S1P regulates intervertebral disc aging by mediating endoplasmic reticulum - mitochondrial calcium ion homeostasis.

Mechanistically, S1P deficiency impeded COP II-mediated transport vesicles formation, which leads to proteins retention in the endoplasmic reticulum (ER) and subsequently ER distension. ER distension increased the contact between the ER and mitochondria, disrupting ER-to-mitochondria calcium flow, resulting in mitochondrial dysfunction and energy metabolism disturbance. Finally, using 2-APB to inhibit calcium ion channels and the senolytic drug dasatinib and quercetin (D + Q) partially rescued the aging and degenerative phenotypes caused by S1P deficiency. In conclusion, our findings suggest that S1P is a critical factor in causing IVDD in the process of aging and highlight the potential of targeting S1P as a therapeutic approach for age-related IVDD.

Hybrid Surgery for symptomatic chronic internal carotid artery occlusion: a single-center experience.

BACKGROUND: Patients with symptomatic chronic internal carotid artery occlusion (ICAO) face a high risk of recurrent stroke despite receiving aggressive medical therapy. This study aimed to evaluate the effectiveness and safety of hybrid surgery in treating symptomatic chronic ICAO. METHODS: This retrospective case series was conducted at a single center. From January 2019 to December 2022, patients with symptomatic chronic ICAO who underwent hybrid surgery were included. We collected baseline data, lesion characteristics, revascularization rates, perioperative complications, and follow-up outcomes. RESULTS: The study enrolled 27 patients, comprising 22 males and 5 females, with symptomatic chronic ICAO. The hybrid surgery achieved a technical success rate of 100% for revascularization (n = 27), with a perioperative complication rate of 14.8% (n = 4). Following a median follow-up of 6.0 months (IQR, 4-10), 21 patients underwent a DSA or CT angiography reexamination, confirming a vascular patency rate of 90.5% (n = 19). One patient required surgery for severe in-stent restenosis, and another experienced asymptomatic occlusion. Clinical follow-ups were conducted for all 26 patients; no new strokes were reported in the qualifying artery territory, with 13 patients scoring 0, 12 scoring 1, and 1 scoring 2 on the mRS. CONCLUSION: Although hybrid surgery represent a promising option for treating chronic ICAO, they are also associated with a relatively high incidence of treatment-related complications. The application of composite surgery should be based on standardized technical guidelines and the careful selection of patients who are genuinely at high risk for recurrent strokes.

The longitudinal changes in multiparametric MRI during neoadjuvant chemotherapy can predict treatment response early in patients with HER2-positive breast cancer.

PURPOSE: To investigate whether longitudinal changes in multiparametric MRI can predict early response to neoadjuvant chemotherapy (NAC) for HER2-positive breast cancer (BC) and to further establish quantitative models based on these features. METHODS: A total of 164 HER2-positive BC patients from three centers were included. MRI was performed at baseline and after two cycles of NAC (early post-NAC). Clinicopathological characteristics were enrolled. MRI features were evaluated at baseline and early post-NAC, as well as longitudinal changes in multiparametric MRI, including changes in the largest diameter (LD) of the tumor (ΔLD), apparent diffusion coefficient (ADC) values (ΔADC), and time-signal intensity curve (TIC) (ΔTIC). The patients were divided into a training set (n = 95), an internal validation set (n = 31), and an independent external validation set (n = 38). Univariate and multivariate logistic regression analyses were used to identify the independent indicators of pCR, which were then used to establish the clinicopathologic model and combined model. The AUC was used to evaluate the predictive power of the different models and calibration curves were used to evaluate the consistency of the prediction of pCR in different models. Additionally, decision curve analysis (DCA) was employed to determine the clinical usefulness of the different models. RESULTS: Two models were enrolled in this study, including the clinicopathologic model and the combined model. The LD at early post-NAC (OR=0.913, 95 % CI=0.953-0.994 p = 0.026), ΔADC (OR=1.005, 95 % CI=1.005-1.008, p = 0.007), and ΔTIC (OR=3.974, 95 % CI=1.276-12.358, p = 0.017) were identified as the best predictors of NAC response. The combined model constructed by the combination of LD at early post-NAC, ΔADC, and ΔTIC showed good predictive performance in the training set (AUC=0.87), internal validation set (AUC=0.78), and external validation set (AUC=0.79), which performed better than the clinicopathologic model in all sets. CONCLUSIONS: The changes in multiparametric MRI can predict early treatment response for HER2-positive BC and may be helpful for individualized treatment planning.

The use of longitudinal CT-based radiomics and clinicopathological features predicts the pathological complete response of metastasized axillary lymph nodes in breast cancer.

BACKGROUND: Accurate assessment of axillary status after neoadjuvant therapy for breast cancer patients with axillary lymph node metastasis is important for the selection of appropriate subsequent axillary treatment decisions. Our objectives were to accurately predict whether the breast cancer patients with axillary lymph node metastases could achieve axillary pathological complete response (pCR). METHODS: We collected imaging data to extract longitudinal CT image features before and after neoadjuvant chemotherapy (NAC), analyzed the correlation between radiomics and clinicopathological features, and developed models to predict whether patients with axillary lymph node metastasis can achieve axillary pCR after NAC. The clinical utility of the models was determined via decision curve analysis (DCA). Subgroup analyses were also performed. Then, a nomogram was developed based on the model with the best predictive efficiency and clinical utility and was validated using the calibration plots. RESULTS: A total of 549 breast cancer patients with metastasized axillary lymph nodes were enrolled in this study. 42 independent radiomics features were selected from LASSO regression to construct a logistic regression model with clinicopathological features (LR radiomics-clinical combined model). The AUC of the LR radiomics-clinical combined model prediction performance was 0.861 in the training set and 0.891 in the testing set. For the HR + /HER2 - , HER2 + , and Triple negative subtype, the LR radiomics-clinical combined model yields the best prediction AUCs of 0.756, 0.812, and 0.928 in training sets, and AUCs of 0.757, 0.777 and 0.838 in testing sets, respectively. CONCLUSIONS: The combination of radiomics features and clinicopathological characteristics can effectively predict axillary pCR status in NAC breast cancer patients.

Cardiovascular and renal safety outcomes of hypoxia-inducible factor prolyl-hydroxylase inhibitor roxadustat for anemia patients with chronic kidney disease: a systematic review and meta-analysis.

This systematic review and meta-analysis were conducted to evaluate the cardiac and kidney-related adverse effects of roxadustat for the treatment of anemia in CKD patients. 18 trials with a total of 8806 participants were identified for analysis. We employed a fixed-effects model for analysis. The pooled result revealed no significant difference in the risk of occurrence of cardiac disorders when comparing CKD patients receiving roxadustat with the placebo (RR = 1.049; CI [0.918 to 1.200]) or ESA (RR = 1.066; CI [0.919 to 1.235]), in both dialysis-dependent (DD) (RR = 1.094; CI [0.925 to 1.293]) or non-dialysis-dependent (NDD) (RR = 1.036; CI [0.916 to 1.171]) CKD patients. No significant difference was observed in the risk of kidney-related adverse events when comparing roxadustat with the placebo (RR = 1.088; CI [0.980 to 1.209]) or ESA (RR = 0.968; CI [0.831 to 1.152]), in DD (RR = 2.649; CI [0.201 to 34.981]) or NDD (RR = 1.053; CI [0.965 to 1.149]) CKD patients. A high risk of hyperkalemia was observed in the roxadustat group in DD (RR = 0.939; CI [0.898 to 0.981]). Incidence of hypertension was higher in the roxadustat for NDD patients (RR = 1.198; CI [1.042 to 1.377]), or compared to the placebo (RR = 1.374; CI [1.153 to 1.638]). In summary, the risk of cardiac or kidney-related events observed in the roxadustat was not significantly increase whether in DD or NDD patients. However, attention must be paid to the occurrence of hyperkalemia for DD patients and hypertension in NDD patients using roxadustat.

Risk Factors for Cerebral Hyperperfusion Syndrome After Combined Revascularization in Adult Patients with Moyamoya Disease.

BACKGROUND: Cerebral hyperperfusion syndrome (CHS) is known as a complication after bypass surgery for Moyamoya disease (MMD). However, the incidence of CHS has not been accurately reported, and there is no consensus on the risk factors associated with it. AIM: The aim of this study was to determine the risk factors associated with postoperative CHS after surgical combined revascularization used to treat adult patients with MMD. OBJECTIVE: To assess the frequency and characteristics of CHS in patients with MMD after revascularization operations. METHODS: Patients who received combined revascularization from Jan 2021 to Nov 2022 were retrospectively reviewed. Preoperative clinical characteristics and radiographic features were recorded. Postoperative CHS after surgery were examined. Multivariate logistic regression analyses were performed to identify the risk factors for CHS. RESULTS: A total of 133 patients (141 hemispheres) were included in this study. Postoperative CHS were observed in 28 hemispheres (19.8%), including focal cerebral hyperperfusion syndrome (FCHS) in 20 hemispheres (14.2%), hemorrhage in 4 (2.8%) hemispheres, seizures in 4 (2.8%) hemispheres. The results of multivariate logistic regression analysis indicated that preoperative hypertension (OR 4.705, 95% CI 1.323 ~ 12.554, p = 0.014), cerebral hemorrhage onset (OR 5.390, 95% CI 1.408 ~ 20.642, p = 0.014) and higher Hct level (OR 1.171, 95% CI 1.051 ~ 1.305, p = 0.004) were significantly associated with CHS after combined revascularization. CONCLUSIONS: Preoperative hypertension, cerebral hemorrhage onset, and higher Hct level were independent risk factors for CHS after combined revascularization.

Impact of qualifying artery on the efficacy of stenting plus medical therapy versus medical therapy alone in patients with symptomatic intracranial stenosis: a post-hoc analysis of the CASSISS trial.

BACKGROUND: A recent trial failed to show any benefit of stenting plus medical therapy over medical therapy alone in patients with symptomatic intracranial stenosis. We aimed to examine whether the symptomatic qualifying artery modifies the effect of stenting plus medical therapy. METHODS: This is a post-hoc analysis of the CASSISS trial that included patients with symptomatic intracranial stenosis, randomly assigned to undergo stenting plus medical therapy or medical therapy alone; 358/380 patients were included. Multivariable logistic regression analysis was used with an interaction term to estimate the altered treatment effect by the qualifying artery. The primary outcome was a composite of stroke or death within 30 days or stroke in the qualifying artery territory beyond 30 days through 1 year. The five secondary outcomes included stroke or death related to the qualifying artery territory at 2 and 3 years. RESULTS: No significant treatment allocation-by-stenosis site interaction was observed (Pinteraction=0.435). Compared with medical therapy alone, the adjusted ORs for stenting plus medical therapy were 2.73 (95% CI 0.42 to 17.65) for internal carotid artery stenosis, 1.20 (95% CI 0.29 to 4.99) for M1 stenosis, 0.23 (95% CI 0.02 to 2.31) for vertebral artery stenosis, and 1.33 (95% CI 0.34 to 5.28) for basilar artery stenosis. Of the five secondary outcomes, none showed a significant treatment allocation-by-stenosis site interaction including stroke in the qualifying artery territory at 2 years (Pinteraction=0.659) and 3 years (Pinteraction=0.493). CONCLUSIONS: Among patients with transient ischemic attacks or ischemic stroke due to severe intracranial atherosclerotic stenosis, there was no evidence that the symptomatic qualifying artery could determine the addition of stenting to medical therapy.

Identification of triple-negative breast cancer and androgen receptor expression based on histogram and texture analysis of dynamic contrast-enhanced MRI.

BACKGROUND: Triple-negative breast cancer (TNBC) is highly malignant and has a poor prognosis due to the lack of effective therapeutic targets. Androgen receptor (AR) has been investigated as a possible therapeutic target. This study quantitatively assessed intratumor heterogeneity by histogram analysis of pharmacokinetic parameters and texture analysis on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to discriminate TNBC from non-triple-negative breast cancer (non-TNBC) and to identify AR expression in TNBC. METHODS: This retrospective study included 99 patients with histopathologically proven breast cancer (TNBC: 36, non-TNBC: 63) who underwent breast DCE-MRI before surgery. The pharmacokinetic parameters of DCE-MRI (Ktrans, Kep and Ve) and their corresponding texture parameters were calculated. The independent t-test, or Mann-Whitney U-test was used to compare quantitative parameters between TNBC and non-TNBC groups, and AR-positive (AR+) and AR-negative (AR-) TNBC groups. The parameters with significant difference between two groups were further involved in logistic regression analysis to build a prediction model for TNBC. The ROC analysis was conducted on each independent parameter and the TNBC predicting model for evaluating the discrimination performance. The area under the ROC curve (AUC), sensitivity and specificity were derived. RESULTS: The binary logistic regression analysis revealed that Kep_Range (p = 0.032) and Ve_SumVariance (p = 0.005) were significantly higher in TNBC than in non-TNBC. The AUC of the combined model for identifying TNBC was 0.735 (p < 0.001) with a cut-off value of 0.268, and its sensitivity and specificity were 88.89% and 52.38%, respectively. The value of Kep_Compactness2 (p = 0.049), Kep_SphericalDisproportion (p = 0.049), and Ve_GlcmEntropy (p = 0.008) were higher in AR + TNBC group than in AR-TNBC group. CONCLUSION: Histogram and texture analysis of breast lesions on DCE-MRI showed potential to identify TNBC, and the specific features can be possible predictors of AR expression, enhancing the ability to individualize the treatment of patients with TNBC.

The deubiquitinase UCHL1 negatively controls osteoclastogenesis by regulating TAZ/NFATC1 signalling.

The ubiquitin‒proteasome system (UPS) plays a key role in maintaining protein homeostasis and bone remodelling. However, the role of deubiquitinating enzymes (DUBs) in bone resorption is still not well defined. Here, we identified the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) as a negative regulator of osteoclastogenesis by using the GEO database, proteomic analysis, and RNAi. Osteoclast-specific UCHL1 conditional knockout mice exhibited a severe osteoporosis phenotype in an ovariectomized model. Mechanistically, UCHL1 deubiquitinated and stabilized the transcriptional coactivator with PDZ-binding motif (TAZ) at the K46 residue, thereby inhibiting osteoclastogenesis. The TAZ protein underwent K48-linked polyubiquitination, which was degraded by UCHL1. As a substrate of UCHL1, TAZ regulates NFATC1 through a nontranscriptional coactivator function by competing with calcineurin A (CNA) for binding to NFATC1, which inhibits NFATC1 dephosphorylation and nuclear transport to impede osteoclastogenesis. Moreover, overexpression of UCHL1 locally alleviated acute and chronic bone loss. These findings suggest that activating UCHL1 may serve as a novel therapeutic approach targeting bone loss in various bone pathological states.

Unique Fluorescent Protein-Encoded Microbeads with Supramaximal Encoding Capacity and High Sensitivity for Multiplex Bioassays.

Fluorescence-encoded microbeads (FEBs) have been widely used as a critical component in multiplexed biomolecular assays. Here, we propose a simple, sustainable, low-cost, and safe strategy for preparing FEBs by assembling fluorescent proteins (FPs) onto magnetic microbeads (MBs) via chemical coupling. Combining the type of FP, the concentration of FP, and the size of the magnetic microbeads as encoding elements, an ultralarge encoding capacity with 506 barcodes was obtained. We demonstrate that the FP-based FEBs have good stability during long-term storage and tolerate the use of an organic solution. Multiplex detection of femtomolar ssDNA molecules was achieved via flow cytometry, and the detection procedure is simple and fast because it does not require amplification and washing strategies. The advantages of this advanced method for multiplex detections including high sensitivity, specificity, accuracy, repeatability, rapidity, and cost-effectiveness show a broad application prospect in basic and applied research fields such as disease diagnosis, food safety, environmental protection, proteomics, genomics, and drug screening.

Abbreviated Versus Full-Protocol MRI for Breast Cancer Neoadjuvant Chemotherapy Response Assessment: Diagnostic Performance by General and Breast Radiologists.

BACKGROUND. Abbreviated protocols could allow wider adoption of MRI in patients undergoing breast cancer neoadjuvant chemotherapy (NAC). However, abbreviated MRI has been explored primarily in screening settings. OBJECTIVE. The purpose of this article was to compare diagnostic performance of abbreviated MRI and full-protocol MRI for evaluation of breast cancer NAC response, stratifying by radiologists' breast imaging expertise. METHODS. This retrospective study included 203 patients with breast cancer (mean age, 52.1 ± 11.2 [SD] years) from two hospitals who underwent MRI before NAC initiation and after NAC completion before surgical resection from March 2017 to April 2021. Abbreviated MRI was extracted from full-protocol MRI and included the axial T2-weighted sequence and precontrast and single early postcontrast T1-weighted sequences. Three general radiologists and three breast radiologists independently interpreted abbreviated and full-protocol MRI in separate sessions, identifying enhancing lesions to indicate residual tumor and measuring lesion size. The reference standard was presence and size of residual tumor on pathologic assessment of post-NAC surgical specimens. RESULTS. A total of 50 of 203 patients had pathologic complete response (pCR). Intraobserver and interobserver agreement for abbreviated and full-protocol MRI for general and breast radiologists ranged from substantial to nearly perfect (κ = 0.70-0.81). Abbreviated MRI compared with full-protocol MRI showed no significant difference for general radiologists in sensitivity (54.7% vs 57.3%, p > .99), specificity (92.8% vs 95.6%, p = .29), or accuracy (83.4% vs 86.2%, p = .30), nor for breast radiologists in sensitivity (60.0% vs 61.3%, p > .99), specificity (94.6% vs 97.4%, p = .22), or accuracy (86.0% vs 88.5%, p = .30). Sensitivity, specificity, and accuracy were not significantly different between protocols for any reader individually (p > .05). Mean difference in residual tumor size on MRI relative to pathology for abbreviated protocol ranged for general radiologists from -0.19 to 0.03 mm and for breast radiologists from -0.15 to -0.05 mm, and for full protocol ranged for general radiologists from 0.57 to 0.65 mm and for breast radiologists from 0.66 to 0.79 mm. CONCLUSION. Abbreviated compared with full-protocol MRI showed similar intraobserver and interobserver agreement and no significant difference in diagnostic performance. Full-protocol MRI but not abbreviated MRI slightly overestimated pathologic tumor sizes. CLINICAL IMPACT. Abbreviated protocols may facilitate use of MRI for post-NAC response assessment by general and breast radiologists.

Netrin-1 mediates nerve innervation and angiogenesis leading to discogenic pain.

Objective: Discogenic low back pain (LBP) is associated with nociceptive nerve fibers that grow into degenerated intervertebral discs (IVD) but the etiopathogenesis of disease is not fully understood. The purpose of this study was to clarify the role of Netrin-1 in causing discogenic LBP. Methods: The level of nociceptive nerve innervation was examined in disc degenerative patients and rat needle-punctured models by immunohistochemistry. Nucleus pulposus (NP) cells were isolated from IVD tissues of rats and induced degeneration by interleukin-1ß (IL-1ß) or tumor necrosis factor α (TNFα). The candidate genes related to neuron outgrowth and migration were selected by Next-generation sequencing (NGS). CRISPR/Cas9 was used to knockdown Netrin-1 in NP cells. The impact of Netrin-1 on nerve innervation were evaluated with P2X2、NF200 staining and microfluidics assay. Meanwhile the CD31 staining and transwell assay were used to evaluate the impact of Netrin-1 in angiogenesis. The proteins and RNA extracted from NP cells related to catabolism and anabolism were examined by western blot assay and RT-qPCR experiment. ChIP and luciferase experiments were used to assess the intracellular transcriptional regulation of Netrin-1. Further, a needle-punctured rat model followed by histomorphometry and immunofluorescence histochemistry was used to explore the potential effect of Netrin-1 on LBP in vivo. Results: The level of nerve innervation was increased in severe disc degenerative patients while the expression of Netrin-1 was upregulated. The supernatants of NP cells stimulated with IL-1ß or TNFα containing more Netrin-1 could promote axon growth and vascular endothelial cells migration. Knocking down Netrin-1 or overexpressing transcription factor TCF3 as a negative regulator of Netrin-1 attenuated this effect. The needle-punctured rat model brought significant spinal hypersensitivity, nerve innervation and angiogenesis, nevertheless knocking down Netrin-1 effectively prevented disc degeneration-induced adverse impacts. Conclusion: Discogenic LBP was induced by Netrin-1, which mediated nerve innervation and angiogenesis in disc degeneration. Knocking down Netrin-1 by CRISPR/Cas9 or negatively regulating Netrin1 by transcription factor TCF3 could alleviate spinal hypersensitivity. The translational potential of this article: This study on Netrin-1 could provide a new target and theoretical basis for the prevention and treatment for discogenic back pain.

Outcomes after superficial temporal artery-middle cerebral artery anastomosis combined with multiple burr hole surgery and dural inversion synangiosis for moyamoya disease in adults.

Objective: Several forms of cerebral revascularization have been carried out to treat moyamoya disease, however, the existing methods are accompanied by a variety of complications. In this study, the authors aimed to evaluate the clinical and angiographic outcomes of a new surgical procedure: superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis combined with multiple burr hole (MBH) surgery and dural inversion synangiosis for the treatment of moyamoya disease in adults. Methods: Patients treated for moyamoya disease from August 2019 to July 2021 were retrospectively reviewed. Clinical data, including perioperative complications and follow-up outcomes, were noted. Preoperative and postoperative angiograms were compared, and the diameters of the frontal branch of the superficial temporal artery (F-STA), the deep temporal artery (DTA), the distal superficial temporal artery (STA) before the bifurcation and the middle meningeal artery (MMA) were measured on preoperative and postoperative angiograms. Meanwhile, a Matsushima score was assigned from postoperative angiograms. Results: This study included 66 patients (67 hemispheres). During the follow-up period, a median of 18 (IQR, 13-21) months, no stroke or death occurred in any of the patients. The clinical outcomes were excellent in 27 patients (40.9%), good in 34 patients (51.6%), fair in 4 patients (6.0%), and poor in 1 patient (1.5%); the overall rate of favorable clinical outcomes (excellent and good) was 92.5%. The modified Rankin Scale (mRS) score was significantly improved at follow-up (P < 0.001). There were 41 hemispheres imaged by cerebral angiography after the operation, at a median postoperative interval of 9 (IQR, 8-12) months; among them, 34 (82.9%) hemispheres had Matsushima scores of grade A and grade B. The average postoperative diameters in the STA, DTA and MMA were increased significantly in 41 hemispheres at follow-up (P < 0.001). Sixteen (24.2%) patients suffered from perioperative complications, including focal hyperperfusion syndrome (HS) in 8 (12.2%) patients, cerebral infarction in 3 (4.5%) patients (including one case accompanied by wound infection), cerebral hemorrhage in 2 (3.0%) patients, seizures in 2 (3.0%) patients, and subdural effusion in 1 (1.5%) patient. Conclusions: The procedure of STA-MCA anastomosis combined with MBH surgery and dural inversion synangiosis may be a safe and effective treatment for adult patients with moyamoya disease.

Identification of the Benignity and Malignancy of BI-RADS 4 Breast Lesions Based on a Combined Quantitative Model of Dynamic Contrast-Enhanced MRI and Intravoxel Incoherent Motion.

The aim of this study was to explore whether intravoxel incoherent motion (IVIM) combined with a dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) quantitative model can improve the ability to distinguish between benign and malignant BI-RADS 4 breast lesions. We enrolled 100 patients who underwent breast MRI at our institution and extracted the quantitative parameters of lesions with a post-processing workstation. Statistical differences in these parameters between benign and malignant BI-RADS 4 lesions were assessed using a two independent samples t-test or a Mann-Whitney U test. Binary logistic regression analysis was performed to establish five diagnostic models (model_ADC, model_IVIM, model_DCE, model_DCE+ADC, and model_DCE+IVIM). Receiver operating characteristic (ROC) curves, leave-one-out cross-validation, and the Delong test were used to assess and compare the diagnostic performance of these models. The model_DCE+IVIM showed the highest area under the curve (AUC) of 0.903 (95% confidence interval (CI): 0.828-0.953, sensitivity: 87.50%, specificity: 85.00%), which was significantly higher than that of model_ADC (p = 0.014) and model_IVIM (p = 0.033). The model_ADC had the lowest diagnostic performance (AUC = 0.768, 95%CI: 0.672-0.846) but was not significantly different from model_IVIM (p = 0.168). The united quantitative model with DCE-MRI and IVIM could improve the ability to evaluate the malignancy in BI-RADS 4 lesions, and unnecessary breast biopsies may be obviated.

The roles and mechanisms of miR-26 derived from exosomes of adipose-derived stem cells in the formation of carotid atherosclerotic plaque.

Background: This study explored the serum concentrations of miR-26 in patients with carotid atherosclerosis (CAS) and defined the roles and mechanisms of miR-26 derived from the exosomes of adipose-derived stem cells (ADSC-exos). Methods: The carotid artery width was diagnosed by ultrasound examination in patients with different degrees of CAS. The serum levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in patients were detected by biochemistry. The serum levels of miR-26 were determined by quantitative polymerase chain reaction (qPCR). A model of CAS in ApoE-/- mice fed with a rich-fat diet was established to analyze the regulatory effects of serum miR-26 on blood lipids in mice. Adipose mesenchymal stem cell lines transfected with miR-26 were established. The regulatory relationship between the expression levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1ß, and the expression levels of miR-26 in the supernatant of each group of cells was determined by qPCR. The ADSC-exos were extracted from ADSCs and injected into model mice through the tail vein. The therapeutic effect of ADSCs expressing miR-26 on model mice was evaluated by detecting the levels of inflammatory factors and blood lipids in the serum of the mice. Results: The degree of atherosclerosis (AS) was positively associated with the intima-media thickness (IMT) of the carotid artery. The serum levels of miR-26 in patients were inversely correlated with the levels of blood lipids (TC, TG, and LDL-C), and positively correlated with HDL-C levels. Similarly, in the CAS mouse model, the serum levels of miR-26 were inversely correlated with the levels of blood lipids (TC, TG, and LDL-C), and positively correlated with HDL-C level. In ADSCs transfected with miR-26, the miR-26 expression in the cell supernatant was negatively regulated by the expression of inflammatory factors, TNF-α, IL-6, and IL-1ß, in the cell supernatant. ADSC-exos expressing miR-26 has positive effects on correcting blood lipids and inflammatory factors in the mouse model of CAS. Conclusions: miR-26 has an active role in CAS and may be a novel target for the treatment of CAS in the future.

Effect of Stenting Plus Medical Therapy vs Medical Therapy Alone on Risk of Stroke and Death in Patients With Symptomatic Intracranial Stenosis: The CASSISS Randomized Clinical Trial.

Importance: Prior randomized trials have generally shown harm or no benefit of stenting added to medical therapy for patients with symptomatic severe intracranial atherosclerotic stenosis, but it remains uncertain as to whether refined patient selection and more experienced surgeons might result in improved outcomes. Objective: To compare stenting plus medical therapy vs medical therapy alone in patients with symptomatic severe intracranial atherosclerotic stenosis. Design, Setting, and Participants: Multicenter, open-label, randomized, outcome assessor-blinded trial conducted at 8 centers in China. A total of 380 patients with transient ischemic attack or nondisabling, nonperforator (defined as nonbrainstem or non-basal ganglia end artery) territory ischemic stroke attributed to severe intracranial stenosis (70%-99%) and beyond a duration of 3 weeks from the latest ischemic symptom onset were recruited between March 5, 2014, and November 10, 2016, and followed up for 3 years (final follow-up: November 10, 2019). Interventions: Medical therapy plus stenting (n = 176) or medical therapy alone (n = 182). Medical therapy included dual-antiplatelet therapy for 90 days (single antiplatelet therapy thereafter) and stroke risk factor control. Main Outcomes and Measures: The primary outcome was a composite of stroke or death within 30 days or stroke in the qualifying artery territory beyond 30 days through 1 year. There were 5 secondary outcomes, including stroke in the qualifying artery territory at 2 years and 3 years as well as mortality at 3 years. Results: Among 380 patients who were randomized, 358 were confirmed eligible (mean age, 56.3 years; 263 male [73.5%]) and 343 (95.8%) completed the trial. For the stenting plus medical therapy group vs medical therapy alone, no significant difference was found for the primary outcome of risk of stroke or death (8.0% [14/176] vs 7.2% [13/181]; difference, 0.4% [95% CI, -5.0% to 5.9%]; hazard ratio, 1.10 [95% CI, 0.52-2.35]; P = .82). Of the 5 prespecified secondary end points, none showed a significant difference including stroke in the qualifying artery territory at 2 years (9.9% [17/171] vs 9.0% [16/178]; difference, 0.7% [95% CI, -5.4% to 6.7%]; hazard ratio, 1.10 [95% CI, 0.56-2.16]; P = .80) and 3 years (11.3% [19/168] vs 11.2% [19/170]; difference, -0.2% [95% CI, -7.0% to 6.5%]; hazard ratio, 1.00 [95% CI, 0.53-1.90]; P > .99). Mortality at 3 years was 4.4% (7/160) in the stenting plus medical therapy group vs 1.3% (2/159) in the medical therapy alone group (difference, 3.2% [95% CI, -0.5% to 6.9%]; hazard ratio, 3.75 [95% CI, 0.77-18.13]; P = .08). Conclusions and Relevance: Among patients with transient ischemic attack or ischemic stroke due to symptomatic severe intracranial atherosclerotic stenosis, the addition of percutaneous transluminal angioplasty and stenting to medical therapy, compared with medical therapy alone, resulted in no significant difference in the risk of stroke or death within 30 days or stroke in the qualifying artery territory beyond 30 days through 1 year. The findings do not support the addition of percutaneous transluminal angioplasty and stenting to medical therapy for the treatment of patients with symptomatic severe intracranial atherosclerotic stenosis. Trial Registration: ClinicalTrials.gov Identifier: NCT01763320.

Astrocyte-derived hepcidin controls iron traffic at the blood-brain-barrier via regulating ferroportin 1 of microvascular endothelial cells.

Brain iron dysregulation associated with aging is closely related to motor and cognitive impairments in neurodegenerative diseases. The regulation of iron traffic at the blood-brain barrier (BBB) is crucial to maintain brain iron homeostasis. However, the specific mechanism has not been clarified in detail. Using various conditional gene knockout and overexpression mice, as well as cell co-culture of astrocyte and bEND.3 in the transwell, we found that astrocyte hepcidin knockdown increased the expression of ferroportin 1 (FPN1) of brain microvascular endothelial cells (BMVECs), and that it also induced brain iron overload and cognitive decline in mice. Moreover, BMVECs FPN1 knockout decreased iron contents in the cortex and hippocampus. Furthermore, hepcidin regulates the level of FPN1 of BMVECs with conditional gene overexpression in vivo and in vitro. Our results revealed that astrocytes responded to the intracellular high iron level and increased the secretion of hepcidin, which in turn diminished iron uptake at BBB from circulation through directly regulating FPN1 of BMVECs. Our results demonstrate that FPN1 of BMVECs is a gateway for iron transport into the brain from circulation, and the controller of this gateway is hepcidin secreted by astrocyte at its endfeet through physical contact with BMVECs. This regulation is indeed the major checkpoint for iron transport from the blood circulation to the brain. This study delineates the pathway and regulation of iron entry into the brain, providing potential therapeutic targets for iron dysregulation-related neurological diseases.

The Guidewire-assisted Drainage Catheter Placement in Chronic Subdural Hematoma.

Background: Chronic subdural hematoma (cSDH) is a common neurosurgical pathology associated with older age. The burr hole drainage is a predominant technique with a lower incidence of recurrence and morbidity. The blind placement of the subdural drain could result in intracerebral hemorrhage. This paper describes a simple and reliable technique for drainage catheter placement in cSDH to reduce intracerebral hemorrhage. Methods: Forty-nine consecutive patients with cSDH were treated with The Guidewire-assisted Drainage Catheter Placement Technique between July 2019 and June 2021. Epidemiological, clinical and radiographical data were collected and reviewed. The operative technique consists of an angular guidewire tip and catheter. Under the navigation of the guidewire, the catheter is inserted into the subdural space and the length of catheter remaining in the subdural space was 4-5 cm. The catheter was tunneled subcutaneously and fixed at the point where it emerged from the scalp. Results: Forty-nine consecutive patients underwent 55 The Guidewire-assisted Drainage Catheter Placement. The gender distribution was 37 men and 12 women. The mean age was 69.3 years. The patients presented with headache (31 patients), weakness of limbs (28 patients), speech disturbances (7 patients), and Altered behavior (6 patients). Neither intracerebral hemorrhages nor post-operative seizure occurred. Forty-seven patients were improved after the operation. The recurrence occurred in one patient. Conclusions: The Guidewire-assisted Drainage Catheter Placement Technique is a reliable method for the insertion of a subdural catheter to evacuate of the Chronic Subdural Hematoma, and is associated with an extremely low risk to cortical structures and cerebral veins.