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Introduction Selecting thrombectomy techniques for acute ischemic stroke (AIS) due to large vessel occlusion (LVO) significantly affects outcomes and costs. This study introduces the Bifurcation-Invisible (BI) sign identified on initial microcatheter angiogram in acute middle cerebral artery occlusions before endovascular thrombectomy. We aimed to evaluate whether this sign is associated with better angiographic outcomes using contact aspiration (CA) versus stent retriever (SR). Methods In this study, we reviewed 285 cases of acute M1-segment middle cerebral artery (M1-MCA) occlusions treated with stent retriever (SR) or contact aspiration (CA). Angiographic success was evaluated using modified Thrombolysis In Cerebral Infarction (mTICI) scores after the first attempt, clinical outcomes by 90-day modified Rankin Scale (mRS) scores, and procedural costs were analyzed. Categorical variables were analyzed using χ2 or Fisher's exact test, and continuous variables using Student's t-test or Mann-Whitney U test. Subgroup multivariate logistic analysis and interaction tests were conducted, with post-hoc analysis applying Bonferroni correction. Results BI-positive patients treated with CA had higher first-pass reperfusion rates (mTICI 2b-3: 64.0% vs. 41.3%, p = 0.005; Bonferroni-corrected p = 0.030) and 19.8% lower device costs (p < 0.05) than those treated with SR. BI-positive CA patients had higher first-pass reperfusion rates (mTICI 2b-3: 64.0% vs. 32.1%; p < 0.001; Bonferroni-corrected p = 0.002) and a 39.9% reduction in device costs (p < 0.05) than BI-negative patients. The interaction tests showed significant interactions between the presence of BI and contact aspiration for first-pass reperfusion rates (p = 0.007) and device costs (p ˂ 0.001). Conclusion The BI sign, a refined version of the BSO sign identified via microcatheter angiography, could guide the selection of contact aspiration, improving recanalization rates and reducing costs in MCA occlusions., (S. Karger AG, Basel.)

Background: Trauma can result in systemic inflammation that leads to organ dysfunction, but the impact on the brain, particularly following extracranial insults, has been largely overlooked., Methods: Building upon our prior findings, we aimed to understand the impact of systemic inflammation on neuroinflammatory gene transcripts in eight brain regions in rats exposed to (1) blast overpressure exposure [BOP], (2) cutaneous thermal injury [BU], (3) complex extremity injury, 3 hours (h) of tourniquet-induced ischemia, and hind limb amputation [CEI+tI+HLA], (4) BOP+BU or (5) BOP+CEI and delayed HLA [BOP+CEI+dHLA] at 6, 24, and 168 h post-injury (hpi)., Results: Globally, the number and magnitude of differentially expressed genes (DEGs) correlated with injury severity, systemic inflammation markers, and end-organ damage, driven by several chemokines/cytokines (Csf3, Cxcr2, Il16, and Tgfb2), neurosteroids/prostaglandins (Cyp19a1, Ptger2, and Ptger3), and markers of neurodegeneration (Gfap, Grin2b, and Homer1). Regional neuroinflammatory activity was least impacted following BOP. Non-blast trauma (in the BU and CEI+tI+HLA groups) contributed to an earlier, robust and diverse neuroinflammatory response across brain regions (up to 2-50-fold greater than that in the BOP group), while combined trauma (in the BOP+CEI+dHLA group) significantly advanced neuroinflammation in all regions except for the cerebellum. In contrast, BOP+BU resulted in differential activity of several critical neuroinflammatory-neurodegenerative markers compared to BU. t-SNE plots of DEGs demonstrated that the onset, extent, and duration of the inflammatory response are brain region dependent. Regardless of injury type, the thalamus and hypothalamus, which are critical for maintaining homeostasis, had the most DEGs. Our results indicate that neuroinflammation in all groups progressively increased or remained at peak levels over the study duration, while markers of end-organ dysfunction decreased or otherwise resolved., Conclusions: Collectively, these findings emphasize the brain's sensitivity to mediators of systemic inflammation and provide an example of immune-brain crosstalk. Follow-on molecular and behavioral investigations are warranted to understand the short- to long-term pathophysiological consequences on the brain, particularly the mechanism of blood-brain barrier breakdown, immune cell penetration-activation, and microglial activation., (© 2024. The Author(s).)

Study Objectives: Connecting resident physician work hours and sleep deprivation to adverse outcomes has been difficult. Our study explores clinical reasoning rather than outcomes. Diagnostic errors are a leading cause of medical error and may result from deficits in clinical reasoning. We used simulated cases to explore relationships between sleep duration and diagnostic reasoning., Methods: Residents were recruited for a 2-month study (inpatient/outpatient). Each participant's sleep was tracked (sleep diary/actigraphy). At the end of each month, residents watched 2 brief simulated clinical encounters and performed "think alouds" of their clinical reasoning. In each session, 1 video was straightforward and the other video contained distracting contextual factors. Sessions were recorded, transcribed, and interpreted. We conducted a thematic analysis using a constant comparative approach. Themes were compared based on sleep duration and contextual factors., Results: Residents (n = 17) slept more during outpatient compared with inpatient months (450.5 ± 7.13 vs 425.6 ± 10.78 hours, P = .02). We found the following diagnostic reasoning themes: uncertainty, disorganized knowledge, error, semantic incompetence, emotional content, and organized knowledge. Themes reflecting suboptimal clinical reasoning (disorganized knowledge, error, semantic incompetence, uncertainty) were observed more in cases with contextual factors (distractors). "Think alouds" from cases with contextual factors following sleep restriction had a greater number of themes concerning for problematic diagnostic reasoning., Conclusions: Residents obtained significantly more sleep during outpatient compared with inpatient months. Several negative clinical reasoning themes emerged with less sleep combined with cases containing contextual distractors. Our findings reinforce the importance of adequate sleep and supervision in house officers, particularly in cases with distracting elements., Citation: Collen J, Durning S, Berk J, Mang J, Alcover K, Jung E. Exploring sleep duration and clinical reasoning process in resident physicians: a thematic analysis. J Clin Sleep Med . 2024;20(8):1279-1289., (© 2024 American Academy of Sleep Medicine.)

Purpose: Accurate surgical reconstruction of arterial vascular supply is a crucial part of living kidney transplantation (LDKT). The presence of multiple renal arteries (MRA) in grafts can be challenging. In the present study, we investigated the impact of ligation versus anastomosis of small accessory graft arteries on the perioperative outcome., Methods: Clinical and radiological outcomes of 51 patients with MRA out of a total of 308 patients who underwent LDKT with MRA between 2011 and 2020 were stratified in two groups and analyzed. In group 1 (20 patients), ligation of accessory arteries (ARAs) and group 2 (31 patients) anastomosis of ARAs was performed., Results: Significant differences were observed in the anastomosis-, surgery-, and warm ischemia time (WIT) in favor of group 1. Students t-test showed comparable serum creatinine levels of 2.33 (± 1.75) to 1.68 (± 0.83) mg/dL in group 1 and 2.63 (± 2.47) to 1.50 (± 0.41) mg/dL in group 2, were seen from 1 week to 1 year after transplant. No increased rates of Delayed graft function (DGF), primary transplant dysfunction and transplant rejection were seen, but graft loss and revision rates were slightly higher when the ARAs were ligated. Analysis of Doppler sonography revealed that segmental perfusion deficits tend to regenerate during the clinical course., Conclusion: Ligation of smaller accessory renal arteries may not affect the outcome of living kidney transplantation, except for a minor increase in the reoperation rate. Segmental perfusion deficits of the graft seem to regenerate in most cases as seen in Doppler sonography., (© 2024. The Author(s).)

Purpose: Management of a failed kidney allograft, and the question whether it should be removed is a challenging task for clinicians. The reported risks for transplant nephrectomy (TN) vary, and there is no clear recommendation on indications or surgical approach that should be used. This study gives an overview of indications, compares surgical techniques, and identifies risk factors for higher morbidity., Methods: Retrospective analysis was conducted on all transplant nephrectomies performed between 2005 and 2020 at Charité Hospital Berlin, Department of Urology. Patient demographics, laboratory parameters, graft survival data, indication for TN, and surgical complications were extracted from medical reports., Results: A total of 195 TN were performed, with graft intolerance syndrome being the most common indication in 52 patients (26.7%), acute rejection in 36 (18.5%), acute infection in 30 (15.4%), and other reasons to stop immunosuppression in 26 patients (13.3%). Rare indications were vascular complications in 16 (8.2%) and malignancies in the allograft in six (3.1%) cases. Extracapsular surgical approach was significantly more often used in cases of vascular complications and earlier allograft removal, but there was no difference in complication rates between extra- and intracapsular approach. Acute infection was identified as an independent risk factor for a complication grade IIIb or higher according to Clavien-Dindo classification, with a HR of 12.3 (CI 2.2-67.7; p = 0.004)., Conclusion: Transplant nephrectomy should only be performed when there is a good indication, and non-elective surgery should be avoided, when possible, as it increases morbidity., (© 2024. The Author(s).)

Objective: To evaluate the relationship between different angiographic patterns of middle cerebral artery M1 segment stenosis and related territorial stroke in patients receiving aggressive medical treatment without stenting., Methods: We retrospectively reviewed our patient registry database to identify ICAS patients diagnosed by digital subtraction angiography between January 2017 and December 2020 and identified 3 different angiographic patterns (normal, shift, and dilation) in 124 patients with M1 stenosis. The association between these patterns and recurrent ischemic stroke in the M1 territory was analyzed., Results: The rates of recurrent M1 territorial stroke and transient ischemic attack in the normal group, shift group, dilation group and shift-dilation group were 34.5%, 35.0%, 78.3%, and 44.4% respectively. In patients with the shift pattern, the rate of recurrent stroke is significantly higher at a deflection angle ≥9.32° than at a deflection angle <9.32°(P < 0.05). In patients with dilation pattern, the rate of recurrent stroke is significantly higher than patients with non-dilation pattern (72.3% vs. 36.8%, P < 0.05)., Conclusions: Angiographic patterns of M1 stenosis may predict recurrent territorial strokes, thus providing a surrogate marker to identify high-risk patients for potential endovascular treatment., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Backgrounds: Dual-antiplatelet therapy (DAPT) with aspirin and clopidogrel for minor strokes or TIAs has been demonstrated in several RCTs. Whether drug selection for mono-antiplatelet therapy (MAPT) following DAPT may influence stroke recurrence has not been clarified, especially for patients with intracranial atherosclerosis stenosis (ICAS). The Thrombelastography Platelet Mapping (TEG-PM) assay claimed to be capable of monitoring platelet function secondary to antiplatelet therapy., Purpose: The aim of this study was to investigate the preventive role of TEG-PM in individualized drug selection for MAPT following DAPT in patients with minor stroke or TIA., Methods: We retrospectively reviewed our patient database to identify individuals with minor stroke or TIA between February 2019 and July 2022. Patients were divided into ICAS and non-ICAS groups, and the efficacy and safety of TEG-PM-guided MAPT for stroke prevention after minor stroke or TIA were investigated in each group., Results: ICAS patients with TEG-PM-guided MAPT had lower rates of recurrent stroke than patients without TEG-PM guidance during a mean follow-up period of 18.1 months (6.3% vs 15.2%; p = 0.04). Patients without ICAS also tended to benefit from TEG-PM-guided MAPT with lower rates of stroke recurrence (2.6% vs 8.7%; p = 0.02). No difference in the safety outcome of any bleeding events was observed in patients with TEG-PM-guided MAPT and those without (ICAS group, 2.1% vs 3.0%; p = 0.68; non-ICAS group, 1.3% vs 2.3%; p = 0.79)., Conclusion: The TEG-PM could be a tangible preprocessing in drug selection for MAPT following DAPT in patients with minor strokes or TIAs, especially for those with non-stented ICASs.

Introduction: The truncal-type occlusion (TTO) sign observed during endovascular thrombectomy is thought to predict the etiology and prognosis of acute ischemic stroke (AIS) due to large vessel occlusion (LVO). However, the interpretation of the present results and the clinical utility of this sign need further investigation. This scoping meta-review aimed to assess the predictive value of the TTO sign, thus identifying methodological limitations in current study designs., Methods: Studies published up to January 2023 were identified by systematically searching PubMed, Embase, and Web of Science. A meta-analysis was performed to quantitatively synthesize the evidence on the predictive value of the TTO sign. An 8-point scale was introduced to narratively summarize the current evidence level and methodological quality of included studies., Results: We included 10 studies in this review. For the prediction of intracranial atherosclerotic stenosis, the sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) of the TTO sign were 0.73, 0.87, 5.5, and 0.31, respectively (all p &lt; 0.05). For recanalization failure after primary thrombectomy, the sensitivity, specificity, PLR, and NLR were 0.44, 0.91, 4.9, and 0.61, respectively (all p &lt; 0.05). The strength of evidence was low due to the methodological limitations and lack of adjustment for potential confounders., Conclusion: The predictive values of the TTO sign for the etiology of LVO-AIS were considerable but seemed limited for current interpretation. Several confounders could influence the determination and predictive value of the TTO sign, requiring methodological adjustments in future research. Endovascular practitioners encountering this sign during thrombectomy should draw specific attention to stroke etiology, thus promoting timely adjustment of intra- and postprocedural strategies., (© 2023 S. Karger AG, Basel.)

Background: Quantitative spatiotemporal analysis of digital subtraction angiography could support clinical decision making for the management of cerebral vascular disease. However, there is a lack of free and user-friendly applications. The objective of our study is to devise a free and simple solution for parametric coding of digital subtraction angiography., New Method: By driving the time-density curves in the region of interest, the digital subtraction angiography images were color-coded and quantitatively analyzed using fully open-source and free software (Fiji/ImageJ). The similarity factor (f 2 ) was used to compare the resolution profiles between time-density curves generated with commercial software on the Siemens workstation (syngo iFlow, Siemens Healthcare, Berlin, Germany) and our method., Results and Comparison With Existing Method: Sixteen patients diagnosed with acute ischemic stroke resulting from acute occlusion of the distal internal carotid artery or the first segment of the middle cerebral artery were selected for analysis. Angiography images were successfully processed with syngo iFlow and Fiji/ImageJ. The images processed with Fiji/ImageJ provided excellent anatomic and hemodynamic details. In all patients, the similarity factor (f 2 ) values of the time-density curves derived from the same region of interest were 99.90 (range 99.85-99.95)., Conclusions: The ImageJ/Fiji software provides a user-friendly and free alternative for parametric coding of digital subtraction angiography., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The brain-computer interface (BCI)-mediated rehabilitation is emerging as a solution to restore motor skills in paretic patients after stroke. In the human brain, cortical motor neurons not only fire when actions are carried out but are also activated in a wired manner through many cognitive processes related to movement such as imagining, perceiving, and observing the actions. Moreover, the recruitment of motor cortexes can usually be regulated by environmental conditions, forming a closed-loop through neurofeedback. However, this cognitive-motor control loop is often interrupted by the impairment of stroke. The requirement to bridge the stroke-induced gap in the motor control loop is promoting the evolution of the BCI-based motor rehabilitation system and, notably posing many challenges regarding the disease-specific process of post stroke motor function recovery. This review aimed to map the current literature surrounding the new progress in BCI-mediated post stroke motor function recovery involved with cognitive aspect, particularly in how it refired and rewired the neural circuit of motor control through motor learning along with the BCI-centric closed-loop., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mang, Xu, Qi and Zhang.)

Blast exposure, commonly experienced by military personnel, can cause devastating life-threatening polysystem trauma. Despite considerable research efforts, the impact of the systemic inflammatory response after major trauma on secondary brain injury-inflammation is largely unknown. The aim of this study was to identify markers underlying the susceptibility and early onset of neuroinflammation in three rat trauma models: (1) blast overpressure exposure (BOP), (2) complex extremity trauma (CET) involving femur fracture, crush injury, tourniquet-induced ischemia, and transfemoral amputation through the fracture site, and (3) BOP+CET. Six hours post-injury, intact brains were harvested and dissected to obtain biopsies from the prefrontal cortex, striatum, neocortex, hippocampus, amygdala, thalamus, hypothalamus, and cerebellum. Custom low-density microarray datasets were used to identify, interpret and visualize genes significant (p < 0.05 for differential expression [DEGs]; 86 neuroinflammation-associated) using a custom python-based computer program, principal component analysis, heatmaps and volcano plots. Gene set and pathway enrichment analyses of the DEGs was performed using R and STRING for protein-protein interaction (PPI) to identify and explore key genes and signaling networks. Transcript profiles were similar across all regions in naïve brains with similar expression levels involving neurotransmission and transcription functions and undetectable to low-levels of inflammation-related mediators. Trauma-induced neuroinflammation across all anatomical brain regions correlated with injury severity (BOP+CET > CET > BOP). The most pronounced differences in neuroinflammatory-neurodegenerative gene regulation were between blast-associated trauma (BOP, BOP+CET) and CET. Following BOP, there were few DEGs detected amongst all 8 brain regions, most were related to cytokines/chemokines and chemokine receptors, where PPI analysis revealed Il1b as a potential central hub gene. In contrast, CET led to a more excessive and diverse pro-neuroinflammatory reaction in which Il6 was identified as the central hub gene. Analysis of the of the BOP+CET dataset, revealed a more global heightened response (Cxcr2, Il1b, and Il6) as well as the expression of additional functional regulatory networks/hub genes (Ccl2, Ccl3, and Ccl4) which are known to play a critical role in the rapid recruitment and activation of immune cells via chemokine/cytokine signaling. These findings provide a foundation for discerning pathophysiological consequences of acute extremity injury and systemic inflammation following various forms of trauma in the brain., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Background: Intracranial atherosclerotic stenosis is a major cause of ischemic stroke. In addition to the Wingspan stent system, several self-expanding stents have been used off-label to treat intracranial atherosclerotic stenosis lesions. The purpose of this review is to assess the existing data on the off-label use of self-expanding stents in intracranial atherosclerotic stenosis, to highlight methodological limitations in current study designs, and thus providing strategies and precautions for clinical practice., Methods: The PubMed, EMBASE, and the Cochrane Library databases were systematically searched for relevant articles published up to April 2022. In addition to the meta analysis of Enterprise, Neuroform EZ and closed cell stent respectively, we used a narrative synthesis to summarize and discuss the appropriate strategies and precautions for the use of each stent., Results: We identified 17 studies (1091 patients with 1124 lesions) reporting 6 types of off-label self-expanding stents. The most common endpoints reported were incidence of short-term complications (range: 0-15.8%, median: 3.8%), long-term complications (range: 0-12.0%, median: 0%). Potential risks include infeasibility of stenting hard lesions or tortuous vessels, stent migration, and in-stent thrombosis. Less is known about the conditions that are appropriate for an optimal stent (e.g., open-cell, close-cell, hybrid cell). There was considerable heterogeneity across studies with regards to study populations and study designs., Conclusions: The potential risks and benefits should be carefully considered when using off-label stents for intracranial atherosclerotic stenosis, particularly given the current evidence power. As a potential option for the Wingspan stent, based on device's approval only, a tailored approach with lesion-specific devices could be beneficial in certain patients.

Background and Purpose: Cochlear vascular micro-thrombosis has been hypothesized as one of the pathogenic mechanisms for sudden sensorineural hearing loss (SSNHL) refractory to regular management. This study aimed to evaluate the feasibility and safety of intra-arterial pulsed-injection urokinase (IAPU) as a salvage therapy for SSNHL after the failure of conventional therapy., Methods: We retrospectively reviewed our patient database to identify refractory SSNHL patients between November 2017 and July 2020. Study outcomes before and after the IAPU therapy were compared between IAPU and conventional therapy groups., Results: Sixty-seven moderate-profound SSNHL patients (29 in IAUP group, 38 in control group) were included in this study. Compared to the control group, patients in the IAPU group showed more significant improvement in pure tone average (PTA) (34.2 ± 23.5 vs. 10.7 ± 13.1, p < 0.001) and degree of hearing recovery (total: 20.7% vs. 5.3%, partial: 24.1% vs. 10.5%, mild: 27.6% vs. 13.2% and non: 27.6% vs. 71.1%) 2 weeks after admission. In the IAPU group, a significant improvement of PTA (86.6 ± 11.5 vs. 54.6 ± 20.1 dB, p < 0.005) was observed on the first day after IAPU treatment., Conclusion: In carefully selected SSNHL cases with a highly suspected vascular origin, IAPU is a safe and effective therapy when conventional treatments have failed. Despite the encouraging findings of our work, large studies are needed to better investigate the strengths and limitations of this salvage therapy.

Purpose: Surgical treatment of patients with renal cell carcinoma (RCC) and an extended tumour thrombus (TT) in the inferior vena cava (IVC) is challenging and often requires a multidisciplinary approach. The aim of this study was to analyse results in the real-world management of RCC patients with an extended IVC TT (level II-IV according to the Mayo classification of macroscopic venous invasion in RCC) in terms of pre-, peri- and postoperative outcome, complications and oncologic outcome., Methods: We investigated 61 patients with evidence of RCC and an extended TT in the IVC undergoing radical nephrectomy and tumour thrombectomy at our tertiary referral centre. Patients and operative characteristics were recorded and complications were analysed using the Clavien-Dindo classification. Follow-up data were retrieved by contacting the treating outpatient urologists, general practitioners and patients., Results: The TT level was II in 36, III in 8 and IV in 17 patients. Complications grade IIIb and higher according to the Clavien-Dindo classification occurred in n = 3 (8.4 %), n = 2 (25.0 %) and n = 5 (29.5 %) patients with level II, III and IV TT, respectively. The overall survival of patients with TT level II, III and IV at 24 months (60 months) was 66.9 % (41.6 %), 83.3 % (83.3 %) and 64.1 % (51.3 %). Presence of primary metastatic disease was the only significant independent predictor for OS.  CONCLUSIONS:  Radical nephrectomy with tumour thrombectomy appears to be a feasible and effective treatment option in the management of patients with RCC and an extended IVC TT., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Penile fracture (PF) is defined as rupture of the tunica albuginea of the corpora cavernosa. While most authors agree that rapid surgical therapy of this rare pathology leads to the best patient outcome, the role of imaging is highly controversial in the published literature. To obtain further evidence concerning the diagnostic accuracies of magnetic resonance imaging (MRI) and ultrasound (US) in the diagnostic assessment of patients with suspected PF., Methods: We systematically reviewed MRI and US examinations performed in our institution between 2000 and 2021 and correlated imaging reports with either intraoperative finding or final clinical diagnosis. Inclusion criteria were: (I) patient age ≥18 years, (II) examination between 2000 and 2021, (III) information available on patient's history and clinical presentation, and (IV) documented final diagnosis in discharge letter. Next to diagnostic accuracy, we describe typical imaging findings such as penile hematoma, tear of the tunica albuginea including location in terms of side and shaft segment affected, and involvement of corpus spongiosum., Results: Overall, 46 of 88 included patients (54.5%) had a confirmed diagnosis of PF. A total of 69 MRI and 31 US examinations were included. Sensitivity and specificity were 91.9% (95% CI: 78.7-97.2%) and 90.6% (95% CI: 75.8-96.8%) for MRI and 71.4% (95% CI: 45.4-88.3%) and 100.0% (95% CI: 81.6-100.0%) for US, respectively., Conclusions: The results of the present study suggest that MRI is more suitable to confirm PF and identify the site of the associated tunica albuginea tear while US is a good tool for ruling out PF., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-21-957/coif). The authors have no conflicts of interest to declare., (2022 Translational Andrology and Urology. All rights reserved.)

Background and Purpose: The diagnostic value of non-contrast CT (NCCT) in acute stroke imaging remains indispensable, especially under emergency conditions with limited resources. The radiological conjugate eye deviation (RCED) has been demonstrated as a NCCT sign to predict acute ischemic stroke (AIS) or AIS secondary to large vessel occlusion (LVO) in recent studies. We performed a meta-analysis to gain a better understanding into the predictive role of RCED for AISs and LVO-AISs., Methods: We conducted a systematic literature search using PubMed, Embase, and Cochrane. The search focused on studies published between January 2000 and August 2020 that reported the predictive value of RCED for the diagnosis of AIS or LVO-AIS. Principal measurements of the meta-analysis were the overall sensitivity, specificity, the positive likelihood ratio (PLR), and the negative likelihood ratio (NLR) of RCED in predicting AIS and LVO-AIS., Results: We included 11 studies (n = 2304). For AIS, RCED had a sensitivity of 0.37 (95% CI 0.27-0.47), a specificity of 0.86 (95% CI 0.73-0.93), the area under the receiver operating characteristic curve (AUC) was 0.58 (95% CI 0.53-0.62), PLR was 2.5 (95% CI 1.5-4.4), and NLR was 0.74 (95% CI 0.65-0.84). For LVO-AIS, RCED had a sensitivity of 0.63 (95% CI 0.46-0.77), a specificity of 0.77 (95% CI 0.71-0.82), AUC was 0.63 (95% CI 0.46-0.77), PLR was 2.7 (95% CI 1.7-4.3), and NLR was 0.49 (95% CI 0.3-0.78)., Conclusion: RCED can be used to predict LVO-AIS. It is expected that this method will be extensively used and validated in acute stroke imaging, especially under emergency conditions with limited resources., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To investigate whether staged angioplasty (SAP) is a safe and effective treatment to prevent hyperperfusion syndrome after carotid artery stenting (CAS)., Methods: A systematic literature search was performed according to established criteria to identify eligible articles published before October 2020. Pooled dichotomous data were presented as odds ratios (OR) and corresponding 95% confidence intervals (CI) using random-effect models. The efficacy endpoints were hyperperfusion syndrome (HPS), hyperperfusion phenomenon (HPP), and intracerebral hemorrhage (ICH). The safety endpoint was post-procedural thromboembolic events. The feasibility of the procedure was assessed by device-related adverse events (vessel dissection and failed angioplasty) in SAP., Results: Ten studies (1030 participants) were eligible. SAP was superior to regular CAS in preventing HPS (OR = 0.35, 95% CI 0.14-0.86, P = 0.02). There was no significant difference in the rate of thromboembolic events between the SAP group and the regular CAS group. The rates of vessel dissection and failed angioplasty with the use of a 3.0-mm-diameter balloon were 5.4% and 0.4%, respectively., Conclusion: SAP may reduce the incidence of post-CAS HPS without increasing procedure-related complications. A 3.0-mm-diameter balloon used in SAP may be appropriate for Asian populations. However, the confounded study design and confused definitions of reporting items hinder the current recommendation of SAP in clinical use.

Stroke is a leading cause of morbidity and mortality worldwide. As the most common type of stroke cases, treatment effectiveness is still limited despite intensive research. Recently, traditional Chinese medicine has attracted attention because of potential benefits for stroke treatment. Among these, luteolin, a natural plant flavonoid compound, offers neuroprotection following against ischemic stroke, although the specific mechanisms are unknown. Here we used network pharmacology, molecular docking, and experimental verification to explore the mechanisms whereby luteolin can benefit stroke recovery. The pharmacological and molecular properties of luteolin were obtained from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The potential targets of luteolin and ischemic stroke were collected from interrogating public databases. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed by Funrich and Database for Annotation, Visualization and Integrated Discovery respectively, a luteolin-target-pathway network constructed using Cytoscape, Autodock vina was used for molecular docking simulation with Discovery Studio was used to visualize and analyze the docked conformations. Lastly, we employed an in vitro model of stroke injury to evaluate the effects of luteolin on cell survival and expression of the putative targets. From 95 candidate luteolin target genes, our analysis identified six core targets . KEGG analysis of the candidate targets identified that luteolin provides therapeutic effects on stroke through TNF signaling and other pathways. Our experimental analyses confirmed the conclusions analyzed above. In summary, the molecular and pharmacological mechanisms of luteolin against stroke are indicated in our study from a systematic perspective.

Cerebral ischemic stroke (CIS) is an acute cerebrovascular disease that is caused by the sudden rupture of blood vessels inside the brain and the intervention of reperfusion to the brain, resulting in severe cerebral injury. Autophagy has been reported to be involved in the occurrence and progression of CIS. Betulinic acid (BA) is a pentacyclic triterpene acid mainly extracted from birch bark. Studies have shown the neuroprotective effects of BA. Here, the effect and mechanism of BA on ischemia-reperfusion induced cerebral injury was explored using a CIS model in vivo via 1 h middle cerebral artery occlusion (MCAO) and 24 h reperfusion in rats and in vitro via oxygen-glucose deprivation/reperfusion (OGD/R) of PC12 cells, respectively. We found that BA not only reduced cerebral injury by reducing oxidative stress but also activated the SIRT1/FoxO1 pathway to suppress autophagy and improve cerebral injury in MCAO rats. These results provide a basis for the potential clinical application of BA.

Purpose: Focal segmental glomerulosclerosis (FSGS) is a common cause for end-stage renal disease that can recur in the graft after kidney transplantation. The incidence of FSGS recurrence is reported in up to 47% of patients, predisposing those to possible poorer transplantation outcomes. Hence, we examined the incidence of FSGS recurrence and the effect on graft outcome in our patient cohort of living donor kidney transplantations (LDKT)., Patients and Methods: We analyzed 194 adult patients who received a LDKT between 2011 and 2017 of which 22 (11%) had FSGS as underlying disease. Demographic data and clinical outcomes, especially regarding recurrence of FSGS, were evaluated., Results: FSGS recurrence was identified in three (14%) patients within three months after transplantation, of whom two patients (9%) lost their graft. There was no significant difference in graft survival comparing FSGS to other reasons for end-stage renal disease., Conclusion: Incidence of FSGS recurrence in the present patient cohort was within the range reported in the literature and comparatively low. Our data support LDKT as a treatment option in patients with end-stage renal disease due to FSGS., Competing Interests: Dr Michael Duerr reports personal fees from Novartis Pharma GmbH and Takeda Pharmaceutical Company Limited, outside the submitted work. All authors declare that they have no other competing interests., (© 2021 Mang et al.)

Objective: In the real-world practice of endovascular thrombectomy (EVT) for acute ischemic stroke (AIS), the analysis of intraprocedural angiographic signs (IPASs) still challenges neurointerventionists. This review provides insights into the significance of these subtle changes for predicting underlying etiology, technical feasibility, and patient prognosis, thus promoting the potential real-time application of these signs., Methods: A systematic literature search was conducted using PubMed, Ovid Medline/Embase, and Cochrane. The search focused on studies published between January 1995 and August 2020 that reported findings related to intraprocedural angiographic manifestations in endovascular recanalization therapy for AIS., Results: We identified 12 IPASs in 22 studies involving 1,683 patients. The IPASs were assigned into 3 subsets according to their clinical meanings., Conclusion: The systematic analysis of IPAS in clinical trials and practice will lead to a better understanding of treatment effects, responses, and mechanisms during EVT. Studies of larger cohorts using more robust statistical methods are needed., (© 2021 American Academy of Neurology.)

Background: The relationship between the neutrophil-to-lymphocyte ratio (NLR) and poor prognostics in acute ischemic stroke (AIS) patients who receive intravenous thrombolysis (IVT) remains controversial. The purpose of this systematic review and meta-analysis was to evaluate the association between the NLR and poor prognosis after IVT. Furthermore, we aimed to determine whether the NLR at admission or post-IVT plays a role in AIS patients who received IVT., Methods: The PubMed, Embase, Web of Science and China National Knowledge Infrastructure databases were searched for relevant articles until October 7, 2020. Cohort and case-control studies were included if they were related to the NLR in AIS patients treated with IVT. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were pooled to estimate the relationship between NLR and poor prognosis after IVT. A random effects model was used to calculate the pooled data., Results: Twelve studies, including 3641 patients, met the predefined inclusion criteria. Higher NLRs were associated with an increased risk of hemorrhagic transformation (HT) (OR = 1.33, 95 % CI = 1.14-1.56, P < 0.001) and a poor 3-month functional outcome (OR = 1.64, 95 % CI = 1.38-1.94, P < 0.001) in AIS patients who received IVT. Subgroup analysis suggested that the NLR at admission rather than post-IVT was associated with a higher risk of HT (OR = 1.33, 95 % CI = 1.01-1.75, P = 0.039). There was no statistically significant difference between higher NLRs and 3-month mortality (OR = 1.14, 95 % CI = 0.97-1.35, P = 0.120)., Conclusions: A high NLR can predict HT and poor 3-month functional outcomes in AIS patients who receive IVT. The NLR at admission rather than the post-IVT NLR was an independent risk factor for an increased risk of HT after IVT.

Background: Primary insomnia (PI) is defined as a sleep disorder with no definite cause or inducement. Electroacupuncture, a treatment of inserting needles into specific points on the body surface and applying electrical stimulation, has been proved effective in treating PI with minimal adverse effects. However, the influence of gender difference on the clinical treatment efficacy of electroacupuncture for PI patients remains unclear. Therefore, we designed a clinical trial to compare the clinical treatment efficacy of electroacupuncture for PI patients with different genders. The research on the mechanism of electroacupuncture suggested it could modulate the sleep and wakefulness by activating or deactivating brain regions via a needling/tactile somatosensory specific stimulus. Therefore, we also designed a resting-state functional magnetic resonance imaging (rs-fMRI) study to detect the spontaneous brain activity of PI patients before and after the electroacupuncture treatment., Method: Thirty PI patients were recruited to accept 5-week electroacupuncture treatment on HT-7. Athens Insomnia Scale (AIS) and Pittsburgh sleep quality index (PSQI) questionnaires were used to evaluate the clinical treatment efficacy. Rs-fMRI was employed to observe the spontaneous brain activity in the resting state at the baseline and after 5 weeks of electroacupuncture treatment, which was measured by the fractional amplitude of low-frequency fluctuations (fALFF)., Result: The AIS and PSQI scores were significantly decreased both in the female PI group and the male PI group after treatment. The decreased PSQI of female patients was significantly more than that of male patients (p < .05). The gender-related difference in the cerebral response to electroacupuncture was mainly in posterior cingulate and supramarginal gyrus., Conclusion: There is a gender-related difference in the clinical treatment efficacy of electroacupuncture for PI patients, and female patients may benefit more from electroacupuncture. Gender-related differences in the cerebral response to electroacupuncture may be one of the factors affecting clinical treatment efficacy., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Introduction: At present, the mechanism of telangiectasia is unknown, but some evidence suggests that it may be related to genetic abnormalities. Telangiectasia may lead to bleeding of multiple sites. CT-negative subarachnoid hemorrhage is rare, which is mostly related to hemorrhage with a little amount of bleeding. CT-negative subarachnoid hemorrhage due to telangiectasia has not been reported., Case Report: In this case report, the patient experienced severe headache with nausea, vomiting, and blurred vision for 12 days, and had a history of hypertension. Physical examination revealed a clear state of mind, normal speech, normal limb muscle strength, 2 transverse fingers of neck stiffness, and negative bilateral Babinski signs. Brain CT, MRI, MRA, and MRV showed no obvious abnormalities. SWI suggested the possibility of capillary dilation. The cerebrospinal fluid was pale yellow in appearance after lumbar puncture., Diagnosis: The patient was diagnosed with subarachnoid hemorrhage (SAH) and capillary dilatation., Interventions: Therapeutic management of blood pressure and brain edema was started., Conclusion: Lumbar puncture should be performed when subarachnoid hemorrhage is clinically suspected and CT is negative. While searching for the cause of subarachnoid hemorrhage, the presence of telangiectasia should be ascertained., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: Our study aimed to evaluate the diagnostic performances of 3 routine examination methods for cerebrovascular disease in a rabbit carotid artery atherosclerosis model., Methods: A total of 12 New Zealand rabbits were included: 4 in a control group and 8 in an experimental group. A clinically relevant atherosclerosis rabbit model was induced by left common carotid artery ligation and a 12-week high-fat diet. Atherosclerosis was further confirmed by a histopathologic analysis. Then carotid ultrasound (US) imaging, high-resolution magnetic resonance imaging (HRMRI), and positron emission tomography (PET)/computed tomography (CT) were performed on this model to evaluate the diagnostic performances., Results: Carotid US showed plaque formation in the left common carotid artery and little plaque in the right common carotid artery in the experimental group. In addition, HRMRI showed stenosis formation in the left common carotid artery in the experimental group. At the horizontal level, plaques were found in the left common carotid artery, and no plaques were found in the right common carotid artery in the experimental group. Also, PET/CT showed local hypermetabolism and vulnerable plaques in the left common carotid artery of the experimental group, whereas no hypermetabolism was found in the right common carotid artery of the experimental group. Moreover, the soft plaques detected by carotid US were different from the vulnerable plaques detected by PET/CT. The unstable plaques on HRMRI were the same as the hypermetabolic vulnerable plaques on PET/CT., Conclusions: High-resolution MRI is recommended for the evaluation of neck and intracranial vascular stenosis and plaque properties in patients with stroke., (© 2020 by the American Institute of Ultrasound in Medicine.)

The influence of cilostazol on learning and memory, and cyclin D1 expression in the cerebral cortex of rats with chronic cerebral ischemia were investigated. A chronic cerebral ischemia model was established using the permanent bilateral common carotid artery occlusion method (2VO), learning and memory capacity was detected using the Morris water maze, and expression changes in apoptosis regulating gene cyclin D1 were tested by RT-PCR. Results of the Morris water maze indicated that significant extensions were found in the escape latent period and swimming path of rats in the ischemia group (2VO group), learning and memory results in the cilostazol group was obviously superior compared to the 2VO group (P<0.05), and the expression of cyclin D1 was observed to increase in both the ischemia and cilostazol intervention groups at the 9th week of ischemia. A significant difference was observed, compared with the sham operation group (P<0.05), the expression level decreased in the ischemia group compared with the cilostazol group, and a significant difference was identified compared with the ischemia group (P<0.05). Cilostazol can reduce nerve function impairment and improve learning and memory functions by affecting changes in apoptosis regulating genes.

Background: Primary insomnia (PI) is characterized by difficulties in initiating sleep or maintaining sleep, which lead to many serious diseases. Acupuncture for PI has drawn attention with its effectiveness and safety. However, the operation of choosing acupoints lacks scientific suggestion. Our trial aims to provide reference and scientific basis for the selection of acupoints and to explore its possible mechanism., Methods: A patient-assessor-blinded, randomized and sham controlled trial was designed to compare the efficacy of 5-weeks acupuncture at a single acupoint, the combination of multi-acupoints, and a sham point. The Pittsburgh sleep quality index and Athens Insomnia Scale questionnaire were used for the primary clinical outcomes, while polysomnography was performed for the secondary clinical outcomes. The resting state functional MRI was employed to detect the cerebral responses to acupuncture. The brain activity in resting state was measured by calculating the fractional amplitude of low-frequency fluctuations (fALFF), which reflected the idiopathic activity level of neurons in the resting state. These results were analyzed by two factorial ANOVA test and post-hoc t-tests., Results: The clinical outcomes suggest that acupuncture could improve clinical symptoms, and the combination of multi-acupoints might lead to a better clinical efficacy. The rs-fMRI results suggested that the brain activity of certain regions was related to the sleep experience, and acupuncture could regulate the activity of these regions. Furthermore, the combination of multi-acupoints could impact more regions which were influenced by the sleep experience., Conclusions: Acupuncture has been proven to be beneficial for PI patients, and the combination of multi-acupoints might improve its efficacy., Trial Registration: This trial has been registered on the U.S. National Library of Medicine (https://clinicaltrials.gov) ClinicalTrials.gov Identifier: NCT02448602 . Registered date: 14/04/2015.

The effects of resveratrol on various conditions have been widely studied previously. This paper aimed to investigate the influence of resveratrol on atherosclerosis (AS). Twenty-four New Zealand male rabbits were randomly and equally assigned to the normal diet group (NDG), fat diet group (FDG), and fat diet with resveratrol group (80 mg/kg/d, RFG). Biochemical indicators from blood samples were analyzed at baseline and 3 months to investigate the effects of resveratrol on blood lipid, lipoprotein-associated phospholipase A2 (Lp-PLA2), liver, and renal function. The indicators including alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and Lp-PLA2. At 3 months, arteries were stained with hematoxylin and eosin to study the influence of resveratrol on the aortic intima, smooth muscle layer, and the intima/media ratio. Comparisons of weight, ALT, AST, CREA, TG, TC, HDL-C, LDL-C, and Lp-PLA2 among the three groups showed no significant difference at baseline. However, at the end of 3 months, significant differences were observed in AST, CREA, TC, HDL-C, LDL-C, and Lp-PLA2 between the three groups ( P < 0.05). In pairwise comparison, CREA, TC, LDL-C, and Lp-PLA2 had significant differences between any two groups ( P < 0.05). In addition, there were significant differences in the AST and HDL-C levels between RFG and NDG groups ( P < 0.05). Meanwhile, the HDL-C levels were also significantly different between the FDG and NDG groups ( P < 0.01). The histologic analysis also showed that the thickness of the aortic intima and the ratio of the intima and aortic tunica media ( P < 0.05) significantly decreased in RFG compared to FDG. Resveratrol may have an antiatherosclerosis effect on a rabbit model of AS., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Lei Xu et al.)

Introduction: Patients with consistent suspicion for prostate cancer (PCa) and multiple negative prebiopsies prior to multiparametric magnetic resonance imaging (mpMRI) are still frequently evaluated for an image-guided biopsy and are reported with heterogeneous detection rates. The inclusion of a systematic biopsy (SB) is also still recommended with predominant sampling within the posterior/peripheral zone of the prostate. The aim of this study was (I) to evaluate PCa detection rates using a modified 10 core SB template including anterior biopsies in combination with mpMRI/ultrasound fusion-guided targeted biopsy (TB) in patients with 3 or more negative prebiopsies and (II) to compare mpMRI index lesion localization with histologically confirmed locali-zation from associated prostatectomy samples., Methods: Overall 1,337 consecutive patients underwent sensor-based registration TB of the prostate and a subsequent 10-core SB between January 2012 and December 2015 at our institution. For this study, 101 patients with ≥3 negative prebiopsies and prostate imaging - reporting data system lesions ≥3 were pooled prospectively and underwent TB and a modified SB including 2 ventral (anterior) biopsies. Detection rates were estimated for the modified SB, TB, and its combination. A subgroup analysis of 35 patients undergoing prostatectomy was performed by a head-to-head comparison of mpMRI index lesion and histologically confirmed PCa index lesion localization., Results: The overall detection rate for PCa was 54.5%. The combination of TB and SB detected 14 (25.4%) more cases missed by TB alone (p < 0.001) and 7 (12.7%) more cases missed by SB alone (p = 0.016), respectively. A postoperative Gleason upgrade was seen in 12/35 (34.3%) cases within the TB group and in 14/35 (40.0%) in the SB group, respectively. The subgroup analysis showed a predominant location of PCa index lesions anteriorly at the level of the midgland. The MRI detection rate of the anteriorly located index lesions was 70.4% (15/21 cases) with a clinically significant Gleason score (≥3 + 4 = 7a [International Society of Urological Pathology grade 2]) in 80.9%. Interestingly a modified SB template detected 90.5% (19/21) of the anteriorly located index lesions., Conclusion: Our data suggest that in patients with multiple prebiopsies PCa seems to be predominantly located anteriorly. We suggest the general integration of anterior biopsies despite TB in repeat biopsy patients., (© 2019 S. Karger AG, Basel.)

Insomnia patients with different gender and age usually had different sleep experience. Primary insomnia (PI) has been considered to be a disorder of hyper-arousal in the physiologic, emotional, or cognitive network. Although the hyper-arousal brain regions can be shown by comparing the brain activity of PI patients with normal people at rest, whether the brain activity of PI patients varied according to age and gender and whether age and gender could affect the distribution of hyper-arousal brain regions are still worthy of further exploration. Hence, a resting state functional magnetic resonance imaging study (No. NCT02448602) was designed to observe the brain activity of thirty PI patients and 15 healthy controls (HCs). The brain activity in resting state was measured by calculating the fractional amplitude of low-frequency fluctuations (fALFF), which reflected the idiopathic activity level of neurons. Multiple regression was performed to investigate the age and gender-related differences of brain activity in PI patients (P < .001, Family Wise Error (FWE) correct P = .05, cluster size >50) with age and gender as covariates. The hyper-arousal brain regions were measured by comparing the fALFF of PI patients and HCs. Multiple regression (P < .001, FWE correct P = .05, cluster size >50) was also performed for PI patients and HCs with group, age, and gender as covariates.The results suggested that the gender-related difference of brain activity mainly existed in superior temporal gyrus, cerebellum posterior lobe, middle frontal gyrus, and the age-related difference mainly existed in cerebellum anterior lobe, superior temporal gyrus, brainstem, parahippocampa gyrus, anterior cingulate, cingulate gyrus. In addition, the altered fALFF regions between PI and HCs mainly existed in superior temporal gyrus, posterior cingulate, anterior cingulate, cingulate gyrus, middle frontal gyrus. Furthermore, the gender factor could not influence the distribution of the altered regions. While the age factor could affect the distribution of the altered regions.

Introduction: In living donor transplantation choosing the right donor and donor side for laparoscopic donor nephrectomy is a challenging task in clinical practice. Knowledge about anomalies in renal blood supply are crucial to evaluate the feasibility of the operative procedure. Few data so far exist whether the existence of a retroaortic left renal vein has an impact on living kidney transplantation outcome for donor and recipient., Materials and Methods: We retrospectively analyzed 221 patients who underwent laparoscopic living donor nephrectomy between 2011 and 2017 for existence of a retroaortic left renal vein. Clinical characteristics and operative outcomes for donors and recipients were analyzed., Results: 221 patients underwent donor nephrectomy between 2011 and 2017; 11 patients (4.98%) showed the feature of a retroaortic left renal vein, and in 8 patients (72.7%) out of those 11 the left kidney was chosen for transplantation. Mean preoperative serum creatinine was 0.77 (0.49-0.98) mg/dL and 1.28 (0.97-1.64) mg/dL at discharge. In recipients mean serum creatinine preoperatively, after 1 week, 1 month,1 year, 2 and 3 years of follow-up was 10.36 (6.09-20.77) mg/dL, 1.71 (0.67-2.72), 1.33 (0.70-1.89), 1.31 (0.95-2.13), 1.31 (0.98-2.13) and 1.33 (1.03-1.84), respectively. Neither donors nor recipients suffered from any operative complications., Conclusions: Laparoscopic living donor nephrectomy of a left kidney with retroaortic renal vein is safe for the donor, without limitation in the outcome for the recipient., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Aims: Extracellular vesicles (EVs) are vital for information exchange between donor and recipient cells. When cells are stressed (e.g., by oxygen glucose deprivation, OGD), the complex information carried by the EVs is altered by the donor cells. Here, we aimed to analyze the proteomic differences between EVs derived from OGD-damaged cells and EVs derived from undamaged cells to explore the potential mechanisms by which EVs aggravate ischemic stroke (IS)., Main Methods: EVs released by rat adrenal gland PC12 cells subjected to 0, 3, 6, or 12 h of OGD were isolated. The proteins from the EVs secreted by each of the OGD groups were profiled using liquid chromatography-tandem mass spectroscopy (LC-MS/MS). We predicted the functions, pathways, and interactions of the differentially expressed proteins using Gene Ontology (GO), KEGG pathways, and STRING. We used parallel reaction monitoring (PRM) to validate our results., Key Findings: We identified several differentially expressed proteins in the OGD groups as compared to the controls: 170 proteins in the 3 h OGD EVs, 44 proteins in the 6 h OGD EVs, and 77 proteins in the 12 h OGD EVs (fold-change ≥1.5; p ≤ 0.05). These proteins were associated with oxidative stress, carbohydrate metabolism, protein synthesis and degradation, and thrombosis., Significance: We identified changes in protein expression in the EVs secreted by OGD-damaged cells, highlighting potential mechanisms by which EVs aggravate IS. Our results also suggested potential protein targets, which may be useful for the prevention and treatment of IS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cerebral ischemic injury is a leading cause of human mortality and disability, seriously threatening human health in the world. Activin A (Act A), as a well-known neuroprotective factor, could alleviate ischemic brain injury mainly through Act A/Smads signaling. In our previous study, a noncanonical Act A/Smads signal loop with self-amplifying property was found, which strengthened the neuroprotective effect of Act A. However, this neuroprotective effect was limited due to the self-limiting behavior mediated by Smad anchor for receptor activation (SARA) protein. It was reported that microRNA-17-5p (miR-17-5p) could suppress the expression of SARA in esophageal squamous cell carcinoma. Thus we proposed that knockdown of miR-17-5p could strengthen the neuroprotective effect of Act A/Smads signal loop through SARA. To testify this hypothesis, oxygen-glucose deficiency (OGD) was introduced to highly differentiated rattus pheochromocytoma (PC12) cells. After the transfection of miR-17-5p mimic or inhibitor, the activity of Act A signal loop was quantified by the expression of phosphorylated Smad3. The results showed that suppression of miR-17-5p up-regulated the expression of SARA protein, which prolonged and strengthened the activity of Act A signaling through increased phosphorylation of downstream Smad3 and accumulation of Act A ligand. Further luciferase assay confirmed that SARA was a direct target gene of miR-17-5p. These practical discoveries will bring new insight on the endogenous neuroprotective effects of Act A signal loop by interfering a novel target: miR-17-5p.

Objective: Nodal is a member of the transforming growth factor β (TGF-β) family, which induces the activation of the cytoplasmic Smad2 and Smad3, both of which play a neuroprotective role against cerebral ischemia-reperfusion (I/R) injury. However, the  role of Nodal in cerebral I/R is unclear. Thus, the aim of the present study was to shed light on the function of Nodal in cerebral I/R injury., Materials and Methods: Cerebral I/R injury was induced in the Sprague Dawley (SD) rats by middle cerebral artery occlusion (MCAO) and reperfusion and in murine hippocampal neuronal cells (HT22) by oxygen-glucose deprivation/reperfusion (OGD/R) stimulation. The lentivirus vectors (Nodal overexpressing lentivirus vector [OE-Nodal] and the short hair RNA of Nodal [sh-Nodal]) were used to upregulate and downregulate Nodal in SD rats or cells., Results: Nodal expression increased in the cerebral I/R models and reached a peak after 12 h of reperfusion. OE-Nodal administration to the cerebral I/R rats significantly reduced the cerebral infarction volume and inhibited the brain cell apoptosis. It also increased the level of superoxide dismutase (SOD), an antioxidant enzyme, and decreased the levels of the lipid peroxides (malondialdehyde [MDA] and lactate dehydrogenase [LDH]), in addition to those of the proinflammatory factors. Consistently, the upregulation of Nodal in HT22 by OGD/R significantly increased the SOD level and decreased the levels of MDA, LDH, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α)., Conclusions: This study revealed that Nodal exerted a protective role during cerebral I/R by inhibiting excessive oxidative stress and inflammation.

Preparations for anesthesiological management of patients build on preoperative patient self-reports concerning risk factors and comorbidities. In this setting, electronic documentation could facilitate innovative computerized functions, although patient-facing digital questionnaires require appropriate tools that patients can access effectively. To explore the feasibility of an electronic application for preoperative data acquisition directly from patients, a digital, tablet-based prototypical application has been developed within a user-centered design process in order to replace a previously used paper-based anamnesis sheet for perioperative risk evaluation. The implemented prototype has been extensively tested and iteratively improved to progressively provide an easy-to-use data entry function. To assess the suitability of this tool for everyday data acquisition by patients and physicians and to identify usability problems, the stepwise development process was accompanied by a heuristic evaluation as well as a think-aloud evaluation, while another 56 participating patients completed a feedback sheet according to ISO 9241/10. The latter method detected additional usability problems that occurred during the use of the application, which contributed to iterative improvements of the prototype. Throughout the development process, 81 issues were identified and largely resolved. After these revisions of the prototype, the number of problems found per tester decreased from 4.75 to 0.96, while the overall rating increased to 6.14 out of 7 points (SD = 1.2). These improvements demonstrate the value and efficiency of such a user-centered design process and illustrate that a user-friendly patient-facing digital data entry can replace preoperative paper questionnaires for anesthesiological management.

Ischemic stroke is caused by obstructed blood supply to the brain. It is a common as well as a serious health problem worldwide, which is often linked to disability and mortality. Here we studied, under the conditions of oxygen glucose deprivation (OGD), the expression of Notch signaling pathway proteins in PC12 cells. PC12 cells were stimulated and converted into neuron-like cells by nerve growth factor. Exposure to OGD was used as an in vitro model of cerebral hypoxia-ischemia. Our findings demonstrate that, after 3 h of OGD exposure, the expression of Notch1, Hes1 and Hes5 significantly increased, on both mRNA and protein levels. This effect gradually reduced with continuous OGD treatment, but the expression levels of these three genes remained higher, compared to untreated controls, even after 24 h of OGD exposure. Our results suggest that OGD exposure up-regulates the expression of Notch1, Hes1 and Hes5, which are important participants in Notch signaling pathway. Since their regulatory roles appear to change dynamically with the extension of OGD, the activation of the Notch pathway may play an important role in cerebral ischemic injury., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The role of stenting for intracranial arterial stenosis (ICAS) has been increasingly debated due to negative results of randomized trials. Thus, exploration of more appropriate devices may hopefully shed light on the endovascular approach, especially for patients with recalcitrant ICAS related to a high risk of stroke. We sought to present and analyze the data of Neuroform EZ stenting for medically refractory ICAS in a single-center series. Materials and methods: Between November 2016 and January 2018, 45 consecutive patients treated with the Neuroform EZ stent were included in our retrospective study. Outcomes evaluation included successful procedure rate, vascular event within 30 days and recurrent stenosis for at least 6 months after the procedure. Results: The technical success rate was 100% for all 46 stenotic lesions. Mean pre-stent stenosis was 86.5 ± 8.7%, improving to 23.7 ± 18.1% after stenting. Combined procedure related vascular event rate was 2.2% ( n = 1) within 30 days after the procedure. No in-stent restenosis was observed during an average follow-up period of 7.3 months. Conclusion: The Neuroform EZ stent system could serve as an off-label but promising optional device for ICAS stenting in a carefully selected subgroup of patients. Further longer-term clinical follow-up is mandatory to validate our initial results.

Activin A, a member of the transforming growth factor-beta superfamily, plays a neuroprotective role in multiple neurological diseases. Endoplasmic reticulum (ER) stress-mediated apoptotic and autophagic cell death is implicated in a wide range of diseases, including cerebral ischemia and neurodegenerative diseases. Thapsigargin was used to induce PC12 cell death, and Activin A was used for intervention. Our results showed that Activin A significantly inhibited morphological changes in thapsigargin-induced apoptotic cells, and the expression of apoptosis-associated proteins [cleaved-caspase-12, C/EBP homologous protein (CHOP) and cleaved-caspase-3] and biomarkers of autophagy (Beclin-1 and light chain 3), and downregulated the expression of thapsigargin-induced ER stress-associated proteins [inositol requiring enzyme-1 (IRE1), tumor necrosis factor receptor-associated factor 2 (TRAF2), apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase (JNK) and p38]. The inhibition of thapsigargin-induced cell death was concentration-dependent. These findings suggest that administration of Activin A protects PC12 cells against ER stress-mediated apoptotic and autophagic cell death by inhibiting the activation of the IRE1-TRAF2-ASK1-JNK/p38 cascade., Competing Interests: Conflicts of interest: None declared.

Background: Taxanes are routinely used to treat men with advanced prostate cancer, yet their molecular mode of action is poorly characterized. Taxanes stabilize microtubules and may hence interfere with a plethora of cellular processes, most notably mitosis. However, prostate cancer is typically a slowly growing tumor suggesting that additional processes play a role in the response to taxanes., Methods: Here, we analyzed the potential effect of taxanes on microtubuli-dependent intracellular transport and signaling processes, specifically, nuclear translocation of the androgen receptor and modulation of the RAS-RAF-MEK-ERK signaling cascade., Results: We show that the androgen-driven nuclear translocation of the androgen receptor remains virtually undisturbed by docetaxel in prostate cancer cells. However, we found a striking down-regulation of activated ERK1/2 together with enhanced cytotoxicity in both docetaxel or cabazitaxel-treated cells that was comparable to direct MEK kinase inhibition. Remarkably, MEK inhibition alone was less effective in inducing cytotoxicity than taxanes indicating that a down-regulation of activated ERK1/2 may be necessary but is not sufficient for taxane-induced antitumoral effects. In line with this notion, we show in a xenograft mouse model that prostate cancer cells that are resistant to docetaxel overexpress activated ERK1/2. Taken together, our findings underscore that the modulation of ERK1/2 activation, in concert with other mechanisms, plays an important role in taxane-induced antineoplastic effects on prostate cancer cells., Conclusions: These results suggest at least partially nonoverlapping effects of docetaxel and androgen deprivation therapy and hence help to understand recent clinical findings. A further elucidation of the mode of action of docetaxel would have important implications to optimize current treatment strategies and biomarker development for men with metastatic prostate cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Activin A (Act A), a member of the transforming growth factor-beta (TGF-β), reduces neuronal apoptosis during cerebral ischemia through Act A/Smads signaling pathway. However, little is known about the effect of Act A/Smads pathway on autophagy in neurons. Here, we found that oxygen-glucose deprivation (OGD)-induced autophagy was suppressed by exogenous Act A in a concentration-dependent manner and enhanced by Act A/Smads pathway inhibitor (ActRIIA-Ab) in neuronal PC12 cells. These results indicate that Act A/Smads pathway negatively regulates autophagy in OGD-treated PC12 cells. In addition, we found that c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways are involved in the OGD-induced autophagy. The activation of JNK and p38 MAPK pathways in OGD-treated PC12 cells was suppressed by exogenous Act A and enhanced by ActRIIA-Ab. Together, our results suggest that Act A/Smads signaling pathway negatively regulates OGD-induced autophagy via suppression of JNK and p38 MAPK pathways in neuronal PC12 cells., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Activin A (Act A), a member of transforming growth factor-β superfamily, plays a neuroprotective role in multiple neurological diseases through Act A/Smads signal activation. Traditionally, the up-regulation of Act A gene and extracellular Act A accumulation show the signal activation as a linear pathway. However, one of our discoveries indicated that Act A could lead a loop signaling in ischemic injury. To clarify the characteristic of this loop signaling in a non-pathological state, we up-regulated the expression of Act A, monitored extracellular Act A accumulation and examined the activity of Act A signaling, which was quantified by the expression of phosphorylated Smad3 and the fluorescence intensity of Smad4 in nuclei. The results demonstrated a noncanonical Act A signal loop with self-amplifying property in PC12 cells. Further, it showed self-limiting behavior due to temporary activation and spontaneous attenuation. This periodic behavior of Act A signal loop was found to be regulated by the level of Smad anchor for receptor activation (SARA). Moreover, increased activity of Act A signal loop could promote PC12 cell proliferation and enhance the survival rate of cells to Oxygen-Glucose Deprivation. These practical discoveries will bring new insight on the functional outcome of Act A signaling in neurological diseases by the further understanding: loop signaling.

Activin A (Act A), a member of transforming growth factor-β (TGF-β) superfamily, is an early gene in response to cerebral ischemia. Growing evidences confirm the neuroprotective effect of Act A in ischemic injury through Act A/Smads signal activation. In this process, regulation networks are involved in modulating the outcomes of Smads signaling. Among these regulators, crosstalk between c-Jun N-terminal kinase (JNK) and Smads signaling has been found in the TGF-β induced epithelial-mesenchymal transition. However, in neural ischemia, the speculative regulation between JNK and Act A/Smads signaling pathways has not been clarified. To explore this issue, an Oxygen Glucose Deprivation (OGD) model was introduced to nerve-like PC12 cells. We found that JNK signal activation occurred at the early time of OGD injury (1 h). Act A administration suppressed JNK phosphorylation. In addition, JNK inhibition could elevate the strength of Smads signaling and attenuate neural apoptosis after OGD injury. Our results indicated a negative regulation effect of JNK on Smads signaling in ischemic injury. Taken together, JNK, as a critical site for neural apoptosis and negative regulator for Act A/Smads signaling, was presumed to be a molecular therapeutic target for ischemia.

We have recently shown that centrosomal protein 57 (CEP57) is overexpressed in a subset of human prostate cancers. CEP57 is involved in intracellular transport processes, and its overexpression causes mitotic defects as well as abnormal microtubule nucleation and bundling. In the present study, we further characterized the prognostic and functional role of CEP57 in prostate cancer. Unexpectedly, we found that high CEP57 expression is an independent prognostic factor for a more favorable biochemical recurrence-free survival in two large patient cohorts. To reconcile this finding with the ability of CEP57 to cause cell division errors and thus potentially promote malignant progression, we hypothesized that alterations of microtubule-associated transport processes, in particular nuclear translocation of the androgen receptor (AR), may play a role in our finding. However, CEP57 overexpression and microtubule bundling had, surprisingly, no effect on the nuclear translocation of the AR. Instead, we found a significant increase of cells with disarranged microtubules and a cellular morphology suggestive of a cytokinesis defect. Because mitotic dysfunction leads to a reduced daughter cell formation, it can explain the survival benefit of patients with increased CEP57 expression. In contrast, we show that a reduced expression of CEP57 is associated with malignant growth and metastasis. Taken together, our findings underscore that high CEP57 expression is associated with mitotic impairment and less aggressive tumor behavior. Because the CEP57-induced microtubule stabilization had no detectable effect on AR nuclear translocation, our results furthermore suggest that microtubule-targeting therapeutics used in advanced prostate cancer such as docetaxel may have modes of action that are at least in part independent of AR transport inhibition., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

The Rho/Rho-kinase signaling pathway plays an important role in cerebral ischemia/reperfusion injury. However, very few studies have examined in detail the changes in the Rho/Rho-kinase signaling pathway in chronic cerebral ischemia. In this study, rat models of chronic cerebral ischemia were established by permanent bilateral common carotid artery occlusion and intragastrically administered 9 mg/kg fasudil, a powerful ROCK inhibitor, for 9 weeks. Morris water maze results showed that cognitive impairment progressively worsened as the cerebral ischemia proceeded. Immunohistochemistry, semi-quantitative RT-PCR and western blot analysis showed that the expression levels of Rho-kinase, its substrate myosin-binding subunit, and its related protein alpha smooth muscle actin, significantly increased after chronic cerebral ischemia. TUNEL staining showed that chronic cerebral ischemia could lead to an increase in neuronal apoptosis, as well as the expression level of caspase-3 in the frontal cortex of rats subjected to chronic cerebral ischemia. Fasudil treatment alleviated the cognitive impairment in rats with chronic cerebral ischemia, and decreased the expression level of Rho-kinase, myosin-binding subunit and alpha smooth muscle actin. Furthermore, fasudil could regulate cerebral injury by reducing cell apoptosis and decreasing caspase-3 expression in the frontal cortex. These findings demonstrate that fasudil can protect against cognitive impairment induced by chronic cerebral ischemia via the Rho/Rho-kinase signaling pathway and anti-apoptosis mechanism.

Background: Several studies have assessed the effects of computer-based cognitive programs (CCP) in the management of age-related cognitive decline, but the role of CCP remains controversial. Therefore, this systematic review evaluated the evidence on the efficacy of CCP for age-related cognitive decline in healthy older adults., Methods: Six electronic databases (through October 2014) were searched. The risk of bias was assessed using the Cochrane Collaboration tool. The standardized mean difference (SMD) and 95% confidence intervals (CI) of a random-effects model were calculated. The heterogeneity was assessed using the Cochran Q statistic and quantified with the I2 index., Results: Twelve studies were included in the current review and were considered as moderate to high methodological quality. The aggregated results indicate that CCP improves memory performance (SMD, 0.31; 95% CI 0.16 to 0.45; p < 0.0001) and processing speed (SMD, 0.50; 95% CI 0.14 to 0.87; p = 0.007) but not executive function (SMD, -0.12; 95% CI -0.33 to 0.09; p = 0.27). Furthermore, there were long-term gains in memory performance (SMD, 0.59; 95% CI 0.13 to 1.05; p = 0.01)., Conclusion: CCP may be a valid complementary and alternative therapy for age-related cognitive decline, especially for memory performance and processing speed. However, more studies with longer follow-ups are warranted to confirm the current findings.

Background and Purpose: Data on the association between PDE4D SNP 87 and the risk of ischemic stroke are contentious and debatable. The present meta-analysis was undertaken to systematically summarize the possible association., Methods: Based on comprehensive search of PubMed, Embase, and CNKI databases, we identified 18 eligible articles examining the relationship between PDE4D SNP 87 and ischemic stroke risk. We evaluated the strength of relationship using odds ratios (ORs) with 95% confidence intervals (CIs)., Results: In the overall analysis, PDE4D SNP 87 was not found to have effects on the risk of ischemic stroke. The null association persisted in the subgroup analyses according to ethnicity and sample size., Conclusions: Our meta-analysis suggests that PDE4D SNP 87 may not represent an independent risk factor for ischemic stroke development.

Objectives: The ABCD2 score has been commonly used to triage patients with transient ischemic attack (TIA) who are at high risk for imminent stroke. However, its accuracy in predicting short-term stroke risk among TIA patients in China remains unclear., Methods: All eligible studies published up to May 2014 were identified by searching Medline, PubMed, Embase, the China Knowledge Resource Integrated Database (CNKI) and the China Biological Medicine Database (CBM-disc), as well as unpublished articles manually scanned. The strength of the associations between treatments and outcomes was estimated by incorporated risk ratios (RRs) and 95% confidence intervals (CIs) using the Mantel-Haenszel statistical method., Results: Eight and 32 studies, which validated the value for predicting the risk of stroke 2 and 7 days after TIA respectively, were included. We calculated the RRs and CIs for 2- and 7-day prediction for stroke (low: RR=0.43, 95% CI=0.17-1.10, I2=0%; moderate: RR=0.42, 95% CI=0.26-0.67, I2=0%; high: RR=0.32, 95% CI=0.21-0.48, I2=0%; and low: RR=0.29, 95% CI=0.20-0.44, I2=0%; moderate: RR=0.27, 95% CI=0.23-0.33, I2=0%; high: RR=0.22, 95% CI=0.18-0.27, I2=1%)., Conclusions: This meta-analysis indicated that the ABCD2 score may highly under-predict the short-term occurrence of stroke after TIA for the Chinese population compared with the original model derived from Caucasian populations, which may lead to neglect of the short-term risk for stroke in the clinical practice.