Mendelian randomization and transcriptome analysis identified immune-related biomarkers for osteoarthritis.

Background: The immune microenvironment assumes a significant role in the pathogenesis of osteoarthritis (OA). However, the current biomarkers for the diagnosis and treatment of OA are not satisfactory. Our study aims to identify new OA immune-related biomarkers to direct the prevention and treatment of OA using multi-omics data. Methods: The discovery dataset integrated the GSE89408 and GSE143514 datasets to identify biomarkers that were significantly associated with the OA immune microenvironment through multiple machine learning methods and weighted gene co-expression network analysis (WGCNA). The identified signature genes were confirmed using two independent validation datasets. We also performed a two-sample mendelian randomization (MR) study to generate causal relationships between biomarkers and OA using OA genome-wide association study (GWAS) summary data (cases n = 24,955, controls n = 378,169). Inverse-variance weighting (IVW) method was used as the main method of causal estimates. Sensitivity analyses were performed to assess the robustness and reliability of the IVW results. Results: Three signature genes (FCER1G, HLA-DMB, and HHLA-DPA1) associated with the OA immune microenvironment were identified as having good diagnostic performances, which can be used as biomarkers. MR results showed increased levels of FCER1G (OR = 1.118, 95% CI 1.031-1.212, P = 0.041), HLA-DMB (OR = 1.057, 95% CI 1.045 -1.069, P = 1.11E-21) and HLA-DPA1 (OR = 1.030, 95% CI 1.005-1.056, P = 0.017) were causally and positively associated with the risk of developing OA. Conclusion: The present study identified the 3 potential immune-related biomarkers for OA, providing new perspectives for the prevention and treatment of OA. The MR study provides genetic support for the causal effects of the 3 biomarkers with OA and may provide new insights into the molecular mechanisms leading to the development of OA.

Prediction of cervical lymph node metastasis in solitary papillary thyroid carcinoma based on ultrasound radiomics analysis.

Objective: To assess the utility of predictive models using ultrasound radiomic features to predict cervical lymph node metastasis (CLNM) in solitary papillary thyroid carcinoma (PTC) patients. Methods: A total of 570 PTC patients were included (456 patients in the training set and 114 in the testing set). Pyradiomics was employed to extract radiomic features from preoperative ultrasound images. After dimensionality reduction and meticulous selection, we developed radiomics models using various machine learning algorithms. Univariate and multivariate logistic regressions were conducted to identify independent risk factors for CLNM. We established clinical models using these risk factors. Finally, we integrated radiomic and clinical models to create a combined nomogram. We plotted ROC curves to assess diagnostic performance and used calibration curves to evaluate alignment between predicted and observed probabilities. Results: A total of 1561 radiomics features were extracted from preoperative ultrasound images. After dimensionality reduction and feature selection, 16 radiomics features were identified. Among radiomics models, the logistic regression (LR) model exhibited higher predictive efficiency. Univariate and multivariate logistic regression results revealed that patient age, tumor size, gender, suspicious cervical lymph node metastasis, and capsule contact were independent predictors of CLNM (all P < 0.05). By constructing a clinical model, the LR model demonstrated favorable diagnostic performance. The combined model showed superior diagnostic efficacy, with an AUC of 0.758 (95% CI: 0.712-0.803) in the training set and 0.759 (95% CI: 0.669-0.849) in the testing set. In the training dataset, the AUC value of the nomogram was higher than that of the clinical and radiomics models (P = 0.027 and 0.002, respectively). In the testing dataset, the AUC value of the nomogram model was also greater than that of the radiomics models (P = 0.012). However, there was no significant statistical difference between the nomogram and the clinical model (P = 0.928). The calibration curve indicated a good fit of the combined model. Conclusion: Ultrasound radiomics technology offers a quantitative and objective method for predicting CLNM in PTC patients. Nonetheless, the clinical indicators persists as irreplaceable.

[Spatial and Temporal Evolution and Impact Factors Analysis of Ecosystem Service Value in the Liaohe River Delta over the Past 30 Years].

An in-depth study of the spatiotemporal variation characteristics and driving factors of ecosystem service values in the Liaohe River Delta is of great significance to its ecological environment governance and protection. Based on the land use data of the Liaohe River Delta for seven periods from 1990 to 2020, the ecosystem service value (ESV) was evaluated according to the equivalent factor coefficient correction method, establishing models for estimating the value of ecosystem services; the spatial and temporal evolution characteristics of the ESV in the study area were comprehensively analyzed; and the driving influencing factors and mechanisms of the ESV were explored. The results showed that:① From 1990 to 2020, the most common land use type in the Liaohe River Delta was cultivated land, and the areas of forest land, wetland, and unutilized land showed a decreasing trend; grassland, water, and construction land showed an increasing trend; and the area of cultivated land was basically unchanged during the 30 year period. ② In terms of the temporal evolution, the ESV in the study area showed a trend of first decreasing, then increasing, and then decreasing. In terms of the spatial distribution of ESV, the total value of ecosystem services as a whole showed a spatial divergence pattern of a high value in the southwest and low value in the northeast. ③ The sensitivity index of all land use types in the Liaohe River Delta was less than 1, indicating that the ESV was inelastic. ④ The value of ecosystem services in the Liaohe River Delta showed positive spatial coherence. On the whole, the Liaohe River Delta was dominated by HH and LL clusters, with HL clusters mostly distributed at the boundaries of LL clusters and LH clusters distributed at the boundaries of HH clusters. ⑤ Among the factors influencing the evolution of ESV in the Liaohe River Delta, DEM had the least influence, and HAI had the greatest influence on the ESV, followed by precipitation. The interaction results of all influencing factors had an enhancing effect on the spatial distribution of the ESV, among which HAI and precipitation had the strongest interaction effect, reaching 95.58%.

ß-sitosterol alleviates dextran sulfate sodium-induced experimental colitis via inhibition of NLRP3/Caspase-1/GSDMD-mediated pyroptosis.

Background: Inflammation-related NLRP3/Caspase-1/GSDMD-mediated pyroptosis is involved in the progression of ulcerative colitis (UC). ß-sitosterol (SIT) was reported to have anti-inflammatory effects on experimental colitis, while the regulation of SIT on pyroptosis is unclear. Therefore, the present study aimed to define the protective and healing effects of SIT on dextran sulfate sodium (DSS)-induced experimental UC rats and human epithelial colorectal adenocarcinoma cells (Caco-2) and explore the underlying mechanisms that are responsible for its effects on NLRP3/Caspase-1/GSDMD-mediated pyroptosis in UC. Methods: UC model rats were established by oral 4% DSS. Following colitis injury, the animals received SIT (doses of 50, 100, and 200 mg/kg) treatment for 2 weeks. For in vitro study, we exposed Caco-2-50 mg/mL DSS with or without SIT (concentrations of 8 and 16 µg/mL). Disease activity index (DAI) and histopathological injury were assessed in vivo. Activation proteins of nuclear factor kappa B (NF-κB) signaling axis, and tight junction-related proteins of zonula occludens-1 (ZO-1) and occludin were detected in colon tissues. TNF-α, IL-1ß, and IL-18 in serum and cell supernatant were measured by enzyme-linked immunosorbent assay (ELISA). Changes in NLRP3/Caspase-1/GSDMD-mediated pyroptosis signaling pathway activation were analyzed both in tissues and cells. Results: Our findings suggested that SIT treatment attenuated the severity of 4% DSS-induced UC by protecting rats from weight and colon length loss, and macroscopic damage. SIT also reduced proinflammatory factors production (TNF-α, IL-1ß, and IL-18) in serum and cell supernatant. Mechanistically, SIT downregulated the expression levels of pyroptosis-related proteins including Caspase-1, cleaved-Caspase-1, NLRP3, GSDMD, and GSDMD-N in colon tissues and Caco-2 cells. Further analysis indicated that SIT maintained the colonic barrier integrity by enhancing the protein expression of ZO-1 and occludin. Conclusion: We confirmed that SIT exerts protective and therapeutic effects on DSS-induced colitis injury by suppressing NLRP3/Caspase-1/GSDMD-mediated pyroptosis and inflammation response. These findings demonstrated that SIT could be a potential medication for UC treatment.

A Mendelian randomization study for drug repurposing reveals bezafibrate and fenofibric acid as potential osteoporosis treatments.

Background: Lipid pathways have been implicated in the pathogenesis of osteoporosis (OP). Lipid-lowering drugs may be used to prevent and treat OP. However, the causal interpretation of results from traditional observational designs is controversial by confounding. We aimed to investigate the causal association between genetically proxied lipid-lowering drugs and OP risk. Methods: We conducted two-step Mendelian randomization (MR) analyses to investigate the causal association of genetically proxied lipid-lowering drugs on the risk of OP. The first step MR was used to estimate the associations of drug target genes expression with low-density lipoprotein cholesterol (LDL-C) levels. The significant SNPs in the first step MR were used as instrumental variables in the second step MR to estimate the associations of LDL-C levels with forearm bone mineral density (FA-BMD), femoral neck BMD (FN-BMD), lumbar spine BMD (LS-BMD) and fracture. The significant lipid-lowering drugs after MR analyses were further evaluated for their effects on bone mineralization using a dexamethasone-induced OP zebrafish model. Results: The first step MR analysis found that the higher expression of four genes (HMGCR, NPC1L1, PCSK9 and PPARG) was significantly associated with a lower LDL-C level. The genetically decreased LDL-C level mediated by the PPARG was significantly associated with increased FN-BMD (BETA = -1.38, p = 0.001) and LS-BMD (BETA = -2.07, p = 3.35 × 10-5) and was marginally significantly associated with FA-BMD (BETA = -2.36, p = 0.008) and reduced fracture risk (OR = 3.47, p = 0.008). Bezafibrate (BZF) and Fenofibric acid (FBA) act as PPARG agonists. Therefore genetically proxied BZF and FBA had significant protective effects on OP. The dexamethasone-induced OP zebrafish treated with BZF and FBA showed increased bone mineralization area and integrated optical density (IOD) with alizarin red staining. Conclusion: The present study provided evidence that BZF and FBA can increase BMD, suggesting their potential effects in preventing and treating OP. These findings potentially pave the way for future studies that may allow personalized selection of lipid-lowering drugs for those at risk of OP.

Design, Synthesis, and Biological Activity of a Novel Series of 2-Ureidonicotinamide Derivatives Against Influenza A Virus.

BACKGROUND: Viral resistance to existing inhibitors and the time-dependent effectiveness of neuraminidase inhibitors have limited the number of antivirals that can be used for prophylaxis and therapeutic treatment of severe influenza infection. Thus, there is an urgent need to develop new drugs to prevent and treat influenza infection. OBJECTIVE: The aims of this study was to design and synthesize a novel series of 2-ureidonicotinamide derivatives and evaluate their anti-IAV activities. Furthermore, we predicted the abilities of these compounds to inhibit the PA-PB1 subunit and forecasted the docking poses of these compounds with RNA polymerase protein (PDB ID 3CM8). METHODS: The novel designed compounds were synthesized using classical methods of organic chemistry and tested in vitro for their abilities inhibiting RNP and against influenza A virus. In addition, the 23 synthesized molecules were subjected to the generated pharmacophore Hypo1 to forecast the activity target PA-PB1 subunit of RNA polymerase. The ADMET pharmacokinetic parameters were calculated by the ADMET modules in Discovery Studio 2016. The docking results helped us demonstrate the possible interactions between these compounds with 3CM8. RESULTS: The synthesized 2-ureidonicotinamide derivatives were characterized as potent anti-influenza inhibitors. The target compounds 7b and 7c demonstrated significant antiviral activities and could be considered as novel lead compounds of antiviral inhibitors. In addition, compound 7b revealed suitable ADME properties expressed and might be a significant RNA polymerase inhibitor targeting the PA-PB1 subunit based on the predictable results and the docking results. CONCLUSION: This study revealed a novel series of compounds that might be useful in the search for an effective drug against the influenza virus.

Urinary levels of dimethoate, bisphenol A and benzo[a]pyrene in first-year students of Hohai University from different geographical regions.

BACKGROUND: The objective of this study was to detect the urinary levels of dimethoate, benzo(a) pyrene (BaP), and bisphenol A (BPA) in first-year Hohai University students with different geographic origins. METHODS: First-morning urine samples were collected from 540 healthy freshmen aged 17 to 19 years. Chemical levels were measured using ß-glucuronidase hydrolysis followed by a high-performance liquid chromatography-tandem mass spectrometry-based method. Geometric means (GMs) of these three chemicals are presented by body mass index (BMI) and location in a volume-based and creatinine-standardized way. RESULTS: GM concentrations of omethoate, BPA and 3-OHBaP were 9.47 µg/L (10.80 µg/g creatinine), 3.54 µg/L (4.04 µg/g creatinine) and 0.34 ng/L (0.39 ng/g creatinine), respectively. The GM concentration of omethoate in males was significantly higher than that in females. The individuals with a BMI higher than 23.9 had higher GM concentrations of omethoate, BPA, and 3-OHBaP. The inhabitants of Southwest China had significantly lower GM concentrations of omethoate, BPA, and 3-OHBaP than those who lived in other locations in China. CONCLUSION: The average level of environmental chemical accumulation in freshmen is lower in Southwest China and differs in youth who live in different regions. In addition, obesity is correlated with higher toxin levels in youth.

SARS-CoV-2 infection in infants under 1 year of age in Wuhan City, China.

BACKGROUND: The clinical characteristics and outcome of COVID-19 in children are different from those in adults. We aimed to describe the characteristics of infants under 1 year of age (excluding newborns) with COVID-19. METHODS: We retrospectively retrieved data of 36 infants with SARS-CoV-2 infection in Wuhan Children's Hospital from January 26 to March 22, 2020. Clinical features, chest imaging findings, laboratory tests results, treatments and clinical outcomes were analyzed. RESULTS: The mean age of the infected infants was 6.43 months, with a range of 2-12 months. 61.11% of the patients were males and 38.89% females. 86.11% of the infants were infected due to family clustering. Cough (77.78%) and fever (47.22%) were the most common clinical manifestations. Chest CT scan revealed 61.11% bilateral pneumonia and 36.11% unilateral pneumonia. 47.22% of the infants developed complications. Increased leucocytes, neutrophils, lymphocytes, and thrombocytes were observed in 11.11, 8.33, 36.11 and 44.44% of infants, respectively. Decreased leucocytes, neutrophils, thrombocyte and hemoglobin were observed in 8.33, 19.44, 2.78 and 36.11% of infants, respectively. Increased C-reactive protein, procalcitonin, lactate dehydrogenase, alanine aminotransferase, creatine kinase and D-dimer were observed in 19.44, 67.74, 47.22, 19.44, 22.22 and 20.69% of infants, respectively. Only one infant had a high level of creatinine. Co-infections with other respiratory pathogens were observed in 62.86% of infants. CD3 (20.69%), CD4 (68.97%), CD19 (31.03%) and Th/Ts (44.83%) were elevated; CD8 (6.9%) and CD16+CD56 (48.28%) was reduced. IL-4 (7.69%), IL-6 (19.23%), IL-10 (50%), TNF-α (11.54%) and IFN-γ (19.23%) were elevated. Up to March 22, 97.22% of infants recovered, while a critical ill infant died. When the infant's condition deteriorates rapidly, lymphocytopenia was discovered. Meanwhile, C-reactive protein, D-dimer, alanine aminotransferase, creatine kinase, creatinine, IL-6 and IL-10 increased significantly. CONCLUSIONS: In the cohort, we discovered that lymphocytosis, elevated CD4 and IL-10, and co-infections were common in infants with COVID-19, which were different from adults with COVID-19. Most infants with COVID-19 have mild clinical symptoms and good prognosis.

[Analysis and evaluation of dynamic accumulation of multiple bioactive constituents in Spatholobi Caulis].

A method was established for simultaneous determination of 21 active constituents including flavanols, isoflavones, flavonols, dihydroflavones, dihydroflavonols, chalcones, pterocarpan, anthocyanidins and phenolic acids in Spatholobi Caulis by ultra fast liquid chromatography with triple quadrupole linear ion trap mass spectrometry(UFLC-QTRAP-MS/MS). Then, it was employed to analyze and evaluate the dynamic accumulation of multiple bioactive constituents in Spatholobi Caulis. The chromatographic separation was performed on a XBridge®C_(18)(4.6 mm×100 mm, 3.5 µm) at 30 ℃ with a gradient elution of 0.3% formic acid aqueous solution-methanol, and the flow rate was 0.8 mL·min~(-1), using multiple-reaction monitoring(MRM) mode. A comprehensive evaluation of the multiple bioactive constituents was carried out by gray correlation analysis(GRA). The 21 target components showed good linearity(r>0.999 0) in the range of the tested concentrations. The average recovery rates of the 21 components were from 97.46% to 103.6% with relative standard deviations less than 5.0%. There were differences in the contents of 21 components in Spatholobi Caulis at diffe-rent harvest periods. Spatholobi Caulis had high quality from early November to early December, which is consistent with the local tradi-tional harvest period. This study reveals the rule of the dynamic accumulation of 21 components in Spatholobi Caulis and provides basic information for the suitable harvest time. At the same time, it provides a new method reference for the comprehensive evaluation of the internal quality of Spatholobi Caulis.

Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study.

BACKGROUND: An outbreak of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was first detected in Wuhan, Hubei, China. People of all ages are susceptible to SARS-CoV-2 infection. No information on severe pediatric patients with COVID-19 has been reported. We aimed to describe the clinical features of severe pediatric patients with COVID-19. METHODS: We included eight severe or critically ill patients with COVID-19 who were treated at the Intensive Care Unit (ICU), Wuhan Children's Hospital from January 24 to February 24. We collected information including demographic data, symptoms, imaging data, laboratory findings, treatments and clinical outcomes of the patients with severe COVID-19. RESULTS: The onset age of the eight patients ranged from 2 months to 15 years; six were boys. The most common symptoms were polypnea (8/8), followed by fever (6/8) and cough (6/8). Chest imaging showed multiple patch-like shadows in seven patients and ground-glass opacity in six. Laboratory findings revealed normal or increased whole blood counts (7/8), increased C-reactive protein, procalcitonin and lactate dehydrogenase (6/8), and abnormal liver function (4/8). Other findings included decreased CD16 + CD56 (4/8) and Th/Ts*(1/8), increased CD3 (2/8), CD4 (4/8) and CD8 (1/8), IL-6 (2/8), IL-10 (5/8) and IFN-γ (2/8). Treatment modalities were focused on symptomatic and respiratory support. Two critically ill patients underwent invasive mechanical ventilation. Up to February 24, 2020, three patients remained under treatment in ICU, the other five recovered and were discharged home. CONCLUSIONS: In this series of severe pediatric patients in Wuhan, polypnea was the most common symptom, followed by fever and cough. Common imaging changes included multiple patch-like shadows and ground-glass opacity; and a cytokine storm was found in these patients, which appeared more serious in critically ill patients.

Methodological and reporting quality evaluation of systematic reviews on acupuncture in women with polycystic ovarian syndrome: A systematic review.

PURPOSE: To evaluate the methodological and reporting quality of systematic reviews (SRs) on acupuncture treatment for women with polycystic ovarian syndrome (PCOS). METHODS: A comprehensive search on multiple databases was performed. Methodological and reporting quality of reviews were assessed by revised assessment of multiple systematic reviews (AMSTAR 2) and preferred reporting items for SRs and meta-analyses (PRISMA), respectively. RESULTS: Ten SRs were included. Among the SRs using AMSTAR 2, two achieved a good overall rating (percentage of items with "yes" > 50%) and severe limitation existed in eleven items (percentage of items with "yes" < 50%). Among the SRs using PRISMA, six reviews achieved a good overall rating (percentage of items with "yes" > 50%), while twelve items were poorly reported (percentage of items with "yes" < 50%). CONCLUSION: There were many deficiencies in the methodological and reporting quality of SRs assessing acupuncture in women with PCOS.

[Efficacy of analgesic and sedative treatments in children with mechanical ventilation in the pediatric intensive care unit].

OBJECTIVE: To compare the efficacy and safety of different analgesic and sedative treatments in children with mechanical ventilation in the pediatric intensive care unit (PICU). METHODS: Eighty children with mechanical ventilation in the PICU who needed analgesic and sedative treatments were equally and randomly divided into midazolam group and remifentanil+midazolam group. The sedative and analgesic effects were assessed using the Ramsay Scale and the Face, Legs, Activity, Cry and Consolability (FLACC) Scale. The following indices were recorded for the two groups: vital signs, ventilator parameters, organ function, total doses of remifentanil and midazolam, duration of mechanical ventilation, length of PICU stay, PICU cost, and incidence of adverse events. RESULTS: Satisfactory sedation was achieved in the two groups, but the remifentanil+midazolam group had a significantly shorter time to analgesia and sedation than the midazolam group. The remifentanil+midazolam group had a significantly higher percentage of patients with grade 3-4 on the Ramsay Scale and a significantly lower dose of midazolam than the midazolam group (P<0.05). Both groups showed decreases in heart rate (HR), mean arterial pressure (MAP), and spontaneous breathing frequency (RRs) after treatment. However, the remifentanil+midazolam group had significantly greater decreases in HR at 3-24 hours after treatment and MAP and RRs at 3-12 hours after treatment than the midazolam group (P<0.05). Compared with the midazolam group, the remifentanil+midazolam group had significantly higher ventilator tidal volume and transcutaneous oxygen saturation at 6 and 12 hours after treatment and significantly lower end-tidal carbon dioxide partial pressure at 6 and 12 hours after treatment (P<0.05). The remifentanil+midazolam group had significantly shorter time to awake, extubation time, duration of mechanical ventilation, and length of PICU stay than the midazolam group (P<0.05). There were no significant differences in PICU cost, incidence of adverse events, and hepatic and renal functions before and after treatment between the two groups (P>0.05). Both groups showed a significant decrease in fasting blood glucose level after treatment (P<0.05). CONCLUSIONS: For children with mechanical ventilation in the PICU, remifentanil+midazolam treatment can rapidly achieve analgesia and sedation, improve the effect of mechanical ventilation, and reduce the dose of sedative compared with midazolam alone, and is well tolerated.

Involvement of PPARs in the regulation of brain CYP2D by growth hormone / 中国药理学与毒理学杂志

OBJECTIVE CYP2D is one of the most abundant subfamily of CYPs in the brain, especially in the cerebellum. Brain CYP2D is responsible for the metabolism of endogenous neurotransmitters such as tyramine and serotonin. Our previous studies have shown brain CYP2D can be regulated by exogenous and endogenous substances with tissue- specificity. The purpose of this study is to examine the effects of cerebral CYP2D on the mice behavior and the regulatory mechanism of brain CYP2D by growth hormone. METHODS Mice received the stereotaxic injection with CYP2D inhibitor quinine in deep cerebellar nuclei of cerebellum. The animals were tested with rotarod apparatus, balance beam, water maze, elevated plus maze and open field. The changes in CYP2D22, PPARαand PPARγ in brain regions and liver were assayed in male growth hormone receptor knockout mice, SH-SY5Y cells and HepG2 cells. RESULTS The inhibition of cerebellum CYP2D significantly affected the spatial learning and exploring ability of mice. Compared with WT mice, CYP2D expression was lower in brain regions from GHR(-/- ) male mice; however, hepatic CYP2D level was similar. Pulsatile GH decreased PPARα mRNA level, and increased mRNA levels of CYP2D6 and PPARα in SH- SY5Y cells. In HepG2 cells, pulsatile GH resulted in decreases in PPARα and PPARγ mRNA levels, but not CYP2D6. PPARα inhibitor induced CYP2D6 mRNA and protein by 1.32-fold and 1.43-fold in SH-SY5Y cells. PPARγ inhibitor decreased CYP2D6 mRNA and protein by 74.76% and 40.93%. PPARα agonist decreased the level of CYP2D22 mRNA in liver and cerebellum, while PPARγ agonist rosiglitazone resulted in diametrically increases. The luciferase assay showed that PPARγ actived the CYP2D6 gene promoter while PPARα inhibited its function. Pulsatile GH declined the binding of PPARα with CYP2D6 promoter by 40%, promoted the binding of PPARγ with CYP2D6 promoter by approximate 60%. The levels of brain and liver PPARα expression in male GHR(-/- ) mice is obviously higher than those in WT mice. The level of PPARγ in male GHR(-/- ) mice was decreased in the frontal cortex and hippocampus, while remained stable in the cerebellum and striatum; meanwhile, PPARγ was increased in the liver. CONCLUSION Brain CYP2D may be involved in learning and memory functions of central system. Masculine GH secretion altered the PPARs expression and the binding of PPARs to CYP2D promoter, leading to the elevated brain CYP2D in a tissue- specific manner. Growth hormone may specifically alter the metabolic and synthetic of important endogenous substances in the central nervous system (such as serotonin) through the specific regulation of brain CYP2D expression.

Comprehensive assessment of the association of WNK4 polymorphisms with hypertension: evidence from a meta-analysis.

The relationship between with-no-lysine [K] kinase 4 (WNK4) gene polymorphisms and hypertension has been widely investigated, However, the studies yielded contradictory results. To evaluate these inconclusive findings comprehensively, we therefore performed a meta-analysis. Ten articles encompassing 16 independent case-control studies with 6089 hypertensive cases and 4881 normotensive controls were selected for this meta-analysis. Four WNK4 gene polymorphisms were identified (G1155942T, G1156666A, T1155547C, and C6749T). The results showed statistically significant associations of G1155942T polymorphism (allelic genetic model: odds ration or OR = 1.62, 95% confidence interval or CI: 1.11-2.38, P = 0.01; dominant model: OR = 1.85, 95% CI: 1.07-3.19, P = 0.03) and C6749T polymorphism (allele contrast: OR = 2.04, 95% CI: 1.60-2.59, P<0.01; dominant model: OR = 2.04, 95%CI: 1.59-2.62, P<0.01; and homozygous model: OR = 5.01, 95% CI: 1.29-19.54, P = 0.02) with hypertension risk. However, neither C1155547T nor G1156666A was associated significantly with hypertension susceptibility. In conclusion, this meta-analysis suggested that WNK4 G1155942T and C6749T gene polymorphisms may contribute to the susceptibility and development of hypertension. Further well-designed studies with larger sample size are required to elucidate the association of WNK4 gene multiple polymorphisms with hypertension risk.

Estrogen receptor α gene PvuII polymorphism and coronary artery disease: a meta-analysis of 21 studies.

The association between the estrogen receptor α gene (ESR1) PvuII polymorphism (c.454-397T>C) and coronary artery disease (CAD) is controversial. Thus, we conducted a meta-analysis to evaluate the relationship. Data were collected from 21 studies encompassing 9926 CAD patients and 16710 controls. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the relationship between PvuII polymorphism and CAD. The polymorphism in control populations in all studies followed Hardy-Weinberg equilibrium. We found a significant association between ESR1 PvuII polymorphism and CAD risk in all subjects. When the data were stratified by region, a significant association between ESR1 PvuII polymorphism and CAD risk was observed in Asian populations but not in Western populations. The current study suggests that ESR1 PvuII polymorphism has an important role in CAD susceptibility.

Interleukin-1 beta increases activity of human endothelial progenitor cells: involvement of PI3K-Akt signaling pathway.

Interleukin-1ß (IL-1ß) is a multifunctional proinflammatory cytokine upregulated in acute phase of heart ischemic disease. Controversial effects of IL-1ß have been demonstrated on endothelial progenitor cells (EPCs) functional activity. The aim of this study was to investigate the in vitro effect of IL-1ß on activity of human origin EPCs and the possible mechanism involved. EPCs were isolated from peripheral blood of healthy volunteers without cardiovascular risk factors and characterized. After ex vivo cultivation, EPCs were stimulated with a series of final concentrations (0, 0.1, 1, and 10 ng/ml) of IL-1ß for 24 h. In some other experiments, EPCs were pretreated with 10 µM LY294002 (Akt inhibitor) for 30 min and then stimulated with 1 ng/ml IL-1ß for 24 h. Cell proliferation, apoptosis, adhesion, and migration were determined, respectively, by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, annexin V/propidium iodide binding assay, adhesion assay, and transwell migration assay. In addition, the vascular endothelial vascular growth factor-A (VEGF-A) production has been examined using quantitative real-time RT-PCR and ELISA assay. Furthermore, the total and phosphorylation level of Akt was determined by Western blot. IL-1ß significantly stimulated EPC proliferation, migration, and adhesion and upregulated the angiogenic growth factor VEGF-A at mRNA and protein level, while exerted no influence on cell apoptosis. However, pretreatment with LY294002 significantly diminished IL-1ß-induced proliferation, migration, adhesion, and VEGF-A production. One nanogram per milliliter IL-1ß for 15 min activated phosphorylation of Akt. These results suggest a potent role for IL-1ß in upregulating EPCs functions. The phosphatidyl-inositol-3-kinase-Akt signaling pathway could be involved in the regulation of EPCs functions induced by IL-1ß.

[Study on the efficiency of the European System for Cardiac Operative Risk Evaluation (EuroSCORE) in predicting in-hospital mortality of the patients with percutaneous coronary intervention].

OBJECTIVE: To investigate the efficiency of European System for Cardiac Operative Risk Evaluation (EuroSCORE) in predicting in-hospital mortality for the patients after percutaneous coronary intervention (PCI). METHODS: Retrospective analysis was conducted on the patients who had undergone PCI in our hospital since year 2005 to 2007. We used both cumulative EuroSCORE score and logistic EuroSCORE to predict the in-hospital morality and to analyze the correlation between the predicted mortality and the actual mortality. RESULTS: According to the additive EuroSCORE, we divided the patients into three groups, the additive EuroSCORE 0-2 were divided into low-risk group, 3-5 were divided into mid-risk group and ≥ 6 into high-risk group. The actual in-hospital mortality rates were 0%, 0.47% and 6.09% respectively. The EuroSCORE model demonstrated an overall relation between the EuroSCORE ranking and the incidence of in-hospital mortality (P<0.001). Results from the multivariable logistic regression analysis showed that the EuroSCORE was an independent in-hospital mortality predictor (P<0.01). CONCLUSION: The EuroSCORE risk model and the in-hospital mortality were significantly correlated, indicating that the model was a promising method for predicting the in-hospital mortality of PCI patients.

Systemic evaluation of platelet and leukocyte activation and interaction in a rat model of pulmonary arterial hypertension.

OBJECTIVES: Thrombosis and inflammation are associated with the pathogenesis of pulmonary arterial hypertension (PAH). However, there are no solid data supporting the involvement of platelet and leukocyte activation and interaction in PAH. The present study thus investigated the activation and interaction of circulating platelets and leukocytes in a rat model of monocrotaline (MCT)-induced pulmonary hypertension. METHODS: Mean pulmonary arterial pressure (mPAP) was monitored in rats (n = 24) before and 2, 3 and 7 weeks after MCT (60 mg/kg)injection. In parallel, activation of circulating platelets and leukocytes and platelet-leukocyte aggregates were measured by whole-blood flow cytometry. RESULTS: Two weeks after MCT injection, mPAP had increased significantly, i.e. from 11.25 ± 0.92 mm Hg at baseline to 15.71 ± 1.66 mm Hg (p < 0.05), and it had increased even further at week 7 (26.83 ± 3.29 mm Hg; p < 0.01). Fibrinogen binding of circulating platelets had increased from the basal level of 1.45 ± 0.61 to 4.08 ± 1.59% 3 weeks after MCT injection (p < 0.01). Platelet responsiveness to ADP was also significantly enhanced. CD11b expression of circulating neutrophils was elevated; i.e. mean fluorescence intensity increased from 1.67 ± 0.38 before MCT injection to 2.37 ± 0.31 3 weeks after MCT injection (p < 0.01), and N-formyl-methionyl-leucyl-phenylalanine (1 × 10⁻7M) stimulation induced more marked elevation of neutrophil CD11b expression in MCT-treated animals. Circulating platelet-neutrophil aggregates were already increased 2 weeks after MCT treatment (14.93 ± 4.22%; p < 0.01) compared to baseline (6.01 ± 2.91%) and remained elevated at 3 weeks (15.19 ± 4.78%; p < 0.01). CONCLUSIONS: MCT-induced PAH in rats is associated with increased platelet and leukocyte activation and platelet-leukocyte interaction in vivo, which may play an important role in the pathogenesis of PAH.

[The self intensification of the pure spectrum in the mixed spectrum].

In the present paper, the influence of the pure spectrum contained in the mixed spectrum was centralized at the origin, and in this way, the influence of the pure spectrum in the result curve reached the maximum value. This process is called the self intensification of the pure spectrum. Farther, considering that the center of the Gaussian function contained in the impure spectrum is much different from that of the pure spectrum, it can be accepted that the influence of the impure spectrum at the origin is approximately the minimum. So the origin was chosen as the analysis point when the authors perform the quantitative analysis according to the spectrum. Therefore we can reduce the subjectivity in choosing the analysis point. In addition, the wavelet coefficients of the result curve at the origin were used for the quantitative analysis. According to the simulated experiment, it was found that the final result is independent of the Gaussian white noise contained in the actual spectrum. Finally, the analytic result of the new method was compared with that of the method reported in the literature, which proved that the new method is much better in terms of the analytic error.