Effect of phrenic nerve stimulation on patients with central sleep apnea: A meta-analysis.

Patients with central sleep apnea (CSA) have a lower quality of life and higher morbidity and mortality. Phrenic nerve stimulation (PNS) is a novel treatment for CSA that has been shown to be safe. However, the effects of PNS on sleep changes are still under debate. This meta-analysis was performed to evaluate the efficacy of PNS in patients with CSA. PubMed, Scopus, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science databases were searched for relevant studies published. We performed random-effects meta-analyses of the changes in apnea-hypopnea index (AHI), central apnea index (CAI), Arousal Index, percent of sleep with O2 saturation <90% (T90), Epworth Sleepiness Scale (ESS) and sleep efficiency. Ten studies with a total of 580 subjects were analyzed. Overall meta-analysis showed AHI [SMD: -2.24, 95% confidence interval (CI): was -3.11 to -1.36(p＜0.00001)], CAI [SMD: -2.32, 95% CI: -3.17 to -1.47 (p＜0.00001)] and Arousal Index (p = 0.0002, SMD (95% CI) -1.79 (-2.74 to -0.85)) significantly reduced after PNS. No significant changes were observed in T90, ESS and sleep efficiency (p > 0.05). Meta-analysis of observational studies demonstrated AHI, CAI and Arousal Index had a decreasing trend between before and after PNS (all, p＜0.05). However, ESS and T90 did not change significantly after PNS (p > 0.05). Meta-analysis of RCTs showed that CSA patients had trends of a lower AHI (I2 = 0%), CAI (I2 = 74%), Arousal Index (I2 = 0%), T90 (I2 = 0%) and ESS (I2 = 0%) after PNS (all, p＜0.05). The use of PNS appears to be safe and feasible in patients with CSA. However, larger, independent RCTs are required to investigate the efficacy and long-term effect of PNS and more attention should be paid to T90 and ESS.

Preliminary Exploration of Clinical Efficacy and Pharmacological Mechanism of Modified Danggui-Shaoyao San in the Treatment of Depression in Patients with Chronic Kidney Disease.

Background: Depression in Chronic Kidney Disease (CKD) seriously affects the prognosis of patients and Modified Danggui-Shaoyao-San (MDSS) is based on the traditional Chinese formula Danggui-Shaoyao-San (DSS) for the treatment of depression, which is further optimized. The aim of this study was to evaluate the clinical efficacy and safety of MDSS for the treatment of depression in CKD, and to explain the molecular mechanism of MDSS for the treatment of depression in CKD through pharmacology and molecular docking. Methods: 62 patients were randomly divided into treatment group (treated with MDSS) and control group (treated with placebo) and assessed by Hamilton Depression Scale, and the primary outcome was to evaluate the efficacy of MDSS in improving depressive symptoms and the effect on liver and kidney function, electrolytes. In addition, we identified the core compounds and potential targets of MDSS through the TCMSP database. The GeneCards, OMIM and Disgenet databases were then used to identify molecular targets for CKD and depression. The target protein-protein interaction network was built using STRING database. Core targets were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Molecular docking was used to verify the relationship between core active compounds and proteins. Results: Clinical results showed that CKD patients in the MDSS group had significantly improved depressive status with no significant adverse effects. By network pharmacology analysis, we found that the compound-target network mainly contained 47 compounds and 69 corresponding targets. 844 terms were analyzed by GO enrichment, and 254 signaling pathways in KEGG. Molecular docking showed that the top active compounds had high affinity with four targets. Conclusion: We preliminarily investigated the efficacy of MDSS in the treatment of depression in CKD and revealed the characteristics of multiple compounds and multiple targets in MDSS.

Uremic mouse model to study vascular calcification and "inflamm-aging".

Calcification and chronic inflammation of the vascular wall is a high-risk factor for cardiovascular mortality, especially in patients with chronic uremia. For the reduction or prevention of rapid disease progression, no specific treatment options are currently available. This study aimed to evaluate an adenine-based uremic mouse model for studying medial vessel calcification and senescence-associated secretory phenotype (SASP) changes of aortic tissue to unravel molecular pathogenesis and provide a model for therapy testing. The dietary adenine administration induced a stable and similar degree of chronic uremia in DBA2/N mice with an increase of uremia blood markers such as blood urea nitrogen, calcium, creatinine, alkaline phosphatase, and parathyroid hormone. Also, renal fibrosis and crystal deposits were detected upon adenine feeding. The uremic condition is related to a moderate to severe medial vessel calcification and subsequent elastin disorganization. In addition, expression of osteogenic markers as Bmp-2 and its transcription factor Sox-9 as well as p21 as senescence marker were increased in uremic mice compared to controls. Pro-inflammatory uremic proteins such as serum amyloid A, interleukin (Il)-1ß, and Il-6 increased. This novel model of chronic uremia provides a simple method for investigation of signaling pathways in vascular inflammation and calcification and therefore offers an experimental basis for the development of potential therapeutic intervention studies.

Identification of diagnostic markers and immune cell infiltration characteristics in antineutrophil cytoplasmic antibody-associated vasculitis by weighted gene co-expression network analysis.

BACKGROUND: Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a group of life-threatening systemic autoimmune diseases. The aim of this study was to determine the relationship between the AAV hub gene and immune cell infiltration, and its value for clinical disease treatment. METHODS: We downloaded the microarray information of 37 AAV patients and 27 controls from Gene Expression Omnibus (GEO). Genes were classified into totally different modules exploitation weighted gene co-expression network analysis (WGCNA). AAV diagnostic indicators were screened and then assessed immune cell infiltration by the least absolute shrinkage and selection operator (LASSO) and CIBERSORT. Finally, Connectivity Map analysis was applied to predict possible AAV glomerulus injury improvement therapies. RESULTS: WGCNA was developed and differentially expressed genes were classified into 6 modules, the black module was most tightly correlated to AAV. Among them, TIMP1 and FCER1G were most closely related to clinical features. Resting mast cells and monocytes emerged as having the foremost distinguished variations in AAV. C3AR1 and FCER1G were involved in AAV development by immune regulation. Connectivity Map analysis indicated the most significant compound was fisetin. CONCLUSIONS: The present study is that the initial to spot immune cell infiltration with microarray data of glomeruli in AAV, which provides novel proof and clues for additional analysis of the molecular mechanisms.

Vascular Calcification in Rodent Models-Keeping Track with an Extented Method Assortment.

Vascular calcification is a multifaceted disease and a significant contributor to cardiovascular morbidity and mortality. The calcification deposits in the vessel wall can vary in size and localization. Various pathophysiological pathways may be involved in disease progression. With respect to the calcification diversity, a great number of research models and detection methods have been established in basic research, relying mostly on rodent models. The aim of this review is to provide an overview of the currently available rodent models and quantification methods for vascular calcification, emphasizing animal burden and assessing prospects to use available methods in a way to address the 3R principles of Russel and Burch: "Replace, Reduce and Refine".

Prevalence and Risk Factors of Type 2 Diabetes and Prediabetes Among 53,288 Middle-Aged and Elderly Adults in China: A Cross-Sectional Study.

BACKGROUND: Diabetes is a metabolic disorder that causes a heavy burden on healthcare systems worldwide. The aim of this study was to determine the prevalence of type 2 diabetes and prediabetes and its associated factors among eight communities in Nanchong, China. METHODS: This was an observational cross-sectional study conducted throughout eight communities in Nanchong, China. The participants were 53,288 individuals aged 45 years or older. The participants' characteristics, comorbidities, health behaviors, family history, and dietary intake were assessed. Multinomial logistic regression models were fitted to identify factors associated with type 2 diabetes and prediabetes. RESULTS: The prevalence of diabetes and prediabetes was 13.9% (95% confidence interval [CI], 13.6-14.2) and 3.1% (95% CI, 2.9-3.2) of the population, respectively. After adjusting for other risk factors, advanced age, overweight, obesity, abdominal obesity, comorbidities, smoking, a family history of diabetes, and Chinese cooking vegetable intake were associated with an increased risk of type 2 diabetes and prediabetes. CONCLUSION: The prevalence of type 2 diabetes in the Chinese population is rising compared with data from the past. The risk factors of type 2 diabetes and prediabetes identified in this study will aid the identification of individuals at a high-risk of diabetes and the implementation of effective health promotion programs and campaigns. CLINICAL TRIAL REGISTRY NUMBER: ChiCTR-HOC-17013200.

Efficacy and safety of renal denervation for hypertension in patients with chronic kidney disease: a meta-analysis.

BACKGROUND: Renal denervation (RDN) is a new treatment for hypertension in patients with chronic kidney disease (CKD), but its efficacy is still debated. This meta-analysis aimed to evaluate the efficacy and safety of RDN for hypertension in patients with CKD. METHODS: PubMed, Web of Science, EMBASE, and Ovid databases were searched for relevant studies published. We performed both fixed- and random-effects meta-analyses of the changes in blood pressure, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR) after RDN. RESULTS: The meta-analysis included 238 patients from 11 single-center, non-randomized, uncontrolled studies. Office blood pressure and 24-hour ambulatory blood pressure (24 h-ABP) showed a significant reduction 1 month after RDN (p < 0.05). This decrease of 24 h-ABP persisted for 24 months after RDN showed difference systolic blood pressure (p < 0.001) and diastolic blood pressure (p = 0.001). The 24 h-ABP exhibited a similar trend in the subgroup analysis. eGFR measurements obtained at each time point of analysis after RDN were not significantly different from those obtained before (p > 0.05). UACR levels were significantly reduced at 3 months and 6 months after RDN (p < 0.001). After RDN, the heart rate showed no significant changes (p > 0.05), and few major complications were encountered. CONCLUSIONS: The meta-analysis showed that RDN may be effective and safe for treating CKD patients with hypertension. Well-designed randomized controlled trials of RDN are urgently needed to confirm the safety and reproducibility of RDN and to assess its impact on clinical outcomes.

Identification of Hub Biomarkers and Immune-Related Pathways Participating in the Progression of Antineutrophil Cytoplasmic Antibody-Associated Glomerulonephritis.

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease that generally induces the progression of rapidly progressive glomerulonephritis (GN). The purpose of this study was to identify key biomarkers and immune-related pathways involved in the progression of ANCA-associated GN (ANCA-GN) and their relationship with immune cell infiltration. Methods: Gene microarray data were downloaded from the Gene Expression Omnibus (GEO). Hub markers for ANCA-GN were mined based on differential expression analysis, weighted gene co-expression network analysis (WGCNA) and lasso regression, followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) of the differential genes. The infiltration levels of 28 immune cells in the expression profile and their relationship to hub gene markers were analysed using single-sample GSEA (ssGSEA). In addition, the accuracy of the hub markers in diagnosing ANCA-GN was subsequently evaluated using the receiver operating characteristic curve (ROC). Results: A total of 651 differential genes were screened. Twelve co-expression modules were obtained via WGCNA; of which, one hub module (black module) had the highest correlation with ANCA-GN. A total of 66 intersecting genes were acquired by combining differential genes. Five hub genes were subsequently obtained by lasso analysis as potential biomarkers for ANCA-GN. The immune infiltration results revealed the most significant relationship among monocytes, CD4+ T cells and CD8+ T cells. ROC curve analysis demonstrated a prime diagnostic value of the five hub genes. According to the functional enrichment analysis of the differential genes, hub genes were mainly enhanced in immune- and inflammation-related pathways. Conclusion: B cells and monocytes were closely associated with the pathogenesis of ANCA-GN. Hub genes (CYP3A5, SLC12A3, BGN, TAPBP and TMEM184B) may be involved in the progression of ANCA-GN through immune-related signal pathways.

Meta-Analytical Accuracy of ANCA Renal Risk Score for Prediction of Renal Outcome in Patients With ANCA-Associated Glomerulonephritis.

Background: To evaluate the diagnostic accuracy of antineutrophil cytoplasmic antibody (ANCA) renal risk score (ARRS) for prediction of renal outcome in patients with ANCA-associated glomerulonephritis (ANCA-GN). Methods: We searched PubMed, EMBASE, Ovid, Web of Science, the Cochrane Library, and ClinicalTrials.gov for studies, which used ARRS to predict end-stage renal disease (ESRD) in patients with ANCA-GN. Two reviewers independently screened articles for inclusion, assessed the quality of studies with both an adapted Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. We calculated the combined patients with ESRD in the ARRS categories and presented the summary and individual estimates based on the ARRS categories. Then, the sensitivity, specificity, diagnostic odds ratio (DOR), positive/negative likelihood ratio, and the area under the receiver operating characteristic (AUROC) curves of the pooled data for ARRS were used to assess the accuracy of the "above the low-risk threshold" (ARRS ≥ 2) and "high-risk grade" (ARRS ≥ 8) for renal outcome of patients with ANCA-GN. The hierarchical summary ROC (HSROC) was used to verify the accuracy value. The clinical utility of ARRS was evaluated by the Fagan plot. Heterogeneity was explored using meta-regression and subgroup analysis. Results: A total of 12 distinct cohorts from 11 articles involving 1,568 patients with ANCA-GN were analyzed. The cumulative patients with ESRD at the maximum follow-up of 60 months was 5% (95% CI: 0.02-0.07; p < 0.001) for ANCA-GN with low ARRS (0-1 points) and significantly increased to 22% (95% CI: 0.15-0.29; p < 0.001) medium ARRS (2-7 points). The combined cumulative patients with ESRD was 59% (95% CI: 0.49-0.69; p < 0.001) high ARRS (8-11 points). The pooled sensitivity of ARRS ≥ 2 in predicting ESRD was 98% with a specificity of 30% and a DOR of 15.08 and the mean AUROC value was 0.82. The pooled sensitivity of ARRS ≥ 8 in predicting ESRD was 58% with a specificity of 86% and a DOR of 7.59. The meta-regression and subgroup analysis indicated that variation in the geographic regions, study design, index risk, follow-up time, age of patient, publication year, and number of patient could be the potential sources of heterogeneity in the diagnosis of ARRS ≥ 8. Conclusion: This meta-analysis emphasized the good performance of the ARRS score in predicting the renal outcome in patients with ANCA-GN. However, these findings should be verified by future large-scale prospective studies.

Stressor-Induced "Inflammaging" of Vascular Smooth Muscle Cells via Nlrp3-Mediated Pro-inflammatory Auto-Loop.

Calcification of the vessel wall as one structural pathology of aged vessels is associated with high cardiovascular mortality of elderly patients. Aging is linked to chronic sterile inflammation and high burden of reactive oxygen species (ROS), leading to activation of pattern recognition receptors (PRRs) such as Nlrp3 in vascular cells. The current study investigates the role of PRR activation in the calcification of vascular smooth muscle cells (VSMCs). Therefore, in vitro cell culture of primary rat VSMCs and ex vivo aortic stimulations were used to analyze osteogenic, senescence and inflammatory markers via real-time PCR, in situ RNA hybridization, Western Blot, photometric assays and histological staining. Induction of ROS and DNA-damage by doxorubicin induces a shift of VSMC phenotype toward the expression of osteogenic, senescence and inflammatory proteins. Induction of calcification is dependent on Nlrp3 activity. Il-1ß as a downstream target of Nlrp3 induces the synthetic, pro-calcifying VSMC phenotype. Inhibition of PRR with subsequent reduction of chronic inflammation might be an interesting target for reduction of calcification of VSMCs, with subsequent reduction of cardiovascular mortality of patients suffering from vessel stiffness.

Methylenetetrahydrofolate reductase genetic polymorphism and the risk of diabetic nephropathy in type 2 diabetic patients.

BACKGROUND: As indicated by numerous studies, there exists a relationship between the polymorphism of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to diabetic nephropathy (DN) in various populations; nonetheless, the findings remain inconsistent. Therefore, we carried out a meta-analysis to determine the relationship between the MTHFR gene polymorphism and DN susceptibility. MATERIALS AND METHOD: Related studies were identified from PubMed, Cochrane Library, EMBASE, and the China National Knowledge Infrastructure database (time period: from building the library to October 2019). The strength of the association was examined using odds ratios (ORs) with 95% confidence intervals (95% CIs). RESULTS: The findings illustrated that the C677T gene polymorphism was significantly associated with an enhanced susceptibility to DN compared to that with diabetes mellitus in allelic (OR = 1.64, 95% CI = 1.34-2.00, P < .001), dominant (OR = 1.85, 95% CI = 1.40-2.46, P < .001), codominant (heterozygote: OR = 1.67, 95% CI = 1.27-2.21, P < .001; homozygote: OR = 2.55, 95% CI = 1.82-3.57, P < .001), and recessive (OR = 1.89, 95% CI = 1.50-2.38, P < .001) models of the overall population. Moreover, as compared with the healthy controls, a significantly augmented susceptibility to DN was found in all 5 genetic comparison models (allelic: OR = 2.06, 95% CI = 1.58-2.67, P < .001; dominant: OR = 2.52, 95% CI = 1.73-3.69, P < .001; codominant: OR = 3.78, 95% CI = 2.50-5.70, P < .001; recessive: OR = 2.41, 95% CI = 1.96-2.97, P < .001). Furthermore, stratifying data by ethnicity revealed substantially augmented vulnerability to DN in not only Caucasian but also Asian populations. CONCLUSION: The present study suggests that the C677T polymorphism was associated with an augmented susceptibility to DN.