The application of saccades to assess cognitive impairment among older adults: a systematic review and meta-analysis.

BACKGROUND: Saccade is a novel and feasible method for cognition assessment and has potential to screen older people with cognitive impairment. OBJECTIVES: To systematically summarize the evidence and determine whether different saccade parameters can effectively identify patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS: English and Chinese databases were searched until 19 April 2022. Studies analyzing saccade parameters in older adults with normal cognition, MCI, or AD were included. Two researchers independently performed the screening, data extraction, and quality appraisal. Meta-analyses were conducted and standard mean differences and 95% confidence intervals were estimated with a random effects model. RESULTS: Thirty-five studies were included, and 26 studies were pooled for the meta-analysis. The results demonstrated that patients with cognitive impairment exhibited longer latency and lower accuracy rates in the prosaccade and antisaccade tasks, along with lower corrected error rates in the antisaccade tasks. However, the pooled results for antisaccades were more stable, providing the ability to distinguish patients with cognitive impairment among older adults. The results of the subgroup analyses revealed that only the accuracy rates of the antisaccades differed significantly between people with MCI and AD. Regarding the differences between older adults with normal cognition and those with MCI, the effect sizes of latency and the accuracy rates of saccades as well as the corrected error rates of antisaccades were significant. CONCLUSIONS: Saccades, especially antisaccades, are a potential screening and assessment tool for distinguishing older adults with MCI or AD from those with normal cognition.

The Role of the Subthalamic Nucleus in Sequential Working Memory in De Novo Parkinson's Disease.

BACKGROUND: Deficits in maintaining and manipulating sequential information online can occur even in patients with mild Parkinson's disease. The subthalamic nucleus may play a modulatory role in the neural system for sequential working memory, which also includes the lateral prefrontal cortex. OBJECTIVES: The objective of this study was to investigate neural markers of sequential working memory deficits in patients with de novo Parkinson's disease. METHODS: A total of 50 patients with de novo Parkinson's disease and 50 healthy controls completed a digit ordering task during functional magnetic resonance imaging scanning. The task separated the maintenance ("pure recall") and manipulation of sequences ("reorder & recall" vs "pure recall"). RESULTS: In healthy controls, individual participants' task accuracy was predicted by the regional activation and functional connectivity of the subthalamic nucleus. Healthy participants who showed lower subthalamic nucleus activation and stronger subthalamic nucleus connectivity with the putamen performed more accurately in maintaining sequences ("pure recall"). Healthy participants who showed greater ordering-related subthalamic nucleus activation change exhibited smaller accuracy costs in manipulating sequences ("reorder & recall" vs "pure recall"). Patients performed less accurately than healthy controls, especially in "reorder & recall" trials, accompanied by an overactivation in the subthalamic nucleus and a loss of synchrony between the subthalamic nucleus and putamen. Individual patients' task accuracy was predicted only by the subthalamic nucleus connectivity. The contribution of the subthalamic nucleus activation or activation change was absent. We observed no change in the lateral prefrontal cortex. CONCLUSIONS: The overactivation and weakened functional connectivity of the subthalamic nucleus are the neural markers of sequential working memory deficits in de novo Parkinson's disease. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Expression and Prognostic Significance of p53 in Glioma Patients: A Meta-analysis.

Glioma is a brain tumor deriving from the neoplastic glial cells or neuroglia. Due to its resistance to anticancer drugs and different disease progress of individuals, patients with high-grade glioma are difficult to completely cure, leading to a poor prognosis and low overall survival. Therefore, there is an urgent need to look for prognostic and diagnostic indicators that can predict glioma grades. P53 is one of the widely studied biomarkers in human glioma. The purpose of this study was to comprehensively evaluate the significance of p53 expression in glioma grades and overall survival. We searched commonly used electronic databases to retrieve related articles of p53 expression in glioma. Overall, a total of 21 studies including 1322 glioma patients were finally screened out. We observed that the frequency of p53 immuno-positivity was higher in high-grade patients than that in low-grade category (63.8 vs. 41.6 %), and our statistic analysis indicated that p53 expression was associated with pathological grade of glioma (OR 2.93, 95 % CI 1.87-4.60, P < 0.00001). This significant correction was also found in 1-, 3- and 5-year overall survival. However, no positive relationship was found between age, sex, tumor size and p53 expression in patients with glioma. In conclusion, our results suggested that p53 immunohistochemical expression might have an effective usefulness in predicting the prognosis in patients with glioma.

Hypoxia-inducible factor-1α mediates up-regulation of neprilysin by histone deacetylase-1 under hypoxia condition in neuroblastoma cells.

Hypoxia-inducible factor (HIF)-1 is the key transcriptional activator mediating both adaptive and pathological responses to hypoxia. The purpose of this study was to find the role of HIF-1 in regulating neprilysin (NEP) at the early stage of hypoxia and explore the underlying mechanism. In this study, we demonstrated that both NEP mRNA and protein levels in neuroblastoma cells were elevated in early stages of hypoxia. Over-expression of HIF-1α gene increased NEP mRNA/protein levels, as well as enzyme activity while knockdown of HIF-1α decreased them. Meanwhile, HIF-1α was shown to bind to histone deacetylase (HDAC)-1 and reduced the association of HDAC-1 with NEP promoter, thus activating NEP gene transcription in a de-repression way. In summary, our results indicated that hypoxia in the early stages would up-regulate NEP expression, in which interaction of HIF-1α and HDAC-1 may play a role. This study suggested that NEP up-regulation might be an adaptive response to hypoxia, which was mediated by HIF-1α binding to HDAC-1 at the early stage of hypoxia.

MiRNA-181c inhibits EGFR-signaling-dependent MMP9 activation via suppressing Akt phosphorylation in glioblastoma.

As the most aggressive malignant primary human brain tumor, glioblastoma is noted with extremely poor patient survival. Previous studies have demonstrated that expression of matrix metalloproteinase-9 (MMP9) in glioblastoma cells is critical for cancer metastasis. However, the molecular signaling pathways that control MMP9 activation remain undefined. Here, we reported a strong negative correlation of microRNA (miRNA)-181c levels with either MMP9 levels or activation of epidermal growth factor receptor (EGFR) signaling in glioblastoma patients. EGF-induced activation of EGFR in a human glioblastoma line, A-172 cells, increased MMP9 expression through activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway, without affecting expression of miRNA-181c. On the other hand, overexpression of miRNA-181c in A-172 cells inhibited MMP9 expression by inhibiting Akt phosphorylation, but not phosphorylation of EGFR receptor. Taken together, these findings suggest that EGFR signaling activates downstream PI3K/Akt to increase MMP9 expression in glioblastoma, while phosphorylation of Akt is a control point by miRNA-181c. Our work thus provides new insights into the molecular basis underlying the metastasis of glioblastoma.

Relationships between PTEN gene mutations and prognosis in glioma: a meta-analysis.

We conducted a meta-analysis in order to investigate the relationships between PTEN gene mutations and the prognosis in glioma. The following electronic databases were searched for relevant articles without any language restrictions: Web of Science (1945 ~ 2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966 ~ 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013). Meta-analyses were conducted using the STATA software (Version 12.0, Stata Corporation, College Station, Texas USA). Hazard ratio (HR) with its corresponding 95 % confidence interval (95%CI) was calculated. Six independent cohort studies with a total of 357 glioma patients met our inclusion criteria. Our meta-analysis results indicated that glioma patients with PTEN gene mutations exhibited a significantly shorter overall survival (OS) than those without PTEN gene mutations (HR = 3.66, 95%CI = 2.02 ~ 5.30, P < 0.001). Ethnicity-stratified subgroup analysis demonstrated that PTEN gene mutations were closely linked to poor prognosis in glioma among Americans (HR = 3.72, 95%CI = 1.72 ~ 5.73, P < 0.001), while similar correlations were not observed among populations in Sweden, Italy, and Malaysia (all P > 0.05). Our meta-analysis provides direct and strong evidences for the speculation of PTEN gene mutations' correlation with poor prognosis of glioma patients.

Physiological effects of microgravity on bone cells.

Life on Earth developed under the influence of normal gravity (1g). With evidence from previous studies, scientists have suggested that normal physiological processes, such as the functional integrity of muscles and bone mass, can be affected by microgravity during spaceflight. During the life span, bone not only develops as a structure designed specifically for mechanical tasks but also adapts for efficiency. The lack of weight-bearing forces makes microgravity an ideal physical stimulus to evaluate bone cell responses. One of the most serious problems induced by long-term weightlessness is bone mineral loss. Results from in vitro studies that entailed the use of bone cells in spaceflights showed modification in cell attachment structures and cytoskeletal reorganization, which may be involved in bone loss. Humans exposed to microgravity conditions experience various physiological changes, including loss of bone mass, muscle deterioration, and immunodeficiency. In vitro models can be used to extract valuable information about changes in mechanical stress to ultimately identify the different pathways of mechanotransduction in bone cells. Despite many in vivo and in vitro studies under both real microgravity and simulated conditions, the mechanism of bone loss is still not well defined. The objective of this review is to summarize the recent research on bone cells under microgravity conditions based on advances in the field.

Circulating adipokine concentrations and the risk of venous thromboembolism: A Mendelian randomization and mediation analysis.

Background: Previous observational studies have suggested that circulating adipokine concentrations are related to a greater risk of venous thromboembolism (VTE). However, it remained unclear whether these observations reflect causality. Objective: This study aimed to investigate the causal relationship between circulating adipokine concentrations (including adiponectin, leptin, PAI-1, MCP-1, leptin receptor, and RETN) and the risk of VTE and its subtypes (DVT and PE) and to determine whether circulating adipokine concentrations are a mediator of venous thromboembolic events in obese patients. Methods: We used Mendelian randomization (MR) analyses to determine the effects of the body mass index (BMI), adiponectin, leptin, PAI-1, MCP-1, leptin receptor, and RETN levels on VTE, DVT, and PE in a cohort of 11,288 VTE cases, 5,632 DVT cases, 5,130 PE cases, and 254,771 controls. We then assessed the proportion of the effect of obesity on VTE, DVT, and PE explained by circulating leptin levels. Result: Genetically predicted higher BMI was related to increased VTE (OR = 1.45, p < 0.001), DVT (OR = 1.63, p < 0.001), and PE (OR = 1.37, p < 0.001) risk, and higher circulating leptin levels increase odds of VTE (OR = 1.96, q < 0.001), DVT (OR = 2.52, q < 0.001), and PE (OR = 2.26, q = 0.005). In addition, we found that the causal effect between elevated serum adiponectin and the decreased risk of VTE (OR = 0.85, p = 0.013, q = 0.053) and PE (OR = 0.81, p = 0.032, q = 0.083) and between MCP-1 and the reduced risk of VTE (OR = 0.88, p = 0.048, q = 0.143) is no longer significant after FDR adjustment. In MR mediation analysis, the mediation effect of circulating leptin levels in the causal pathway from BMI to PE was estimated to be 1.28 (0.95-1.71, p = 0.10), accounting for 39.14% of the total effect. Conclusion: The circulating leptin level is a risk factor for VTE, DVT, and PE, but it might be a potential mediator of BMI on the risk of PE, and thus, interventions on the circulating leptin level in obesity might reduce the risk of PE. Adiponectin is a potential protective factor for both VTE and PE.

Comprehensive Analysis of Differential Gene Expression and Correlated Immune Infiltration in Bladder Cancer.

Background: Bladder cancer (BCa) is one of the most common urinary tract malignancies. Our study aimed to provide promising biomarkers for BCa screening and prognosis. Methods: BCa samples were obtained from Gene Expression Omnibus (GEO) datasets. Differentially expressed genes (DEGs) were analysed by GO/KEGG analysis. Univariate Cox hazard analysis and Kaplan Meier Curve clarified the relevance of DEGs and survival. Receiver operating characteristic (ROC) curve showed the discrimination ability of DEGs in BCa patient outcome prediction. RT-PCR was used to validate gene expression. Results: Overall, 61 common up regulated and 170 common down-regulated genes in BCa were obtained. DEGs were mainly enriched in proliferation and metastasis processes. CDC20, COL14A1, SPARCL1, TMOD1, RHOJ, FXYD6 and MFAP4 had clinical relevance to survival with high accuracy. CDC20, SPARCL1 and TMOD1 are promising biomarkers of BCa. CDC20, SPARCL1 and TMOD1 are involved in cancer immune infiltration. Conclusion: CDC20, SPARCL1 and TMOD1 are promising biomarkers of bladder cancer. In addition, CDC20, SPARCL1 and TMOD1 are involved in cancer immune infiltration, which provides new targets in immune therapy in bladder cancer.

Study on safety and efficacy of regorafenib combined with transcatheter arterial chemoembolization in the treatment of advanced hepatocellular carcinoma after first-line targeted therapy.

Background: Targeted drug therapy and transcatheter arterial chemoembolization (TACE) is the most effective control method for middle and late-stage hepatocellular carcinoma (HCC). Regorafenib as the second-line treatment of patients with advanced HCC, combined with TACE treatment still achieved good results in clinic. However, there is no relevant research at present. However, there is no relevant research at present. This study was to investigate the efficacy and safety of regorafenib combined with TACE in the treatment of patients with advanced HCC after the failure of first-line targeted treatment. Methods: Fifty-nine patients with advanced HCC received second-line regorafenib treatment between October 2019 and September 2021 were enrolled in the study. Patients were treated with routine TACE. Oral administration of regorafenib was started 1 week after the operation for 3 weeks and then stopped for 1 week. Objective response rate (ORR), disease control rate (DCR), median progression-free survival (m-PFS), and safety were evaluated according to the modified Response Evaluation Criteria in Solid Tumors (m-RECIST). In our study, most of the analyses are descriptive. Results: One patient achieved complete response (CR), and 24 patients achieved partial response (PR). stable disease (SD) was observed in 14 patients, while progression disease (PD) was observed in 20 patients. The ORR was 42.3% (25/59), and the DCR was 66.1% (39/59). The longest follow-up was 23 months, and the shortest was 1 month. Disease progression was found in 45 patients during follow-up. Among these patients, the longest interval before the detection of disease progression was 16 months, and the shortest was 1 month. Among patients who had disease progression, the median PFS was 8 months. Adverse events (AEs) were observed in 59 patients. These included hand-foot reaction (n=50, 84.7%), weight decrease (n=18, 30.5%), hypertension (n=8, 13.6%), proteinuria (n=1, 1.7%), weakness (n=12, 20.3%), diarrhea (n=1, 1.7%), and hoarseness (n=9, 15.3%). No treatment-related death occurred. Conclusions: Regorafenib combined with TACE achieved a good ORR and DCR among patients with advanced HCC receiving second-line targeted therapy, with only 9 patients experiencing grade 3 or 4 adverse reactions. Therefore, regorafenib combined with TACE is effective and safe in the treatment of advanced HCC.

Study on efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with regorafenib and PD-1 antibody versus continued TACE combined with regorafenib in patients with hepatocellular carcinoma after failed second-line treatment with regorafenib.

Background: At present, there is no standard for the posterior treatment of hepatocellular carcinoma (HCC). This study isTo evaluate and compare the safety and efficacy of transcatheter arterial chemoembolization (TACE) combined with regorafenib and anti-PD-1 antibody with continued TACE combined with regorafenib in patients with HCC after the failure of second-line treatment with regorafenib. Methods: We enrolled patients with advanced HCC who were treated with sorafenib and sequential regorafenib. All patients were treated with TACE and found to have tumor progression in 2021. After tumor progression, patients were treated with TACE combined with regorafenib and PD-1 antibody or with continued TACE combined with regorafenib according to the wishes of the patient. Efficacy was evaluated after 1 month of treatment. The objective response rate (ORR), disease-control rate (DCR), and safety were evaluated according to adverse reactions of patients. Results: Nine patients were treated with TACE combined with regorafenib and PD-1 antibody, and the 9 patients continued to receive TACE combined with regorafenib. There was no significant difference in baseline data between the 2 groups. In the PD-1 group five patients achieved a partial response (PR), three achieved stable disease (SD), and one patient had progressive disease (PD) after 1 month of treatment. The ORR was 55.6% and the DCR was 88.9%. In the continued TACE-regorafenib group, four patients achieved PR, one achieved SD, and four patients achieved PD after 1 month of treatment, while the ORR was 44.4% and the DCR was 55.6%. There was a significant difference in the DCR between the two groups (P=0.012), while adverse events were similar in both. Conclusions: TACE combined with regorafenib and PD-1 antibody had a higher DCR and was more effective than continued TACE combined with regorafenib in patients with HCC who failed second-line treatment with regorafenib. However, PD-1 antibody therapy might increase the risk of death by causing an uncontrollable immune response. Given the risk of an immune response, patients may choose to continue TACE combined with regorafenib, given the similar ORR of the two treatments.

Deep learning-based hemodynamic prediction of carotid artery stenosis before and after surgical treatments.

Hemodynamic prediction of carotid artery stenosis (CAS) is of great clinical significance in the diagnosis, prevention, and treatment prognosis of ischemic strokes. While computational fluid dynamics (CFD) is recognized as a useful tool, it shows a crucial issue that the high computational costs are usually required for real-time simulations of complex blood flows. Given the powerful feature-extraction capabilities, the deep learning (DL) methodology has a high potential to implement the mapping of anatomic geometries and CFD-driven flow fields, which enables accomplishing fast and accurate hemodynamic prediction for clinical applications. Based on a brain/neck CT angiography database of 280 subjects, image based three-dimensional CFD models of CAS were constructed through blood vessel extraction, computational domain meshing and setting of the pulsatile flow boundary conditions; a series of CFD simulations were undertaken. A DL strategy was proposed and accomplished in terms of point cloud datasets and a DL network with dual sampling-analysis channels. This enables multimode mapping to construct the image-based geometries of CAS while predicting CFD-based hemodynamics based on training and testing datasets. The CFD simulation was validated with the mass flow rates at two outlets reasonably agreed with the published results. Comprehensive analysis and error evaluation revealed that the DL strategy enables uncovering the association between transient blood flow characteristics and artery cavity geometric information before and after surgical treatments of CAS. Compared with other methods, our DL-based model trained with more clinical data can reduce the computational cost by 7,200 times, while still demonstrating good accuracy (error<12.5%) and flow visualization in predicting the two hemodynamic parameters. In addition, the DL-based predictions were in good agreement with CFD simulations in terms of mean velocity in the stenotic region for both the preoperative and postoperative datasets. This study points to the capability and significance of the DL-based fast and accurate hemodynamic prediction of preoperative and postoperative CAS. For accomplishing real-time monitoring of surgical treatments, further improvements in the prediction accuracy and flexibility may be conducted by utilizing larger datasets with specific real surgical events such as stent intervention, adopting personalized boundary conditions, and optimizing the DL network.

Age differences in the fronto-striato-parietal network underlying serial ordering.

Maintaining the ability to arrange thoughts and actions in an appropriate serial order is crucial for complex behavior. We aimed to investigate age differences in the fronto-striato-parietal network underlying serial ordering using functional magnetic resonance imaging. We exposed 25 young and 27 older healthy adults to a digit ordering task, where they had to reorder and recall sequential digits or simply to recall them. We detected a network comprising of the lateral and medial prefrontal, posterior parietal, and striatal regions. In young adults, the prefrontal and parietal regions were more activated and more strongly connected with the supplementary motor area for "reorder & recall" than "pure recall" trials (psychophysiological interaction, PPI). In older adults, the prefrontal and parietal activations were elevated, but the PPI was attenuated. Individual adults who had a stronger PPI performed more accurately in "reorder & recall" trials. The decreased PPI appeared to be compensated by increased physiological correlations between the prefrontal/parietal cortex and the striatum, and by that between the striatum and the supplementary motor area.

Altered transposition asymmetry in serial ordering in early Parkinson's disease.

INTRODUCTION: The ability to arrange thoughts and actions in an appropriate serial order is impaired in Parkinson's disease (PD). However, it is unclear how serial order is represented and manipulated and how the representation or manipulation is altered in the early stages of PD. We aimed to analyze the pattern of performance errors in serial ordering versus serial recall in nondemented PD patients with mild clinical symptoms and healthy adults to identify the underlying principles of serial ordering. METHODS: PD patients (N = 57) and healthy controls (N = 40) completed the adaptive digit ordering and digit span forward tests. We focused on items recalled in incorrect positions (transposition) and analyzed the tendency to recall transposed items too early (anticipation) versus too late (postponement). We also analyzed the tendency to recall the item displaced by the error (fill-in) versus the item following the error in the target output order (infill) after anticipation errors. RESULTS: PD patients not only made more transposition errors but also showed distinct error patterns. The patients made more anticipations but not postponements, and more fill-ins but not in fills than healthy controls in the ordering test (transposition asymmetry). Individual patients' percentage of anticipations was negatively correlated with their daily exposure to D2/3 receptor agonists. Patients' error pattern in the forward test was normal. CONCLUSION: The increase in anticipations in PD suggests an increase in the forward-specific variability in the representation of serial order. Their increase in fill-ins suggests a deficit in the chaining mechanism involved in the manipulation of serial order.

Expression of the DJ-1 protein in the serum of Chinese patients with Parkinson's disease.

DJ-1 is one of the important genes found in Parkinson's disease (PD). Studies have shown that the DJ-1 protein levels are elevated in the cerebrospinal fluid (CSF) and plasma of sporadic PD patients, and the DJ-1 protein levels in the CSF and plasma may serve as biomarkers of PD. However, Japanese scholars previously reported that there was no difference in the levels of the DJ-1 protein in serum between sporadic PD patients and controls. Therefore, whether the serum DJ-1 protein levels are different between PD patients and controls in Chinese patients as well as whether serum DJ-1 protein can serve as a biomarker of PD are unknown. The present study aimed to determine whether there was a difference in serum DJ-1 protein levels between Chinese PD patients and controls. The subjects included 18 primary PD patients and 7 controls. Blood was collected by venipuncture, and serum was collected by centrifugation after the blood was coagulated. The serum DJ-1 protein levels were detected by both Western blot and ELISA. There were differences in the serum DJ-1 protein levels among different individuals. The serum DJ-1 concentration in PD patients was 11.3±10.1ng/ml, and that in controls was 18.1±12.8ng/ml (P>0.05). In conclusion, similar to the study conducted by Japanese scholars, we found no significant difference in the serum DJ-1 protein levels between PD patients and controls in Chinese subjects. The levels of the DJ-1 protein in serum may not be a biomarker of PD. In addition, there may be differences in the serum DJ-1 protein levels between Chinese and Japanese patients.

Impacts of blending ground, surface, and saline waters on lead release in drinking water distribution systems.

The impacts of distribution water quality changes caused by blending different source waters on lead release from corrosion loops containing small lead coupons were investigated in a pilot distribution study. The 1-year pilot study demonstrated that lead release to drinking water increased as chlorides increased and sulfates decreased. Silica and calcium inhibited lead release to a lesser degree than sulfates. An additional 3-month field study isolated and verified the effects of chlorides and sulfates on lead release. Lead release decreased with increasing pH and increasing alkalinity during the 1-year pilot study; however, the effects of pH and alkalinity on lead release, were not clearly elucidated due to confounding effects. A statistical model was developed using nonlinear regression, which showed that lead release increased with increasing chlorides, alkalinity and temperature, and decreased with increasing pH and sulfates. The model indicated that primary treatment processes such as enhanced coagulation and RO (reverse osmosis membrane) were related to lead release by water quality. Chlorides are high in RO-finished water and increase lead release, while sulfates are high following enhanced coagulation and decrease lead release.

Circulating MicroRNA as Potential Source for Neurodegenerative Diseases Biomarkers.

An increasing number of circulating micro-ribonucleic acids (microRNAs, miRNAs) have been discovered its potential as biomarkers to diagnose neurodegenerative diseases (NDs) by many researchers. However, there were obvious inconsistencies among previous studies, and thus we performed this meta-analysis to evaluate whether miRNA is an effective biomarker with high accuracy to diagnose the NDs. PubMed, MEDLINE, EMBASE, the Cochrane Library, and other related databases were used to search eligible articles. The data of sensitivity and specificity were employed to plot the summary receiver operator characteristic (SROC) curve and calculate the area under the SROC curve (AUC). I (2) test were used to estimate the heterogeneity among different studies. In addition, the possible sources of heterogeneity were further explored by subgroup analyses and meta-regression. All analyses were performed by STATA 12.0 software. In this meta-analysis, eight publications with 459 NDs patients and 340 healthy controls were included to investigate the diagnostic performance of circulating miRNAs for NDs. The overall sensitivity and specificity, positive likelihood ratio (PLR), negative likelihood ration (NLR), and diagnostic odds ratio (DOR) were 0.83 (95% confidence interval (CI) 0.77-0.88), 0.87 (95% CI 0.83-0.89), 6.2 (95% CI 4.9-7.9), 0.19 (95% CI 0.14-0.27), 33 (95% CI 20-52), and 0.91 (95% CI: 0.88-0.93), respectively. The overall SROC curve was plotted with AUC of 0.91 (95% CI 0.88-0.93), which indicated an excellent diagnostic performance of circulating miRNA for NDs. Subgroup analysis based on miRNA profile demonstrated that multiple-miRNA assay had higher diagnostic accuracy for NDs when compared with single-miRNA assay. In conclusion, the circulating miRNAs may be the potential biomarkers in the clinical diagnosis of NDs, and the diagnostic accuracy would be better by using multiple-miRNA assay. However, large-scale studies are still needed to explore the relation between the circulating miRNA dysregulation and the pathological mechanism of NDs.

Role of miRNA-146 in proliferation and differentiation of mouse neural stem cells.

Neural stem cells (NSCs) have been defined as neural cells with the potential to self-renew and eventually generate all cell types of the nervous system. NSCs serve as an ideal cell type for nervous system repair. In the present study, miR-146 overexpression and predicted target (notch 1) were used to study proliferation and differentiation of mouse NSCs. shRNA were used to demonstrate the function of Notch 1 in proliferation of mouse NSCs and luciferase reporter assay was used to assess and confirm the binding sequence of 3'-UTR between Notch 1 and miR-146. Results showed that miR-146 overexpression and knockdown of notch 1 inhibited proliferation of mouse NSCs under serum-free cultural conditions and promoted spontaneous differentiation of mouse NSCs under contained serum cultural conditions respectively. Mouse NSCs spontaneously underwent differentiation into neurogenic cells with contained serum medium. However, when miR-146 was overexpressed, differentiation efficiency of glial cells from NSCs was increased, suggesting that Notch1 promoted NSC proliferation and repressed spontaneous differentiation of NSC in serum-free medium. In conclusion, our results demonstrate that miR-146 promoted spontaneous differentiation of NSCs, and this mechanism was influenced by miR-146, as well as its target (notch 1) and downstream gene.

A Cyclooxygenase-2 Inhibitor Reduces Vascular Wall Thickness and Ameliorates Cognitive Impairment in a Cerebral Small Vessel Diseases Rat Model.

Cerebral small vessel disease (CSVD) is a group of diseases that originate from changes in cerebral small vessels and that cause many conditions, such as cognitive impairment. However, there is no effective therapy for these diseases. Recent studies have suggested that inflammation is associated with this disease. Cyclooxygenase-2 (cox-2) is an inflammatory mediator; however, whether a cox-2 inhibitor could protect against the CSVD progression remains unknown. In the present study, stroke-prone spontaneously hypertensive rats (SHRsp) were used as a model of CSVD, and Sprague Dawley (SD) rats served as the control. SHRsp were treated with the cox-2 inhibitor celecoxib or vehicle. The Morris water maze test was performed, and vascular morphometry and the expression of collagen I and fibronectin were examined in cerebral small vessels and cerebral tissue. The results revealed that thickened small veesel walls, increased expression of collagen I and fibronectin and impaired cognitive function in SHRsp compared with SD rats. Additionally, celecoxib significantly down-regulated the expression of collagen I and fibronectin, attenuated the increase in vascular wall thickness and ameliorates the cognitive impairment. Our study indicated that this cox-2 inhibitor may serve as a promising candidate for the pharmacological intervention of CSVD.