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The management of intracerebral hemorrhage (ICH) requires prompt diagnostic assessment and recognition. Accurate localization and categorization of ICH-type is crucial. There are two main categories of ICH: 1) hemorrhagic stroke (HS), which occurs in the deeper or subcortical regions of the brain, where the arterial network tapers to fine end-arteries, and, 2) cerebral amyloid angiopathy hemorrhage (CAAH), which occurs at the superficial or cortical-subcortical region of the grey and white matter junction. Computed tomography (CT) and magnetic resonance imaging (MRI) are the most used imaging tools in diagnosing ICH. However, availability, time, and cost often prevent emergent MRI use. Therefore, CT remains the primary tool in the diagnosis of ICH. The assessment of imaging studies is time-dependent, and a radiologist should do a detailed diagnostic evaluation. Human error can occur in a pressured clinical setting, even for highly trained medical professionals. Assisted or automated computer-aided analysis of CT/MRI may help to reduce the assessment time, improve the diagnostic accuracy, better differentiate between types of ICH, and reduce the risk of human errors. This review evaluates CT and MRI's role in distinguishing between the two varieties of ICH-HS and CAAH. It focuses on how CT could be utilized as the preferred diagnostic tool. In addition, we discuss the role of automation using machine learning (ML) and the role or advantages of ML in the automated assessment of CT for the detection and classification of HS and CAAH. We have included our observations for future research and the requirements for further evaluation. [ABSTRACT FROM AUTHOR]

• A novel symmetric independent antenna pair (SIAP) sensor was designed for precise detection and monitoring of ischemia stroke (IS). • The SIAP sensor demonstrates its capability to differentiate between intracerebral hemorrhage and cerebral ischemia. • Animal experiments have confirmed that the SIAP sensor can effectively detect compensatory increases in cerebral blood flow on the healthy hemisphere following IS. Unlike intracerebral hemorrhage (ICH), the initial intracranial dielectric constant changes in IS are subtle and difficult to detect. Considering that the brain is approximately axisymmetric and the IS-affected hemisphere does not impact the healthy hemisphere, this study proposes a symmetric independent antenna pair (SIAP) sensor. The SIAP sensor consists of two inverted F-antennas positioned symmetrically at 150°, with additional shielding on the ground plane to minimize crosstalk. A realistic brain anatomical model was developed to analyze its Front to Back Ratio (FBR) performance and electromagnetic (EM) wave energy distribution. Subsequently, electromagnetic simulation experiments specific to IS were conducted. Additionally, experiments on rabbits with IS and ICH were carried out. The observed trends in S11 amplitude changes between the ICH and IS groups were distinct, with changes significantly higher in the ICH group compared to the IS group, yet both markedly higher than in the healthy state. This further validates the sensor's capacity to differentiate between ICH and IS. Notably, animal experiments have underscored the sensor's capacity to identify compensatory increases in cerebral blood flow in the unaffected hemisphere post-cerebral ischemia. These findings underscore the potential of the SIAP sensor as a novel approach for swift and accurate IS diagnosis and real-time monitoring. [ABSTRACT FROM AUTHOR]

Yi-Qi-Huo-Xue Decoction (YQHXD), a traditional Chinese medicine formula, has demonstrated efficacy in the clinical treatment of intracerebral hemorrhage (ICH) for over a decade. Nevertheless, the precise pharmacotherapeutic compounds of YQHXD capable of penetrating into cerebral tissue and the pharmacological underpinnings of YQHXD remain ambiguous. The active components of YQHXD in rat brains was analyzed by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. The potential targets, pathways and biological progresses of YQHXD ameliorating ICH induced injury was predicted by network pharmacology. Moreover, collagenase-induced ICH rat model, primary cortex neurons exposed to hemin and molecular docking were applied to validate the molecular mechanisms of YQHXD. Eleven active components of YQHXD were identified within the brains. Employing the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, our investigation concentrated on the roles of autophagy and the BDNF/TrkB signaling pathway in the pharmacological context. The pharmacological results revealed that YQHXD alleviated neurological dysfunction, brain water content, brain swelling, and pathological injury caused by ICH. Meanwhile, YQHXD inhibited autophagy influx and autophagosome in vivo, and regulated cortex neuronal autophagy and TrkB/BDNF pathway both in vivo and in vitro. Subsequently, N-acetyl serotonin (NAS), a selective TrkB agonist, was employed to corroborate the significance of the BDNF/TrkB pathway in this process. The combination of NAS and YQHXD did not further enhance the protective efficacy of YQHXD in ICH rats. Additionally, outcomes of molecular docking analysis revealed that nine compounds of YQHXD exhibited potential regulatory effects on TrkB. Ipsilateral neuronal autophagy and BDNF/TrkB pathway were activated 72 h after ICH. YQHXD effectively resisted injury induced by ICH, which was related with suppression of ipsilateral neuronal autophagy via BDNF/TrkB pathway. This study provides novel insights into the therapeutic mechanisms of traditional Chinese medicine in the context of ICH treatment. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhage (ICH) is a neurosurgical emergency. Combined decompressive hemicraniectomy (DHC) and minimally invasive parafascicular surgery (MIPS) may provide a practical method of managing subcortical ICH. 1) To present a case series of combined DHC-MIPS for the treatment of subcortical-based ICH; 2) to describe technical nuances of DHC-MIPS; and 3) to provide a literature overview of MIPS for ICH. The following inclusion criteria were used: 1) Glasgow Coma Scale (GCS) score <3–4; 2) admission within 6 hours of onset; 3) increased intracranial pressure caused by hemorrhage; 4) patient unresponsive to medical management; 5) hemorrhage >30 cm3; 6) subcortical location; and 7) midline shift (mm). Before DHC, sulcal cannulation used the following coordinates: intersection of tragus-frontal bone and midpoint of midpupillary line and midline; coronal suture: 3–4 cm posterior to this point). Three patients were selected: a 62-year old woman, a 45-year old woman, and a 36-year-old man. GCS and ICH scores on admission were 7 and 3, 3 and 4, and 3 and 4, respectively. ICH was located in left basal ganglia in patients 1 and 3 and right basal ganglia in patient 2, all with intraventricular extension. ICH volume was 81.7, 68.2, and 42.3 cm3, respectively. The postoperative GCS score was 11, 10, and 6, respectively. There were no intraoperative complications or mortalities. Evacuation was within 15 minutes in all patients. The modified Rankin Scale score was 3, 4, and 5, respectively, with semi-independence in case 1. Combined DHC-MIPS, with the use of craniometric points, can provide a unique and simple surgical option for the management of subcortical ICH. [ABSTRACT FROM AUTHOR]

• Astrocytosis left around delayed lesion without TNFα secretion after ICH. • FTY720 lessened delayed lesion including delayed WMI and neuron loss. • FTY720 inhibited glial responses and TNFα secretion of microglia after ICH. • FTY720 reduced iron content in delayed lesion without affecting volume of hematoma and initial lesion after ICH. • FTY720 improved the long-term outcome including depressive-like behavior and recognition memory impairment without affecting grip motor function recovery after ICH. 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. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhage (ICH) remains the most lethal type of stroke, and effective clinical therapies that can speed up hematoma resolution after ICH are still lacking. While the beneficial effects of IL-10 on ICH recovery have been demonstrated, the clinical translation of IL-10 requires effective delivery methods by which sufficient IL-10 can be delivered to ICH-affected regions in the brain. Here we report the use of a phosphatidylserine (PS) liposome (PSL)-based nanoparticle system for microglia/macrophage-targeted delivery of IL-10 in ICH. We first prepared IL-10-conjugated PSL (PSL-IL10) and characterized their immunomodulating effects in vitro. Then we evaluated the therapeutic effects, including hematoma absorption, short-term outcomes, and neuroinflammation, of intranasally administered PSL-IL10 (3 μg IL-10 per mouse, 2 h post-ICH) in a collagenase-induced ICH mouse model. We also isolated microglia/macrophages from the mouse brains with ICH to analyze their morphology, phagocytosis ability, and polarization. Our study reveals that, 1) PSL-IL10 treatment resulted in significantly improved outcomes and accelerated hematoma resolution in the acute phase of ICH; 2) PSL-IL10 inhibited glial activation and down-regulated pro-inflammatory cytokine production; 3) PSL-IL10 induced Iba1+ cells with a stronger phagocytosis ability; 4) PSL-IL10 activated STAT3 and upregulated CD36 expression in microglia/macrophage. These findings collectively show that PSL-IL10 is a promising nanotherapeutic for effectively ameliorating ICH. [Display omitted] • An efficient and targeted delivery method is needed for Interleukin-10-based intracerebral hemorrhage therapy. • Phosphatidylserine-liposomes offer a promising avenue for targeted delivery to microglia/macrophages in the brain. • Intranasally administered nanotherapeutic exhibits significantly enhanced therapeutic outcomes in a mouse model. • The study represents an innovative nanotherapeutic strategy for the effective treatment of intracerebral hemorrhage. [ABSTRACT FROM AUTHOR]

Peroxisome-proliferator-activated receptor co-activator-1α (PGC-1α) is a transcriptional co-activator that coordinately regulates genes required for mitochondrial biogenesis, which stimulates mitochondrial activity. It is also a major factor in the up-regulation of antioxidant activities that are a response to oxidative stress. However, the role of PGC-1α after intracerebral hemorrhage (ICH) has not been studied. The purpose of the present work was to investigate the effects and mechanism of PGC-1α after ICH in the brain. Brain injury was induced by injecting autologous arterial blood (50 μL) into the rat brain. PGC-1α siRNAs were injected into rat brains 24 h prior to ICH. Then, 72 h after ICH, brains were collected for investigation. Post-assessment included western blot analysis, RT-PCR assay, neurobehavioral function testing, measurement of brain water content, high-performance liquid chromatography (HPLC), and projection electron microscopy on ICH rat models. The concentration of PGC-1α was higher in the ipsilateral striatum after ICH, peaking around 72 h after ICH. The expression of NRF-1, TFAM, SOD2, UCP2, mitochondrial DNA, ATP concentration, mitochondrial quantity, and brain water content were increased 72 h after ICH. However, the neurological score was decreased 72 h after ICH. Treatment with PGC-1α siRNAs significantly decreased the neurological score, ATP concentration, number of mitochondria, expression of NRF-1, TFAM, SOD2, UCP2, and mitochondrial DNA, and increased brain water content and formation of mitochondrial myelin layer structures. In conclusion, our data suggest that PGC-1α protects rat brains via a mitochondrial pathway following ICH. Key words: PGC-1α intracerebral hemorrhage(ICH); mitochondrial; neuroprotection. [ABSTRACT FROM AUTHOR]

Urocortin exerts neuroprotective effects in intracerebral hemorrhage (ICH) of rats. For pre-clinical trial, we intended to study the neuroprotective efficacy of human UCN (hUCN)-1, -2 and -3 in treating ICH rats. ICH was induced by infusing bacterial collagenase VII (0.23 U in sterile saline) to the striatum. The hUCN-1, -2, and -3 were administrated (2.5 μg/kg, i.p.) at 1 h after ICH insult, respectively. Neurological deficits were evaluated by modified Neurological Severity Scores. Brain edema and hematoma expansion was evaluated by coronal T2-WI and DWI magnetic resonance imaging on 1, 3, 6, 24, and 56 h after ICH insult. Blood–brain barrier permeability was evaluated by Evans blue assay on day 3 after ICH. Brain lesion volume was evaluated by morphormetric measurement on day 7 after ICH. Our results demonstrated that the hUCN-1 significantly reduced hematoma, blood–brain barrier disruption and neurological deficits on day 3, and brain lesion volume on day 7 after ICH insult. The prediction of secondary structure of the hUCNs clarifies that the percentage of alpha-helix, random coil and extended strand between rat-UCN (rUCN)-1 and hUCN-1 are the same. The structure similarity between human- and rat-UCN-1 may be one of the reasons that both can exert similar therapeutic potential in ICH rats. [ABSTRACT FROM AUTHOR]

Abstract: Healthy SD rats were randomly divided into 3 groups as sham operation (group A), ICH (group B), and HBO2 (group C). The behavioral change and angiogenesis in brain tissue of rats in each group were observed. The protein expression of PCNA, vWF, HIF1-α, and VEGF in rat brain was measured by immunohistochemistry, while the mRNA expression level of HIF1-α and VEGF was determined using quantitative real-time PCR. This study has investigated the effect of HBO2 on intracephalic angiogenesis in rats with intracerebral hemorrhage (ICH). There were significant differences in behavior score between HBO2 and ICH groups at 14, 21, and 28days. A large number of vessel-like structures and microvessels were observed in perihematomal brain tissues in HBO2 group. There were significant differences in HIF1-α and VEGF protein and HIF1-α mRNA level between HBO2 and ICH groups at 14, 21, and 28days; at 7, 14, 21, and 28days, the differences in PCNA and vWF protein expression between the 2 groups were statistically significant. At 21 and 28days, the expression levels of VEGF mRNA in the 2 groups differed significantly from each other. Our results indicate that HBO2 can significantly promote the expression of HIF1-α and VEGF at both mRNA and protein levels in rats with ICH, increase the protein expression of both PCNA and vWF, promote the formation of new blood vessels, and promote the recovery of behavioral ability, hence resulting in a rapid rehabilitation. [Copyright &y& Elsevier]

Highlights: [•] Fully novel rat model of ICH with ventricular extension, one week of MRI follow-up. [•] Brain edema peaking at 48h after hemorrhage in all groups. [•] Progressive hydrocephalus in most of the subjects, peaking in ⩾200μL groups. [•] Worst neurological outcome in groups injected with ⩾200μL of autologus blood. [•] Mortality rate similar to the clinical scenario in ⩾200μL groups. [ABSTRACT FROM AUTHOR]

Highlights: [•] Administering SMTC decreased the activity of NADH-d in the ICH brain. [•] SMTC treatment reduced activation of gelatinolytic enzymes after ICH. [•] SMTC decreased the loss of laminin- and occludin-stained vessels in the ICH brain. [•] SMTC treatment reduced neuronal death in the perihematomal region. [•] The administration of SMTC improved neurological deficits after ICH. [ABSTRACT FROM AUTHOR]

Background: Anticoagulated patients with intracranial hemorrhage represent a major management challenge. Our goal is to determine how patient characteristics and management decisions influence outcome. Methods: A systematic review of the literature identified relevant reported cases. Variables describing patient characteristics, management, and outcome were extracted. Statistical analyses were carried out using analysis of variance and Fisher's exact test. Results: A total of 242 patients from our updated dataset met inclusion criteria. Tissue plane of the hemorrhage (P < 0.0001), indication for anticoagulation (P < 0.0001), type of anticoagulant (P = 0.0173), and history of hypertension (P = 0.0418) were significantly associated with outcome. Older age (P < 0.0001), supratentorial index hemorrhages (P = 0.0018), failure to restart anticoagulation (P < 0.0001), and larger hematoma volume (P < 0.0001) were associated with worse outcome. Surgical evacuation was associated with improved outcome (P = 0.0011). There was a trend toward an association between the occurrence of a hemorrhagic or thromboembolic complication and risk of death (P = 0.0882). Sex and sidedness of the index hemorrhage were not significantly associated with outcome. Conclusions: Our results provide prognostic information that may assist management of these patients. Our results also suggest that it may be unwise to withhold anticoagulation indefinitely after an index hemorrhage. As thromboembolic or hemorrhagic complications may be associated with worse outcome, efforts to avoid them may be wise. The studies that comprise our dataset have important limitations and a prospective study will be required to confirm these results. [Copyright &y& Elsevier]

Highlights: [•] Causes of bleeding. [•] Natural history of ICH. [•] ICH animal models. [•] Systemic responses after ICH. [•] Therapeutic targets and ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Highlights: [•] RBC lysis aggravates ICH-induced inflammatory injury through TLR signaling. [•] Molecules released from dead cells mediate ICH-induced inflammatory injury. [•] Multiple inflammatory pathways are therapeutic targets for treating ICH. [•] TLR signaling may provide novel therapeutic targets for the treatment of ICH. [•] Researches on ICH pathogenesis will help to identify novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Intracerebral hemorrhage (ICH) is a major clinical concern with anticoagulation therapy. The effect of a new oral direct FXa inhibitor, edoxaban, was determined in a rat model of ICH and compared with a direct thrombin inhibitor, melagatran, and heparin. Methods: To induce ICH, 0.1 U collagenase type VII was injected into the striatum of male Wistar rats under anesthesia with thiopental or halothane. Immediately after ICH induction, edoxaban, melagatran, or heparin were infused intravenously. Five hours after ICH induction, the brain was removed and ICH size was measured. To estimate the margin of safety, antithrombotic effects were evaluated in a rat venous thrombosis model. Results: Edoxaban at 6mg/kg/h significantly increased ICH volume (1.8-fold) and prolonged prothrombin time (PT) 2.8-fold compared to the vehicle group. No deaths were observed with edoxaban. Melagatran at 1mg/kg/h increased ICH volume at 1mg/kg/h (2.8-fold) with 6.1-fold PT prolongation. At 3mg/kg/h, all rats died due to severe ICH (3.9-fold). Heparin at both 100 and 500U/kg/h significantly increased ICH. At 500U/kg/h, 5 out of 8 rats died. The doses required for 50% inhibition of thrombosis of edoxaban, melagatran, and heparin were 0.045mg/kg/h, 0.14mg/kg/h, and 55U/kg/h, respectively. The safety margins between antithrombotic and ICH exacerbation effects of these anticoagulants were 133, 7.1, and 1.8, respectively. Conclusion: The safety margin of edoxaban was wider than that of melagatran or heparin. These results suggest that edoxaban may be preferable from the perspective of ICH exacerbation risk. [Copyright &y& Elsevier]

Background: Chronic renal failure (CRF) is associated with a high incidence of stroke. In particular, the mortality rate for intracerebral hemorrhage (ICH) patients with hemodialysis (HD) due to advanced stage CRF is high, and the annual number of such cases is increasing. Therefore, we retrospectively investigated 5 years of clinical data from patients with ICH in our institution to reveal differences in the clinical courses of HD and non-HD patients and to identify risk factors for poor outcomes in ICH patients with HD. Methods: Three hundred sixty-six consecutive patients with nontraumatic spontaneous ICH, 91% of whom did not receive HD (non-HD group) and 9% of whom received HD for the treatment of CRF (HD group), were enrolled. Clinical data, including the presence of intraventricular hemorrhage (IVH), microbleeds, modified Rankin scale scores, previous medical disease history, the presence of HD, and the days on which ICH occurred, were evaluated. Results: In a comparison of HD patients and non-HD patients, the HD patients had higher rates of hematomas in the basal ganglia, IVH, use of antihypertensive drugs, antidiabetic drugs, and antiplatelet/anticoagulants. The mortality rate was higher in the HD group (44%) than in the non-HD group (21%). In the HD group, the risk factors associated with mortality were hematoma volume, the presence of IVH, and lack of antihypertensive drug use. Eighty-five percent of the ICH occurred on intermittent HD days or before the HD procedure on an HD day. Conclusions: Mortality in ICH patients with HD was associated with lack of antihypertensive drug use. Therefore, strict control of blood pressure is needed in HD patients to prevent ICH, especially on intermittent HD days or before the HD procedure. [ABSTRACT FROM AUTHOR]

Highlights: [•] Motor skills training improved the motor deficit after intracerebral hemorrhage. [•] Neurons in the motor cortex were activated by the training after the lesion. [•] Training after the lesion caused synaptic plasticity in the motor cortex. [•] Training after the lesion caused synaptic plasticity in the striatum. [ABSTRACT FROM AUTHOR]

Highlights: [•] G-CSF can up-regulate perihematomal VEGF and AQP4 expression after ICH. [•] G-CSF activates STAT3 and ERK pathways to up-regulate VEGF and AQP4 respectively. [•] G-CSF has protective effects on perihematomal tissue injuries following ICH. [•] The above effects of G-CSF on ICH were VEGF and AQP4 dependent. [Copyright &y& Elsevier]

Highlights: [•] Pharmacologically induced hypothermia (PIH) was achieved in an intracerebral hemorrhage (ICH) stroke model of the mouse. [•] PIH initiated either 1 or 24h after ICH reduced brain edema, BBB disruption, and cell death in the ICH brain. [•] PIH decreased the expression of MMP-9 and caspase-3 and increased the bcl-2 level in the ICH brain. [•] PIH treatment showed potential of improving functional recovery after hemorrhagic stroke. [Copyright &y& Elsevier]

Highlights: [&#x2022;] Carvacrol has protective effects on ICH. [&#x2022;] Carvacrol alleviates cerebral edema in a dose-dependent manner. [&#x2022;] Carvacrol reduces AQP4 expression after ICH. [ABSTRACT FROM AUTHOR]

Highlights: [•] We assessed the therapeutic effect of iPSCs in experimental ICH rat. [•] Therapeutic effects of iPSCs in rat ICH model were observed. [•] The grafted iPSCs exhibited neural cell-specific biomarkers in the brain of ICH rats. [•] The levels of BDNF and VEGF were enhanced in the surrounding region of hematoma. [•] Functional improvement is partially due to neuronal replacement and neurophic factors. [ABSTRACT FROM AUTHOR]

Highlights: [•] rt-PA treatment does not prolong active bleeding in experimental ICH. [•] rt-PA treatment does not increase hematoma volume in experimental ICH. [•] 72h observation does not show increased mortality of rt-PA-treated mice. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: We aimed to investigate the expression of T cell immunoglobulin and mucin domain 3 (Tim-3) on peripheral blood cells in spontaneous intracerebral hemorrhage (ICH) patients and to analyze its clinical significance. Design and methods: Tim-3 expression on peripheral immunocytes from ICH patients and healthy volunteers was measured by flow cytometry. The correlation between Tim-3 expression and the clinical indices was estimated using linear regression. Results: Tim-3 expressions on peripheral CD3+ T cells and CD8+ T cells in ICH patients are significantly downregulated, while Tim-3 expressions on CD14+ monocytes and CD16+CD56+ NK cells are increased. Furthermore, Tim-3 expression on peripheral CD8+ T cells was negatively correlated with the inflammatory response, the disease severity and the outcome of ICH patients. However, there was no relationship between Tim-3 expression and blood glucose concentration. Conclusions: Altered expression of Tim-3 might play an important role in the pathogenesis of ICH, demonstrating that Tim-3 might be a novel candidate molecule for prognosis evaluation of ICH patients. [Copyright &y& Elsevier]

Objective: To describe epidemiology in relation to gender differences and treatment modalities 10 years after intracranial aneurysm rupture in the Stockholm cohort 1996–1999. Methods: A total of 468 consecutive patients with aneurysmal subarachnoid hemorrhage were followed-up in a retrospective cohort design 10 years after rupture. Information on medical history, clinical variables, and treatments were obtained from patient records. Causes of death were obtained from patient records and The Swedish Cause of Death Register. Incidence of ruptured aneurysms per 100,000 people were calculated from male, female, and overall population data per year from 1996–1999. Results: Ten years after aneurysm rupture 63.9% (n = 296) of patients were still alive. The overall 28-day case fatality was 19.4%; most often deaths were due to the initial hemorrhage. There were no significant differences in survival time between patients treated with clipping (8.4 years, 95% confidence interval 8.1–8.8), compared with endovascularly treated patients (8.2 years, 95% confidence interval 7.4–9.1) (log rank P = 0.550). The female incidence was higher than that of men, and women were significantly older at the onset of aneurysm rupture (55.7 vs. 52.8 years, P = 0.027). Conclusions: Ten years after rupture, most treated patients were still alive. The mortality was highest in the first month after rupture, due to the initial hemorrhage. Gender differences were apparent in incidence, but 10 years after the rupture mortality rates and survival times were equal between men and women. Survival time was equal between patients within active treatment modalities. [Copyright &y& Elsevier]

Highlights: [•] We reprogrammed ICH patient's skin cells into iPSCs. [•] The iPSCs can differentiate into NES cells and neural cells in vitro. [•] Therapeutic effects of iPSC-derived NES cells in rat ICH model were observed. [•] The grafted NES cells differentiated into neural cells in the brain of ICH rats. [•] Functional improvement of ICH rat is partially due to neuronal replacement. [ABSTRACT FROM AUTHOR]

Highlights: [•] We examined the efficacy of ethyl pyruvate (EP) after ICH in mice. [•] EP protected primary neuron from hemoglobin-induced cell death in vitro. [•] EP reduced cell degeneration, brain edema and improved neurological function. [•] EP inhibited microglia and NF-κB activation, TNF-α and IL-1β production. [ABSTRACT FROM AUTHOR]

Highlights: [•] HNG attenuated behavioral deficits and brain edema after ICH. [•] HNG decreased ICH-induced cell insults in hemorrhagic core and peripheral fields. [•] HNG reduced ICH-induced lesion volume. [•] HNG suppressed ICH-induced apoptosis through PI3K-Akt/GSK-3β signaling pathway. [ABSTRACT FROM AUTHOR]

Highlights: [•] Red fluorescent protein (RFP) expression was evaluated as a cell viability marker in an intracerebral hemorrhage model. [•] Fluorescence loss correlated with cell death as measured by MTT assay. [•] The RFP transgene was incorporated into HO-2 knockout and wild-type mice. [•] HO-2 had no effect on fluorescence loss, in agreement with other outcome measures. [Copyright &y& Elsevier]

Highlights: [•] R-7050, a novel TNFR antagonist, reduces neurovascular injury after ICH. [•] Pharmacological inhibition of TNFR improves outcomes after ICH. [•] TNFR may represent a viable therapeutic target after ICH. [ABSTRACT FROM AUTHOR]

Summary: Human umbilical cord blood (HUCB) is now considered as a valuable source for stem cell-based therapies. Previous studies showed that intravascular injection of the HUCB significantly improves neurological functional recovery in a model of intracerebral hemorrhage (ICH). To extend these findings, we examined the behavioral recovery and injured volume in the presence of increasing doses of human umbilical cord blood derived mononuclear cells (HUC-MCs) after intracerebral hemorrhage in rats. The experimental ICH was induced by intrastriatal administration of bacterial collagenase IV in adult rats. One day after the surgery, the rats were randomly divided into 4 groups to receive intravenously either BrdU positive human UC-MCs (4×106, 8×106 and 16×106 cells in 1ml saline, n =10, respectively) as treated groups or the same amount of saline as lesion group (n =10). There was also one group (control n =10) that received only the vehicle solution of collagenase. The animals were evaluated for 14 days with modified limb placing and corner turn tests. The transplanted human UC-MCs were also detected by immunohistochemistry with labeling of BrdU. Two weeks after infusion, there was a significant recovery in the behavioral performance when 4×106 or more UC-MCs were delivered (P <0.05–0.001). Injured volume measurements disclosed an inverse relationship between UC-MCs dose and damage reaching significance at the higher UC-MCs doses. Moreover, human UC-MCs were localized by immunohistochemistry only in the injured area. Intravenously transplanted UC-MCs can accelerate the neurological function recovery of ICH rat and diminish the striatum lesion size by demonstrating a dose relationship between them. [Copyright &y& Elsevier]

Abstract: Cerebral edema is a devastating consequence of brain injury leading to cerebral blood flow compromise and worsening parenchyma damage. In the present study, we investigated the effects of arginine-vasopressin (AVP) V1a receptor inhibition following an intracerebral hemorrhagic (ICH) brain injury in mice and closely assessed the role it played in cerebral edema formation, neurobehavioral functioning, and blood–brain-barrier (BBB) disruption. To support our investigation, SR49059, an AVP V1a receptor competitive antagonist, and NC1900, an arginine-vasopressin analogue, were used. Male CD1 mice (n =205) were randomly assigned to the following groups: naïve, sham, ICH, ICH with SR49059 at 0.5mg/kg, ICH with SR49059 at 2mg/kg, ICH with NC1900 at 1ng/kg, ICH with NC1900 at 10ng/kg, and ICH with a combination of SR49059 at 2mg/kg and NC1900 at 10ng/kg. ICH was induced by using the collagenase injection model and treatment was given 1h after surgery. Post assessment was conducted at 6, 12, 24, and 72h after surgery and included brain water content, neurobehavioral testing, Evans Blue assay, western blotting, and hemoglobin assay. The study found that inhibition of the AVP V1a receptor significantly reduced cerebral edema at 24 and 72h post-ICH injury and improved neurobehavioral function while reducing BBB disruption at 72h. Western blot analysis demonstrated increased protein expression of aquaporin 4 (AQP4) in vehicle, which was reduced with AVP V1a receptor inhibition. Our study suggests that blockage of the AVP V1a receptor, is a promising treatment target for improving ICH-induced brain injury. Further studies will be needed to confirm this relationship and determine future clinical direction. [Copyright &y& Elsevier]

Apolipoprotein E (Apo E) is an important genetic risk factor for multiple neurological, vascular and cardiovascular diseases. Previously, we reported Apo E isoprotein-specific modulation of tissue plasminogen activator (tPA) using an in vitro blood-clotting assay. Here, we studied the conformational changes of Apo E2, E3 and E4 in the presence of tPA and vice versa using circular dichroism (CD) and dual polarization interferometry (DPI). We report isoprotein and state-specific intermolecular interactions between the Apo E isoforms and tPA. Apo E2 interaction with immobilized tPA leads to significant conformational changes which are not observed with Apo E3 or E4. Additionally, tPA induces changes in helicity of lipidated Apo E2 whereas no detectible changes were observed in Apo E3 or E4. The Tukey''s test for interaction indicated a significant (P<0.001) interaction between tPA and Apo E2 in the lipidated environment. These results may be important regarding the mechanism by which Apo E has isoprotein-specific effects on many biological processes and diseases involving blood clotting, proteolysis and perfusion. [Copyright &y& Elsevier]

Atrial fibrillation (AF) is an important risk factor for stroke. According to a pooled analysis of controlled clinical trials with warfarin, anticoagulation therapy reduces stroke risk by 62%. However, clinicians must decide whether the benefit of long-term anticoagulation therapy with available agents outweighs the risk of bleeding for individual patients. Guidelines issued by the American College of Chest Physicians and by the joint American College of Cardiology, American Heart Association, and the European Society of Cardiology task force recommend antithrombotic therapy to protect AF patients from stroke based on risk-stratification algorithms. Risk factors for stroke AF patients include age ≥75 years; hypertension; thyrotoxicosis; diabetes; cardiovascular disease; congestive heart failure; and history of stroke, transient ischemic attack, or thromboembolism. Patients at high risk for stroke experience greater absolute benefit from anticoagulation therapy than patients at low risk. The guidelines are consistent in recommendations for high-risk patients (warfarin therapy, international normalized ratio 2.0 to 3.0) and low-risk patients (aspirin 325 mg), but differ for intermediate-risk patients with diabetes or heart disease. The guidelines continue to evolve, and future guidelines are likely to incorporate new clinical data, including the CHADS2 algorithm for determining risk and the results of the Atrial Fibrillation Follow-up Investigation of Rhythm Management trial, the Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation study, and the Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation II to V trials. [Copyright &y& Elsevier]

Stroke is a major clinical problem, and acute pharmacological intervention with neuroprotective agents has so far been unsuccessful. Recently, there has been considerable interest in the potential therapeutic benefit of nitrone-derived free radical trapping agents as neuroprotective agents. Nitrone compounds have been shown to be beneficial in animal models of various diseases, and the prototypic compound α-phenyl-N-tert-butylnitrone (PBN) has been extensively demonstrated to be neuroprotective in rat models of transient and permanent focal ischemia. The nitrone radical trapping agent disodium 2,4-disulfophenyl-N-tert-butylnitrone (NXY-059) has also been shown to be neuroprotective in these models. Furthermore, it has recently been shown to improve neurological function and reduce infarct volume in a primate model of permanent focal ischemia even when given 4 hr postocclusion. While radical trapping activity is demonstrable with NXY-059 and other nitrone compounds such as PBN, this activity is weak. Arguments for and against ascribing radical trapping as the therapeutic mechanism of action are discussed. This compound is well tolerated in human stroke patients and can be administered to produce plasma concentrations exceeding those effective in animal models; crucially, at the same time, it has also been shown to be effective in animal models. NXY-059 may thus be the first compound to be examined in stroke patients using drug exposure and time to treatment that have been shown to be effective in animal models of stroke. [Copyright &y& Elsevier]

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]

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]

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: Cerebral venous thrombosis developing after surgical or endovascular obliteration of arteriovenous fistula (AVF) is a rare but devastating complication that has not been adequately reported. Case Description: Two patients presenting with AVF (1 pial, 1 dural) and large venous pouches were successfully treated by surgical and endovascular means and were neurologically intact postoperatively. Rapid neurologic deterioration was seen on postoperative day 5 in the first patient and postoperative day 2 in the second patient. Both patients had massive cerebral venous thromboses on brain imaging and surgical exploration. One patient died and the other was severely disabled. Conclusion: Rapid occlusion of a high-flow AVF resulting in significant venous stasis can precipitate thrombosis of the venous system distal to the fistulous point. In the presence of large venous pouches and significant venous stasis, strict therapeutic anticoagulation may be required to prevent cerebral venous thrombosis. Therapeutic anticoagulation, though feasible following endovascular treatment, may prove particularly challenging after open surgical interventions given the risk of hemorrhagic complications. [ABSTRACT FROM AUTHOR]

Background: The authors report a case of lateral posterior choroidal artery pseudoaneurysm that caused a spontaneous thalamic hemorrhage. The case supports obtaining computed tomographic angiography (CTA) even in seemingly routine cases of hypertensive hemorrhage and demonstrates a possibly unreported type of aneurysm causing thalamic hemorrhage. Case Description: A 60-year-old man with a history of hypertension presented with a spontaneous right thalamic hemorrhage, and CTA showed a focus of contrast inside the hematoma. One month later, the patient was well but a CTA showed that the hematoma had resolved but that there was enlargement of the contrast-enhancing lesion in the thalamus. Catheter angiography showed an aneurysm of the lateral posterior choroidal artery. This was excised via an occipital interhemispheric supratentorial subcallosal approach. The patient recovered fully and returned to work 3 months later. Conclusion: The case shows the need to carefully review CTA after ICH, even in cases of seemingly typical hypertensive ICH. [ABSTRACT FROM AUTHOR]