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Ischemic stroke is considered to be a complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. MicroRNAs participated in various physiopathological processes; common single-nucleotide polymorphisms (SNPs) in pre-miRNAs have been shown to be associated with susceptibility to several human diseases. We evaluated the associations of the hsa-mir-196-a2/rs11614913 T/C, hsa-mir-146a/rs2910164 C/G, and hsa-mir-499/rs3746444 A/G polymorphisms in pre-miRNAs with the risk of ischemic stroke in a Chinese population. The three polymorphisms were identified in 296 ischemic stroke patients and 391 healthy controls using polymerase chain reaction-restriction fragment length polymorphism. The frequency of the allele G of hsa-mir-499/rs3746444 A/G showed significant association with ischemic stroke when compared with controls (OR = 1.509, 95%CI = 1.151-1.978, P = 0.003). Increased ischemic stroke risks were associated with rs3746444 A/G genotypes in different genetic model (homozygote comparison: P = 0.045, OR = 2.084, 95%CI = 1.019-4.262; heterozygote comparison: P = 0.024, OR = 1.489, 95%CI = 1.063-2.087; dominant genetic model: P = 0.007, OR = 1.563, 95%CI = 1.135-2.153). Similar results were obtained by adjusted fully risk factors. However, we failed to find any association between the alleles and genotypes of rs2910164 C/G and rs11614913 T/C SNPs and ischemic stroke, respectively (p > 0.05). The present study provided evidence that hsa-mir-499/rs3746444 A/G polymorphism might be associated with a significantly increased risk of ischemic stroke in a Chinese population, indicating that the common genetic polymorphism in pre-microRNAs contributed to the pathogenesis of ischemic stroke.
The purpose of this investigation was to describe the effect of antibacterial stewardship and evaluate the trends and correlation of antibacterial resistance and usage from 2009 to 2013 in a tertiary-care teaching hospital in northwest China. Antibacterial usage was expressed as defined daily doses per 100 patients per day (DDDs/100 PDs). Hospital-wide population-level data and time series analysis were used to evaluate the trends and determine associations between antibacterial exposure and acquisition of resistance. Yearly consumption of overall antibacterials significantly decreased from 66.54 to 28.08 DDDs/100 PDs (β = -10.504, p < 0.01). The resistant rates of the five most frequently isolated species (including Escherichia coli, Acinetobacter baumannii, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae) significantly decreased or remained stable, and none of them showed a statistically significant upward trend. The medical quality indicators got better or remained stable. Autoregressive integrated moving average (ARIMA) models demonstrated that the monthly resistance rate of P. aeruginosa to imipenem was strongly correlated with antipseudomonal carbapenems usage (β = 34.94, p < 0.001), as did the correlation of P. aeruginosa to meropenem with antipseudomonal third-generation cephalosporins usage (β = 32.76, p < 0.01) and K. pneumoniae to amikacin with aminoglycosides usage (β = 22.01, p < 0.001). The decreased antibacterial use paralleled the improved bacterial resistance without deteriorating medical quality indicators during antimicrobial stewardship. It also suggests that optimum antibiotic use is necessary to alleviate the threat posed by resistant microorganisms at the hospital level.
Baicalin is an important active component of the medicinal herb Scutellaria baicalensis Georgi and has shown a variety of pharmacological actions. The present study aimed to evaluate the neuroprotective effects of baicalin against diabetes‑associated cognitive deficits (DACD) in rats and to elucidate the potential molecular mechanisms of action. A rat model of diabetes mellitus was prepared by intraperitoneal injection of streptozotocin. After the successful establishment of the diabetic rat model, baicalin (50, 100 and 200 mg/kg) or vehicle was administrated for seven weeks. Learning and memory function were assessed using the Morris water maze test. At the end of the experiment, the activities of acetylcholinesterase (AChE) and choline acetylase (ChAT) were determined using commercial kits. Furthermore, the expression of proteins involved in mitogen‑activated protein kinase (MAPK) cascades [extracellular signal‑regulated kinase (ERK), c‑Jun N‑terminal kinase (JNK) and p38], brain‑derived neurotrophic factor (BDNF) and apoptosis‑associated proteins [caspase‑3, B-cell lymphoma 2 (Bcl‑2) and Bcl-2-associated X protein (Bax)] were detected by western blot analysis. Caspase‑3 activity was also analyzed using a commercial kit. The results demonstrated that diabetic rats exhibited decreases in body weight, decreases in the percentage of time spent in the target quadrant and the number of times of crossing the platform in the water maze test, as well as decreases in neuronal survival, ChAT, phosphorylated (p)ERK, BDNF and Bcl‑2. Furthermore, diabetic rats showed increases in escape latency and mean path length in the water maze test, increases in the levels of hippocampal AChE, p‑JNK, p‑p38, caspase‑3 and Bax as well as plasma glucose. However, in diabetic rats treated with baicalin, all of the abovementioned observations were obviously reversed. The findings suggested that baicalin exerts neuroprotective effects against DACD via modulation of MAPK cascades, BDNF and apoptosis.
Glutathione S-transferase (GST), a phase II metabolizing enzyme, plays an important role in the cellar defense system, and its activity may modulate leukemia risk. A large body of evidence has shown the possible relevance of functional polymorphisms of the genes that encode GSTs μ, π, and θ (GSTM1, GSTP1, and GST1, respectively) to the genetic susceptibility of chronic myeloid leukemia (CML). Because of the lack of available conclusive data, we performed a meta-analysis of all relevant available studies to derive a more precise estimation of the relationship. A comprehensive literature search of PubMed and Web of Knowledge electronic databases was conducted to collect relevant studies until December 20, 2013, and the extracted data were statistically analyzed using Review Manager version 5.2. Finally, 16 eligible studies were identified in the literature. The GSTT1 null genotype was associated with an increased risk of CML, as were the double null GSTT1 and GSTM1 genotypes. These findings suggest that heritable GST status influences the risk of developing CML and that more attention should be paid to carriers of these susceptibility genes.
Aim:To evaluate single-dose and multiple-dose pharmacokinetics of cytotoxic T-lymphocyte-associated antigen 4 fusion protein (CTLA4Ig) in healthy volunteers and patients with rheumatoid arthritis (RA). Methods:The clinical trials included two phase I open studies: study 1 was an open-label dose-escalation study in 27 healthy volunteers and study 2 was a single-group, open-label study in patients with rheumatoid arthritis. In study 2, 9 patients were arranged to receive 10 mg/kg of CTLA4Ig at 0, 2, 4, 8, 12, and 16 weeks. The concentration-time data obtained by a validated ELISA method were subjected to non-compartmental pharmacokinetic analysis by DAS 2.1 software. Results: In study 1, serum CTLA4Ig concentrations climbed rapidly to the peak and declined slowly with a t 1/2 of 15.1±2.6 d, 14.2±2.3 d, and 11.8±1.2 d after a single infusion of 1, 10, and 20 mg/kg, respectively. C max and AUC 0-∞ increased proportionally with the dose. In study 2, the steady-state condition for CTLA4Ig following multiple doses of 10 mg/kg appeared to be attained at the fourth dose (d 56), with peak and trough concentrations of 239.8±45.3 mg/L and 20.5±7.9 mg/L, respectively. After multiple infusions, serum concentrations dropped slowly and the terminal half-life was 12.6±4.7 d. Conclusion: Intravenous infusion of CTLA4Ig was well tolerated in healthy volunteers and patients with rheumatoid arthritis. CTLA4Ig exhibited linear pharmacokinetics over the dose range of 1 to 20 mg/kg in healthy volunteers. The pharmacokinetics in RA patients appeared to be similar to that in healthy volunteers. No system accumulation appeared upon repeated infusions of 10 mg/kg every 4 weeks.
BackgroundTriple-negative breast cancer (TNBC) is associated with an aggressive clinical course due to the lack of therapeutic targets. Therefore, identifying reliable prognostic biomarkers and novel therapeutic targets for patients with TNBC is required. Proline, glutamic acid, leucine rich protein 1 (PELP1) is a novel steroidal receptor co-regulator, functioning as an oncogene and its expression is maintained in estrogen receptor (ER) negative breast cancers. PELP1 has been proposed as a prognostic biomarker in hormone-related cancers, including luminal-type breast cancers, but its significance in TNBC has not been studied.MethodsPELP1 immunoreactivity was evaluated using immunohistochemistry in 129 patients with TNBC. Results were correlated with clinicopathological variables including patient’s age, tumor size, lymph node stage, tumor grade, clinical stage, histological type, Ki-67 LI, as well as clinical outcome of the patients, including disease-free survival (DFS) and overall survival (OS).ResultsPELP1 was localized predominantly in the nuclei of carcinoma cells in TNBC. With the exception of a positive correlation between PELP1 protein expression and lymph node stage (p = 0.027), no significant associations between PELP1 protein expression and other clinicopathological variables, including DFS and OS, were found. However, when PELP1 and Ki-67 LI were grouped together, we found that patients in the PELP1/Ki-67 double high group (n = 48) demonstrated significantly reduced DFS (p = 0.005, log rank test) and OS (p = 0.002, log rank test) than others (n = 81). Multivariable analysis supported PELP1/Ki-67 double high expression as an independent prognostic factor in patients with TNBC, with an adjusted hazard ratio of 2.020 for recurrence (95 % CL, 1.022–3.990; p = 0.043) and of 2.380 for death (95 % CL, 1.138–4.978; p = 0.021).ConclusionsWe found that evaluating both PELP1 and Ki-67 expression in TNBC could enhance the prognostic sensitivity of the two biomarkers. Therefore, we propose that PELP1/Ki-67 double high expression in tumors is an independent prognostic factor for predicting a poor outcome for patients with TNBC.
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