Ultra high b-value diffusion weighted imaging enables better molecular grading stratification over histological grading in adult-type diffuse glioma.

PURPOSE: Accurate preoperative radiological staging of adult-type diffuse glioma is crucial for effective prognostic stratification and selection of appropriate therapeutic interventions. The purpose of this study was to compare the effectiveness of apparent diffusion coefficient (ADC) maps generated from ultrahigh b-value diffusion-weighted imaging (DWI) for molecular grading with that for histological grading of adult-type diffuse glioma, and to evaluate the correlation between these ADC maps and molecular and histological biomarkers. METHODS: This study retrospectively enrolled forty adult-type diffuse glioma patients, diagnosed using the 2021 WHO classification criteria. Preoperative imaging data, including multiple b-value DWI and conventional magnetic resonance imaging, were collected. Tumors were graded using both histological and molecular criteria. Histogram analysis was conducted to generate 14 parameters for each tumor. Receiver operating characteristic curves and the area under the curve (AUC) were used to evaluate tumor grading and molecular status differentiation. Analysis of histological biomarkers was performed by calculating the Pearson and Spearman correlation coefficients of continuous and hierarchical variables, respectively. RESULTS: The intensity-related parameters for molecular grading were found to be superior to those for histological grading for the identification of WHO grade 4 (WHO4) adult-type diffuse glioma. The AUC of both grading systems increased with increasing b-values, with ADC8000-based histogram parameters showing the best results (molecular grading, square root: AUC = 0.897; histological grading, median: AUC = 0.737). The intensity-related parameters could also differentiate molecular WHO4 gliomas from histologically lower-grade gliomas (ADC8000-based square root: AUC = 0.919), and different ADC8000-based kurtosis was observed between molecular and histological WHO4 gliomas (AUC = 0.833). Significant correlations between the Ki-67 index and molecular status prediction for IDH, CDKN2A, and EGFR were also demonstrated. CONCLUSION: The histogram parameters derived from high b-value ADC maps were found to be more effective for differentiating molecular grades of WHO4 adult-type diffuse glioma than for differentiating histological grades.

Diffusion tensor imaging versus intraoperative subcortical mapping for glioma resection: a systematic review and meta-analysis.

Maintaining the integrity of crucial fiber tracts allows functional preservation and improved recovery in patients with glioma resection. Diffusion tensor imaging (DTI) and intraoperative subcortical mapping (ISM) are commonly required for pre- and intraoperative assessment of white matter fibers. This study investigated differences of clinical outcomes in glioma resection aided by DTI or ISM. A comprehensive literature retrieval of the PubMed and Embase databases identified several DTI or ISM studies in 2000-2022. Clinical data, including extent of resection (EOR) and postoperative neurological deficits, was collected and statistically analyzed. Heterogeneity was regressed by a random effect model and the Mann-Whitney U test was used to test statistical significance. Publication bias was assessed by Egger test. A total of 14 studies with a pooled cohort of 1837 patients were included. Patients undergoing DTI-navigated glioma surgery showed a higher rate of gross total resection (GTR) than ISM-assisted surgical resection (67.88%, [95% CI 0.55-0.79] vs. 45.73%, [95% CI 0.29-0.63], P = 0.032). The occurrence of early postoperative functional deficit (35.45%, [95% CI 0.13-0.61] vs. 35.60% [95% CI 0.20-0.53], P = 1.000), late postoperative functional deficit (6.00%, [95% CI 0.02-0.11] vs. 4.91% [95% CI 0.03-0.08], P = 1.000) and severe postoperative functional deficit (2.21%, [95% CI 0-0.08] vs. 5.93% [95% CI 0.01-0.16], P = 0.393) were similar between the DTI and ISM group, respectively. While DTI-navigation resulted in a higher rate of GTR, the occurrence of postoperative neurological deficits between DTI and ISM groups was comparable. Together, these data indicate that both techniques could safely facilitate glioma resection.

Metal-Organic Framework (MOF) Derivatives as Promising Chemiresistive Gas Sensing Materials: A Review.

The emission of harmful gases has seriously exceeded relative standards with the rapid development of modern industry, which has shown various negative impacts on human health and the natural environment. Recently, metal-organic frameworks (MOFs)-based materials have been widely used as chemiresistive gas sensing materials for the sensitive detection and monitoring of harmful gases such as NOx, H2S, and many volatile organic compounds (VOCs). In particular, the derivatives of MOFs, which are usually semiconducting metal oxides and oxide-carbon composites, hold great potential to prompt the surface reactions with analytes and thus output amplified resistance changing signals of the chemiresistors, due to their high specific surface areas, versatile structural tunability, diversified surface architectures, as well as their superior selectivity. In this review, we introduce the recent progress in applying sophisticated MOFs-derived materials for chemiresistive gas sensors, with specific emphasis placed on the synthesis and structural regulation of the MOF derivatives, and the promoted surface reaction mechanisms between MOF derivatives and gas analytes. Furthermore, the practical application of MOF derivatives for chemiresistive sensing of NO2, H2S, and typical VOCs (e.g., acetone and ethanol) has been discussed in detail.

Establishment and validation of a prediction model for self-absorption probability of chronic subdural hematoma.

Background: Chronic subdural hematoma (CSDH) is common in elderly people with a clear or occult traumatic brain injury history. Surgery is a traditional method to remove the hematomas, but it carries a significant risk of recurrence and poor outcomes. Non-surgical treatment has been recently considered effective and safe for some patients with CSDH. However, it is a challenge to speculate which part of patients could obtain benefits from non-surgical treatment. Objective: To establish and validate a new prediction model of self-absorption probability with chronic subdural hematoma. Method: The prediction model was established based on the data from a randomized clinical trial, which enrolled 196 patients with CSDH from February 2014 to November 2015. The following subjects were extracted: demographic characteristics, medical history, hematoma characters in imaging at admission, and clinical assessments. The outcome was self-absorption at the 8th week after admission. A least absolute shrinkage and selection operator (LASSO) regression model was implemented for data dimensionality reduction and feature selection. Multivariable logistic regression was adopted to establish the model, while the experimental results were presented by nomogram. Discrimination, calibration, and clinical usefulness were used to evaluate the performance of the nomogram. A total of 60 consecutive patients were involved in the external validation, which enrolled in a proof-of-concept clinical trial from July 2014 to December 2018. Results: Diabetes mellitus history, hematoma volume at admission, presence of basal ganglia suppression, presence of septate hematoma, and usage of atorvastatin were the strongest predictors of self-absorption. The model had good discrimination [area under the curve (AUC), 0.713 (95% CI, 0.637-0.788)] and good calibration (p = 0.986). The nomogram in the validation cohort still had good discrimination [AUC, 0.709 (95% CI, 0.574-0.844)] and good calibration (p = 0.441). A decision curve analysis proved that the nomogram was clinically effective. Conclusions: This prediction model can be used to obtain self-absorption probability in patients with CSDH, assisting in guiding the choice of therapy, whether they undergo non-surgical treatment or surgery.

The circ_FAM53B-miR-183-5p-CCDC6 axis modulates the malignant behaviors of papillary thyroid carcinoma cells.

Papillary thyroid carcinoma (PTC) is a common thyroid malignancy. Circular RNAs (circRNAs) have been implicated in the development of PTC. Here, we explored the function and mechanism of circRNA family with sequence similarity 53, member B (circ_FAM53B) in PTC pathogenesis. Circ_FAM53B, microRNA (miR)-183-5p and coiled-coil domain containing 6 (CCDC6) levels were gauged by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or Western blotting. The direct relationship between miR-183-5p and circ_FAM53B or CCDC6 was verified by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Our data showed that circ_FAM53B expression was reduced in PTC tissues and cells. Circ_FAM53B expression restrained proliferation, migration, and invasion and triggered apoptosis of PTC cells, as well as hindered HUVEC tube formation. Circ_FAM53B repressed miR-183-5p expression. MiR-183-5p re-expression reversed the effects of circ_FAM53B on cell behaviors. MiR-183-5p targeted and inhibited CCDC6, and circ_FAM53B upregulated CCDC6 through miR-183-5p competition. MiR-183-5p knockdown repressed cell proliferation, migration, invasion, and tube formation and facilitated apoptosis by upregulating CCDC6. Furthermore, circ_FAM53B reduced tumor growth in vivo. Collectively, our findings suggest that circ_FAM53B affects PTC cell biological behaviors via the miR-183-5p-CCDC6 axis.

Risk Factor Analysis of the Conservative Treatment in Chronic Subdural Hematomas: A Substudy of the ATOCH Trial.

INTRODUCTION: The objective of the study was to analyze the risk factors for worsening of the disease progression in patients with chronic subdural hematomas (CSDH) during wait-and-observation treatment regimen and conservative treatment with atorvastatin. METHODS: A total of 196 patients with CSDH were recruited (98 in the atorvastatin group and 98 in the blank placebo group). Receiver operating characteristic (ROC) curve analysis was used to identify the optimal cutoff for the hematoma volume by testing surgical and nonsurgical outcomes. Other measures, including univariate and multivariate analyses, were performed to identify the potential significant factors indicative of the outcome of therapeutic efficacy of conservative treatment through the characteristics of the baseline indicators at enrollment. RESULTS: Over a median treatment duration of 2 months, lower total cholesterol, higher hematoma volume, and more midline shift were independent risk factors for worse outcomes of atorvastatin treatment for CSDH, and only a higher hematoma volume was an independent risk factor for spontaneous absorption in the placebo group. ROC analysis of all of the data showed that the optimal threshold of hematoma volume was 68.5 ml (sensitivity 73.5%, specificity 74%) in response to the greatest chance of switching to surgery. CONCLUSIONS: Critical independent predictors of atorvastatin monotherapy treatment success included higher total cholesterol, lower hematoma volume, and less midline shift in atorvastatin monotherapy, and higher hematoma volume was the only independent risk factor in close follow-up observation patients without any pharmacotherapy. Initial hematoma volume more than 68.5 ml may help clinicians to determine individual risk assessments and to make optimal treatment decisions. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov . Identifier NCT02024373.

A Protective Role of Tumor Necrosis Factor Superfamily-15 in Intracerebral Hemorrhage-Induced Secondary Brain Injury.

Destabilization of blood vessels by the activities of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) following intracerebral hemorrhage (ICH) has been considered the main causes of aggravated secondary brain injury. Here, we show that tumor necrosis factor superfamily-15 (TNFSF15; also known as vascular endothelial growth inhibitor), an inhibitor of VEGF-induced vascular hyper-permeability, when overexpressed in transgenic mice, exhibits a neuroprotective function post-ICH. In this study, we set-up a collagenase-induced ICH model with TNFSF15-transgenic mice and their transgene-negative littermates. We observed less lesion volume and neural function perturbations, together with less severe secondary injuries in the acute phase that are associated with brain edema and inflammation, including vascular permeability, oxidative stress, microglia/macrophage activation and neutrophil infiltration, and neuron degeneration, in the TNFSF15 group compared with the littermate group. Additionally, we show that there is an inhibition of VEGF-induced elevation of MMP-9 in the perihematomal blood vessels of the TNFSF15 mice following ICH, concomitant with enhanced pericyte coverage of the perihematomal blood vessels. These findings are consistent with the view that TNFSF15 may have a potential as a therapeutic agent for the treatment of secondary injuries in the early phase of ICH.

Risk Factors for Atorvastatin as a Monotherapy for Chronic Subdural Hematoma: A Retrospective Multifactor Analysis.

Chronic subdural hematoma (CSDH) is a common form of intracranial hemorrhage in the aging population. We aimed to investigate the predictive factors for atorvastatin efficacy as a monotherapy for moderate CSDH. We retrospectively reviewed the medical records of patients who were diagnosed with moderate CSDH and received atorvastatin monotherapy between February 5, 2014, and November 7, 2015, in multiple neurosurgical departments. Univariate, multivariate and receiver operating characteristic curve analyses were performed to identify the potential significant factors indicative of the good therapeutic efficacy or poor therapeutic efficacy of atorvastatin for mild CSDH, such as age, sex, history of injury, Markwalder grading scale-Glasgow Coma Scale (MGS-GCS), Activities of Daily Life-the Barthel Index scale (ADL-BI), American Society of Anesthesiologists Physical Status classification system (ASA-PS), blood cell counts, serum levels and computed tomography findings. A total of 89 patients (75 men and 14 women) aged 24-88 years (mean age 61.95 ± 15.30 years) were followed-up for 24 weeks. Computed tomography findings at admission showed mixed-density hematoma in 22 patients, isodense hematoma in 13 patients, high-density hematoma in 26 patients, and low-density hematoma in 28 patients. In total, 3, 80, and 6 patients had MGS-GCS grades of 0, 1, and 2, respectively. The efficacy rate at 6 months was 87.6% (78/89). Eleven patients were switched to surgery due to a worsened neurological condition, of whom 8, 1, 1, and 1 had high-density, low-density, isodense and mixed-density hematomas, respectively. These patients were switched to surgery over a range of 2-27 days, with a median interval of 12 days after the medication treatment. Univariate and multivariate analyses, confirmed by ROC curves, revealed that high-density hematoma, basal cistern compression, and hematoma volume to be independent risk factors for the efficacy of atorvastatin monotherapy in patients with moderate CSDH. Atorvastatin is an effective monotherapy for the treatment of mild CSDH. High-density hematoma, basal cistern compression, and hematoma volume are independent predictors of the efficacy of atorvastatin as a non-surgical treatment. The results suggested that ADL-BI was more sensitive than the MGS-GCS and ASA-PS for determining patient outcomes in our moderate CSDH cohort.

The sirtuin 1 activator SRT1720 alleviated endotoxin-induced fulminant hepatitis in mice.

The metabolic sensor sirtuin 1 (SIRT1) also functions as a checkpoint in inflammation, and SRT1720 is a highly active and selective SIRT1 activator shown to alleviate inflammatory injury in several recent experimental studies. In the present study, the potential effects and underlying mechanisms of SRT1720 on lipopolysaccharide (LPS)-induced fulminant hepatitis in D-galactosamine (D-Gal)-sensitized mice were investigated. The results indicated that treatment with SRT1720 inhibited LPS/D-Gal-induced elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), alleviated the histological abnormalities, suppressed the induction of tumor necrosis factor alpha (TNF-α) and IL-6, mitigated the phosphorylation of c-Jun N-terminal kinase (JNK), downregulated the activities of caspase 8, caspase 9 and caspase 3, decreased the level of cleaved caspase 3, reduced the TUNEL-positive cells, and improved the survival rate of the LPS/D-Gal-exposed mice. These data indicated that treatment with the SIRT1 activator SRT1720 alleviated LPS/D-Gal-induced fulminant hepatitis, which might be attributed to the suppressive effects of SRT1720 on TNF-α production and the subsequent activation of the apoptosis cascade.

The surgical resection of dysplastic cerebellar gangliocytoma assisted by intraoperative sonography: illustrative case.

BACKGROUND: Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease) is an extremely rare, slow-growing hereditary mass lesion that is mainly characterized by both specific neuroradiological features and secondary hydrocephalus. Patients may present with symptoms of cerebellar mass lesion and increased intracranial pressure. As an important part of Cowden syndrome, Lhermitte-Duclos disease in adults is typically marked by PTEN gene mutation. OBSERVATIONS: The clinical management of a 31-year-old woman who suffered Lhermitte-Duclos disease was introduced in this case report. Subtotal resection was performed with the assistance of intraoperative sonography to relieve obstructive hydrocephalus, and prophylactic C1 laminectomy was performed to prevent possible postoperative progression of the residual lesion. Perioperative care and surgical process were clearly revealed in an accompanying video. Intraoperative sonography of Lhermitte-Duclos disease presents hyperechoic distorted thickening cortices surrounded by hypoechoic edema belt. The patient did not report any significant neurological complications or sequelae after the lesion resection. LESSONS: The authors first reported the use of intraoperative sonography in resection of adult-onset Lhermitte-Duclos disease. Hopefully, the educative case report can provide a feasible experience in the diagnosis and treatment of Lhermitte-Duclos disease.

Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15.

Hemangioblastoma (HB) is an abnormal intracranial buildup of blood vessels that exhibit a great potential for hemorrhage. Surgical options are limited, and few medications are available for treatment. We show here by immunohistochemical analysis that HB lesions display highly increased levels of VEGF expression and macrophage/microglia infiltration compared with those in normal brain tissues. In the meantime, TNF superfamily 15 (TNFSF15) (also known as vascular endothelial growth inhibitor), an antiangiogenic cytokine, is highly expressed in normal brain blood vessels but diminished in HB lesions. We set up a brain hemangioma model by using mouse bEnd.3 cells of a T antigen-transformed endothelial cell line that produce a large amount of VEGF. When implanted in mouse brains, these cells form lesions that closely resemble the pathologic characteristics of HB. Retroviral infection of bEnd.3 cells with TNFSF15 leads to inhibition of VEGF production and retardation of hemangioma formation. Similar results are obtained when wild-type bEnd.3 cells are implanted in the brains of transgenic mice overexpressing TNFSF15. Additionally, TNFSF15 treatment results in enhanced pericyte coverage of the blood vessels in the lesions together with reduced inflammatory cell infiltration and decreased hemorrhage. These findings indicate that the ability of TNFSF15 to counterbalance the abnormally highly angiogenic and inflammatory potential of the microenvironment of HB is of therapeutic value for the treatment of this disease.-Yang, G.-L., Han, Z., Xiong, J., Wang, S., Wei, H., Qin, T.-T., Xiao, H., Liu, Y., Xu, L.-X., Qi, J.-W., Zhang, Z.-S., Jiang, R., Zhang, J., Li, L.-Y. Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15.

Atorvastatin Protects Against Cerebral Aneurysmal Degenerative Pathology by Promoting Endothelial Progenitor Cells (EPC) Mobilization and Attenuating Vascular Deterioration in a Rat Model.

BACKGROUND Endothelial injury is the early pathological change of cerebral aneurysm (CA) formation. In addition to its lipid-lowering activity, atorvastatin (ATR) also reportedly promotes vascular repair via mobilizing endothelial progenitor cells (EPC). Here, we investigated the influence of ATR on vascular worsening after CA induction in rats. MATERIAL AND METHODS Adult male Sprague-Dawley rats were randomly assigned to 3 groups: a control (CTR) group, a CA group, and a CA+ATR treatment group. Circulating EPC level and hematological and lipid profiles were measured 3 months after CA induction. Verhoeff-Van Gieson staining and transmission electron microscopy were performed to assess pathological changes in the artery wall. RT-PCR was also performed to evaluate the expression of inflammation-related genes in the aneurysmal wall. RESULTS ATR significantly restored the impaired level of circulating EPC without changing hematological and lipid profiles 3 months after CA induction. ATR markedly inhibited endothelial injury, media thinning, and CA enlargement, accompanied by reduced vascular inflammation. CONCLUSIONS Our preliminary results demonstrate that the mobilization of EPC and improvement of endothelial function by ATR contribute to the prevention of cerebral aneurysm. Further studies are warranted to investigate the detailed mechanism.

Nitrogen-Doped Carbon Coated WS2 Nanosheets as Anode for High-Performance Sodium-Ion Batteries.

Due to the cost-effectiveness of sodium source, sodium-ion batteries (SIBs) have attracted considerable attention. However, SIBs still have some challenges in competing with lithium-ion batteries for practical applications. Particularly, the high rate capability and cycling stability are posing big problems for SIBs. Here, nitrogen-doped carbon-coated WS2 nanosheets (WS2/NC) were successfully synthesized by a high-temperature solution method, followed by carbonization of polypyrrole. When used as anode electrodes for SIBs, WS2/NC composite exhibited high-rate capacity at 386 and 238.1 mAh g-1 at 50 and 2,000 mA g-1, respectively. Furthermore, even after 400 cycle, the composite electrode could still deliver a capacity of ~180.1 mAh g-1 at 1,000 mA g-1, corresponding to a capacity loss of 0.09% per cycle. The excellent electrochemical performance could be attributed to the synergistic effect of the highly conductive nature of the nitrogen-doped carbon-coating and WS2 nanosheets. Results showed that the WS2/NC nanosheets are promising electrode materials for SIBs application.

Safety and Efficacy of Atorvastatin for Chronic Subdural Hematoma in Chinese Patients: A Randomized ClinicalTrial.

Importance: Chronic subdural hematoma (CSDH) is a trauma-associated condition commonly found in elderly patients. Surgery is currently the treatment of choice, but it carries a significant risk of recurrence and death. Nonsurgical treatments remain limited and ineffective. Our recent studies suggest that atorvastatin reduces hematomas and improves the clinical outcomes of patients with CSDH. Objective: To investigate the safety and therapeutic efficacy of atorvastatin to nonsurgically treat patients with CSDH. Design, Setting, and Participants: The Effect of Atorvastatin on Chronic Subdural Hematoma (ATOCH) randomized, placebo-controlled, double-blind phase II clinical trial was conducted in multiple centers in China from February 2014 to November 2015. For this trial, we approached 254 patients with CSDH who received a diagnosis via a computed tomography scan; of these, 200 (78.7%) were enrolled because 23 patients (9.1%) refused to participate and 31 (12.2%) were disqualified. Interventions: Patients were randomly assigned to receive either 20 mg of atorvastatin or placebo daily for 8 weeks and were followed up for an additional 16 weeks. Main Outcomes and Measures: The primary outcome was change in hematoma volume (HV) by computed tomography after 8 weeks of treatment. The secondary outcomes included HV measured at the 4th, 12th, and 24th weeks and neurological function that was evaluated using the Markwalder grading scale/Glasgow Coma Scale and the Barthel Index at the 8th week. Results: One hundred ninety-six patients received treatment (169 men [86.2%]; median [SD] age, 63.6 [14.2] years). The baseline HV and clinical presentations were similar between patients who were taking atorvastatin (98 [50%]) and the placebo (98 [50%]). After 8 weeks, the HV reduction in patients who were taking atorvastatin was 12.55 mL more than those taking the placebo (95% CI, 0.9-23.9 mL; P = .003). Forty-five patients (45.9%) who were taking atorvastatin significantly improved their neurological function, but only 28 (28.6%) who were taking the placebo did, resulting in an adjusted odds ratio of 1.957 for clinical improvements (95% CI, 1.07-3.58; P = .03). Eleven patients (11.2%) who were taking atorvastatin and 23 (23.5%) who were taking the placebo underwent surgery during the trial for an enlarging hematoma and/or a deteriorating clinical condition (hazard ratio, 0.47; 95% CI, 0.24-0.92; P = .03). No significant adverse events were reported. Conclusions and Relevance: Atorvastatin may be a safe and efficacious nonsurgical alternative for treating patients with CSDH. Trial Registration: ClinicalTrials.gov Identifier: NCT02024373.

Atorvastatin enhances angiogenesis to reduce subdural hematoma in a rat model.

BACKGROUND AND PURPOSE: Statins are active in reducing plasma lipids, suppressing inflammation and promoting angiogenesis. Because angiogenesis is critical for the absorbance of subdural hematoma (SDH), we hypothesize that atorvastatin promotes angiogenesis to enhance hematoma absorption. METHODS: SDH was induced in adult Wistar rats and treated with 3mg/kg, 8mg/kg of atorvastatin, or vehicle saline daily for 7days. The treated rats were examined for the level of CD34+/CD133+ endothelial progenitor cells (EPCs) in the circulation by flow cytometry, hematoma volumes by magnetic resonance imaging (MRI), and changes in cognitive functions. We also examined angiogenesis in the hematoma wall by transmission electronic microscopy and immunohistochemistry for the expression of vascular endothelial growth factor (VEGF), matrix metalloprotease 9 (MMP 9) and angiopoietin. RESULTS: SDH volume was significantly reduced and neurological deficits improved in rats receiving the low dose atorvastatin compared to those receiving either the high dose of atorvastatin or saline. Consistent with these outcome measures, the low dose atorvastatin increased the expression of angiopoient-1 and VEGF and reduced MMP9 expression in the connective tissue of the SDH wall, resulting in an increased vascular density and enhanced vascular maturation. CONCLUSIONS: The low-dose atorvastatin is effective in reducing SDH and improving neurological deficits in a rat model, primarily by promoting angiogenesis and vascular maturation.

Intravenous transfusion of endothelial colony-forming cells attenuates vascular degeneration after cerebral aneurysm induction.

Cerebral aneurysm (CA) rupture is a major cause of subarachnoid hemorrhage with high morbidity and mortality. Using an animal model, we examined the potential of endothelial colony-forming cells (ECFCs) transfusion on vascular degeneration after CA induction and underlying mechanisms. CA was induced in the right anterior cerebral artery-olfactory artery (ACA/OA) bifurcations in Sprague-Dawley rats with or without ECFCs transfusion. The degeneration of internal elastic lamina (IEL), media thickness and CA size were evaluated. Expression of matrix metalloproteinase-2 and 9 (MMP-2 and 9), tissue inhibitor of metalloproteinase-1 (TIMP-1), macrophage chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), nuclear factor κB (NF-κB), endothelial nitric oxide synthase (eNOS), B-cell leukemia/lymphoma-2 (Bcl-2), and inducible nitric oxide synthase (iNOS) were analyzed by quantitative real-time polymerase chain reaction. The macrophages infiltration and apoptosis of smooth muscle cells (SMCs) were examined immunohistologically. Rats in CA+ECFCs transfusion group showed a notable reduction in IEL degeneration, media thinning and CA size compared with those in CA+saline group. ECFCs transfusion inhibited the MMP-driven wall destruction by downregulating MMP-2, MMP-9 expression and upregulating TIMP-1. ECFCs transfusion dramatically decreased VCAM-1 and NF-κB expression, increased eNOS expression and caused no change in MCP-1 expression, which was accompanied by reduced macrophages infiltration. Moreover, ECFCs transfusion reversed downregulation of Bcl-2 expression and upregulation of iNOS expression, and decreased SMCs apoptosis. Collectively, these findings suggest that ECFCs transfusion confers protection against degeneration of aneurysmal wall by inhibiting inflammatory cascades and SMCs apoptosis.

Effects of atorvastatin on chronic subdural hematoma: a preliminary report from three medical centers.

INTRODUCTION: Chronic subdural hematoma (CSDH) is common and more prevalent in the aged population. Surgical intervention is the treatment of choice, but its outcomes may not be satisfactory because of recurrence and physical infirmity associated with aging. Aberrant angiogenesis and localized inflammation contribute to the formation of CSDH. Atorvastatin is active in promoting angiogenesis and modulating inflammation. We hypothesize that atorvastatin is effective in reducing CSDH and have tested the hypothesis in a preliminary prospective study of small cohort of patients. METHODS: Twenty-three patients with CT- or MRI-confirmed CSDH were recruited from three regional medical centers and evaluated using Markwalder's Grading Scale (MGS) and the Glasgow Coma Scale (GCS). These patients received oral atorvastatin 20 mg/day for 1-6 months (3.02±1.77 months) and were followed for 3 to 36 months (18.62±13.13) after the therapy. Hematoma volume, neurological functions and daily activities (measured using the Activities of Daily Life-the Barthel Index scale, ADL-BI) were compared before and after treatment with Linear Trend Chi-Square test. RESULTS: Twenty-two of the 23 patients experienced improvements in symptoms, and the reduction in hematoma volume from 48.70±20.38 ml to 16.64±14.28 ml (paired-sample t-test, p<0.01) within the first month of the treatment. Hematoma was completely resolved in 17 patients (77.3%) and shrank by more than 73.99%±11.17% in 5 patients (22.7%) 3 months after the treatment was initiated. One patient experienced an initial relief of symptoms, but his condition deteriorated with an enlarged hematoma during the 4th week of treatment and underwent surgery. At 6 months, 18 patients presented no hematoma by CT or MRI and four patients, whose hematoma was completely resolved at 3 months, were not followed. None of these 22 patients relapsed during the entire follow-up period of 3-36 months. All have improved MGS, GCS, and ADL-BI. No atorvastatin-related side effects were documented. CONCLUSION: Results of this preliminary prospective study show that the oral administration of atorvastatin is safe and effective in treating CSDH, offering a cost-effective alternative to surgery. A prospective randomized clinical trial is required to validate the effect of atorvastatin.

Progesterone increases circulating endothelial progenitor cells and induces neural regeneration after traumatic brain injury in aged rats.

Vascular remodeling plays a key role in neural regeneration in the injured brain. Circulating endothelial progenitor cells (EPCs) are a mediator of the vascular remodeling process. Previous studies have found that progesterone treatment of traumatic brain injury (TBI) decreases cerebral edema and cellular apoptosis and inhibits inflammation, which in concert promote neuroprotective effects in young adult rats. However, whether progesterone treatment regulates circulating EPC level and fosters vascular remodeling after TBI have not been investigated. In this study, we hypothesize that progesterone treatment following TBI increases circulating EPC levels and promotes vascular remodeling in the injured brain in aged rats. Male Wistar 20-month-old rats were subjected to a moderate unilateral parietal cortical contusion injury and were treated with or without progesterone (n=54/group). Progesterone was administered intraperitoneally at a dose of 16mg/kg at 1 h post-TBI and was subsequently injected subcutaneously daily for 14 days. Neurological functional tests and immnunostaining were performed. Circulating EPCs were measured by flow cytometry. Progesterone treatment significantly improved neurological outcome after TBI measured by the modified neurological severity score, Morris Water Maze and the long term potentiation in the hippocampus as well as increased the circulating EPC levels compared to TBI controls (p<0.05). Progesterone treatment also significantly increased CD34 and CD31 positive cell number and vessel density in the injured brain compared to TBI controls (p<0.05). These data indicate that progesterone treatment of TBI improves multiple neurological functional outcomes, increases the circulating EPC level, and facilitates vascular remodeling in the injured brain after TBI in aged rats.

Changes and function of circulating endothelial progenitor cells in patients with cerebral aneurysm.

Endothelial dysfunction is a trigger for the formation of cerebral aneurysm (CA). The circulating endothelial progenitor cell (EPC) plays an important role in postnatal vasculogenesis and reduction of endothelial injury. In this study, we tested the hypothesis that decreased number and impaired function of circulating EPCs correlate with CA formation in patients. Blood circulating EPCs were identified by flow cytometry. The level of plasma vascular endothelial growth factor (VEGF) was measured by ELISA. Circulating EPCs from patients (n = 27) were cultured in vitro, and the function of EPCs was evaluated by cell migration and senescence-associated ß-galactosidase activity. The number of circulating EPCs was significantly decreased in both unruptured and ruptured CA patients compared with healthy control subjects. Impaired migratory capacity and elevated cellular senescence of cultured EPCs were observed in patients with CA (ruptured and unruptured). The percentages of EPC senescence in patients with CAs were significantly and negatively correlated with the number of circulating EPCs. In addition, there were higher levels of plasma VEGF in CA patients compared with healthy control subjects. Our results show that the numbers and functions of circulating EPCs are reduced in patients with CAs. These findings suggest that the decreased number and impaired function of circulating EPCs in CA patients may contribute to the pathophysiological process of aneurysm formation.