[Association between depression and chronic diseases among middle-aged and older Chinese adults].

OBJECTIVE: To examine the association between depressive symptoms and chronic diseases among middle-aged and older Chinese adults within a national investigation. METHODS: Data used in current analysis were obtained from a nationally representative, cross-sectional population-based survey of China health and retirement longitudinal study, which were conducted in 2011 using four-stage probability-proportional-to-size sampling methods. A total of 10 420 participants who were aged 45 years and above from 28 provinces in mainland China were included. Information on demographic characteristics (e.g., age, gender, education level), lifestyle factors (e.g., smoking status and drinking frequency) and chronic diseases (e.g., hypertension, diabetes, and stroke) were collected by well-trained interviewers at the interviewees' homes using a standardized questionnaire. Depressive symptoms were measured using the 10-item version of the center for epidemiological studies depression scale (CESD-10, which was a widely used standard tool in Chinese population, and elevated depressive symptoms were defined by a cut-off ≥10. Multivariate Logistic regression analysis was carried out to assess the association between depressive symptoms and chronic diseases (including hypertension, diabetes, heart disease, dyslipidemia and stroke), adjusting for age, gender, education level, marital status, ethnicity, place of residence, bady mass index (BMI) and other potential confounding factors. RESULTS: Among the 10 420 participants, the mean age was (59.2±9.4) years, and 48.2% of them were men. There were 3 900 (37.4%) participants who had a depression rating score of 10 or greater, indicative of elevated depressive symptoms. The results of multivariate Logistic regression analysis demonstrated that diabetes (OR=1.230, 95%CI: 1.080-1.401), hypertension (OR=1.335, 95%CI: 1.205-1.480), heart disease (OR=1.953, 95%CI: 1.711-2.229), and stroke (OR=2.269, 95%CI: 1.704-3.020) were significantly associated with depressive symptoms (P < 0.05), after full adjustment of age, gender, education level, marital status, ethnicity, residency and other potential confounders. While no significant relationship was found between dyslipidemia and depressive symptoms (P>0.05). The prevalence of elevated depressive symptoms increased parallel with the number of chronic diseases (Ptrend < 0.001). CONCLUSION: Depressive symptoms were significantly associated with chronic diseases (including diabetes, hypertension, heart disease, and stroke), which suggests that psychological factors, such as depressive symptoms should be taken into consideration in the prevention and control of chronic diseases.

MiR-92a contributes to the cardiovascular disease development in diabetes mellitus through NF-κB and downstream inflammatory pathways.

OBJECTIVE: To explore the role of microRNA-92a (miR-92a) during the development of cardiovascular disease (CAD) in diabetes mellitus (DM) patients, and to investigate its correlation with NF-κB and downstream inflammatory cytokines in diabetes mellitus-associated cardiovascular disease (DM-CAD). PATIENTS AND METHODS: Expression of miR-92a in DM and DM-CAD patients was estimated by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Receiver operating characteristic (ROC) analysis was used to estimate the capability of miR-92a to discriminate between DM-CAD and DM patients. Nuclear factor-κB (NF-κB) p65 protein expression and serum concentrations of monocyte chemotactic protein-1 (MCP-1), endothelin-1 (ET-1) and intercellular adhesion molecule-1 (ICAM-1) were investigated. Correlations between miR-92a and NF-κB p65, inflammatory factors were assessed. Risk analysis based on miR-92a was performed for DM-CAD patients. RESULTS: MiR-92a expression was increased in DM-CAD group compared with both DM and healthy groups (all p<0.05). The expression of miR-92a was associated with FIB and HbA1c of DM-CAD patients. MiR-92a could be used to distinguish DM-CAD patients from DM patients with an area under the ROC curve (AUC) of 0.866. Moreover, miR-92a was demonstrated to be a risk factor for DM-CAD onset. Expression levels of NF-κB p65, ET-1, MCP-1, and ICAM-1 were all elevated in DM-CAD patients and shown positive correlations with miR-92a. CONCLUSIONS: Expression of miR-92a in DM-CAD patients is up-regulated, and serves as a potential marker to predict the CAD in DM patients. MiR-92a may contribute to the development of CAD through activation of NF-κB and downstream inflammatory pathways.

Pharmacokinetics of once daily prolonged-release formulation of tacrolimus in children with primary nephrotic syndrome.

OBJECTIVE: Tacrolimus prolonged-release(PR) formulation is a new once-daily formulation of the calcineurin inhibitor tacrolimus, which is currently used in adult liver or kidney transplant patients,and is also gradually widely used in children with nephrotic syndrome.The present study was undertaken to preliminarily investigate the pharmacokinetic characteristics of tacrolimus PR in pediatric nephrotic syndrome recipients. METHODS: This single-center open-label prospective study was performed in pediatric nephrotic syndrome recipients. Pharmacokinetic samples were collected from eight pediatric subjects with nephrotic syndrome from Department of Pediatric Nephrology in Peking University First Hospital between June and August 2011. They followed administration of single oral doses of tacrolimus PR formulation at 0.02 mg/kg (n=2), 0.05 mg/kg (n=2) and 0.10 mg/kg (n=4). Blood samples were taken before the dose and 1, 2, 4, 6, 8, 10, 12 and 24 h after drug intake. No other medicines or interacting food or drinks were taken during the study period. Blood concentrations were measured using an enzyme multiplied immunoassay technique. Pharmacokinetic analysis was performed using WinNolin Phoenix software Version 6.0(Pharsight, Cary, NC,USA). RESULTS: The pharmacokinetic data were best described by a non-compartment model. Pharmacokinetic parameters of tacrolimus PR formulation in the 3 ascending doses groups (0.02 mg/kg,0.05 mg/kg and 0.10 mg/kg) were as follows: the maximum drug concentrations (Cmax/D) were (1.7±1.0) µg/L, (3.1±1.9) µg/L, (8.0±3.5) µg/L, respectively; Areas under the drug concentration-time curve(AUC0-∞/D) were (47.2±47.1) h×µg/L, (84.0±13.1) h×µg/L, (175.6±107.1) h×µg/L, respectively; Oral clearance rates were (0.8±0.9) L/(h×kg), (0.4±0.1) L/(h×kg), (1.9±1.3) L/(h×kg), respectively; Body weight normalized distribution volumes were (7.0±3.4) L/kg, (12.4±8.4) L/kg and (73.6±68.6) L/kg, respectively. Both mean Cmax normalized level for the administered dose(Cmax/D) and mean AUC0-∞ normalized level for the administered dose (AUC0-∞/D) were higher in the 0.05 mg/kg dosage group than in the 0.02 and 0.10 mg/kg dosage group. There were two peaks in the drug concentrations in every dose group;a primary peak appeared at the end of about 2 h followed by a small secondary peak at h 12, which was more noticeable in the 0.10 mg/kg dose group than in the two lower dosages. CONCLUSION: The pharmacokinetic characteristics of tacrolimus PR formulation were initially explored in pediatric patients with nephritic syndrome. The data presented form a basis for subsequent larger scale studies on pharmacokinetics of tacrolimus PR formulation in nephritic syndrome children.

The influence of CYP3A5*3 and BCRPC421A genetic polymorphisms on the pharmacokinetics of felodipine in healthy Chinese volunteers.

WHAT IS KNOWN AND OBJECTIVE: The role of CYP3A5 in drug metabolism has been receiving attention because CYP3A5 may be more involved in the metabolism of CYP3A substrates in vivo than previously thought. The polymorphism of transporters, such as P-gp (P-glycoprotein) and breast cancer-related protein (BCRP), influences the metabolism of these substrates, and felodipine is a substrate of P-gp. The aim of this study was to evaluate the pharmacogenetic variability in the disposition of felodipine in healthy Chinese subjects. METHODS: A single dose of 5 mg felodipine was orally administered to 45 healthy Chinese subjects. The serum concentration of felodipine was measured by using LC/MS/MS. We detected the SNPs of cytochromes P450 enzymes and transporters, which play vital roles in drug metabolism and have a high frequency of mutation in Chinese population. RESULTS AND DISCUSSION: The area under the plasma concentration-time curve (AUC) within the time points 0 to 72 h (AUC(0-72) ) after felodipine administration was significantly higher in subjects possessing the BCRP421AA alleles than in those with the BCRP421 CC or CA genotype (P = 0·034). The subjects with CYP3A5*3/*3 (n = 27) had higher felodipine exposure than CYP3A5*1/*3 (n = 15) (P = 0·035). WHAT IS NEW AND CONCLUSION: This study showed that the genetic polymorphisms of CYP3A5*3 and BCRPC421A might explain the variability in the pharmacokinetics of felodipine in the Chinese population.

TNF-α was involved in calcium hydroxide-promoted osteogenic differentiation of human DPSCs through NF-κB/p38MAPK/Wnt pathway.

It has been reported that calcium hydroxide can induce proliferation, migration, and mineralization in dental pulp stem cells (DPSCs), but the underlying molecular mechanisms are still unclear. In this study, we sought to explore the role of calcium hydroxide in the cell proliferation and directional differentiation of DPSCs and to study the regulatory effect of NF-κB, p38MAPK, and Wnt signaling on differentiation of DPSCs. CCK8 cell assay, Wound Healing Assay, and Alkaline Phosphatase Staining Assay were respectively used to determine the proliferation rate, migration and ALP expression of DPSCs. Alizarin Red Staining Assay was used to observe the mineralization of DPSCs. RT-PCR analysis and Western Blot Analysis displayed the expression of related fators at mRNA and protein level, respectively. In the present study, we found that NF-κB, p38MAPK, and Wnt signaling could abolish calcium hydroxide-induced proliferation of DPSCs. The inhibition of NF-κB, p38MAPK, and Wnt signaling suppressed the migration, ALP expression, and mineralization of DPSCs. NF-κB, p38MAPK, and Wnt signaling involved in directional differentiation of DPSCs. Moverover, calcium hydroxide could activate NF-κB, p38MAPK, and Wnt pathway by regulating TNF-α. Our study showed that NF-κB, p38MAPK, and Wnt signaling pathway were involved in calcium hydroxide-induced proliferation, migration, mineralization, and osteogenic differentiation in DPSCs. Calcium hydroxide affected NF-κB, p38MAPK, and Wnt pathway by regulating TNF-α.

Comparing the effectiveness of pharmacist-managed warfarin anticoagulation with other models: a systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Anticoagulation management services are well known to improve the quality of patient care and to reduce the rates of hospitalization and emergency department visits following adverse events related to anticoagulation therapy. The complexity of managing warfarin has led to the development of a variety of specialized models managed by pharmacists, physicians, nurses, and self-managed care. The aim of the study is to compare the effectiveness of pharmacist-managed anticoagulation control of warfarin with other models. METHODS: We performed a systematic literature search of the PubMed, Medline@Web of Knowledge, EMBASE, Cochrane Library and Cumulative Index to Nursing and Allied Health Literature to identify randomized controlled trials (RCTs) from database inception up to July 2015. The search terms used for the study were 'warfarin', 'pharmacists', 'Vitamin K antagonist', 'anticoagulation' and 'management model.' We used the Cochrane Collaboration's tool from the Cochrane Handbook to assess the risk of bias of RCTs. We performed statistical analyses using RevMan 5.3 and used the Grading of Recommendations, Assessment, Development, and Evaluations profiler to rate the quality of evidence of the outcomes. The anticoagulation control outcomes were the percentage of time within the standard and expanded therapeutic range and thrombosis events; the safety outcomes were bleeding events and mortality, and patients' satisfaction of anticoagulation service. RESULTS AND DISCUSSION: Eight RCTs from 981 potentially relevant publications with a total of 1493 patients were included. Meta-analysis of the RCTs showed that a significant difference existed between pharmacist-managed care and other models for satisfaction (mean difference (MD) = 0·41, 95% CI, 0·01-0·81, P = 0·04, low-quality evidence) with heterogeneity, and the percentage of time within the standard therapeutic range (MD = 3·66, 95% CI 2·20-5·11, P < 0·00001, high-quality evidence) without heterogeneity. However, the pharmacist-managed group demonstrated no significant improvement on the percentage of time within the expanded therapeutic range (MD = 2·85, 95% CI -0·56 to 6·26, P = 0·10, moderate-quality evidence) with heterogeneity, mortality [odds ratio (OR) = 0·97, 95% CI, 0·44-2·11, P = 0·09, high-quality evidence] without heterogeneity, the prevention of bleeding events (OR = 0·89, 95% CI, 0·56-1·44, P = 0·64, high-quality evidence) without heterogeneity, and thrombosis events (OR = 0·81, 95% CI, 0·34-1·92, P = 0·64, high-quality evidence) without heterogeneity. WHAT IS NEW AND CONCLUSION: The advantage of pharmacist-managed warfarin anticoagulation therapy in terms of anticoagulation control, safety and mortality are unclear, but resulted in significantly better patient satisfaction. Compared with other models, the superiority of pharmacist-managed warfarin anticoagulation needs to be further evaluated and validated in future research.

Hsp90 modulates the stability of MLKL and is required for TNF-induced necroptosis.

The pseudokinase mixed lineage kinase domain-like protein (MLKL) is a key component of tumor necrosis factor (TNF)-induced necroptosis and plays a crucial role in necroptosis execution. However, the mechanisms that control MLKL activity are not completely understood. Here, we identify the molecular chaperone Hsp90 as a novel MLKL-interacting protein. We show that Hsp90 associates with MLKL and is required for MLKL stability. Moreover, we find that Hsp90 also regulates the stability of the upstream RIP3 kinase. Interference with Hsp90 function with the 17AAG inhibitor destabilizes MLKL and RIP3, resulting in their degradation by the proteasome pathway. Furthermore, we find that Hsp90 is required for TNF-stimulated necrosome assembly. Disruption of Hsp90 function prevents necrosome formation and strongly reduces MLKL phosphorylation and inhibits TNF-induced necroptosis. Consistent with a positive role of Hsp90 in necroptosis, coexpression of Hsp90 increases MLKL oligomerization and plasma membrane translocation and enhances MLKL-mediated necroptosis. Our findings demonstrate that an efficient necrotic response requires a functional Hsp90.

Impact of pharmacist intervention on antibiotic use and prophylactic antibiotic use in urology clean operations.

WHAT IS KNOWN AND OBJECTIVE: The use of prophylactic antibiotics in clean operations was routine in China before 2011. Along with the appeal for using antibiotics rationally by WHO in 2011, China launched a national special rectification scheme on clinical use of antibiotics from April that year. The scheme, aimed at achieving rational use of antibiotics, made pharmacists part of the responsible medical team. Our objective was to describe the impacts of pharmacist intervention on the use of antibiotics, particularly in urology clean operations. METHODS: Pharmacists participated in antibiotic stewardship programmes of the hospital and urological clinical work and conducted real-time interventions at the same time from 2011 to 2013. Data on the use of antibiotics between 2010 and 2013 in urology were collected. RESULTS: Comparison of the 2013 data with those of 2010 showed that antibiotic use density [AUD= DDDs*100/(The number of patients who were treated the same period*Average days in hospital). DDDs = Total drug consumption (g)/DDD. DDD is the Defined Daily Dose] decreased by 57·8(58·8%); average antibiotic cost decreased by 246·94 dollars; the cost of antibiotics as a percentage of total drug cost decreased by 27·7%; the rate of use of antibiotics decreased from 100% to 7·3%. WHAT IS NEW AND CONCLUSION: The study illustrates how an antibiotic stewardship programme with pharmacist participation including real-time interventions can promote improved antibiotic-prescribing and significantly decrease costs.

FOXC2 promotes colorectal cancer metastasis by directly targeting MET.

Metastasis is the major cause of death in colorectal cancer (CRC). Although multiple genes have been identified to be responsible for the development of CRC, the molecular changes that enable CRC cells to undergo early local invasion and to form distant metastatic colonies still remain largely unknown. Herein, we investigated the role of Forkhead box protein C2 (FOXC2) and explored the underlying mechanisms in invasion and metastasis of CRC. We show that both high FOXC2 expression and nuclear localization of FOXC2 are significantly correlated with advanced TNM (T=primary tumor; N=regional lymph nodes; M=distant metastasis) stages. FOXC2 enhanced the invasive abilities of CRC cells in vitro and promoted local invasion and distant metastasis in an orthotopic mouse metastatic model of CRC. Microarray analysis revealed that overexpression of FOXC2 increased the proto-oncogene MET tyrosine kinase expression and activated the hepatocyte growth factor (HGF)-MET signaling pathway. Furthermore, luciferase reporter assays and chromatin immunoprecipitation assays revealed that FOXC2 directly associated with MET promoter to increase the transcriptional activity of MET. Inhibition of MET attenuates the invasive phenotype and metastatic potential of FOXC2-overexpressing CRC cells, indicating that MET is a major mediator of FOXC2-promoted metastasis. In addition, FOXC2 expression was positively correlated with MET expression in CRC tissue samples. Our findings suggest that FOXC2 has a crucial role in CRC metastasis by regulating HGF-MET signaling via inducing MET expression, highlighting FOXC2 as a potential therapeutic target for preventing or reducing metastasis in CRC.

Protective effect of ginsenoside against acute renal failure via reduction of renal oxidative stress and enhanced expression of ChAT in the proximal convoluted tubule and ERK1/2 in the paraventricular nuclei.

Generation of reactive oxygen species significantly contributes to the pathogenesis of acute renal failure (ARF) induced by myoglobin release. Ginsenosides (GS), the principal active ingredients of ginseng, is considered as an extremely good antioxidative composition of Chinese traditional and herbal drugs. The purpose of the present study was to investigate the protective effect of ginsenoside in rats with ARF on the changes of cholinergic nervous system in the kidney as well as on the involvement of mitogen-activated protein kinases (MAPK) in the hypothalamic paraventricular nuclei (PVN). In our assay, glycerol-induced acute renal failure in rats was employed to study the protective effects of ginsenoside. Our results indicated that the treatment of ARF rats with ginsenosides for 48 h significantly reduced lipid peroxidation, restored the superoxide dismutase (SOD) level. Meanwhile, the obvious increase of choline acetyltransferase-immunoreactivity (ChAT-IR) in the proximal convoluted tubular cells (PCT) was observed by immunohistochemistry in ARF+GS group. The same effect was also observed in the changes of p-ERK1/2-IR in the hypothalamic paraventricular nuclei. Our results suggest that ginsenoside administered orally may have a strong renal protective effect against glycerol-induced ARF, reduce the renal oxidative stress, and ginsenoside can also activate the cholinergic system in PCT, simultaneously MAPK signal pathway in the PVN was also activated.

Changes in and shortcomings of drug stockpiling, vaccine development and related policies during outbreaks of avian influenza A H5N1, H1N1, and H7N9 among humans.

The purpose of this paper is to provide a reference for the future stockpiling of drugs and developing vaccines for treatment of emerging infectious diseases by summarizing the status of drug stockpiling, vaccine development, and related policies during three major outbreaks of avian influenza among humans (H5N1 in 2003, H1N1 in 2009, and H7N9 in 2013). Documents regarding drug stockpiling and vaccine development during three influenza outbreaks have been reviewed. Results indicated that the response to pandemic influenza outbreaks has improved markedly in terms of stockpiles of antivirals and vaccine development. These improvements also suggest advances in related policy planning. These trends also foreshadow better prospects for prevention and control of emerging infectious diseases. However, the rationality of drug stockpiling and international cooperation still needs to be enhanced.

Identification of cellular proteins interacting with influenza A virus PB1-F2 protein.

UNLABELLED: The influenza A virus (IAV) protein PB1-F2, which is encoded by an alternative ORF of the PB1 polymerase gene, has been implicated as an important virulence factor and apoptosis inducer. However, the molecular mechanism of PB1-F2 function remains elusive. In this study, eight cellular proteins were identified as potential PB1-F2 interacting partners using the yeast two-hybrid system. Two positive candidate proteins, guanine nucleotide binding protein (G protein) beta polypeptide 2 (Gß2) and macrophage migration inhibitory factor (MIF), were selected to be further characterized. The interaction of MIF and Gß2 with PB1-F2 was confirmed by both GST pull-down and co-immunoprecipitation assays. Confocal laser microscopy showed that the interaction between PB1-F2 and the two cellular proteins occurred in the cytoplasm. The novel interactions between PB1-F2 and host proteins provide further pieces of evidence in the investigation of the pathogenic mechanism of IAV. KEYWORDS: influenza A virus; PB1-F2; yeast two-hybrid; protein-protein interaction.

Exenatide pharmacokinetics in healthy Chinese subjects.

OBJECTIVES: Exenatide is an adjunctive treatment for Type 2 diabetes. This was the first study to evaluate the pharmacokinetics, safety and tolerability of therapeutic doses (5 microg and 10 microg) of exenatide after single and multiple subcutaneous injections in healthy adult Chinese subjects. METHODS: 24 healthy volunteers were randomized to receive either 5 microg or 10 microg of exenatide by subcutaneous injection. Subjects received a single injection of exenatide on Day 1, twice daily on Days 2 and 3, and once on Day 4. Serial blood samples were drawn for pharmacokinetic assessment at pre-dose and up to 12 h post dose on Day 1 and Day 4. Adverse events, vital signs, 12-lead ECG, body weight and clinical laboratory evaluations were assessed. RESULTS: Exenatide, 5 microg and 10 microg, was rapidly absorbed with a median tmax of 1 h after single and multiple doses. Exenatide Cmax and AUCtau,ss were (geometric mean (90% CI)) 145 (119 - 176) pg/ml and 370 (297 - 460) pg x h/ml, respectively, after multiple dosing with 5 microg. The Cmax and AUCtau,ss were 311 (271 - 357) pg/ml and 878 (785 - 983) pg x h/ml, respectively, for 10 microg. Mean half-life (t1/2, range 0.99 - 1.25 h), apparent volume of distribution (Vz/F, 19.2 - 22.3 l), and apparent clearance (CL/F, range 11.4 - 13.5 l/h) remained consistent between single and multiple doses and across the two dose levels. Both the accumulation ratios and linearity index approached 1.0. The most common adverse events were gastrointestinal in nature and mild in severity. The frequency of adverse events increased with dose, such that 8% of subjects who received 5 microg and 42% of subjects who received 10 microg experienced adverse events. CONCLUSIONS: Exenatide was rapidly absorbed, with similar pharmacokinetic properties following single and multiple doses. Exenatide exposure after multiple doses approximately doubled from 5 microg to 10 microg.

The interobserver and intraobserver reliability of the cooney classification of distal radius fractures between experienced orthopaedic surgeons.

Various classification systems have been proposed for fractures of the distal radius, but the reliability of these classifications are seldom addressed. The objective of this study was to determine the interobserver and intraobserver reliability of the Cooney classification. Five orthopaedic surgeons with more than 10 years' experience in orthopaedic trauma assessed 43 sets of radiographic files according to the Cooney classification separately. Kappa statistics were used to analyse the interobserver and intraobserver reliability. There was moderate and substantial interobserver and intraobserver reliability of the Cooney classification without subtype, but only slight reliability when the subgroups were considered. These results question the value of this classification system for treatment decision making.