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Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by progressive occlusion of the internal carotid artery and the formation of an abnormal compensatory capillary network at the base of the brain. Genomics studies identified Ring finger protein 213 (RNF213) as a common genetic factor that increases the susceptibility to MMD in East Asian people. However, the function of RNF213 and its roles in pathogenesis of MMD is unclear. Here, we showed that genetic knockout of Rnf213 in mice causes significant pericytes reduction and blood-brain barrier impairment in the cortex. These phenotypes are accompanied with microglia activation and elevated level of proinflammatory cytokines. Additionally, Rnf213 deficient mice showed reduced expression of tight junction proteins, including Occludin, Claudin-5 and ZO-1. Together, these data suggested that RNF213 might contribute to the pathogenesis of MMD through disruption of pericyte homeostasis and blood-brain barrier integrity by dysregulation of inflammatory responses and tight junction formation.

Background Progressive multiple sclerosis (PMS) is an uncommon and severe subtype of MS that worsens gradually and leads to irreversible disabilities in young adults. Currently, there are no applicable or reliable biomarkers to distinguish PMS from relapsing–remitting multiple sclerosis (RRMS). Previous studies have demonstrated that dysfunction of N6-methyladenosine (m6A) RNA modification is relevant to many neurological disorders. Thus, the aim of this study was to explore the diagnostic biomarkers for PMS based on m6A regulatory genes in the cerebrospinal fluid (CSF). Methods Gene expression matrices were downloaded from the ArrayExpress database. Then, we identified differentially expressed m6A regulatory genes between MS and non-MS patients. MS clusters were identified by consensus clustering analysis. Next, we analyzed the correlation between clusters and clinical characteristics. The random forest (RF) algorithm was applied to select key m6A-related genes. The support vector machine (SVM) was then used to construct a diagnostic gene signature. Receiver operating characteristic (ROC) curves were plotted to evaluate the accuracy of the diagnostic model. In addition, CSF samples from MS and non-MS patients were collected and used for external validation, as evaluated by an m6A RNA Methylation Quantification Kit and by real-time quantitative polymerase chain reaction. Results The 13 central m6A RNA methylation regulators were all upregulated in MS patients when compared with non-MS patients. Consensus clustering analysis identified two clusters, both of which were significantly associated with MS subtypes. Next, we divided 61 MS patients into a training set (n = 41) and a test set (n = 20). The RF algorithm identified eight feature genes, and the SVM method was successfully applied to construct a diagnostic model. ROC curves revealed good performance. Finally, the analysis of 11 CSF samples demonstrated that RRMS samples exhibited significantly higher levels of m6A RNA methylation and higher gene expression levels of m6A-related genes than PMS samples. Conclusions The dynamic modification of m6A RNA methylation is involved in the progression of MS and could potentially represent a novel CSF biomarker for diagnosing MS and distinguishing PMS from RRMS in the early stages of the disease.

Ischemic stroke is a common and debilitating disease that can cause permanent neurological damage. Gucy1a3, which encodes the α1 subunit of soluble guanylyl cyclase, has been reported to be associated with functional recovery after ischemic stroke. However, the mechanism is still not well understood. In the present study, we investigated the effects of Gucy1a3 on (i) post-stroke recovery; (ii) vascular endothelial growth factor A (VEGFA) and hypoxia inducible factor 1 alpha (HIF-1α) expression; and (iii) angiogenesis after ischemic stroke. A permanent middle cerebral artery occlusion (pMCAO) model was established using wild-type and Gucy1a3 knockout C57BL/6J male mice. Neurological deficits, infarct volume, microvascular density, and VEGFA and HIF-1α expression levels of mice were evaluated. Our results suggest that loss of Gucy1a3 increased the infarct volume and aggravated neurological deficits after pMCAO. In addition, the Gucy1a3 knockout brains exhibited significantly lower microvessel densities and VEGFA and HIF-1α expression levels than the wild-type brains at 96 hours post-pMCAO. The study shows that the expression of GUCY1A3 after ischemic stroke may play a substantial role in neurological function recovery and is related to angiogenesis in the peri-infarct region. The beneficial effects of GUCY1A3 might be mediated through the HIF-1α/VEGFA signaling pathway.

Secondary brain injury following intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) is life threatening, and effective therapeutic strategies are lacking. This study aimed to understand the molecular pathogenesis of ICH- or SAH-induced secondary brain injury and provide insights regarding potential therapeutic options.Original data of tissue microarray studies were downloaded from the Gene Expression Omnibus database. We identified the differentially expressed genes (DEGs) for each disease and common DEGs between ICH and SAH. Functional enrichment analyses were then analyzed, and a protein-protein interaction network was constructed to strictly select hub genes. Additionally, immune infiltration analyses were used to identify the common differently distributed cells in both diseases. Finally, animal model microarrays were used for external validation.We identified 158 common DEGs. The common DEGs were significantly enriched in cytotoxicity and inflammation pathways. The top 10 hub genes were then filtered through the protein-protein interaction networks. Moreover, natural regulatory T, T helper 17, and dendritic cells and monocytes and macrophages were identified as common differentially distributed immune cells. Additionally, target microRNAs and related drugs of hub genes were predicted.This study identified a variety of key genes and their respective molecular functions involved in both ICH and SAH for better understanding of the cytotoxic and inflammatory pathogenesis of secondary brain injury. The predicted targeted microRNAs and related drugs of hub genes not only could provide insights into the novel therapeutic strategies, but also could aid in future studies and drug discovery.

Background and purpose In China, stroke center certification was launched in 2015, but little is known about its impact on intravenous thrombolysis. This study aimed to evaluate the effects of stroke center certification on the use of intravenous thrombolysis during a five-year period in South China. Methods We retrospectively collected data regarding the use of recombinant tissue plasminogen activator (rt-PA) in 21 cities of Guangdong from 2015 to 2020. The annual thrombolysis rate was defined as the number of patients who underwent intravenous rt-PA therapy divided by the number of those who had acute ischemic stroke within the same year. The density of stroke centers was calculated as the number of stroke centers divided by the corresponding residents. Spearman’s correlation analysis was used to determine the correlations between the annual thrombolysis rates and the number/density of stroke centers. Paired t-test was used to compare differences in growth in annual thrombolysis rates before and after having stroke centers. Results From 2015 to 2020, the annual rt-PA thrombolysis rates of Guangdong increased from 1.4% to 7.2%, which was accompanied by an increase in the number of stroke centers from 0 to 82 and density of stroke centers from 0.00 to 0.71 per million population. The average annual rt-PA use in stroke centers was higher than that in non-stroke centers from 2016 to 2020 (all P Conclusions Stroke center certification may partially drive the increased use of rt-PA thrombolysis. Stroke center certification should be continually promoted to facilitate access to intravenous thrombolysis for patients with acute ischemic stroke.

Background: Studies exploring the predictive performance of major risk factors associated with future stroke events are insufficient, and a useful tool to predict individual risk is not available. Therefore, personalized advice for preventing future stroke in patients with moyamoya disease (MMD) cannot provide evidence-based recommendations. The aim of this study was to develop a novel nomogram with reliable validity to predict the individual risk of future stroke for adult MMD patients.Methods: This study included 450 patients from seven medical centers between January 2013 and December 2018. Follow-ups were performed via clinical visits and/or telephone interviews from initial discharge to December 2019. The cohort was randomly assigned to a training set (2/3, n = 300) for nomogram development and a test set (1/3, n = 150) for external validation. The Kaplan-Meier analyses and receiver operating characteristic (ROC) curves were applied to assess the clinical benefits of this nomogram.Results: Diabetes mellitus, a family history of MMD, a past history of stroke or transient ischemic attack, clinical manifestation, and treatment were identified as major risk factors via the least absolute shrinkage and selection operator (LASSO) method. A nomogram including these predictors was established via a multivariate Cox regression model, which displayed excellent discrimination [Harrell's concordance index (C-index), 0.85; 95% confidence interval (CI): 0.75–0.96] and calibration. In the external validation, the nomogram was found to have good discrimination (C-index, 0.81; 95% CI: 0.68–0.94) and calibration. In the subgroup analysis, this predictive nomogram also showed great performance in both ischemic-type (C-index, 0.90; 95% CI: 0.77–1.00) and hemorrhagic-type MMD (C-index, 0.72; 95% CI: 0.61–0.83). Furthermore, the nomogram was shown to have potential in clinical practice through Kaplan-Meier analyses and ROC curves.Conclusions: We developed a novel nomogram incorporating several clinical characteristics with relatively good accuracy, which may have considerable potential for evaluating individual future stroke risk and providing useful management recommendations for adult patients with MMD in clinical practice.

Background. Delayed diagnosis and noneffective treatment contribute to the shorter life expectancy in patients with progressive multiple sclerosis (PMS). Studies demonstrate the key role of autoimmunity in PMS, but the prognostic value of immune-associated factors remains unknown. Thus, this study aimed to develop an immune-associated gene (IAG) signature related to overall survival (OS) and conduct an immune cell infiltration analysis using PMS data. Methods. The differentially expressed IAGs were identified based on gene expression profiles (from the Gene Expression Omnibus database) and IAGs (from the ImmPort database). Univariate and least absolute shrinkage and selection operator (LASSO)-penalized Cox regression analyses were used to develop the IAG signature related to OS. Kaplan–Meier analyses were conducted, and receiver operating characteristic (ROC) curves were generated to assess the performance. Additionally, the differential distribution of immune cells was identified by Wilcoxon rank-sum tests and correlations with IAGs were analyzed using Spearman correlation analyses. Moreover, univariate and multivariate Cox regression analyses were used to identify the independent prognostic factors to develop a prognostic nomogram. Results. The training group, consisting of 57 PMS lesions and 52 control tissues, was obtained through batch normalization to remove the inter-batch difference. A total of 206 differentially expressed IAGs were identified, and 38 of them were associated with OS. Thereafter, a 4-IAG signature was constructed to calculate the risk score and thus classify PMS patients into high- and low-risk groups according to mean risk score. Patients in the high-risk group had a lower survival time than those in the low-risk group. The Kaplan–Meier plots and ROC curves demonstrated a good performance in both the training and internal validation groups. Additionally, five differentially abundant immune cell types were identified and their relationships with IAGs were analyzed. Finally, risk score, cortical region, and naive B cells were identified as independent prognostic factors, and a nomogram incorporating these factors was developed to predict the OS in PMS. Conclusion. The novel IAG signature may be a reliable tool for assisting neurologists in predicting the OS for PMS patients in clinical settings. These findings may facilitate personalized treatment and provide insights into the complex mechanism of PMS.

Background: The use of antiplatelet agents in ischemic moyamoya disease (MMD) is controversial. This study aimed to investigate the effectiveness and safety of antiplatelet therapy compared with conservative treatment and surgical revascularization in ischemic MMD patients.Methods: Ischemic MMD patients were retrospectively enrolled from eight clinical sites from January 2013 to December 2018. Follow-up was performed through clinical visits and/or telephone interviews from first discharge to December 2019. The primary outcome was the episodes of further ischemic attacks, and the secondary outcome was the individual functional status. Risk factors for future stroke were identified by the LASSO-Cox regression model. Propensity score matching was applied to assemble a cohort of patients with similar baseline characteristics using the TriMatch package.Results: Among 217 eligible patients, 159 patients were included in the analyses after a 1:1:1 propensity score matching. At a mean follow-up of 33 months, 12 patients (7.5%) developed further incident cerebral ischemic events (surgical:antiplatelet:conservative = 1:3:8; p = 0.030), 26 patients (16.4%) developed a poor functional status (surgical:antiplatelet:conservative = 7:12:7; p = 0.317), and 3 patients (1.8%) died of cerebral hemorrhage (surgical:antiplatelet:conservative = 1:2:0; p = 0.361). The survival curve showed that the risk of further cerebral ischemic attacks was lowest with surgical revascularization, while antiplatelet therapy was statistically significant for preventing recurrent risks compared with conservative treatment (χ2 = 8.987; p = 0.011). No significant difference was found in the functional status and bleeding events. The LASSO-Cox regression model revealed that a family history of MMD (HR = 6.93; 95% CI: 1.28–37.52; p = 0.025), a past history of stroke or transient ischemic attack (HR = 4.35; 95% CI: 1.09–17.33; p = 0.037), and treatment (HR = 0.05; 95% CI: 0.01–0.32; p = 0.001) were significantly related to the risk of recurrent strokes.Conclusions: Antiplatelet agents were effective and safe in preventing further cerebral ischemic attacks in adult patients with ischemic MMD. They may be a replacement therapy for patients with surgical contraindications and for patients prior to revascularization.

Background: Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system with a variable natural history of relapse and remission. Previous studies have found many differentially expressed genes (DEGs) in the peripheral blood of MS patients and healthy controls, but the value of these genes for predicting the risk of relapse remains elusive. Here we develop and validate an effective and noninvasive gene signature for predicting relapse-free survival (RFS) in MS patients.Methods: Gene expression matrices were downloaded from Gene Expression Omnibus and ArrayExpress. DEGs in MS patients and healthy controls were screened in an integrated analysis of seven data sets. Candidate genes from a combination of protein–protein interaction and weighted correlation network analysis were used to identify key genes related to RFS. An independent data set (GSE15245) was randomized into training and test groups. Univariate and least absolute shrinkage and selection operator–Cox regression analyses were used in the training group to develop a gene signature. A nomogram incorporating independent risk factors was developed via multivariate Cox regression analyses. Kaplan–Meier methods, receiver-operating characteristic (ROC) curves, and Harrell's concordance index (C-index) were used to estimate the performance of the gene signature and nomogram. The test group was used for external validation.Results: A five-gene signature comprising FTH1, GBP2, MYL6, NCOA4, and SRP9 was used to calculate risk scores to predict individual RFS. The risk score was an independent risk factor, and a nomogram incorporating clinical parameters was established. ROC curves and C-indices demonstrated great performance of these predictive tools in both the training and test groups.Conclusions: The five-gene signature may be a reliable tool for assisting physicians in predicting RFS in clinical practice. We anticipate that these findings could not only facilitate personalized treatment for MS patients but also provide insight into the complex molecular mechanism of this disease.

Although familial forms of cerebral cavernous malformation are mainly attributed to three CCM genes ( KRIT1, CCM2 and PDCD10), no mutation is identified in sporadic cerebral cavernous malformation cases with a unique lesion, indicating additional genes for sporadic cerebral cavernous malformation. To screen the candidate genes, we conducted whole exome sequencing in 31 sporadic cerebral cavernous malformation patients and 32 healthy controls, and identified 5 affected individuals carrying 6 heterozygous deleterious mutations in RNF213 but no RNF213 mutation in healthy individuals. To further confirm RNF213 was associated with cerebral cavernous malformation, we generated rnf213a homozygous knockout zebrafish and found mutation of rnf213a in zebrafish led to a mulberry-like cluster of disordered-flow vascular channels which was reminiscent of human cerebral cavernous malformation. In addition, we revealed kbtbd7 and anxa6 were significantly downregulated due to rnf213a mutation through transcriptomic sequencing and RT-qPCR analysis. Based on the mulberry-like phenotype partly rescued by mRNA of kbtbd7 as well as anxa6, we suggested that rnf213a promoted mulberry-like cluster via downregulation of kbtbd7 and anxa6. Altogether, we firstly demonstrate RNF213is a novel candidate gene for sporadic cerebral cavernous malformation and the mutation of rnf213a is responsible for the mulberry-like cluster in zebrafish.

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X20914996 for Mutations of RNF213 are responsible for sporadic cerebral cavernous malformation and lead to a mulberry-like cluster in zebrafish by Jing Lin, Jie Liang, Jun Wen, Man Luo, Jiaoxing Li, Xunsha Sun, Xiaowei Xu, Jianli Li, Dongxian Wang, Jie Wang, Huimin Chen, Rong Lai, Fengyin Liang, Chuan Li, Fei Ye, Jingjing Zhang, Jinsheng Zeng, Shulan Yang and Wenli Sheng in Journal of Cerebral Blood Flow & Metabolism

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X20914996 for Mutations of RNF213 are responsible for sporadic cerebral cavernous malformation and lead to a mulberry-like cluster in zebrafish by Jing Lin, Jie Liang, Jun Wen, Man Luo, Jiaoxing Li, Xunsha Sun, Xiaowei Xu, Jianli Li, Dongxian Wang, Jie Wang, Huimin Chen, Rong Lai, Fengyin Liang, Chuan Li, Fei Ye, Jingjing Zhang, Jinsheng Zeng, Shulan Yang and Wenli Sheng in Journal of Cerebral Blood Flow & Metabolism

Supplemental material, sj-pdf-2-jcb-10.1177_0271678X20914996 for Mutations of RNF213 are responsible for sporadic cerebral cavernous malformation and lead to a mulberry-like cluster in zebrafish by Jing Lin, Jie Liang, Jun Wen, Man Luo, Jiaoxing Li, Xunsha Sun, Xiaowei Xu, Jianli Li, Dongxian Wang, Jie Wang, Huimin Chen, Rong Lai, Fengyin Liang, Chuan Li, Fei Ye, Jingjing Zhang, Jinsheng Zeng, Shulan Yang and Wenli Sheng in Journal of Cerebral Blood Flow & Metabolism

Supplemental material, sj-pdf-2-jcb-10.1177_0271678X20914996 for Mutations of RNF213 are responsible for sporadic cerebral cavernous malformation and lead to a mulberry-like cluster in zebrafish by Jing Lin, Jie Liang, Jun Wen, Man Luo, Jiaoxing Li, Xunsha Sun, Xiaowei Xu, Jianli Li, Dongxian Wang, Jie Wang, Huimin Chen, Rong Lai, Fengyin Liang, Chuan Li, Fei Ye, Jingjing Zhang, Jinsheng Zeng, Shulan Yang and Wenli Sheng in Journal of Cerebral Blood Flow & Metabolism

Objective We aimed to develop a simple and user-friendly scoring system to predict all-cause hospital-acquired infections (HAIs) after acute ischemic stroke (AIS) in the Chinese population. Methods AIS patients from a retrospective cohort study at our center were included from January 2016 to December 2018. HAIs were diagnosed based on the current criteria from Ministry of Health of the People’s Republic of China. Stepwise logistic regression models were performed to screen independent predictors of HAI after AIS. A scoring system was developed by including each of the above significant predictors. Results Among 1211 patients, 76 patients (6.28%) developed HAI. Age, baseline National Institute of Health stroke scale (NIHSS) score, and dysphagia were independent predictors of HAI. For the AND score, A refers to age, N refers to NIHSS, and D refers to dysphagia. The AND score showed a high area under the receiver operating characteristics (AUROC) curve (0.679), which comprised age (65–74 years was 4 points, 75–84 years was 6 points, ≥85 years was 8 points), NIHSS score ≥10 (5 points), and dysphagia (6 points). Conclusions We developed a simple scoring system to predict all-cause infections after AIS patients without a ventilator in the Chinese population.

Objective We aimed to evaluate the association between serum uric acid levels at the onset and prognostic outcome in patients with acute ischaemic stroke. Methods We retrospectively analysed the outcomes of 1166 patients with ischaemic stroke who were hospitalized in our centre during August 2008 to November 2012. Correlations of serum uric acid levels and prognostic outcomes were analysed. Results Men had higher serum uric acid levels and better neurological functional outcomes compared with women. There was a strong negative correlation between serum uric acid levels and unfavourable neurological functional outcomes. Generalized estimated equation analysis showed that a higher serum uric acid level (>237 µmol/L) was a protective factor for neurological functional outcome in male, but not female, patients. Among five trial of ORG 10172 in acute stroke treatment classification subtypes, only patients with the large-artery atherosclerosis subtype had a significant protective effect of serum uric acid levels on neurological outcome. Conclusions Our study shows that high serum uric acid levels are a significant protective factor in men and in the large-artery atherosclerosis subtype in patients with ischaemic stroke. This is helpful for determining the prognostic value of serum uric acid levels for neurological outcome of acute ischaemic stroke.

Ocular myasthenia gravis, an autoimmune disease, is characterized by extraocular muscle weakness. Myasthenia gravis is closely associated with the functional status of the thymus gland. The efficacy of thymectomy for non-thymomatous ocular myasthenia gravis remains controversial. Here, we present the first systematic review and meta-analysis of studies assessing the outcome of thymectomy in patients with non-thymomatous ocular myasthenia gravis and found that the pooled rate of complete stable remission was 0.5074 with considerable heterogeneity. Furthermore, subgroup analysis showed that the efficacy of thymectomy differed according to geographical location. Furthermore, thymectomy outcomes are better in children than they are in adults. Thymectomy clearly represents an effective treatment for patients with non-thymomatous ocular myasthenia gravis. However, more multicenter, randomized, controlled clinical trials are now required to confirm these conclusions.

The ring finger protein 213 gene (RNF213) rs112735431 was significantly associated with intracranial artery stenosis/occlusion disease (ICASO) in Japan and Korea and to a lesser degree in China. We conducted a case–control study to examine the prevalence and correlates of the RNF213 rare variants in Chinese patients with symptomatic ICASO. A total of 503 cases including 390 ischemic stroke patients (ICASO-IS), 113 intracranial hemorrhage patients (ICASO-ICH) and 227 control subjects were recruited. The snapshot technique was used for RNF213 rare variants analysis, including rs112735431, rs148731719, rs37144111 and rs138130613. Moreover, a meta-analysis was performed to explore the relationship between RNF213 variants and ICASO in Asian. In our case–control study, we found that the rs138130613 variant was significantly associated with ICASO-IS (OR = 9.92, 95% CI 1.24–79.19, p = 0.03). The mean age of first ischemic stroke onset of variant carriers was earlier than the noncarriers (51.3 ± 18.0 versus 66.0 ± 12.9 years old, p = 0.02), but the conventional atherosclerotic risk factors and the characteristics of artery stenosis did not differ between them. In addition, the meta-analysis showed significant association between the rs112735431 polymorphism and the ICASO or ICASO-IS, and this variant was found more often in women and young-onset patients in Asia. This study suggests that the RNF213 rs112735431 and rs138130613 are genetic risk variants for ischemic stroke with intracranial artery stenosis/occlusion in China and rs112735431 is also associated with the high risk of ICASO in Asia. Further large-scale investigation of the RNF213 gene will provide new insights into pathogenetic mechanisms of symptomatic ICASO.

A number of studies assessed the association of ring finger protein 213 (RNF213) gene polymorphisms with moyamoya disease (MMD), but the results were not entirely consistent. This meta-analysis was performed to explore the relationship between RNF213 polymorphisms and moyamoya disease in Asian population. A systematic search from the PubMed, MEDLINE, EMBASE, ISI web of science, CNKI, China CBM and WANFANG DATA databases was conducted to retrieve published studies until March 2015. Statistical analyses were performed using the STATA12.0 software. Fixed or random effects model, subgroup analysis, sensitivity analysis, and publication bias were used to improve the comprehensive analysis. Eight papers including 904 MMD patients and 2258 controls were recruited in the meta-analysis. rs112735431 was closely associated with the risk of MMD among Asian population in all genetic models (dominant model: OR 103.39, 95 % CI 52.25-204.55, P = 1.69e-40; recessive model: OR 16.45, 95 % CI 6.00-45.10, P = 5.33e-08; additive model: OR 61.49, 95 % CI 22.07-171.33, P = 3.32e-15), especially in the Japanese population. Subgroup analysis revealed highly statistically significant higher risk in the patients with family histories. Although another polymorphism rs148731719 showed no significant association with the MMD, rs138130613 was found to be related to the higher risk in Chinese population (dominant model: OR 8.34, 95 % CI 1.72-40.47, P = 0.008). Our meta-analysis strengthens RNF213 rs112735431 is closely associated with the increased risk of MMD in Japanese, and the screening combined with rs112735431 and rs138130613may improve the detection rate for MMD in China.

To examine the morphological changes of the pituitary glands and linear growth of childhood nasopharyngeal carcinoma (NPC) cases who accepted radiotherapy. A total of 90 children (i.e., age less than 18 years) who were diagnosed as NPC at Sun Yat-sen University Cancer Center from January 2009 to January 2016 were identified by reviewing medical records. Two radiologists reviewed and measured the pre-radiation, post-radiation, and the latest available pituitary gland heights independently. Patients' current height information was collected by telephone interviews. We compared the pituitary height differences using paired t-tests and estimated the pituitary height trajectories within each sex by mixed regression models. Height-for-age Z-score was calculated for each patient using the WHO growth reference data for 5–19 years as reference. Most of the included participants were of male sex (75.6%) and over half were diagnosed at stage IV (58.4%). Among the 90 included participants, 89 had one repeated measurement of the pituitary height and 79 had two repeated measurements of the pituitary height. Seventy six of the 89 childhood NPC participants had reduced pituitary heights after radiation and accounted for 85.4% of the whole population. The means of the pituitary heights before and after radiotherapy were 6.4 ± 1.3 mm and 5.6 ± 1.2 mm (P < 0.001), respectively. The mean of height-for-age Z-score for childhood NPC cases was significantly below zero (−0.54, 95% CI = −0.74, −0.34). We concluded that childhood NPC cases had decreased pituitary heights and stunted linear growth after radiotherapy.

Summary Aim A recent genome-wide association study identified a strong association of covert magnetic resonance imaging infarcts with the single nucleotide polymorphism (SNP) rs2208454. The aim of this study was to determine whether the rs2208454 polymorphism is associated with an increased risk for ischemic stroke (IS). Methods Ischemic stroke patients (n = 712) and control subjects (n = 774) from a southern Chinese Han population were included. The snapshot technique was used for genotype analysis. Results Compared with the GT+GG or GG genotype, the frequency of the TT genotype was significantly higher in IS than in controls. After adjusting for age, gender, family history of IS, hypertension history, and history of diabetes mellitus, a significant correlation between the TT genotype and IS persisted (TT vs. GT+GG: adjusted OR = 1.79, 95% CI: 1.16–2.77; TT vs. GG: adjusted OR = 1.88, 95% CI: 1.20–2.94). In subgroup analyses, SNP rs2208454 was significantly associated with large artery atherosclerosis (LAA) (TT vs. GG: adjusted OR = 2.16, 95% CI: 1.19–3.93), but failed to show significant association with small-artery occlusion or cardioembolism IS subtypes. Conclusions Single nucleotide polymorphism rs2208454 confers an increased risk for IS in a southern Chinese Han population. When the IS subtype was examined, the effect of the SNP was restricted to LAA.

Ischemic stroke (IS) is a multifactorial disorder caused by both genetic and environmental factors. The combined effects of multiple susceptibility genes might result in a higher risk for IS than a single gene. Therefore, we investigated whether interactions among multiple susceptibility genes were associated with an increased risk of IS by evaluating gene polymorphisms identified in previous meta-analyses, including methylenetetrahydrofolate reductase (MTHFR) C677T, beta fibrinogen (FGB, β-FG) A455G and T148C, apolipoprotein E (APOE) e2–4, angiotensin-converting enzyme (ACE) insertion/deletion (I/D), and endothelial nitric oxide synthase (eNOS) G894T. In order to examine these interactions, 712 patients with IS and 774 controls in a Chinese Han population were genotyped using the SNaPshot method, and multifactor dimensionality reduction analysis was used to detect potential interactions among the candidate genes. The results of this study found that ACE I/D and β-FG T148C were significant synergistic contributors to IS. In particular, the ACE DD + β-FG 148CC, ACE DD + β-FG 148CT, and ACE ID + β-FG 148CC genotype combinations resulted in higher risk of IS. After adjusting for potential confounding IS risk factors (age, gender, family history of IS, hypertension history and history of diabetes mellitus) using a logistic analysis, a significant correlation between the genotype combinations and IS patients persisted (overall stroke: adjusted odds ratio [OR] = 1.57, 95% confidence interval [CI]: 1.22–2.02, P < 0.001, large artery atherosclerosis subtype: adjusted OR = 1.50, 95% CI: 1.08–2.07, P = 0.016, small-artery occlusion subtype: adjusted OR = 2.04, 95% CI: 1.43–2.91, P < 0.001). The results of this study indicate that the ACE I/D and β-FG T148C combination may result in significantly higher risk of IS in this Chinese population.

This article was migrated. The article was not marked as recommended. Objective：The aim of this study was to identify the disciplines that strongly correlated with neurology, and to compare the differences between neurology and other disciplines in targeted integration. Method: Scores of 18 disciplines (six clinical disciplines, seven basic disciplines, and five social science/humanities disciplines) and college entrance examinations of 275 eight-year program medical students from Sun Yat-Sen University were collected. Correlation between any two subject scores were determined. Results: Student scores in neurology had significant correlation with the scores of four clinical subjects, five basic subjects, and one social science/ humanities subject. Internal medicine scores showed significant correlation with the scores of three clinical subjects and two basic subjects. Scores from obstetrics and gynecology, pediatrics and psychiatry significantly correlated with one to three clinical subjects scores. No significant correlation was found between surgery scores and other subjects. With the exception of medical statistics, there was no significant correlation between scores from social science/humanities subjects and scores from either clinical or basic subjects. No subject scores significantly correlated with the college entrance examination scores. Conclusion: Neurology is associated with more clinical and basic disciplines than other subjects. Neurological education should involve a targeted integration with other closely related disciplines.

The etiology of isolated vertigo has been a substantial diagnostic challenge for both neurologists and otolaryngologists. This study was designed to detect recurrent isolated vertigo due to cerebral hypoperfusion using perfusion-weighted magnetic resonance imaging (PWI).We recruited isolated vertigo patients whose clinical condition was suspected to be caused by hypodynamics of the brain; these individuals formed the case group. We generated two additional groups: a negative group composed of vertigo patients whose symptoms were caused by problems associated with the ear and a healthy control group. Each subject underwent PWI, and seven regions of interest (ROIs) were chosen. The relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), and mean transit time (MTT) were obtained from each ROI. We further calculated the absolute difference of relative parameter values between two mirrored ROIs.The significant difference in the relative MTT from the mirrored cerebellar ROI (|rMTTleft-right|) of the case group was larger than those from the negative and healthy control groups (p = 0.026 and p = 0.038, respectively). Signal differences in |rrCBVleft-right| and |rrCBFleft-right| were not found among the three groups.In summary, disequilibrium in the rMTT of the bilateral cerebellum in the case group implied that hypoperfusion of the posterior circulation could trigger recurrent isolated vertigo and could be shown efficiently using PWI.

Ischemic stroke (IS) is a heterogeneous multifactorial disorder caused by both genetic and environmental factors. A genome-wide association study on stroke in Caucasians identified a variant on chromosome 4q25 that is significantly associated with IS, with the strongest risk for cardioembolic stroke (CES). The current study aims to investigate the association of the rs1906591 variant on 4q25 with IS through a case-control study in a Chinese Han population. A total of 712 IS patients and 774 control subjects were involved in the current research. Stroke subtyping was performed according to the Trial of Org 10172 in Acute Stroke Treatment criteria. The genotypes were determined using the SNaPshot technique. The association of the genotypes with the risk of IS was estimated using logistic regression analysis. The rs1906591 single nucleotide polymorphism variant was associated with the CES subtype in both recessive and additive models (recessive model: odds ratio [OR] = 2.58, 95% confidence interval [CI] 1.47–4.53, p = 0.001, adjusted OR = 2.71, 95% CI 1.48–4.96, p = 0.001; additive model: OR = 2.50, 95% CI 1.19–5.25, p = 0.015, adjusted OR = 2.83, 95% CI 1.24–6.50, p = 0.013). This result indicates that patients with the AA genotype have a higher rate of CES than other genotypes. However, the rs1906591 variant was not significantly associated with the overall incidence of stroke or other stroke subtypes. The rs1906591 variant is significantly associated with CES in the Chinese Han population, but not with other stroke subtypes.

Aims : Meta-analysis was performed to investigate the association between 1425G/A SNP in PRKCH (the gene encoding for protein kinase C η) and ischemic stroke among Chinese and Japanese populations. Methods : The databases of MEDLINE, PubMed, Chinese Biomedical Database, China National Knowledge Infrastructure, and WANFANG DATA until September 2011 were searched for published case-control studies on 1425G/A SNP in PRKCH and ischemic stroke. Strict selection criteria and exclusion criteria were determined, and pooled odds ratio (OR) and the 95% confidence interval (CI) were calculated using a fixed or random effects model to determine the strength of the genetic association. The publication bias was further evaluated by calculating the fail-safe number in the included studies. Results : Five studies, comprising 3686 cases and 4589 controls, passed all the criteria and therefore were included in the meta-analysis. Test for heterogeneity showed that P values ( P = 0.76, 0.24, respectively) in the two meta-analyses were both greater than 0.05, therefore the fixed effects model was performed. Statistically significant association between 1425G/A SNP in PRKCH and ischemic stroke was identified (OR = 1.34; 95% CI, 1.22–1.47), and the association was even stronger between 1425G/A SNP in PRKCH and lacunar infarction (OR = 1.44; 95% CI, 1.28–1.63). The fail-safe number ( N fs 0.05 ) for 1425G/A SNP in PRKCH with ischemic stroke and lacunar infarction was 59 and 44, respectively, which were greater than the number of studies included in the analyses. Conclusions : SNP 1425G/A in PRKCH was associated with ischemic stroke, particularly lacunar infarction, in Chinese and Japanese populations. More studies of different subtypes of stroke need to be done to confirm the results in other Asian populations.

Introduction The ABCB1 C3435T polymorphism limits oral bioavailability of clopidogrel and may influence prognosis of patients treated with clopidogrel. Several studies have examined the association between the C3435T polymorphism and risk of adverse clinical events in clopidogrel treated patients, but the results were inconsistent. To assess the role of the C3435T polymorphism in the impact on clinical outcomes, a meta-analysis was conducted. Methods 6 studies with 10,153 subjects were included in this meta-analysis. Fixed- or random-effects model was chosen according to heterogeneity. Publication bias was evaluated by fail-safe numbers. Results The association of the C3435T polymorphism with risk of overall recurrent ischemic events in clopidogrel treated patients was not statistically significant for all genetic models (OR = 1.13, 95%CI: 0.78–1.64, P = 0.51; OR = 1.15, 95%CI: 0.99–1.33, P = 0.07; OR = 1.19, 95%CI: 0.81–1.76, P = 0.37). Significant association was identified between the C3435T polymorphism and risk of short-term recurrent ischemic events (OR = 1.55, 95% CI: 1.09-2.20, P = 0.01; OR = 1.41, 95% CI: 1.06-1.87, P = 0.02; OR = 1.77, 95% CI: 1.19-2.63, P = 0.005). No statistically significant association between the C3435T polymorphism and stent thrombosis (OR = 0.79, 95% CI: 0.47-1.32, P = 0.37) or bleeding (OR = 0.98, 95% CI: 0.79-1.21, P = 0.82) was identified. The results may be affected by publication bias. Conclusions This meta-analysis failed to show an association between the ABCB1 C3435T polymorphism and risk of overall recurrent ischemic events, stent thrombosis or bleeding in clopidogrel treated patients. However, the association between TT homozygotes of the C3435T polymorphism and risk of short-term recurrent ischemic events may exist, but needs more studies to confirm.

In a rat renal allograft model, the long-term effect of conversion from cyclosporin A (CsA) to sirolimus on recipient kidneys and growth factor expression were compared with continuous use or withdrawal of CsA. Kidneys from Fisher 344 rats were orthotopically transplanted into Lewis rats. Four Fisher 344 to Lewis allograft groups were treated post-transplant as follows: (i) CsA (transplant to week 8) then sirolimus (weeks 8-24); (ii) CsA (transplant to week 24); (iii) CsA (transplant to week 8) then vehicle (weeks 8-24); (iv) control vehicle (transplant to week 24). A fifth group underwent syngeneic isograft (Lewis to Lewis) with no drug treatment. Proteinuria was measured every 4 weeks and grafts harvested at 24 weeks for morphological and immunohistochemical analysis. Conversion from CsA to sirolimus resulted in a significant decrease in proteinuria at 24 weeks, a lower Banff sum score and lower expression of transforming growth factor mRNA compared with continuous use or withdrawal of CsA. In conclusion, conversion from CsA to sirolimus retarded progression of chronic allograft nephropathy in the rat model.

Background A number of studies assessed the association of tissue plasminogen activator(TPA) gene polymorphisms with ischemic stroke, but the results were contradictory. We aimed to explore the role of TPA -7351C/T SNP in the susceptibility to ischemic stroke through a meta-analysis. Methods The PubMed, MEDLINE, EMBASE, China Biological Medicine Database and WANFANG DATA databases were searched until August 2012. The strict selection criteria and exclusion criteria were determined, and odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Stroke subtype was determined using Trial of Org 10172 in Acute Treatment criteria (TOAST). Statistical analyses were performed using the STATA12.0 software. Results A total of 2,299 ischemic stroke cases and 1,948 controls in seven case-control studies were included in the meta-analysis. Significant association between -7351C/T polymorphism in the TPA gene and ischemic stroke was observed in all comparison models (TT+CT versus CC, TT versus CT+CC and T versus C). In the subgroup analysis by ethnicity, TT homozygote carriers had a 142% increased risk of ischemic stroke compared with the C allele carriers among East-Asians (TT versus CT+CC: OR = 2.42, 95% CI = 1.07–5.48), but not in South-Asians and Caucasians, and significantly increased risks were found for T versus C among both East-Asians (OR = 1.33, 95% CI = 1.05–1.68) and Caucasians(OR = 1.16, 95% CI = 1.02–1.31). Further stratification for stroke subtype in three Caucasian studies showed the association between -7351C/T polymorphism and Large-artery atherosclerosis (LAA), but not Small-vessel occlusion (SVO) and Cardioembolism (CE). Conclusions This meta-analysis suggested that the -7351C/T polymorphism in TPA gene would be a risk factor for ischemic stroke, especially among East-Asians compared with Caucasians, but not in South-Asians, and it may play a role in the pathogenesis of LAA in Caucasians, but not in SVO and CE.