptosis-induced neuronal damage after intracerebral hemorrhage (ICH) has been documented recently. Previous studies have reported that RIP3 and its complex are recognized as central mediators of necroptosis. In this study, the role of RIP3 in the activation of CaMKII and AIF was investigated. We induced ICH in C57BL/6 mice by injecting collagenase IV into the basal ganglia. ICH mice were pretreated with the mPTP inhibitor CsA and the CAMKII inhibitor Kn-93, RIP3 siRNA or RIP3 rAAV. Brain edema and neurobehavior were evaluated. The expression of RIP3, p-MLKL, AIF, and CaMKII proteins was evaluated by western blotting, immunofluorescence (IF) and immunoprecipitation (IP). Significant increases in RIP3, p-MLKL, CaMKII and AIF expression were observed in ICH mice, and RIP3-AIF colocalized in the nucleus. Overexpression of RIP3 by rAAV upregulated AIF expression in both the cytoplasm and nucleus, while CaMKII expression was increased in the cytoplasm. The interaction of RIP3-AIF and RIP3-CaMKII was detected after ICH injury. These complexes were inhibited by CsA with Kn-93 or RIP3 siRNA pretreatment, which reduced brain edema and neurological deficits. Our findings revealed that ICH induced necroptotic neuronal death through the RIP3-CaMKII complex and the RIP3-AIF signaling pathway. Moreover, blockade of mPTP opening could suppress the pathogenesis of necroptosis. [ABSTRACT FROM AUTHOR]

Iron has a key role in the activation of the autophagic pathway in rats with intracerebral hemorrhage (ICH), and hepcidin has the ability to reduce brain iron in ICH-rats. We therefore hypothesized that hepcidin might be able to inhibit autophagy by reducing iron in an ICH brain. Here, we investigated the effects of Ad-hepcidin and/or hepcidin peptide on autophagic activities in ICH models in vitro and in vivo. We demonstrated that ad-hepcidin and hepcidin peptide both inhibited hemin-induced increase in LC3-II/LC3-I conversion ratio and reversed the reduction in p62 content in cortical neurons in vitro. We also showed that ad-hepcidin inhibited ICH-induced increase in LC3-II/LC3-I conversion ratio and reversed ICH-induced reduction in p62 content in the brain cortex of rats in vivo. Based on these findings plus previous data on the effects of ad-hepcidin and/or hepcidin peptide on iron contents in ICH models, we suggested that hepcidin-induced inhibition of autophagy might be mediated via reducing iron in hemin-treated neurons in vitro and ICH-rat brain in vivo. • Hepcidin inhibits LC3-II/LC3-I conversion ratio increase in ICH models in vitro and in vivo. • Hepcidin reverses the reduction in p62 content in ICH models in vitro and in vivo. • Inhibition of autophagy by hepcidin might be mediated by reducing iron in ICH models. [ABSTRACT FROM AUTHOR]

Background: Microglia plays a vital role in neuroinflammation, contributing to the pathogenesis of intracerebral hemorrhage (ICH)-induced brain injury. Mesenchymal stem cells (MSCs) hold great potential for treating ICH. We previously revealed that MSCs ameliorate the microglial pyroptosis caused by an ischemic stroke. However, whether MSCs can modulate microglial pyroptosis after ICH remains unknown. This study aimed to investigate the neuroprotective effects of hypoxia-preconditioned olfactory mucosa MSCs (OM-MSCs) on ICH and the possible mechanisms., Methods: ICH was induced in mice via administration of collagenase IV. At 6 h post-ICH, 2-4×10 5 normoxic/hypoxic OM-MSCs or saline were intracerebrally administered. To evaluate the neuroprotective effects, the behavioral outcome, apoptosis, and neuronal injury were measured. Microglia activation and pro-inflammatory cytokines were applied to detect neuroinflammation. Microglial pyroptosis was determined by western blotting, immunofluorescence staining, and transmission electron microscopy (TEM)., Results: The two OM-MSC-transplanted groups exhibited significantly improved functional recovery and reduced neuronal injury, especially the hypoxic OM-MSCs group. Hypoxic OM-MSCs attenuated microglial activation as well as the levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Moreover, we found that hypoxia-preconditioned OM-MSCs ameliorated pyroptosis by diminishing the levels of pyroptosis-associated proteins in peri-hematoma brain tissues, decreasing the expression of the microglial nod-like receptor family protein 3 (NLRP3) and caspase-1, and reducing the membrane pores on microglia post-ICH., Conclusions: Our study showed that hypoxic preconditioning augments the therapeutic efficacy of OM-MSCs, and hypoxia-preconditioned OM-MSCs alleviate microglial pyroptosis in the ICH model., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-2590). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

The graphical abstract indicates that NDRG2 negatively regulates GLT1 expression in astrocytes following hemorrhage-related stimulation and that downregulation of astrocytic NDRG2 promotes the interstitial glutamate clearance, thus alleviating glutamate neurotoxicity after OxyHb induction. Our findings suggest a novel mechanism for the regulation of GLT1 in astrocytes through the NDRG2/NF-κB pathway and provide a potential therapeutic target for astrocytes after hemorrhagic brain injury. • NDRG2 deletion mitigates the secondary brain injury after ICH. • NDRG2 inhibition astrocytes-drived neurotoxicity following OxyHb stimulation. • NDRG2 negatively regulates astrocytic GLT1 via NF-κB p65 signaling. N-myc downstream-regulated gene 2 (NDRG2), a newly identified astrocytic stress response gene, is involved in the regulation of astrocytic morphology and function, and has been indicated to be a potential therapeutic target for some central nervous system (CNS) diseases. However, the role of NDRG2 in intracerebral hemorrhage (ICH) remains unknown. Here, we reported that NDRG2 suppression exerted neuroprotection effect against hemorrhagic brain injury in ICH mice and in oxyhemoglobin (OxyHb)-treated cells. Ndrg2 knockout (Ndrg2 −/−) mice exhibited reduced hematoma volume and neuronal apoptosis in perihematoma although Ndrg2 deficiency showed little effect on the initial hematoma volume after ICH induction by collagenase injection. Moreover, contrary to the increase in NDRG2 expression after ICH, the expression of glutamate transporter 1 (GLT1) in astrocytes was dramatically decreased in WT (Ndrg2 +/+) mice, while which could be more maintained in Ndrg2 knockout mice following ICH. Furthermore, in terms of the mechanism of epigenetic regulation of GLT1 by NDRG2, the results showed that NDRG2 directly interacted with NF-κB, and inhibited the nuclear import and DNA binding activity of the NF-κB p65 subunit after OxyHb treatment in primary astrocytes, decreasing GLT1 transcription and impairing glutamate uptake. Overall, our findings indicate that NDRG2 plays a key role in the pathology of ICH by regulating astrocytic GLT1 expression; thus suppressing NDRG2 may be a potential therapeutic target for ICH. [ABSTRACT FROM AUTHOR]

Background: Prostaglandin E1 (PGE1) exerts various pharmacological effects such as membrane stabilization, anti-inflammatory functions, vasodilation, and platelet aggregation inhibition. We have previously demonstrated that PGE1 has a beneficial impact on patients suffering from intracerebral hemorrhage (ICH). The related mechanism underlying PGE1's beneficial effect on ICH treatment needs further exploration., Methods: The present study elucidates the mechanism of PGE1 on ICH treatment using a neuronal apoptosis model in vitro . The mouse primary cortical neurons were pretreated with different concentrations of PGE1, followed by the treatment with hemin, the main catabolite in whole blood, to mimic the clinical ICH., Results: Comparing with the vehicle-treated group, PGE1 prevented cultured cortical neurons from the accumulation of inhibited intracellular levels of reactive oxygen species (ROS), amelioration of mitochondrial membrane potential, and hemin-induced apoptosis. The reduction of ROS and apoptosis were associated with the up-regulation of Heme oxygenase-1 (HO-1) expression. Knockdown of nuclear transcription factor erythroid 2-related factor (Nrf2) by siRNA attenuated the upregulation of HO-1 as well as the protective effect of PGE1., Conclusions: Our work suggests that the Nrf2/HO-1 molecular pathway may play a crucial role in treating ICH patients with PGE1 and may represent novel molecular targets, resulting in discovering new drugs for ICH treatment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5839). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: Minimally Invasive Surgery Plus Recombinant Tissue Plasminogen Activator for Intracerebral Hemorrhage Evacuation (MISTIE) procedure was recently tested in a large phase III randomized trial showing a significant probability of functional benefit in those cases that reached the goal hematoma evacuation of ≤15 mL residual (or ≥70% removal). Benefit of thrombolysis was also identified in cases with large intraventricular hemorrhage, and achieving at least 85% volume reduction in the Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR) III trial., Objective: To protocolize steps in the MISTIE and CLEAR procedures in order to maximize hematoma evacuation and minimize complications., Methods: We articulate data-driven lessons and expert opinions surrounding the factors of patient selection, catheter placement, and dosing, which impacted safety and surgical performance in the MISTIE and CLEAR trials., Results: Modifiable factors to maximize evacuation efficiency include optimizing catheter placement and pursuing aggressive dosing to achieve treatment goals, while strictly adhering to the safety steps as articulated in the respective trials. Prognostic factors that are viewed as nonmodifiable include greater initial intracerebral hemorrhage volume with irregular shape, smaller intraventricular bleeds, and the uncommon but consequential development of new bleeding during the dosing period despite strict protocol adherence., Conclusions: Surgeon education in this tutorial is aimed at maximizing the benefit of the MISTIE and CLEAR procedures by reviewing case selection, safety steps, treatment objectives, and technical nuances. Key lessons include stability imaging, etiology screening, and technical adherence to the protocol in order to achieve defined thresholds of evacuation., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Background: To explore the mechanisms of raw rhubarb and wine-processed rhubarb treatment in a rat model of intracerebral hemorrhage (ICH)., Methods: After adapting to their environment, 30 male Wistar rats were divided into 5 treatment groups: blank control group (CK) (normal saline), sham operation group (SICH) (normal saline), ICH model group (ICH) (normal saline), ICH + raw rhubarb enema group (RO) (raw rhubarb 3.60 g/kg), and ICH + wine-processed rhubarb enema group (WRO) (wine-processed rhubarb 3.60 g/kg). The rhubarb enema (once a day) was given since 3 days before ICH treatment, and was consistently given until 12 hours, 24 hours, 3 days, and 7 days post operation. Serum oxidative stress and inflammatory markers were detected by ELISA, and differences between raw rhubarb and wine-processed rhubarb treatment in ICH rats were screened by proteomics and metabolomics., Results: Both rhubarb treatments effectively improved oxidative stress and inflammatory responses. After ICH, the proteins and metabolites in the brain tissue were significantly altered. Compared with raw rhubarb, wine-processed rhubarb had a better protective effect by dysregulating amino acid metabolism in the ICH model., Conclusions: Our study provides a basis for further research into the mechanisms of rhubarb treatment from different processing technologies, and promotes the application of rhubarb as a therapeutic approach to ICH., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-7831). The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Objective: To observe the effect of acupuncture at "Baihui" (GV 20) through "Qubin" (GB 7) on NLRP3 inflammatory corpuscle in rats with intracerebral hemorrhage (ICH), and to explore the action mechanism of acupuncture on promoting the recovery of neural function in rats with ICH., Methods: Forty SPF six-week-old male SD rats were randomly divided into a sham operation group, a model group, a non-acupoint group and an acupuncture group, 10 rats in each group. The rats in the model group, non-acupoint group and acupuncture group were intervened with autologous blood injection to prepare ICH model, while the rats in the sham operation group were only intervened with operation but not injection with autologous blood. About 3 hours after the establishment of the model, the rats in the acupuncture group were intervened with acupuncture at "Baihui" (GV 20) through "Qubin" (GB 7), once every 12 hours, for 7 days; the rats in the non-acupoint group were intervened with acupuncture at the non-acupoint [parallel to the "Baihui" (GV 20), 1 cm next to the midline] on the affected side, and other treatment was the same as the acupuncture group. At the end of the intervention, the composite nerve function score of each group was evaluated; the histomorphology of the hemorrhage penumbra was observed by HE staining; the expression of NLRP3 inflammatory corpuscle in the brain was detected by immunohistochemistry; the relative protein expression levels of NLRP3, interleukin-1β (IL-1β) and interleukin-18 (IL-18) in brain were detected by the method of Western blot., Results: Seven days into intervention, compared with the sham operation group, each item score and total score of composite nerve function in the model group were significantly reduced ( P <0.01, P <0.05). There was edema and karyopyknosis in brain neuron as well as necrocytosis and inflammatory cell infiltration in the model group. Compared with the model group and the non-acupoint group, the total score of composite nerve function and the scores of symmetrical movement of limbs (LS) and proprioception of tentacles (VP) in the acupuncture group were increased ( P <0.01, P <0.05), and the cell necrosis and inflammatory cell infiltration were relieved. Compared with the sham operation group, NLRP3 inflammatory corpuscle expression and the relative protein expression levels of NLRP3, IL-1β and IL-18 in brain tissue in the model group were increased ( P <0.01); compared with the model group and the non-acupoint group, NLRP3 inflammatory corpuscle expression and the relative protein expression levels of NLRP3, IL-1β and IL-18 in brain tissue in the acupuncture group were reduced ( P <0.01)., Conclusion: Acupuncture at "Baihui" (GV 20) through "Qubin" (GB 7) could downregulate the expression of NLRP3, IL-1β and IL-18 in the brain tissue of ICH rats, inhibit the inflammatory response, and promote the recovery of neural function.

Objectives: Examine the incidence and predictors of PTSD symptoms in a cohort of patients with ICH., Patients and Methods: This study uses a prospective cohort of 108 patients with complete follow-up data including a questionnaire regarding stress symptoms (PCL-S: PTSD checklist specific for a stressor) at 3, 6, and 12 months., Results: The incidence of novel stress symptoms following ICH was approximately 6.5%. Age was negatively associated with PTSD symptoms with only trend-level significance (3 months: OR = 0.83, p = 0.087; 6 months: OR = 0.70, p = 0.015; 12 months: OR = 0.88, p =  0.087). Gender did not affect PTSD symptom development, (t = 1.34, p =  0.18). Pre-morbid functioning, initial stroke prognosis, total number of complications, and length of hospital/ICU stay were not associated with PTSD symptoms; however, each was significantly correlated with poorer functional outcomes. Yet, poorer functional outcomes were observed in those with higher reports of PTSD symptoms (r = 0.24, p = 0.01)., Conclusion: Functional outcomes in ICH are correlated with PTSD symptoms, however the mechanism and relationship are difficult to elucidate. Further research is needed to determine possible mechanisms by which a stroke patient may develop PTSD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: For patients hospitalized after acute ischemic stroke (AIS), the preadmission comorbidities, level of consciousness (LOC), age and neurologic deficit (PLAN) score can help to identify those who may have a poor outcome. Implementing the PLAN score in other types of stroke may also have predictive value. Our study aimed to evaluate the PLAN score's prognostic accuracy in predicting 1-year mortality and severe disability after intracerebral hemorrhage (ICH)., Methods: We analyzed data found in the China National Stroke Registry (CNSR) of 2,453 hospitalized patients in 132 urban Chinese hospitals, diagnosed with ICH from September 2007 to August 2008. The outcomes analysis included 30-day mortality, modified Rankin Scale score (mRS) of 5-6 at discharge, and 1-year mortality. Univariate and multivariate analysis was performed, and we calculated consistency statistics (C statistic). We evaluated the PLAN score performance using area under the curve (AUC) calculations., Results: We found that the 30-day mortality was 12.6%, the frequency of a mRS 5-6 at discharge was 20.6%, and 1-year mortality was 21.9%. The PLAN score had good predictive value in 30-day mortality (C statistic, 0.82), death or severe dependence at discharge (0.84), and 1-year mortality (0.82)., Conclusions: In patients hospitalized for ICH, the 30-day mortality, death or severe dependence at discharge and 1-year mortality can be predicted by the PLAN score. Similarly to patients hospitalized after AIS, the PLAN score can help to identify patients likely to have poor outcomes following hospitalization for ICH., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Traumatic subarachnoid hemorrhage (SAH) is the second most frequent intracranial hemorrhage and a common radiologic finding in computed tomography. This study aimed to estimate the risk of mortality in adult trauma patients with traumatic SAH concurrent with other types of intracranial hemorrhage, such as subdural hematoma (SDH), epidural hematoma (EDH), and intracerebral hemorrhage (ICH), compared to the risk in patients with isolated traumatic SAH. We searched our hospital's trauma database from 1 January, 2009 to 31 December, 2018 to identify hospitalized adult patients ≥20 years old who presented with a trauma abbreviated injury scale (AIS) of ≥3 in the head region. Polytrauma patients with an AIS of ≥3 in any other region of the body were excluded. A total of 1856 patients who had SAH were allocated into four exclusive groups: (Group I) isolated traumatic SAH, n = 788; (Group II) SAH and one diagnosis, n = 509; (Group III) SAH and two diagnoses, n = 493; and (Group IV) SAH and three diagnoses, n = 66. One, two, and three diagnoses indicated occurrences of one, two, or three other types of intracranial hemorrhage (SDH, EDH, or ICH). The adjusted odds ratio with a 95% confidence interval (CI) of the level of mortality was calculated with logistic regression, controlling for sex, age, and pre-existing comorbidities. Patients with isolated traumatic SAH had a lower rate of mortality (1.8%) compared to the other three groups (Group II: 7.9%, Group III: 12.4%, and Group IV: 27.3%, all p < 0.001). When controlling for sex, age, and pre-existing comorbidities, we found that Group II, Group III, and Group IV patients had a 4.0 (95% CI 2.4-6.5), 8.9 (95% CI 4.8-16.5), and 21.1 (95% CI 9.4-47.7) times higher adjusted odds ratio for mortality, respectively, than the patients with isolated traumatic SAH. In this study, we demonstrated that compared to patients with isolated traumatic SAH, traumatic SAH patients with concurrent types of intracranial hemorrhage have a higher adjusted odds ratio for mortality.

Most intracerebral hemorrhage (ICH) survivors have poor long-term outcomes, such as cognitive deficits and depression. Delayed lesions of ICH include neuron loss and white matter injury and the pathology of the lesions involves iron deposition and glial responses, which contribute to depressive-like behavior and cognitive impairment in animals. This study aimed to investigate the effects of FTY720 (0.3 mg/kg/day for 4 weeks) on iron deposition, glial responses, histological abnormalities and behavioral dysfunction in mice with ICH. The primary adverse long-term outcomes in our study of ICH mice were depressive-like behavior and impaired recognition memory. We found that FTY720 safely ameliorated depressive-like behavior and impaired recognition without affecting recovery of grip function and locomotor activity 28 days post-ICH. Moreover, we measured neuron loss, white matter lesions, lesion volume and iron deposition at day 28, which were attenuated in the FTY720-treated group compared to the ICH-control group, without changing initial hematoma volume on day 1 post-ICH. Long-term elevation of glial responses, including microglia activity and astrogliosis with tumor necrosis factor alpha (TNFα) expression was demonstrated by Western blot and immunofluorescence staining, which we found was attenuated by FTY720 treatment. Hence, FTY720 could become a novel therapeutic agent for improving long-term outcomes after ICH., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cell death is deeply involved in pathophysiology of brain injury after intracerebral hemorrhage (ICH). Necroptosis, one of the recently discovered forms of cell death, plays an important role in various diseases, including ICH. Previous studies have suggested that a considerable number of neurons undergoes necroptosis after ICH. However, necroptosis of microglia after ICH has not been reported to date. The present study demonstrated for the first time that necroptosis occurred in the microglia surrounding the hematoma after ICH in C57 mice, and melatonin, a hormone that is predominantly synthesized in and secreted from the pineal gland, exerted a neuroprotective effect by suppressing this process. When we further explored the potential underlying mechanism, we found that melatonin inhibits RIP3-mediated necroptosis by regulating the deubiquitinating enzyme A20 (also known as TNFAIP3) expression after ICH. In summary, we have demonstrated the role of microglial necroptosis in the pathogenesis of ICH. More importantly, A20 was identified as a novel target of melatonin, which opens perspectives for future research.

Purpose: To examine clinical factors, including established electroencephalography (EEG) consensus recommendations, that may influence EEG-prescription in critically-ill intracerebral hemorrhage (ICH) patients in the neurointensive care unit., Methods: Retrospective analysis of 330 ICH patients admitted to a neurointensive care unit at an academic medical center between 01/2013-12/2015. We compared EEG prescription patterns with current EEG consensus recommendations, and employed univariate and multivariable logistic regression modeling to determine clinical variables associated with EEG ordering., Results: Seventy-eight (41%) of 190 subjects underwent EEG in accordance with EEG-consensus guidelines, demonstrating an overall accuracy (probability that EEG prescription aligned with EEG consensus recommendations) of 64.6% (95%-CI59.1-69.7). Factors independently associated with EEG ordering included fulfillment of EEG consensus recommendations, lower admission Glasgow Coma Scale (GCS), and presence of clinical seizures. The unadjusted and adjusted C-statistics for fulfillment of consensus recommendations was 0.74 (95%-CI 0.69-0.80) and 0.85 (95%-CI 0.81-0.90), respectively. Among 83 subjects undergoing EEG (25.2%), EEG findings informed clinical decision-making in 50 patients (60%)., Conclusions: EEG appeared underused in ICH, since <50% of patients who fulfilled guideline criteria underwent EEG. Prescription of EEG was related to factors beyond those included in consensus recommendations. Validation of our findings and their association with outcome is required., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Inflammation and apoptosis are two key factors contributing to secondary brain injury after intracerebral hemorrhage (ICH). In the present study, we explored the neuroprotective role of methylene blue (MB) in ICH rats and studied the potential mechanisms involved. Rats were subjected to local injection of collagenase IV in the striatum or sham surgery. We observed that MB treatment could exert a neuroprotective effect on ICH by promoting neurological scores, decreasing the brain water content, alleviating brain-blood barrier disruption, and improving the histological damages in the perihematomal areas. Furthermore, we demonstrated that the various mechanisms underlying MB's neuroprotective effects linked to inhibited apoptosis and inhibited neuroinflammation. In addition, wortmannin, a selective inhibitor of phosphoinositide 3-kinase (PI3K), could reverse the antiapoptotic and anti-inflammatory effects of MB, which suggested that the PI3K-Akt pathway played an important role. In conclusion, these data suggested that MB could inhibit apoptosis and ameliorate neuroinflammation after ICH, and its neuroprotective effects might be exerted via the activation of the PI3K/Akt/GSK3β pathway., (© 2018 Wiley Periodicals, Inc.)

Background: Experimental animal model studies have shown neuroprotective properties of magnesium. We assessed the relationship between admission magnesium and admission stroke severity and 3-month clinical outcomes in patients with acute intracerebral hemorrhage (ICH)., Methods: The present study included 323 patients with acute ICH who were prospectively identified. Demographic characteristics, lifestyle risk factors, National Institute of Health Stroke Scale (NIHSS) score, hematoma volumes, and other clinical features were recorded at baseline for all participants. Patients were divided into three groups based on the admission magnesium levels (T1: <0.84; T2: 0.84-0.91; T3: ≥0.91 mmol/L). Clinical outcomes were death, poor functional outcome (defined by modified rankin ccale [mRS] scores 3-6) at 3 months., Results: After 3-month follow-up, 40 (12.4%) all-cause mortality and 132 (40.9%) poor functional outcome were documented. Median NIHSS scores for each tertile (T1 to T3) were 8.0, 5.5, and 6.0, and median hematoma volumes were 10.0, 8.05, and 12.4 ml, respectively. There was no significant association between baseline NIHSS scores (P=0.176) and hematoma volumes (P=0.442) in T3 and T1 in multivariable linear regression models. Compared with the patients in T1, those in T3 were associated with less frequency of all-cause mortality [adjusted odds ratio (OR), 0.10; 95% confidence interval (CI), 0.02-0.54; P-trend=0.010] but not poor functional outcome (adjusted OR, 1.80; 95%CI, 0.71-4.56; P-trend=0.227) after adjustment for potential confounders., Conclusion: Elevated admission serum magnesium level is associated with lower odds of mortality but not poor functional outcome at 3 months in patients with acute ICH., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Primary intraventricular hemorrhage (PIVH) is a rare type of Intracerebral Hemorrhage (ICH), which is poorly understood. This study aimed to investigate gender differences in patients' characteristics, management and outcome at discharge and 90 days after PIVH., Methods: Consecutive patients with PIVH from a single center in China were enrolled over a 7- year period. Gender differences in demographics, risk factors, etiological subtypes, treatment, and outcomes were examined. The logistic regression models were used in the study to identify the predictors of poor outcome., Results: In total, 174 patients were analyzed, and 77 (44.3%) of them were women. Women with PIVH were younger (p = 0.047), with lower systolic and diastolic blood pressure (p = 0.02 and p = 0.004, respectively). They had more cases caused by Moyamoya disease (p = 0.038). There were fewer patients with hypertension (p = 0.008), smoking (p＜0.001), chronic alcoholism (p＜0.001), harbored lower hemoglobin (p＜0.001) and Absolute Monocyte Count (AMC) (p = 0.04) at admission compared with men. There were no differences between female and male patients regarding the mortality and poor outcome in the multivariable-adjusted models ((OR = 0.57; 95% CI, 0.15-2.14) and (OR = 0.86; 95% CI, 0.32-2.37), respectively). In subgroup analysis after adjustment, the gender specific independent predictors for unfavorable outcome were higher with a Graeb score (OR = 1.78; 95% CI, 1.01-3.13) or AMC (OR = 9.66; 95% CI, 1.20-12.87) in women, and lower Glasgow coma scale (GCS) score (OR = 0.64; 95% CI, 0.47-0.87) or acute hydrocephalus (OR = 0.17; 95% CI, 0.03-0.86) in men., Conclusion: Women with PIVH exhibit some distinctive baseline features compared with men. The gender difference of the PIVH does not appear to affect the neurological outcome. The predictors of poor outcomes are Graeb score and AMC in women and GCS score and acute hydrocephalus in men., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Long noncoding RNAs (lncRNAs) have emerged as an important class of molecules that have been associated with brain function and neurological disease, but the expression profiles of lncRNAs after intracerebral hemorrhage (ICH) remain to be elucidated. In this study, we determined the expression pattern of nuclear factor-k-gene binding (NF-kB) interacting lncRNA (NKILA) after ICH and examined its respective effects on the endoplasmic reticulum stress (ERS)/autophagy pathway, hippocampal neuron loss, and the NF-kB pathway after type VII collagenase-induced ICH in rats. The regulatory mechanisms of NKILA were investigated by an intraperitoneal injection of small interfering (siRNA) against NKILA into rats after ICH. NKILA inhibition mediated by siRNA against NKILA was shown to significantly reduce ERS and autophagy, activate the NF-kB pathway, decrease neurological deficits, brain edema, and injury, and induce blood-brain barrier breakdown, further leading to hippocampal neuron loss and the production of inflammation cytokines. Taken together, the demonstration that NKILA induces the ERS/autophagy pathway and inhibits the NF-kB pathway after ICH supports the concept that NKILA functions as a novel target that is required for the attenuation of brain injuries after ICH., (© 2018 Wiley Periodicals, Inc.)

Background and purpose The pathogenesis of brain injury after intracerebral hemorrhage is thought to be due to mechanical damage followed by ischemic, cytotoxic, and inflammatory changes in the underlying and surrounding tissue.In recent years, there has been a greater research interest into the various inflammatory biomarkers and growth factors that are secreted during intracerebral hemorrhage. The biomarkers investigated in this study are tumor necrosis factor alpha (TNF alpha), C-reactive protein (CRP), homocysteine (Hcy), and vascular endothelial growth factor (VEGF). The aim of this study was to further investigate the effects of these biomarkers in predicting the acute severity outcome of intracerebral hemorrhage (ICH). Methods We conducted a retrospective chart review of patients with spontaneous ICH with TNF alpha, CRP, VEGF, and Hcy levels drawn on admission. Forty-two patients with spontaneous ICH with at least one of the above labs were included in the study. Primary outcomes included death, Glasgow Coma Scale (GCS) on admission, early neurologic decline (END), and hemorrhage size. Secondary outcomes included GCS on discharge, ICH score, functional outcome risk stratification scale of intracerebral hemorrhage (FUNC score), change in hemorrhage size, need for surgical intervention, and length of intensive care unit (ICU) stay. Results Forty-two patients with spontaneous intracerebral hemorrhage (ICH) were analyzed, 12 patients (28.5%) required surgical intervention, and four patients (9.5%) died. Only low VEGF serum values were found to predict mortality. TNF alpha, CRP, Hcy, and VEGF levels in our patients with ICH were not found to predict early neurologic decline and were not correlated with GCS on admission, initial hemorrhage size, change in hemorrhage size, need for surgical intervention, ICH score, FUNC score, midline shift, and length of ICU stay. CRP and Hcy were elevated in 58% and 31% of patients tested, respectively. GCS on admission and ICH score were significantly associated with mortality. Conclusion After careful statistical review of the data obtained from this patient population, only low VEGF values were found to be a significant predictor of mortality. However, elevated CRP and Hcy levels were associated with a non-significant trend in hemorrhage size and mortality suggesting that CRP and Hcy-lowering therapies may decrease hemorrhagic stroke risk and severity., Competing Interests: The authors have declared that no competing interests exist.

Stroke causes death or long-term disabilities and threatens the general health of the population worldwide. Recent studies have suggested that miRNAs are dysregulated and can be used as biomarkers for diagnosis and prognosis in stroke. The intracerebral hemorrhage (ICH) accounts for 15% of all the stroke cases. However, at present, little is known regarding the functions and clinical implications of miRNAs in ICH. In the present study, we established the collagenase-induced rat ICH model to mimic human ICH syndrome. We profiled the expression of 728 rat miRNAs at different time points in rat brain tissues and plasma post-ICH and identified a set human brain-enriched miRNAs that had changed expression level in the plasma of rat ICH. Among them, the expression levels of miR-124 displayed significantly synchronous alterations in rat plasma and brain tissue during ICH progression. They were significantly elevated at the acute injury phase (day 1 and 2), gradually decreased during the delayed recovery phase (day 7, 14 and 30), and finally restored to normal levels at late recovery phase (day 60). We further determined the plasma expression profile of miR-124 from human ICH patients. Similar to the pattern observed in rat ICH model, our results indicated that immediately after patients reached the hospital, the average plasma concentrations of miR-124 increased more than 100-fold in 24 h, then decreased gradually on day 2, 7, 14 and to near normal level on day 30. Taken together, these results strongly suggested that plasma concentration of miR-124 is a promising candidate biomarker for the early detection and predictive prognosis of human ICH.