Meta-analysis of the association between CHCHD10 Pro34Ser variant and the risk of amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS), one of the motor neuron diseases, appears to be caused by genetic and environmental risk factors. However, the influence of Pro34Ser variant of CHCHD10 gene in increasing risk of ALS remains indeterminate. This study conducted a meta-analysis to establish the association between Pro34Ser variant of CHCHD10 gene and risk of ALS. METHODS: PubMed, Web of Science, and Embase databases were systematically searched for genome-wide association studies or case-control studies published up to March 28, 2020, on the association between Pro34Ser variant and risk of ALS. Data from eligible studies were extracted and analyzed. RESULTS: Twelve case-control studies involving 7442 patients with sporadic ALS and 75,371 controls were analyzed. The Pro34Ser variant was not associated with increased risk of ALS disease based on fixed-effects meta-analysis (Pro34Ser-positive vs Pro34Ser-negative: OR 1.23, 95% CI 0.90 to 1.69, P = 0.201). CONCLUSION: Existing evidence suggests that Pro34Ser variant in CHCHD10 is not associated with risk of ALS, particularly in Caucasian participants. However, our results ought to be validated using large, well-designed studies, especially in Asian and African populations.

CDKN2B methylation is associated with carotid artery calcification in ischemic stroke patients.

BACKGROUND: Cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B) near chromosome 9p21 have been associated with both atherosclerosis and artery calcification, but the underlying mechanisms remained largely unknown. Considering that CDKN2A/2B is a frequently reported site for DNA methylation, this study aimed to evaluate whether carotid artery calcification (CarAC) is related to methylation levels of CDKN2A/2B in patients with ischemic stroke. METHODS: DNA methylation levels of CDKN2A/2B were measured in 322 ischemic stroke patients using peripheral blood leukocytes. Methylation levels of 36 CpG sites around promoter regions of CDKN2A/2B were examined with BiSulfite Amplicon Sequencing. CarAC was quantified with Agatston score based on results of computed tomography angiography. Generalized liner model was performed to explore the association between methylation levels and CarAC. RESULTS: Of the 322 analyzed patients, 187 (58.1%) were classified as with and 135 (41.9%) without evident CarAC. The average methylation levels of CDKN2B were higher in patents with CarAC than those without (5.7 vs 5.4, p = 0.001). After adjustment for potential confounders, methylation levels of CDKN2B were positively correlated with cube root transformed calcification scores (ß = 0.591 ± 0.172, p = 0.001) in generalized liner model. A positive correlation was also detected between average methylation levels of CDKN2B and cube root transformed calcium volumes (ß = 0.533 ± 0.160, p = 0.001). CONCLUSIONS: DNA methylation of CDKN2B may play a potential role in artery calcification.

Hypertension unawareness among Chinese patients with first-ever stroke.

BACKGROUND: The low rates of hypertension treatment and control, partly due to its unawareness, are the main causes of the high stroke incidence in China. The purpose of this study was to evaluate hypertension unawareness amongst patients with first-ever stroke and to detect factors associated with its unawareness. METHODS: We selected those diagnosed with hypertension from patients with first-ever stroke registered in the Nanjing Stroke Registry Program between 2004 and 2014. These hypertensives were divided as being aware or unaware of their hypertension by using a brief questionnaire conducted shortly after the stroke. Multivariate logistic regression analysis was performed to identify potential factors associated with hypertension unawareness. RESULTS: Of the 5309 patients with first-ever stroke, 3732 (70.3%) were diagnosed with hypertension. Among which, 593 (15.9%) were unaware of their hypertension at the time of stroke onset. Lower-level of education (primary school or illiteracy) and smoking were associated positively with hypertension unawareness; while advanced age, overweight, diabetes mellitus, heart diseases and family history of stroke were associated negatively with hypertension unawareness. Annual data analyzed indicated that the rate of hypertension awareness increased during the past 11 years (r = 0.613, P = 0.045 for trends). CONCLUSIONS: A substantial proportion (15.9%) of Chinese patients with hypertension had not been aware of this covert risk until an overt stroke occurred. Hypertension unawareness was associated with lower educational levels and smoking, which address the importance of health education especially in these individuals.

Osteo-immunomodulatory effects of macrophage-derived extracellular vesicles treated with biphasic calcium phosphate ceramics on bone regeneration.

Literature on osteoimmunology has demonstrated that macrophages have a great influence on biomaterial-induced bone formation. However, there are almost no reports clarifying the osteo-immunomodulatory capacity of macrophage-derived extracellular vesicles (EVs). This study comprehensively investigated the effects of EVs derived from macrophages treated with biphasic calcium phosphate (BCP) ceramics (BEVs) on vital events associated with BCP-induced bone formation such as immune response, angiogenesis, and osteogenesis. It was found that compared with EVs derived from macrophages alone (control, CEVs), BEVs preferentially promoted macrophage polarization towards a wound-healing M2 phenotype, enhanced migration, angiogenic differentiation, and tube formation of human umbilical vein endothelial cells, and induced osteogenic differentiation of mesenchymal stem cells. Analysis of 15 differentially expressed microRNAs (DEMs) related to immune, angiogenesis, and osteogenesis suggested that BEVs exhibited good immunomodulatory, pro-angiogenic, and pro-osteogenic abilities, which might be attributed to their specific miRNA cargos. These findings not only deepen our understanding of biomaterial-mediated osteoinduction, but also suggest that EVs derived from biomaterial-treated macrophages hold great promise as therapeutic agents with desired immunomodulatory capacity for bone regeneration.

Predictive Value of Skeletal Muscle Function Test Combined with Climbing Test for Postoperative Cardiopulmonary Complications in Patients with COPD and Concurrent Lung Cancer.

Purpose: To explore the predictive value of skeletal muscle function measurement combined with stair climbing test for postoperative cardiopulmonary complications in patients with chronic obstructive pulmonary disease (COPD) and non-small cell lung cancer (NSCLC). Patients and Methods: A prospective study was conducted from June 2022 to July 2023 at West China Hospital of Sichuan University, including 335 COPD patients with lung cancer who underwent surgery. The patients were divided into two groups based on the occurrence of postoperative cardiopulmonary complications: the complication group and the non-complication group. The demographic data, including gender, age, smoking history, quadriceps strength, body mass index (BMI), respiratory muscle strength, 6-minute walk test (6MWD), stair climbing test, and preoperative pulmonary function tests, were compared between the two groups. Logistic regression analysis was performed to evaluate the predictive power of each parameter for postoperative cardiopulmonary complications. Results: Among the enrolled patients, 103 (30.7%) developed postoperative cardiopulmonary complications. Significant differences were observed between the two groups in terms of quadriceps strength, respiratory muscle strength, 6MWD, smoking history, stair climbing test, DLCO%, FEV1%, heart rate, oxygen saturation, surgical duration, surgical approach, resection range, and blood loss (P<0.05). Logistic regression analysis revealed that respiratory muscle strength, quadriceps strength, stair climbing test, FEV1%, DLCO%, ΔHR, ΔSPO2, surgical approach were identified as risk factors for postoperative cardiopulmonary complications in patients with COPD and lung cancer. Conclusion: Skeletal muscle function measurement, stair climbing test, FEV1, surgical approach, and DLCO% can serve as assessment tools for surgical risk in patients with COPD and lung cancer. They can predict the occurrence of postoperative cardiopulmonary complications to a certain extent, providing valuable predictive value for these complications in patients with COPD and NSCLC.

Current levels and composition profiles of microplastics in irrigation water.

Land-based sources have been considered the most important sources of microplastic pollution to the coastal and marine environment. The number of research studies examining microplastic pollution in freshwater and inland water systems is increasing, but most research focuses on rivers, reservoirs, and lakes. This study investigated the spatial-temporal distribution, characteristics, sources, and risks of microplastics in irrigation water in Taiwan. The results showed that microplastics were widely and unevenly distributed along the irrigation system and were abundant at sites surrounded by a dense population and sites that received lateral canal and urban runoff input. The abundance of microplastics ranged from 1.88 items/L to 141 items/L, and samples collected in May had the highest microplastic concentrations. Polypropylene, polyethylene, and polystyrene were identified as the predominant polymers. Fibers (36-64%) were the most typical and abundant shape, and 333-1000 µm size (49-63%) and white/transparent (45-51%) were the dominant size and colors among all samples. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were used to assess the impact of the rainy season and typhoons and addressed the dramatic changes in distinct population densities. The polymer risk index was calculated to evaluate the environmental risk of microplastics in irrigation water, and the results revealed a high microplastic risk throughout the year except in November and January. This study provided a valuable reference and impetus for a better understanding of the microplastic profile and source apportionment in irrigation water, which was important for environmental management.

The Thr105Ile Variant (rs11558538) of the Histamine N-methyltransferase Gene may be associated with Reduced Risk of Parkinson Disease: A Meta-analysis.

Background: Previous studies have reported conflicting results regarding the potential association between the risk of Parkinson's disease (PD) and the single nucleotide polymorphism, rs11558538 (Thr105Ile), in the histamine N-methyltransferase (HNMT) gene. We performed a systematic review and meta-analysis to improve our understanding of the association between them. Methods: We systematically searched several online databases to identify relevant studies regarding the association between rs11558538 and PD. We extracted data on the frequencies of genotypes (Thr/Thr, Thr/Ile, and Ile/Ile) and alleles (Thr and Ile) at the rs11558538 locus in patients with PD and healthy controls. Associations between genotype and PD risk were assessed in terms of odds ratios (OR) and 95% confidence intervals (CI). Results: The final meta-analysis included six case-control studies and data from the International Parkinson's Disease Genomics Consortium (IPDGC) data base on the association between HNMT rs11558538 and PD, involving 22,855 patients and 65,367 controls. Among the studies, substantial heterogeneity was observed (I2 = 84.42 for genotype and I2 = 73.39 for allele). Both the Ile (log OR: -0.31; 95% CI: -0.5 to -0.12; p < 0.001) and Thr/Ile+Ile genotypes (log OR: -0.32; 95% CI: -0.55 to -0.08; p < 0.001) were associated with a decreased risk of sporadic PD across all study populations. Subgroup analysis showed the protective effect of Thr/Ile+Ile genotypes in non-Chinese cohorts (log OR: -0.66; 95% CI: -0.67 to -0.04; p < 0.001) but not in Chinese cohorts (log OR: -0.26; 95% CI: -0.63 to 0.11; p = 0.13). Conclusion: Our findings suggest that the HNMT rs11558538T polymorphism may protect against PD, particularly in patients from the United States and Europe.

Phgdh serves a protective role in Il­1ß induced chondrocyte inflammation and oxidative­stress damage.

The primary pathological changes observed in osteoarthritis (OA) involve inflammation and degeneration of chondrocytes. 3­phosphoglycerate dehydrogenase (Phgdh), a rate­limiting enzyme involved in the conversion of 3­phosphoglycerate to serine, serves as a crucial molecular component of cell growth and metabolism. However, its effects on chondrocytes in OA have not been determined. In the present study, a rat model of OA was used to investigate the expression levels of Phgdh in vivo and in vitro. Additionally, the role of Phgdh in extracellular matrix (ECM) synthesis, inflammation, apoptosis and oxidative stress levels of chondrocytes was detected in vitro. Phgdh expression was decreased in OA, and Phgdh overexpression promoted ECM synthesis, decreased levels inflammatory cytokines, such as Il­6, TNF­α, a disintegrin and metalloproteinase with thrombospondin motifs 5 and MMP13, and decreased apoptosis. Furthermore, expression of Phgdh effectively increased expression levels of the cellular antioxidant enzymes catalase and superoxide dismutase 1, and decreased the levels of reactive oxygen species in chondrocytes; and this may have been regulated by a Kelch like ECH associated protein 1/nuclear factor erythroid 2­related factor 2 axis. Taken together, these results suggest that Phgdh may be used to manage the progression of OA.

Insulin enhances neointimal hyperplasia following arterial injury through the PI3K/Akt pathway in type 1 diabetic rats.

Although insulin is known to affect neointimal hyperplasia via distinct signaling pathways, how neointimal hyperplasia is affected in insulin­deficient type 1 diabetes remains unknown. The aim of the current study was to investigate two major signaling branches of insulin action regulating neointimal hyperplasia following arterial injury in type 1 diabetes with or without exogenous insulin administration. Rats were treated with vehicle (control group), streptozotocin (STZ) alone (STZ group; uncontrolled type 1 diabetes) or STZ followed by insulin (STZ + I group; controlled type 1 diabetes). Subsequently, a type 1 diabetic rat model of carotid artery balloon injury was established. Following this, the intima­to­media area ratios were examined for evidence of neointimal hyperplasia in the carotid arteries of the rats by performing hematoxylin­eosin staining. Furthermore, the protein expression of extracellular signal­regulated kinase (ERK), phosphorylated (p­) ERK, protein kinase B (Akt) and p­Akt in the carotid arteries of the rats was determined via immunoblotting. Moreover, an in vitro model of type 1 diabetes was induced by incubation of primary vascular smooth muscle cells (VSMCs) with glucose and/or insulin. Cellular proliferation and signaling protein expression levels in VSMCs were determined by measuring the incorporation of tritiated thymidine and performing immunoblotting, respectively. The results demonstrated that compared with that in control rats, neointimal hyperplasia and expression of p­Akt in uncontrolled type 1 diabetic rats were significantly decreased. This decrease was recovered in controlled type 1 diabetes with insulin therapy. Furthermore, the difference in the expression of p­ERK between groups was not significant. Additionally, the results of the cell experiments were consistent with those from the animal studies. In conclusion, the preferential signaling along the phosphatidylinositol 3­kinase/Akt pathway of insulin action in response to insulin restoration may contribute to neointimal hyperplasia. The present study provides a novel approach for the further treatment of neointimal hyperplasia in type 1 diabetes.

Premorbid dietary intake of protein is associated with early outcomes but not with severity of ischemic stroke.

BACKGROUND AND OBJECTIVES: Dietary protein intake has been associated with reduced risk of stroke. This study aimed to examine the relationship between premorbid dietary intake of protein and both stroke severity and neurological outcomes in patients with acute ischemic stroke. METHODS AND STUDY DESIGN: Consecutive patients with first-ever ischemic stroke in Jinling Hospital were screened for eligibility of participation. A validated foodfrequency questionnaire (FFQ) was performed to collect necessary data for calculating pre-stroke dietary intakes. Stroke severity was assessed by the National Institutes of Health Stroke Scale (NIHSS) at baseline. Neurological outcomes were assessed by the modified Rankin scale (mRS) 90 days after stroke onset. Multivariable logistical regression was applied to analyze the impacts of dietary protein intake on stroke severity or neurological outcomes. RESULTS: Of the 201 enrolled patients, 110 (54.7%) were classified as minor (NIHSS ≤5) and 91 (45.3%) as major stroke (NIHSS ≥6). After adjusting for potential confounders, multivariable logistic regression did not detect significant association between total (odds ratio (OR)=0.98, p=0.15), animal (OR=1.01, p=0.87) or plant protein intake (OR=0.96, p=0.07) and stroke severity. According to the 90-day mRS, 127 patients (63.2%) were determined with good (mRS ≤2), and 74 (36.8%) with poor outcomes (mR 3-6). Multivariable logistic regression detected that premorbid dietary intake of total protein was positively associated with good neurological outcomes (OR=1.05, p=0.04). CONCLUSIONS: Higher level of premorbid protein intake may be associated with favorable neurological outcomes independent of stroke severity.

CDKN2B Methylation and Aortic Arch Calcification in Patients with Ischemic Stroke.

AIM: CDKN2A/2B near chromosome 9p21 has been proposed as a potential genetic etiology for both atherosclerosis and arterial calcification. DNA methylation, which can change the expression of CDKN2A/2B, may be an underlying mechanism for this association. This study aimed to evaluate whether CDKN2A/2B methylation is related to aortic arch calcification (AAC) in patients with ischemic stroke. METHODS: DNA methylation levels of CDKN2A/2B was measured using venous blood samples in 322 patients with ischemic stroke. A total of 36 CpG sites around promoter regions of CDKN2A/2B were examined. AAC was quantified with Agatston score based on results of computed tomography angiography. RESULTS: There were 248 (77.0%) patients with and 74 (23.0%) patients without evident AAC. Compared with patients without AAC, patients with AAC had higher methylation levels of CDKN2B (5.72 vs 4.94, P＜0.001). Using a generalized linear model, positive correlation between methylation levels and log-transformed calcification scores was detected at CDKN2B (ß=0.275±0.116, P= 0.018). CONCLUSION: Patients with higher levels of DNA methylation of CDKN2B may bear increased risk for AAC. Further studies to reveal the underlying mechanisms of this association are warranted for establishing a cause-effect relationship.

Fine-Mapping of ABO Gene Identifies Two Novel SNPs Associated with Large Artery Atherosclerotic Stroke in a Chinese Han Population.

Recently, a single nucleotide polymorphism (SNP) rs505922 in ABO gene was related to large artery atherosclerotic (LAA) stroke in Caucasian populations by genome-wide association study (GWAS). This study aimed to determine whether ABO gene polymorphisms are associated with LAA stroke in Chinese Han population. A case-control study was designed, and 644 patients with LAA stroke and 642 healthy controls were enrolled. Ten tagging SNPs (tSNPs) located in ABO gene were genotyped. Associations between genotypes and LAA stroke were analyzed with logistic regression model after adjustment of potential confounders. Although rs505922 was not associated with LAA stroke (TT genotype, adjusted OR = 1.32; 95 % CI, 0.94 to 1.87), two novel SNPs, rs8176668 (AT genotype, adjusted OR = 0.71; 95 % CI, 0.55 to 0.92) and rs2073824 (AA genotype, adjusted OR = 0.72; 95 % CI, 0.57 to 0.92), were associated with LAA stroke. Haplotype analysis indicated that haplotype TC (adjusted OR = 0.72; 95 % CI, 0.54 to 0.95; P = 0.018) in block 1 and haplotype ACA in block 2 (OR = 0.73; 95 % CI, 0.58 to 0.91; P = 0.005) were associated with LAA stroke. Multifactor dimensionality reduction (MDR) analysis in the single-locus model indicated that rs2073824 was the most important attributor for predicting risk of LAA stroke. No significant SNP-SNP interactions among the tested SNPs were detected. The results indicated that the genetic variants in ABO gene may influence the risk of LAA stroke in Chinese Han population.

The impacts of premorbid hypertension treatment on functional outcomes of ischemic stroke.

BACKGROUND AND PURPOSE: The low rate of hypertension control is a major cause for the high rate of stroke morbidity and mortality in China. This study aimed to evaluate the impacts of premorbid hypertension treatment on the functional outcomes in patients with acute ischemic stroke and hypertension. METHODS: Patients with first-ever ischemic stroke and hypertension were screened from Nanjing Stroke Registry Program for eligibility. Functional outcomes were followed at 3 months with modified Rankin Scale (mRS). A good functional outcome was defined as mRS≤2. Potential factors associated with good functional outcomes were analyzed with multivariate logistic regression. RESULTS: A total of 660 patients with both ischemic stroke and hypertension were included, of whom 284 (43.0%) were on antihypertensives before stroke. In univariate analysis, more patients with hypertension treatments had good outcomes than those without (47.7% vs 31.0%, P=0.0001). After adjusted for age, heart diseases, baseline stroke severity, systolic blood pressure at admission, pneumonia, intravenous thrombolysis, and hospital stay, multivariate logistic regression indicated that premorbid hypertension treatment was related to an increased likelihood of good functional outcomes (OR: 2.21, 95% CI: 1.30 to 3.74, P=0.003). CONCLUSIONS: Less than half of the Chinese patients with hypertension were on drug treatment prior to stroke onset. Lack of premorbid hypertension treatment may have deteriorated functional outcomes of stroke. These findings emphasized the importance of improving hypertension treatment in Chinese, especially in whom at high risk of cerebrovascular diseases.

Shared and discrepant susceptibility for carotid artery and aortic arch calcification: A genetic association study.

Genome-wide association studies (GWASs) have identified several risk loci for coronary artery calcification. Four single-nucleotide polymorphisms (SNPs, rs1537370, rs1333049, rs2026458 and rs9349379) were associated with coronary artery calcification with P values less than 5 × 10(-8) in GWASs. It is unclear if these associations exist in other vascular beds. Thus, we evaluated the impacts of these four SNPs on carotid artery and aortic arch calcification in this study. Computed tomography was applied to quantify the calcification of carotid artery and aortic arch. 860 patients with stroke completed calcification quantification and genotype testing were included in data analysis. Each SNP was evaluated for the association with carotid artery calcification, and with aortic arch calcification using generalized linear model. Among the four tested SNPs, rs2026458 was associated with calcification in both carotid artery (ß = 0.31, 95% confidence interval [CI] 0.10-0.52, P = 0.003) and aortic arch (ß = 0.32, 95% CI 0.10-0.54, P = 0.004), while rs1333049 was only associated with carotid artery calcification (ß = 0.28, 95% CI 0.06-0.50, P = 0.011). In gender-stratified analyses, rs2026458 had significant impacts on carotid artery (P = 0.003) and aortic arch calcification (P = 0.008) in male, but not in female patients; while rs1537370 was significantly associated with carotid artery calcification in female (P = 0.013), but not in male patients. In conclusion, SNPs associated with coronary artery calcification may also increase the risk of calcification in other arteries such as carotid artery and aortic arch.

Mitochondrial DNA haplogroups and short-term neurological outcomes of ischemic stroke.

Stroke is one of the leading causes of death and long-term disability worldwide. Mitochondrial DNA (mtDNA) is a potential contributor for the sex differences of ischemic stroke heritability. Although mtDNA haplogroups were associated with stroke onset, their impacts on stroke outcomes remain unclear. This study aimed to evaluate the impacts of mtDNA haplogroups on short-term outcomes of neurological functions in patients with ischemic stroke. A total of 303 patients were included, and their clinical data and mtDNA sequences were analyzed. Based on the changes between baseline and 14-day follow-up stroke severity, our results showed that haplogroup N9 was an independent protective factor against neurological worsening in acute ischemic stroke patients. These findings supported that mtDNA variants play a role in post-stroke neurological recovery, thus providing evidences for future pharmacological intervention in mitochondrial function.