Prognostic impact of white blood cell counts on clinical outcomes in patients with chronic renal insufficiency undergoing percutaneous coronary intervention.

Objective: To determine whether the inclusion of white blood cell (WBC) counts in the SYNTAX score (SS) or SS II models could improve the models' performance for risk stratification in individuals with chronic renal insufficiency (CRI) following percutaneous coronary intervention (PCI). Methods: In total, 2,313 patients with CRI, who were subjected to PCI and had data available on in-hospital WBC (ih-WBC) counts, were recruited. Patients were divided into 3 groups as per their ih-WBC counts (low, medium, and high). The primary endpoints were all-cause mortality (ACM) and cardiac mortality (CM). The secondary endpoints incorporated myocardial infarction, stroke, unplanned revascularization, and major adverse cardiovascular and cerebrovascular events (MACCEs). Results: During a median follow-up of 3 years, the high WBC group had the highest incidences of CM (2.4% vs. 2.1% vs. 6.7%; p < 0.001), ACM (6.3% vs. 4.1% vs. 8.2%; p < 0.001), unplanned revascularization (8.4% vs. 12.4% vs. 14.1%; p < 0.001), and MACCEs (19.3% vs. 23.0% vs. 29.2%; p < 0.001) among the three groups. Multivariable Cox regression analysis depicted that the risk of ACM and CM in the high WBC group was 2.577 (95% confidence interval [CI]: 1.504-4.415, p < 0.001) and 3.850 (95% CI: 1.835-8.080, p < 0.001) times that in the low WBC group after adjusting for other confounding factors. A combination of ih-WBC counts with SS or SS II significantly improved the risk assessment and prediction of ACM and CM. Conclusion: The ih-WBC counts was associated with the risk of occurrence of ACM, CM, unplanned revascularization, and MACCEs in individuals with CRI following PCI. It provides an incremental predictive value for the occurrence of ACM and CM when included in SS or SS II models.

Characterization of an Aging-Based Diagnostic Gene Signature and Molecular Subtypes With Diverse Immune Infiltrations in Atherosclerosis.

Objective: Advancing age is a major risk factor of atherosclerosis (AS). Nevertheless, the mechanism underlying this phenomenon remains indistinct. Herein, this study conducted a comprehensive analysis of the biological implications of aging-related genes in AS. Methods: Gene expression profiles of AS and non-AS samples were curated from the GEO project. Differential expression analysis was adopted for screening AS-specific aging-related genes. LASSO regression analysis was presented for constructing a diagnostic model, and the discriminatory capacity was evaluated with ROC curves. Through consensus clustering analysis, aging-based molecular subtypes were conducted. Immune levels were estimated based on the expression of HLAs, immune checkpoints, and immune cell infiltrations. Key genes were then identified via WGCNA. The effects of CEBPB knockdown on macrophage polarization were examined with western blotting and ELISA. Furthermore, macrophages were exposed to 100 mg/L ox-LDL for 48 h to induce macrophage foam cells. After silencing CEBPB, markers of cholesterol uptake, esterification and hydrolysis, and efflux were detected with western blotting. Results: This study identified 28 AS-specific aging-related genes. The aging-related gene signature was developed, which could accurately diagnose AS in both the GSE20129 (AUC = 0.898) and GSE43292 (AUC = 0.685) datasets. Based on the expression profiling of AS-specific aging-related genes, two molecular subtypes were clustered, and with diverse immune infiltration features. The molecular subtype-relevant genes were obtained with WGCNA, which were markedly associated with immune activation. Silencing CEBPB triggered anti-inflammatory M2-like polarization and suppressed foam cell formation. Conclusion: Our findings suggest the critical implications of aging-related genes in diagnosing AS and modulating immune infiltrations.

Non-high-density lipoprotein cholesterol and risk of cardiovascular disease in the general population and patients with type 2 diabetes: A systematic review and meta-analysis.

AIMS: To examine the relationship of non-high-density lipoprotein cholesterol (non-HDL-C) level with cardiovascular disease (CVD) risk in type 2 diabetes patients and the general population by conducting a meta-analysis. METHODS: We made a comprehensive literature search for relevant observational studies investigating the relationship of non-HDL-C level with CVD risk in the general population and type 2 diabetes patients using the PubMed and Embase databases. Pooled risk ratio (RR) with 95% confidence intervals (CI) was calculated for the highest versus the reference lower non-HDL-Cl. RESULTS: A total of 13 studies with 156,381 individuals were included. The pooled RR of CVD was 1.59 (95% CI 1.46-1.72) in the general population and 1.99 (95% CI 1.57-2.51) in type 2 diabetes patients. Subgroup analysis showed the similar effect of non-HDL-C on CVD risk between men (RR1.98; 95% CI 1.70-2.30) and women (RR 1.63; 95% CI 1.35-1.96). However, elevated non-HDL-C was not associated with higher risk of cardiovascular mortality in the general population (RR 1.64; 95% CI 0.96-2.80) and type 2 diabetes patients (RR 1.08; 95% CI 0.57-2.07). CONCLUSIONS: Elevated non-HDL-C level is associated with an increased risk of CVD in the general population and type 2 diabetes patients.

Association of early menopause with angiographically-derived SYNTAX score: Observational study.

Association of early menopause with increased risk of cardiovascular events has been confirmed in previous studies. SYNTAX score (SX-score) can comprehensively quantify severity of coronary artery disease (CAD) and predict the outcomes of patients with CAD. However, the association of early menopause with SX-score has never been reported.We prospectively included 1875 consecutive postmenopausal patients who underwent coronary angiography (CAG) and were angiographically diagnosed with CAD from January 2011 to December 2013. SX-score was calculated using the SX-score algorithm based on diagnostic angiogram. Ordinal logistic regression analysis was used to investigate the association between early menopause and SX-score.Patients with early menopause were more likely to have a history of hypertension, diabetes, hyperlipidemia, and less likely to smoking. Besides, they have higher fasting glucose, hemoglobin A1C (HbA1c), total cholesterol (TC), low-density lipoprotein (LDL), triglyceride (TG), and body mass index (BMI) compared with the patients without early menopause. Moreover, patients with early menopause have higher SX-score and multi-vessel diseases. Ordinal logistic regression analysis showed that age, hypertension, diabetes, and early menopause exerted independent influences on SX-score. The patients undergone oophorectomy, early menopause was highly associated with SX-score.Early menopause was an independent predictor of SX-score in postmenopausal patients with CAD.

miRNA­145 inhibits myocardial infarction­induced apoptosis through autophagy via Akt3/mTOR signaling pathway in vitro and in vivo.

The present study investigated the effects of micro (mi)RNA­145 on acute myocardial infarction (AMI) and the potential underlying mechanism. A total of 6 AMI and 6 normal rat tissues were investigated for the present study. It was demonstrated that miRNA­145 expression was downregulated in the AMI rat model, compared with the control group. Downregulation of miRNA­145 increased cardiac cell apoptosis, suppressed phosphorylated (p)­RAC­Î³ serine/threonine­protein kinase (Akt3) and p­mechanistic target of rapamycin (mTOR) protein expression levels and suppressed autophagy in an in vitro model of AMI. However, overexpression of miRNA­145 decreased cardiac cell apoptosis, induced p­Akt3 and p­mTOR protein expression and promoted autophagy in the in vitro model of AMI. The inhibition of Akt3 (GSK2110183, 1 nM) decreased the effect of the miRNA­145 upregulation on cell apoptosis in the in vitro model of AMI. Chloroquine diphosphate (5 µM) inhibited the regulatory effect of miRNA­145 upregulation on autophagy to adjust cell apoptosis, in the in vitro model of AMI. The results of the present study demonstrate that miRNA­145 inhibits myocardial infarction­induced apoptosis via autophagy associated with the Akt3/mTOR signaling pathway in vivo and in vitro.

Weighted gene co­expression network analysis in identification of key genes and networks for ischemic­reperfusion remodeling myocardium.

Acute myocardial infarction induces ventricular remodeling, which is implicated in dilated heart and heart failure. The pathogenical mechanism of myocardium remodeling remains to be elucidated. The aim of the present study was to identify key genes and networks for myocardium remodeling following ischemia­reperfusion (IR). First, the mRNA expression data from the National Center for Biotechnology Information database were downloaded to identify differences in mRNA expression of the IR heart at days 2 and 7. Then, weighted gene co­expression network analysis, hierarchical clustering, protein­protein interaction (PPI) network, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were used to identify key genes and networks for the heart remodeling process following IR. A total of 3,321 differentially expressed genes were identified during the heart remodeling process. A total of 6 modules were identified through gene co­expression network analysis. GO and KEGG analysis results suggested that each module represented a different biological function and was associated with different pathways. Finally, hub genes of each module were identified by PPI network construction. The present study revealed that heart remodeling following IR is a complicated process, involving extracellular matrix organization, neural development, apoptosis and energy metabolism. The dysregulated genes, including SRC proto­oncogene, non­receptor tyrosine kinase, discs large MAGUK scaffold protein 1, ATP citrate lyase, RAN, member RAS oncogene family, tumor protein p53, and polo like kinase 2, may be essential for heart remodeling following IR and may be used as potential targets for the inhibition of heart remodeling following acute myocardial infarction.

The anti-inflammatory effect of microRNA-383-3p interacting with IL1R2 against homocysteine-induced endothelial injury in rat coronary arteries.

MicroRNAs (miRs) are widely reported to be novel biomarkers involved in the process of coronary atherosclerosis (CAS). Hence, this study aims to explore the function of miR-383-3p targeting IL1R2 on inflammatory injury of coronary artery endothelial cells (CAECs) in CAS. The underlying regulatory mechanisms of miR-383-3p were analyzed in concert with the treatment of miR-383-3p mimics, miR-383-3p inhibitors, and the combination of miR-383-3p inhibitors and siRNA against IL1R2 in homocysteine (HCY)-induced CAECs. MTT, Hoechst 33258 staining, and tube formation assay were employed in order to measure cell viability, apoptosis, and tube formation, respectively. The levels of IL-1ß, IL-6, IL-10, and IL-18 were determined by ELISA. IL1R2 was verified as the target gene of miR-383-3p by dual-luciferase reporter gene assay. MiR-383-3p was down-regulated in myocardial tissues of AS rats while IL1R2 was the reciprocal. The up-regulation of miR-383-3p decreased the levels of IL1R2, caspase-1, IL-1ß, IL-6, and IL-18 expressions, as well as cell apoptosis rate in the HCY-induced CAECs, while IL-10 expression, cell viability, and tube formation ability were increased. These results were contraindicated in the HCY-induced CAECs treated by miR-383-3p inhibitors. In conclusion, miR-383-3p mediating IL1R2 prevents HCY-induced apoptosis and inflammation injury in CAECs through the inhibition of the activation of inflammasome signaling pathway. These findings highly indicate that miR-383-3p may be beneficial in the prevention of CAS and other cardiovascular diseases.

Associations of proteins relevant to MAPK signaling pathway (p38MAPK-1,HIF-1 and HO-1) with coronary lesion characteristics and prognosis of peri-menopausal women.

BACKGROUND: The present study was intended to explore whether three proteins within MAPK signaling pathway (i.e. p38MAPK-1, HIF-1 and HO-1) were correlated with peri-menopausal women's coronary lesion features and prognosis. METHODS: Altogether 1449 peri-menopausal women were divided into non-coronary artery disease (CAD) group (n = 860) and CAD group (n = 589), including 167 pre-menopausal CAD populations and 422 post-menopausal CAD populations. General information about CAD risk parameters were gathered, including age, family history of CAD or hypertension or diabetes mellitus, bilirubin, cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) and so on. Coronary angiography results were judged, and CAD score was calculated with application of Genisin scoring method. Besides, detection of MAPK-1 levels was implemented with Strept Avidin-Biotin Complex (SABC) method, while HIF-1 and HO-1 expressions in the serum were determined utilizing ELISA detection kit. Correlations among protein expressions, characteristics of coronary lesions and prognosis of CAD populations were finally evaluated. RESULTS: Hypertension, hyperlipoidemia, diabetes and smoking history were more prevalent among postmenopausal CAD women than premenopausal CAD women (P < 0.05). Furthermore, postmenopausal women seemed to be significantly associated with multiple (i.e. double and triple) vessel lesions and severe lesion types (type B and C), when compared with premenopausal CAD group (P < 0.05). Similarly, remarkably elevated expressions of p38MAPK-1, HIF-1 and HO-1 were found within postmenopausal CAD populations in comparison to premenopausal ones (P < 0.05). The internal CysC, hs-CRP, TG and LDL-C concentrations all accorded with the following tendency: postmenopausal CAD women > premenopausal CAD women > non-CAD women. Moreover, p38MAPK-1, HIF-1 and HO-1 expressions were up-regulated with increasing number of vessel lesions and severity of coronary lesions among peri-menopausal women. Besides, among both pre-menopausal and post-menopausal CAD groups, positive correlations could be observed between MAPK-1 and TG (r s = 0.271; r s = 0.476), between HIF-1α and LDL-C (r s = 0.077; r s = 0.470), as well as between HO-1 and CysC (r s = 0.492; r s = 0.190) or hs-CRP (r s = 0.569; r s = 0.542) (all P < 0.05). MAPK-1, HIF-1α and HO-1 were also, respectively, positively correlated with CysC (r s = 0.415), hs-CRP (r s = 0.137), and TG (r s = 0.142), regarding post-menopausal CAD women (all P < 0.05). Finally, only SBP and TG were regarded as independent risk factors for CAD prognosis (i.e. high Genisin score) among premenopausal women (OR = 1.02, 95%CI: 1.01-1.18, P = 0.043; OR = 1.82, 95%CI: 1.01-3.33, P = 0.047). CONCLUSIONS: Expressions of p38MAPK-1, HIF-1 and HO-1 could serve as predictive roles for coronary lesions among peri-menopausal women.

[Prevalence and significance of immunoglobulin G-anti-cyclic citrullinated peptide antibodies in primary Sjogren's syndrome patients].

OBJECTIVE: To investigate the prevalence and significance of IgG-anti-cyclic citrullinated peptides (CCP) antibody in PSS patients. METHODS: A total of 120 patients diagnosed with PSS were investigated in the first affiliated hospital of Baotou Medical College from March 2006 to December 2009. IgG-anti-CCP antibody was assayed by enzyme-linked immunosorbent assay (ELISA), also anti-Sjogren's syndrome type A (SSA) and Sjogren's syndrome type B (SSB) antibody were assayed by immunoblotting. Erythrocyte sedimentation rate (ESR) was assayed by westergren in serum, and C reactive protein (CRP), IgA, IgM, IgG and IgM-RF were detected by immune turbidimetric. At the same time, clinical symptoms and involvement of important organs were observed. Following up the patients above 3 years, the primary Sjogren's syndrome (PSS) patients who had progressed to rheumatoid arthritis (RA) were evaluated. RESULTS: The positive rate of anti-CCP antibody in the PSS patients was 19.17%; After 3 years, more patients who were positive for anti-CCP antibody had progressed to RA (χ² = 5.015,P=0.022) than the patients in negative group; The patients in anti-CCP antibody positive group were more prone to joint involvement (χ² = 8.058,P<0.05), more swollen joints (U=152.00, P<0.05) and longer morning stiffness (U=100.00, P<0.05) than the patients with negative anti-CCP antibody, but the involvement of vital organs in the two groups had no significant difference (χ² = 0.208,0.099,0.000 and 0.122, P>0.05); The positive rate of anti-SSA and SSB antibody in anti-CCP antibody positive group and negative group had no significant difference (χ² = 0.008 and 0.56, P>0.05); Multiple linear regression showed that the level of anti-CCP antibody was positively correlated with IgM-RF levels in the PSS patients (B=0.61, 95% CI=0.36-0.86, P<0.05), but had no significant correlation with ESR, CRP, IgA, IgM and IgG levels (P>0.05).There were no significant differences in the level of ESR, CRP, IgA, IgM and IgG between anti-CCP antibody positive group and negative group (P>0.05), but the level of IgM-RF in anti-CCP antibody positive group was significantly higher than that in the negative group (U=623.50, P<0.05). CONCLUSION: Positive rate of IgG-anti-CCP antibody in PSS is 19.17%, also it is associated with joint involvement and more prone to progressing to RA.

Effects of muscarinic acetylcholine 3 receptor(208-227) peptide immunization on autoimmune response in nonobese diabetic mice.

The second extracellular loop (LFWQYFVGKRTVPPGECFIQFLSEPTITFGTAI, aa 205-237) of muscarinic acetylcholine 3 receptor (M3R) has been reported to be an epitope for autoantibodies generated during certain autoimmune disorders, including Sjögren's syndrome (SS). Autoantibodies against M3R(228-237) have been shown to interfere with the function of M3R. However, few studies have been performed on the M3R(205-227) peptide of the second extracellular loop. In the current study, we sought to investigate the effect of M3R(208-227) peptide immunization on autoimmune response in NOD/LtJ mice. We synthesized the M3R(208-227) peptide and immunized NOD/LtJ mice to investigate whether peptide-specific antibodies could be generated and whether immunization would lead to changes in autoimmune response in NOD/LtJ mice. Our results demonstrate that the secretions of Th-1, Th-2, and Th-17 cytokines are downregulated and lymphocytic infiltration is improved in the salivary glands and lacrimal glands following immunization with M3R(208-227) peptide in NOD/LtJ mice, suggesting that peptide immunotherapy using the M3R(208-227) peptide may represent a potential therapeutic alternative.

Microemulsions of N-alkylimidazolium ionic liquid and their performance as microreactors for the photocycloaddition of 9-substituted anthracenes.

The phase behavior of the ternary system consisting of an ionic liquid (1-tetradecyl-3-methylimidazolium bromide [C14mim]Br), p-xylene, and water were investigated. Depending on the composition of the ternary system, formation of hexagonal and lamellar liquid crystals as well as microemulsions was observed. 1H NMR spectroscopy study, 2D ROESY spectroscopic analysis, and rheological measurements of the microemulsions indicated that p-xylene is preferably located in the hydrophobic core and the palisade shells of the microemulsions. The sizes of the microemulsion droplets for the samples with water/[C14mim]Br ratio of 78:22 are measured by both dynamic light scattering (DLS) and transmission electron microscopy with the freeze-fracture technique (FF-TEM). Upon change of the mole ratio of the solubilized xylene to [C14mim]Br from 0 to 2.4, the diameters of the microemulsion droplets increase from ca. 20 to 90 nm and size distribution gets broad. These microemulsions can solubilize and preorientate anthracene derivatives with a polar 9-substituent, and thus may enhance the head-to-head cyclomers in the photocyclization of these substrates.

Enhanced stereoselectivity in photoelectrocyclization of tropolone ethers via confinement in chiral inductor-modified lyotropic liquid crystals.

Photochemistry of tropolone methyl ether ( 1) and optically pure ( S)-tropolone-2-methylbutyl ether ( 4) has been examined in lyotropic liquid crystals (LCs) in the presence of a chiral inductor. LCs significantly enhance the influence of chiral inductors during the photoelectrocyclization of the tropolone ethers. Chiral inductors that lead to 1:1 mixtures of enantiomers or diastereomers in solution give products in up to 40% enantiomeric excess for 1 and 35% diastereomeric excess for 4 in LCs.

Studies on the stability of the chloramphenicol in the microemulsion free of alcohols.

Microemulsion composed of Span20 + Tween20 isopropyl myristate (IPM) + H2O were investigated as potential drug delivery systems for eye drops. The system is important in that all its components are food grade so that the microemulsion is almost free of toxicity and irritation. The phase transition was investigated using the electrical conductivity measurements. The chloramphenicol is used to treat the eye diseases such as trachoma and keratitis. However, this drug in the common eye drops hydrolyzes easily. The main product of the hydrolysis is glycol. Here, the chloramphenicol was trapped into the oil-in-water (o/w) microemulsions free of alcohols. Its stability was investigated by the high performance liquid chromatography (HPLC) assays in the accelerated experiments of 3 months. The location of the chloramphenicol molecules in the microemulsion formulations was determined by means of dynamic light scattering (DLS) and 1H NMR spectroscopy. The results of HPLC revealed that the content of the glycols in the microemulsion formulation was much lower than that in the commercial eye drops at the end of the accelerated experiments. It implied that the stability of the chloramphenicol in the microemulsion formulations was increased remarkably. The results of DLS and NMR confirmed that the chloramphenicol molecules should be trapped into the hydrophilic shells of the microemulsion drops, which were composed of many oxyethylene groups. The benzene rings of the chloramphenicol molecules were near the group of alpha2-CH2 and the oxyethylene groups of the surfactant molecules. It was this reason that enabled the chloramphenicol molecules in the microemulsions to be screened from the bulk water and its stability to be increased remarkably.

Phase behavior of the microemulsions and the stability of the chloramphenicol in the microemulsion-based ocular drug delivery system.

Microemulsion systems composed of Span20/80+Tween20/80+n-butanol+H2O+isopropyl palmitate (IPP)/isopropyl myristate (IPM) were investigated as model systems of drug carriers for eye drops. Effects of chloramphenicol, normal saline, sodium hyaluronate and various oils on the phase behavior were studied. The phase transition was investigated by the electrical conductivity measurements. The electrical conductivity of the microemulsion was affected by the encapsulation of the drug into the system, and the addition of normal saline and sodium hyaluronate. The chloramphenicol is used to treat the diseases such as trachoma and keratitis. However, this drug in the common eye drops hydrolyzes easily. The main product of the hydrolysis is glycols. Here, the chloramphenicol was trapped into the oil-in-water (o/w) microemulsions and its stability was investigated by the high performance liquid chromatography (HPLC) assays in the accelerated experiments of 3 months. Its location in the microemulsion formulations was determined by means of 1H NMR spectroscopy. The results of HPLC revealed that the contents of the glycols in the microemulsion formulations were much lower than that in the commercial eye drops at the end of the accelerated experiments. It implied that the stability of the chloramphenicol in the microemulsion formulations was increased remarkably. The NMR experiments confirmed that the chloramphenicol molecules should be trapped into the hydrophilic shells of the microemulsion drops, which was composed of many oxyethylene groups. The nitro-groups of the chloramphenicol molecules were near the alpha2-CH2 of the surfactant molecules and the benzene rings of the chloramphenicol molecules were near the oxyethylene groups of the surfactant molecules. It was this reason that enabled the chloramphenicol molecules in the microemulsions to be screened from the bulk water and its stability to be increased remarkably.