Using the PEAR1 Polymorphisms Rs12041331 and Rs2768759 as Potential Predictive Markers of 90-Day Bleeding Events in the Context of Minor Strokes and Transient Ischemic Attack.

In this study, we explored the relationship between the platelet endothelial aggregation receptor 1 (PEAR1) polymorphisms, platelet reactivity, and clinical outcomes in patients with minor stroke or transient ischemic attack (TIA). Randomized controlled trial subgroups were assessed, wherein patients received dual antiplatelet therapy for at least 21 days. Platelet reactivity was measured at different time intervals. Genotypes were categorized as wild-type, mutant heterozygous, and mutant homozygous. Clinical outcomes were evaluated after 90 days. The rs12041331 polymorphism predominantly influenced adenosine diphosphate channel platelet activity, with the AA genotype displaying significantly lower residual platelet activity to the P2Y12 response unit (p < 0.01). This effect was more evident after 7 days of dual antiplatelet treatment (p = 0.016). Mutant A allele carriers had decreased rates of recurrent stroke and complex endpoint events but were more prone to bleeding (p = 0.015). The rs2768759 polymorphism majorly impacted arachidonic acid (AA) channel platelet activity, which was particularly noticeable in the C allele carriers. Our regression analysis demonstrated that rs12041331 AA + GA and rs2768759 CA predicted 90-day post-stroke bleeding. In conclusion, the PEAR1 polymorphisms rs12041331 and rs2768759 interfere with platelet aggregation and the performance of antiplatelet drugs. These genetic variations may contribute to bleeding events associated with minor stroke and TIA.

Integrative Analysis of Inflammatory Response-Related Gene for Predicting Prognosis and Immunotherapy in Glioma.

Inflammatory response plays a crucial role in the development and progression of gliomas. Whereas the prognostic esteem of inflammatory response-related genes has never been comprehensively explored in glioma, the RNA-seq information and clinical data of patients with glioma were extracted from TCGA, CGGA, and Rembrandt databases. The differentially expressed genes (DEGs) were picked out between glioma tissue and non-tumor brain tissue (NBT). Then, the least absolute shrinkage and selection operator (LASSO) regression analysis was performed to construct the prognostic signature in the TCGA cohort and verified in other cohorts. Kaplan-Meier survival analyses were conducted to compare the overall survival (OS) between the high and low-risk groups. Univariate and multivariate Cox analyses were subsequently used to confirm the independent prognostic factors of OS, and then, the nomogram was established based them. Furthermore, immune infiltration, immune checkpoints, and immunotherapy were also probed and compared between high and low-risk groups. The four genes were also analyzed by qRT-PCR, immunohistochemistry, and western blot trials between glioma tissue and NBT. The 39 DEGs were identified between glioma tissue and NBT, of which 31 genes are associated to the prognosis of glioma. The 8 optimal inflammatory response-related genes were selected to construct the prognostic inflammatory response-related signature (IRRS) through the LASSO regression. The effectiveness of the IRRS was verified in the TCGA, CGGA, and Rembrandt cohorts. Meanwhile, a nomogram with better accuracy was established to predict OS based on the independent prognostic factors. The IRRS was highly correlated with clinicopathological features, immune infiltration, and genomic alterations in glioma patients. In addition, four selective genes also verified the difference between glioma tissue and NBT. A novel prognostic signature was associated with the prognosis, immune infiltration, and immunotherapy effect in patients with gliomas. Thus, this study could provide a perspective for glioma prognosis and treatment.

Burden of Common Neurologic Diseases in Asian Countries, 1990-2019: An Analysis for the Global Burden of Disease Study 2019.

BACKGROUND AND OBJECTIVES: Based on the Global Burden of Diseases, Injuries, and Risk Factors (GBD) study, neurologic disorders are a major cause of morbidity and mortality worldwide. However, there has been no comprehensive assessment of neurologic disorders in Asia. Data from the GBD 1990-2019 study were investigated to provide new details for neurologic disorders in Asia. METHODS: The burden of common neurologic disorders in Asia was calculated for 1990 and 2019 as incidence, prevalence, deaths, and disability-adjusted life-years (DALYs). Thirteen common neurologic disorders were analyzed. Data are presented as totals and by sex, age, year, location, risk factors, and sociodemographic index (SDI) and shown as counts and rates. RESULTS: In 2019, the most burdensome neurologic disorders in Asia for the absolute number of DALYs were stroke (98.8 million, 95% uncertainty interval [UI] 91.0-107.0), migraine (24.6 million, 95% UI 3.4-56.4), and Alzheimer disease (AD) and other dementias (13.5 million, 95% UI 5.9-29.8). From 1990 to 2019, the absolute number of DALYs and deaths caused by combined neurologic disorders (deaths by 60.7% and DALYs by 17.6%) increased, but the age-standardized rates (deaths by 34.1% and DALYs by 36.3%) decreased. The burden of neurologic disorders peaked among individuals aged 65-74 years and was higher among male than among female individuals; moreover, this burden varied considerably across Asian subregions and countries. Risk-attributable DALYs accounted for 86.9%, 28.5%, and 11.1% of DALYs for stroke, AD and other dementias, and multiple sclerosis, respectively. SDI was associated with both stroke and communicable neurological disorders. In terms of crude rate, the higher the SDI value, the higher the prevalence of stroke, and the lower all metrics of communicable neurological disorders. DISCUSSION: Neurologic disorders were the leading cause of DALYs and the second leading cause of deaths in Asia in 2019, and the burden may likely increase with the growth and aging of the Asian population. Urgent measures are needed for prevention, treatment, rehabilitation, and support services for common neurologic disorders regionally and nationally.

Associations of deep medullary veins with vascular risk factors, laboratory indicators, and cerebral small vessel disease: A population-based study.

OBJECTIVE: Deep medullary veins (DMVs) were not considered a typical marker of cerebral small vessel disease (CSVD) due to limited understanding of their involvement in pathology of CSVD. This study aimsto investigate potential vascular risk factors for DMVs and their associations with CSVD. METHODS: In total, 1909 community-dwelling participants were included in this analysis. Demographic, clinical, laboratory, and imaging data were collected. DMV scores (0-18) werecalculated as the sum of bilateral frontal, parietal, and occipital regional scores using a semiquantitative visual scale (0-3). The presence, total burden, and imaging markers of CSVD were assessed. Linear regression analyses were conducted to explore potential vascular factors for DMV scores. Binary and ordinal logistic regression analyses were performed to investigate the associations of DMV scores with CSVD and its markers. RESULTS: Mean age was 61.8 (SD 6.5) years, and 1027 (53.8%) of participants were men. The median DMV scores were14 (IQR 12-16). DMV scores wererelated to age, male sex, body mass index, diastolic blood pressure, hypercholesterolaemia, atrial fibrillation, current drinking, total cholesterol, triglycerides, low-density lipoprotein, hemoglobin A1c, leukocytes, lymphocytes, hemoglobin, and platelets (p < .05). DMV scores wereassociated with the presence and total burden of CSVD (Rothwell's scale), modified white matter hyperintensity burden, and enlarged perivascular spaces in centrum semiovale (p < .05). However, these associations between DMV scores and CSVD disappeared after adjusting for potential confounders. CONCLUSION: Several conventional vascular factors were associated with DMVs. The relationship between DMVs and CSVD was vulnerable, suggesting decreased visible and discontinuous DMVs may differ mechanistically from traditional markers of CSVD.

Thyroid Function in Causal Relation to MRI Markers of Cerebral Small Vessel Disease: A Mendelian Randomization Analysis.

CONTEXT: Observational studies have provided insufficient information on the association between thyroid function and the risk of cerebral small vessel disease (CSVD); moreover, the causality of this link is still unclear. OBJECTIVE: This study aims to investigate whether genetically predicted variation within thyroid function is causally associated with the risk of CSVD using 2-sample Mendelian randomization (MR) analysis. METHODS: In this 2-sample MR study with genome-wide association variants, we estimated the causal effects of genetically predicted thyrotropin (thyroid-stimulating hormone, TSH; n = 54 288), free thyroxine (FT4; n = 49 269), hypothyroidism (n = 51 823), and hyperthyroidism (n = 51 823) on 3 neuroimaging markers of CSVD, including white matter hyperintensity (WMH; n = 42 310), mean diffusivity (MD; n = 17 467), and fractional anisotropy (FA, n = 17 663). The primary analysis was conducted by the inverse variance-weighted MR method, followed by sensitivity analyses using MR-PRESSO, MR-Egger, weighted median, and weighted mode methods. RESULTS: Genetically increased TSH was associated with increased MD (ß = .311, 95% CI 0.0763, 0.548, P = .01). Genetically increased FT4 was associated with increased FA (ß = .540, 95% CI 0.222, 0.858, P < .001). Sensitivity analyses using different MR methods showed similar directions but lower precision. No significant associations of hypothyroidism or hyperthyroidism with WMH, MD, or FA were found (all P > .05). CONCLUSION: This study indicated that genetically predicted increased TSH was associated with increased MD, as well as increased FT4 with increased FA, implying the causal effect of thyroid dysfunction on white matter microstructural injury. There were no significant causal relationships of hypothyroidism or hyperthyroidism with CSVD. Further investigations should verify these findings and clarify the underlying pathophysiological mechanisms.

The nonalcoholic fatty liver risk in prediction of unfavorable outcome after stroke: A nationwide registry analysis.

Few researches have looked at the relationship between nonalcoholic fatty liver disease (NAFLD) at the time of admission and the long-term outcomes of patients suffering from acute ischemic stroke (AIS). We aimed to probe the relationship between NAFLD risk evaluated by NAFLD indices and long-term endpoints, along with the prognostic value of merging NAFLD indices with established risk markers for the prognosis of AIS patients. The fatty liver index (FLI) and the Hepatic steatosis index (HSI) were used to evaluate NAFLD risk in the Third China National Stroke Registry (CNSR-III), a large, prospective, national, multicenter cohort registry study. NAFLD was defined as FLI ≥35 for males and FLI ≥ 20 for females, as well as HSI>36. Death or major disability (modified Rankin Scale score ≥3) were the primary outcomes following the beginning of a stroke. On patient outcomes, the prognostic performance of two objective NAFLD parameters was evaluated. NAFLD was detected in 32.10-51.90% of AIS patients. After 1-year, 14.5% of the participants had died or suffered a severe outcome. After controlling for known risk factors, NAFLD was associated with a modest probability of adverse outcome (odds ratio,0.72[95% CI, 0.61-0.86] for FLI; odds ratio,0.68[95% CI, 0.55-0.85] for HSI). The inclusion of the two NAFLD indicators in the conventional prediction model was justified by the integrated discrimination index, continuing to increase the model's overall predictive value for long-term adverse outcomes. NAFLD risk was linked to a lower risk of long-term death or major disability in people with AIS. The predictive value of objective NAFLD after AIS was demonstrated in our study.

Implication of heart rate variability on cerebral small vessel disease: A potential therapeutic target.

OBJECTIVE: This study aimed to investigate the relationships of heart rate variability (HRV) with the presence, severity, and individual neuroimaging markers of cerebral small vessel disease (CSVD). METHOD: A total of 4676 participants from the Third China National Stroke Registry (CNSR-III) study were included in this cross-sectional analysis. CSVD and its markers, including white matter hyperintensity (WMH), lacunes, enlarged perivascular spaces (EPVS), cerebral microbleeds (CMBs), and brain atrophy (BA), were evaluated. Two common HRV parameters, including the square root of the mean of the sum of the squares of differences between adjacent N-N intervals (RMSSD) and the standard deviation of all N-N intervals (SDNN), were used to evaluate the function of the autonomic nervous system (ANS). Binary or ordinal logistic regression analyses were performed to investigate the association between HRV and CSVD. In addition, two-sample mendelian randomization (MR) analyses were performed to investigate the causality of HRV with CSVD. RESULTS: RMSSD was significantly associated with total burden of CSVD (Wardlaw's scale, common odds ratio [cOR] 0.80, 95% confidence interval [CI] 0.67-0.96, p = 0.02; Rothwell's scale, cOR 0.75, 95% CI 0.60-0.93, p = 0.008) and the presence of CSVD (Rothwell, OR 0.75, 95% CI 0.60-0.93, p = 0.008). However, no significant associations between SDNN and the presence or total burden of CSVD were observed. Moreover, RMSSD was related to WMH burden (OR 0.80, 95% CI 0.66-0.96, p = 0.02), modified WMH burden (cOR 0.82, 95% CI 0.69-0.97, p = 0.02), and Deep-WMH (OR 0.75, 95% CI 0.62-0.91, p = 0.003), while SDNN was related to Deep-WMH (OR 0.80, 95% CI 0.66-0.96, p = 0.02) and BA (cOR 0.80, 95% CI 0.68-0.95, p = 0.009). Furthermore, adding HRV to the conventional model based on vascualr risk factors enhanced the predictive performance for CSVD, as validated by the integrated discrimination index (p < 0.05). In addition, no causality between HRV and CSVD was observed in two-sample MR analyses. CONCLUSION: Decreased HRV may be a potential risk factor of CSVD, implying the possible role of the ANS in the pathogenesis of CSVD.

Diffuse-type Tenosynovial Giant Cell Tumor Invading the Temporal Bone: Three Cases.

Diffuse-type tenosynovial giant cell tumor (D-TSGCT) is a destructive benign tumor-like proliferative disease that occurs in synovial tissue characterized by villous nodular hyperplasia of joints, tendon sheaths, and synovium. D-TSGCT invading the temporal bone originating from the temporomandibular joint (TMJ) is very rare. Here, we report 3 cases of temporal bone D-TSGCT originating from the TMJ. The tumors in the three cases were originating from the TMJ and further invading the middle ear, the carotid foramen or the temporal lobe respectively. The second patient clearly involved the carotid foramen. The third patient clearly affected the temporal lobe. Lesions were completely removed in 3 cases, and all 3 patients were followed up for 30, 20, and 7 months, and none had recurrence. There are very few reports describing such cases. Although this report is not representative of most scenarios, there is still a potential that it provides a relatively reliable surgical idea for similar cases.

Associations of Life's Simple 7 With Cerebral Small Vessel Disease.

BACKGROUND: The purpose of this study is to examine the associations of Life's Simple 7 (LS7) with risks of cerebral small vessel disease (CSVD) and its magnetic resonance imaging markers. METHODS: Community-dwelling residents in Lishui city in China from the cross-sectional survey of the PRECISE study (Polyvascular Evaluation for Cognitive Impairment and Vascular Events) were included in this study from 2017 to 2019. LS7 was analyzed as the total score, medical score (derived from the 3 metrics based on medical history and testing), and behavioral score (based on 4 metrics based on behaviors), and categorized as poor, intermediate, or ideal. A CSVD score or a modified CSVD score was derived from 4 magnetic resonance imaging markers (lacunes, microbleeds, perivascular spaces, and white matter hyperintensity) at baseline. Binary logistic regression or ordinal logistic regression model was used to estimate the relationship of LS7 scores with CSVD and magnetic resonance imaging markers. RESULTS: A total of 3061 participants were included in this study. Compared with poor total LS7 score, ideal LS7 total score was associated with reduced adjusted odds of higher CSVD score (common odds ratio [cOR], 0.73 [95% CI, 0.58-0.90]) and higher modified CSVD score (cOR, 0.78 [95% CI, 0.64-0.95]). Compared with poor LS7 medical score, ideal LS7 medical score was associated with reduced adjusted odds of higher CSVD score (cOR, 0.65 [95% CI, 0.53-0.80]) and higher modified CSVD score (cOR, 0.67 [95% CI, 0.56-0.81]). Higher total LS7 score and LS7 medical score were associated with a lower risk of white matter hyperintensities and lacunes. Higher LS7 behavioral score was associated with lower risk of lacunes. CONCLUSIONS: Ideal LS7 score, indicating excellent cardiovascular health, was associated with lower total CSVD burden. Optimizing the risk factors captured by LS7 may reduce the progression of CSVD.

Aspirin platelet reactivity on platelet function and clinical outcome in minor stroke or transient ischemic attack.

OBJECTIVE: Whether aspirin platelet reactivity affects platelet function and clinical outcomes with different antiplatelet therapies in patients with mild stroke or transient ischemic attack (TIA) remains unclear. We conducted a subgroup analysis of the PRINCE trial. MATERIALS AND METHODS: Patients with mild stroke or TIA were randomized into aspirin+ticagrelor, or aspirin+clopidogrel groups; aspirin reaction units (ARU) were measured at the baseline and after 7 ± 2 days to assess response to treatment. High on-treatment platelet reactivity (HPR) was defined as ≥550 ARU (poor response to aspirin). The platelet functions of ticagrelor and clopidogrel were measured using the VerifyNow P2Y12 assay for P2Y12 reaction units (PRU); HPR to P2Y12 was defined as >208 PRU (poor response to P2Y12). Clinical outcomes included stroke and clinical vascular and bleeding events after 90 days. RESULTS: Among 628 enrolled patients, 69 (11%) were poor aspirin responders. After 7 ± 2 days, the proportion of poor P2Y12 responders for ticagrelor versus clopidogrel significantly reduced in poor (2.6% versus 27.4%) and good (14.3% versus 29.4%) aspirin responders. There were significant interactions between treatment groups, and between treatment groups and aspirin platelet reactivity for poor P2Y12 responders (P = 0.01). After 90 ± 7 days, there were no significant interactions between treatment groups and aspirin platelet reactivity for new stroke risk (good aspirin responders: 5.5% versus 8.8%, hazard ratio [HR]: 0.61; 95% confidence interval [CI], 0.32 to 1.16; P = 0.13; poor aspirin responders: 8.6% versus 8.8%, HR: 0.97, 95% CI: 0.20-4.81; P = 0.97; P for interaction = 0.60). Major bleeding was less frequent in poor than good aspirin responders (ticagrelor/aspirin: 0.4%/0%; clopidogrel/aspirin: 1.4%/0%). CONCLUSIONS: In patients with minor stroke or TIA, clopidogrel, and particularly ticagrelor, decreased platelet function in poor versus good aspirin responders. The poor platelet reactivity of aspirin could not sufficiently reduce the risk of recurrent stroke with ticagrelor or clopidogrel; however, HPR (poor aspirin response) may have a protective effect on clinically relevant major bleeding.

Association of Serum Cystatin C With Cerebral Small Vessel Disease in Community-Based Population.

BACKGROUND: The aim of this study was to investigate the relationship between serum cystatin C levels and the presence and severity of cerebral small vessel disease (CSVD). METHODS: Community-dwelling residents in the Lishui city in China from the cross-sectional survey of the PRECISE (Poly-Vascular Evaluation for Cognitive Impairment and Vascular Events) cohort study were included in present study from 2017 to 2019. Total CSVD burden and modified total CSVD burden score, as well as the markers of CSVD on magnetic resonance imaging, including white matter hyperintensity, lacunes, cerebral microbleeds, and perivascular spaces, were assessed at baseline survey. Participants were divided into 4 groups according to the quartiles of cystatin C. The association of serum cystatin C with total CSVD burden and imaging markers was analyzed using ordinal or binary logistic regression models. Furthermore, 2-sample Mendelian randomization analysis was performed to investigate the genetically predicted effect of cystatin C on CSVD. RESULTS: A total of 3061 participants were included in this study. The mean age of the participants was 61.2±6.7 years, and 1637 (53.5%) were women. Higher level of cystatin C was associated with an increased total CSVD burden and modified total CSVD burden (Q4 versus Q1: common odds ratio [OR], 1.30 [95% CI, 1.03-1.64] and 1.32 [95% CI, 1.01-1.73]) after adjustment for covariates. Further, compared with the first quartile of cystatin C, subjects in the last quartile had higher risk of lacunes (OR, 1.99 [95% CI, 1.05-3.76]), modified white matter hyperintensity burden (common OR, 1.42 [95% CI, 1.07-1.90]), and moderate-to-severe perivascular spaces (OR, 2.15 [95% CI, 1.29-3.59]) but not cerebral microbleeds. The Mendelian randomization analysis showed that a genetically predicted higher cystatin C level was associated with increased risk of lacunar stroke (OR, 1.16 [95% CI, 1.06-1.27]). CONCLUSIONS: In this community-based study, we found a possible association between cystatin C and CSVD, especially for lacunes, that was independent of estimated glomerular filtration rate.

Association of inflammatory markers with cerebral small vessel disease in community-based population.

BACKGROUND: This study investigated the relationships of neutrophil count (NC), neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) with cerebral small vessel disease (CSVD). METHODS: A total of 3052 community-dwelling residents from the Poly-vasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study were involved in this cross-sectional study. CSVD burden and imaging markers, including white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMBs) and enlarged perivascular spaces in basal ganglia (BG-EPVS), were assessed according to total CSVD burden score. The associations of NC, NLR and SII with CSVD and imaging markers were evaluated using logistic regression models. Furthermore, two-sample Mendelian randomization (MR) analysis was performed to investigate the genetically predicted effect of NC on CSVD. The prognostic performances of NC, NLR and SII for the presence of CSVD were assessed. RESULTS: At baseline, the mean age was 61.2 ± 6.7 years, and 53.5% of the participants were female. Higher NC was suggestively associated with increased total CSVD burden and modified total CSVD burden (Q4 vs. Q1: common odds ratio (cOR) 1.33, 95% CI 1.05-1.70; cOR 1.28, 95% CI 1.02-1.60) and marginally correlated with the presence of CSVD (OR 1.29, 95% CI 1.00-1.66). Furthermore, elevated NC was linked to a higher risk of lacune (OR 2.13, 95% CI 1.25-3.62) and moderate-to-severe BG-EPVS (OR 1.67, 95% CI 1.14-2.44). A greater NLR was related to moderate-to-severe BG-EPVS (OR 1.68, 95% CI 1.16-2.45). Individuals with a higher SII had an increased risk of modified WMH burden (OR 1.35, 95% CI 1.08-1.69) and moderate-to-severe BG-EPVS (OR 1.70, 95% CI 1.20-2.41). MR analysis showed that genetically predicted higher NC was associated with an increased risk of lacunar stroke (OR 1.20, 95% CI 1.04-1.39) and small vessel stroke (OR 1.21, 95% CI 1.06-1.38). The addition of NC to the basic model with traditional risk factors improved the predictive ability for the presence of CSVD, as validated by the net reclassification index and integrated discrimination index (all p < 0.05). CONCLUSIONS: This community-based population study found a suggestive association between NC and CSVD, especially for BG-EPVS and lacune, and provided evidence supporting the prognostic significance of NC.

BMI, Blood Pressure, and Plasma Lipids among Centenarians and Their Offspring.

BACKGROUND: The burden of cardiovascular diseases (CVDs) is increasing substantially due to population growth and aging. Determining effective prevention and understanding the underlying mechanisms remain desirable pursuits for increasing the quality of life. As centenarians and their offspring may have genetic advantages, they may present with healthier cardiovascular-related profiles. METHODS: We launched a cross-sectional household-based survey of centenarian families, including 253 centenarians, 217 centenarian offspring, and 116 offspring spouses without centenarian parents from county-level Chinese longevity city Rugao. Among offspring and offspring spouses were the following arrangements: 101 paired offspring and offspring spouses who lived together, 116 unpaired offspring, and 16 unpaired spouses. We investigated their cardiovascular-related health status including waist circumference, body mass index (BMI), blood pressure, and plasma lipids and compared results among centenarians, centenarian offspring, and offspring spouses. RESULTS: Centenarians ranged from 99 to 109 years with a median age of 100 years. Centenarian offspring, with a median age of 70 years, and offspring spouses, with a median age of 69 years, shared similar age. Results of blood pressure, plasma lipid levels, and BMI displayed no significant difference between centenarian offspring and offspring spouses. However, centenarians appeared to have lower waist circumference, BMI, TC, LDL-C, TG, and diastolic blood pressure but higher levels of systolic blood pressure (p < 0.05). Multivariate analysis showed the prevalence of obesity, hypertension, and dyslipidemia was similar between centenarian offspring and offspring spouses, while centenarians appeared to have a lower prevalence of obesity and a higher prevalence of hypertension (p < 0.05). CONCLUSIONS: Centenarians and centenarian offspring did not present healthier BMI, blood pressure, or plasma lipids than offspring spouses. Further research on longevity and cardiovascular diseases are desirable.

Genetically predicted childhood obesity and adult atrial fibrillation: A mendelian randomization study.

BACKGROUND AND AIMS: It is unclear whether the association of childhood obesity with adult atrial fibrillation observed in observational studies reflects causal effects. The aim of this study was to evaluate the association of childhood obesity with adult atrial fibrillation using genetic instruments. METHODS AND RESULTS: We used a two-sample Mendelian randomization (MR) design to evaluate the association between childhood obesity and adult atrial fibrillation. Two sets of genetic variants (15 single nucleotide polymorphisms [SNPs] for childhood body mass index [BMI] and 12 SNPs for dichotomous childhood obesity) were selected as instruments. Summary data on SNP-childhood obesity and SNP-atrial fibrillation associations were obtained from recently published genome-wide association studies. Effect estimates were evaluated using inverse-variance weighted (IVW) methods. Other MR analyses, including MR-Egger, simple and weighted median, weighted MBE and MR-PRESSO methods were performed in sensitivity analyses. The IVW models showed that both a genetically predicted one-standard deviation increase in childhood BMI (kg/m2) and higher log-odds of childhood obesity were associated with a substantial increase in the risk of atrial fibrillation (OR = 1.22, 95% CI: 1.11-1.34, P < 0.001; OR = 1.09, 95% CI: 1.04-1.14, P < 0.001). MR-Egger regression showed no evidence of genetic pleiotropy for childhood BMI (intercept = 0.000, 95% CI: -0.024 to 0.023), but for childhood obesity (intercept = -0.036, 95% CI: -0.057 to -0.015). Similar results were observed using leave-one-out and other MR methods in sensitivity analyses. CONCLUSIONS: This MR analysis found a consistent association between genetically predicted childhood obesity and an increased risk of adult atrial fibrillation. Further research is warranted to validate our findings.

MicroRNA-744-5p inhibits glioblastoma malignancy by suppressing replication factor C subunit 2.

Glioblastoma (GBM) is the most common malignant primary brain tumor, accounting for ~57% of all gliomas and 48% of all malignant primary central nervous system tumors in the United States. Abnormal expression of the replication factor C subunit 2 (RFC2) gene and microRNA (miR)-744-5p is associated with tumorigenic characteristics, including cellular proliferation, migration and invasiveness. However, the mechanism underlying the interaction between miR-744-5p and RFC2 in GBM remains unknown. Reverse transcription-quantitative (RT-q) PCR analysis of RFC2 and miR-744-5p was performed using GBM tumor tissues and cells, and the association between miR-744-5p and RFC2 was determined by dual-luciferase reporter assay. Cell Counting Kit 8, 5-bromo-2-deoxyuridine (BrdU), wound-healing and cellular adhesion assays, as well as the detection of caspase-3 activity and western blotting were used to detect cellular proliferation, migration and adhesion, caspase-3 activity, and Bax and Bcl-2 protein expression, respectively, in GBM cells. The results of the present study demonstrated that RFC2 expression was increased in GBM tissues and cell lines. Overexpression of RFC2 promoted cellular proliferation, migration, adhesion and an increase in Bcl-2 protein levels, and suppressed cellular caspase-3 activity and Bax protein expression, while silencing RFC2 resulted in the opposite effect. The effects of miR-744-5p inhibition were similar to those of RFC2 overexpression. Moreover, miR-744-5p was found to target RFC2 in GBM cells, and inhibiting the expression of RFC2 suppressed GBM tumorigenesis. In conclusion, the present study demonstrated that miR-744-5p targets RFC2 and suppresses the progression of GBM by repressing cellular proliferation, migration and Bcl-2 protein expression, and effectively promoting caspase-3 activity and Bax protein expression. These findings suggest a new target for the clinical treatment and improved prognosis of patients with GBM in the future.

Long-term outcome in meningiomas involving the major dural sinuses with combined therapy of subtotal resection and early postoperative gamma knife radiosurgery.

INTRODUCTION: Total resection of meningiomas involving the major dural sinuses (MIMDS) is still challenging for neurosurgeons. Gamma knife radiosurgery (GKRS) was shown to have a high probability of tumor control. The current study evaluated the clinical outcomes of patients who underwent subtotal resection alone or in combination with postoperative GKRS for the treatment of WHO grade I MIMDS. METHODS: From January 2006 to December 2016, 204 patients with MIMDS underwent Simpson IV subtotal resection in Wuhan Union Hospital. In 151 patients, no additional treatment was performed, while the tumor remnant was treated with GKRS in 53 patients. All patients were monitored with regular MR follow-ups. We retrospectively reviewed the clinical data, radiological characteristics, and outcomes of these 204 patients. Progression-free survival (PFS) was determined by Kaplan-Meier analysis. Related factors were determined by univariate Cox regression analyses. RESULTS: The mean follow-up period was 75.5 months. The tumor recurrence/progression rates were 13.9% in the microsurgery group and 3.8% in the combined therapy group (p = 0.045). The 5- and 10- year progression-free survival (PFS) rates were 92.3 and 80.7%, respectively, in the microsurgery group and 100.0 and 88.5% in the combined therapy group. Treatment approach was found to be an independent prognostic factor for tumor recurrence/progression in the univariable analyses (p=0.04). CONCLUSIONS: Compared with microsurgery alone, targeted Simpson grade IV resection combined with early gamma knife treatment resulted in longer progression-free survival without increased complications for WHO grade I MIMDS.

Efficacy of unilateral hemilaminectomy for intraspinal tumor resection: a systematic review and meta-analysis.

BACKGROUND: To evaluate, via a meta-analysis, the clinical effect of unilateral hemilaminectomy for intraspinal tumor removal. METHODS: PubMed, Springer, Wanfang Data, CBM, CNKI, and other databases were searched for relevant randomized controlled trials (RCT), in Chinese and other languages, that involved comparisons of unilateral hemilaminectomy with other techniques for intraspinal tumor removal. RESULTS: Thirteen RCTs were finally included, with a total of 1,424 patients. Unilateral hemilaminectomy for intraspinal tumor removal was found to reduce the amount of intraoperative hemorrhage (Z =45.67, P<0.00001), operative time (Z =55.35, P<0.00001), length of hospital stay (Z =111.67, P<0.00001), and inbed time (Z =142.08, P<0.00001) of patients. Compared with the traditional operative methods, unilateral hemilaminectomy for intraspinal tumor removal can improve the cure rate of patients [odds ratio (OR) =3.84; 95% confidence interval (CI), 2.1-7.01; Z =4.38; P<0.001) and reduce the incidence of spinal deformities (OR =0.11; 95% CI, 0.04-0.34; Z =3.83; P=0.001). It does not increase the risks of postoperative cerebrospinal fluid leak (OR =0.63; 95% CI, 0.21-1.88; Z =0.82; P=0.41), postoperative infection (OR =0.74; 95% CI, 0.31-1.77; Z =0.67; P=0.50), pain (OR =0.29; 95% CI, 0.07-1.18; Z =1.73; P=0.08), myasthenia (OR =-0.04; 95% CI, -0.07 to 0.01; Z =2.29; P=0.02), and other complications. CONCLUSIONS: Unilateral hemilaminectomy for the microsurgical removal of intraspinal tumors has the advantages of minimal operative trauma, fast recovery, and better postoperative stability of the vertebral column.

Using arterial-venous analysis to characterize cancer metabolic consumption in patients.

Understanding tumor metabolism holds the promise of new insights into cancer biology, diagnosis and treatment. To assess human cancer metabolism, here we report a method to collect intra-operative samples of blood from an artery directly upstream and a vein directly downstream of a brain tumor, as well as samples from dorsal pedal veins of the same patients. After performing targeted metabolomic analysis, we characterize the metabolites consumed and produced by gliomas in vivo by comparing the arterial supply and venous drainage. N-acetylornithine, D-glucose, putrescine, and L-acetylcarnitine are consumed in relatively large amounts by gliomas. Conversely, L-glutamine, agmatine, and uridine 5-monophosphate are produced in relatively large amounts by gliomas. Further we verify that D-2-hydroxyglutarate (D-2HG) is high in venous plasma from patients with isocitrate dehydrogenases1 (IDH1) mutations. Through these paired comparisons, we can exclude the interpatient variation that is present in plasma samples usually taken from the cubital vein.

Outcomes of Two-Isocenter Gamma Knife Radiosurgery for Patients with Typical Trigeminal Neuralgia: Pain Response and Quality of Life.

OBJECTIVE: To evaluate the effectiveness and safety of 2-isocenter Gamma Knife surgery (GKS) by reviewing patients with trigeminal neuralgia (TN) from the last 10 years. METHODS: A total of 247 patients were followed up and the Barrow Neurological Institute scale was used to evaluate pain degree. Patients' age, gender, pain duration and location, preoperative/postoperative Barrow Neurological Institute scale score, time to initial pain relief, recurrence time, and complications were documented and analyzed. RESULTS: Patients who underwent a 2-isocenter GKS achieved earlier initial pain relief. The median time of initial pain relief was 2.0 months. Kaplan-Meier analysis showed that the patients with a shorter history of TN and the patients without preoperative surgery achieved earlier initial pain relief. During the 122.8 months of follow-up, the median time of recurrence-free pain relief was 49.7 months. Age was found to be a risk factor of recurrence. Patients who underwent 2-isocenter GKS had a higher rate of postoperative facial numbness, but only 9 cases reported bothersome facial numbness. Multibranch involvement was a risk factor for postoperative facial numbness. CONCLUSIONS: Compared with other modalities, 2-isocenter GKS was a safe and highly effective option for patients with TN. However, more data need to be collected to verify its long-term effect.

Galangin increases ERK1/2 phosphorylation to decrease ADAM9 expression and prevents invasion in A172 glioma cells.

Galangin (3,5,7­trihydroxyflavone), is a natural flavonoid present in plants. Galangin is reported to exhibit anti­cancer properties against various cancer types. The aim of the present study was to display the effects of galangin on glioma and its mechanism of action in A172 human glioma cancer cells. The results clearly indicated that treatment of galangin inhibited A172 cell migration and invasion under non­toxic doses. A human proteinase array assay was conducted to elucidate the potential effects of galangin, and the obtained results demonstrated that treatment of galangin inhibited ADAM9 protein expression and mRNA expression, that are known to contribute to cancer progression. Sustained extracellular signal­regulated kinase (Erk)1/2 activation was also monitored, which contributed to ADAM9 protein expression and mRNA inhibition as investigated using western blotting analysis and reverse transcription­quantitative polymerase chain reaction experiment. Erk1/2 inhibition by inhibitor or small interfering (si)Erk transfection markedly terminated galangin­inhibited A172 migration and invasion via an Erk1/2 activation mechanism. Collective results suggested that galangin may act as an effective chemotherapeutic agent for glioma cancer depending on its ability to bring about ADAM9 and Erk1/2 activation.