Long-term survival of patients with chest pain syndrome and angiographically normal or near-normal coronary arteries: the additional prognostic value of dipyridamole echocardiography test (DET).

AIMS: Patients with normal coronary arteries have a heterogeneous prognosis. Aim of this study was to assess whether dipyridamole stress echocardiography positivity identifies a prognostically less benign subset. METHODS AND RESULTS: We selected 457 patients (245 males; 56+/-10 years) who underwent stress high-dose dipyridamole echocardiography and had angiographically non-significant (<50% visually assessed) stenosis in any major vessel and preserved left ventricular function. All patients were followed up for a median of 7.1 years (first quartile 5 and third quartile 10.5). Dipyridamole echocardiography test (DET) positivity for regional dysfunction occurred in 43(9%) patients. Kaplan-Meier survival estimates showed a significant better outcome for those patients with negative dipyridamole echocardiography test compared with those with a positive test (90 vs. 75.7%, at 140 months of follow-up, P=0.0018). At multivariable analysis, mild or moderate irregularity on coronary arteriogram (HR=3.3, CI 95%=1.7-6.2), diabetes (HR=3.5, CI 95%=1.4-9.2), and wall motion score index at peak stress (HR=6.7, CI 95%=2.5-17.8) were independent predictors of all-cause death. CONCLUSION: DET adds incremental value to the prognostic stratification achieved with clinical and angiographic data in the subset of patients with normal or near-normal coronary arteries.     

Deoxyelephantopin decreases the release of inflammatory cytokines in macrophage associated with attenuation of aerobic glycolysis via modulation of PKM2

Growing evidence suggests that activated immune cells undergo metabolic reprogramming in the regulation of the innate inflammatory response. Remarkably, macrophages activated by lipopolysaccharide (LPS) induce a switch from oxidative phosphorylation to aerobic glycolysis, and consequently results in release of proinflammatory cytokines. Pyruvate Kinase M2 (PKM2) plays a vital role in the process of macrophage activation, promoting the inflammatory response in sepsis and septic shock. Deoxyelephantopin (DET), a naturally occurring sesquiterpene lactone from Elephantopus scaber, has been shown to counteracts inflammation during fulminant hepatitis progression, but the underlying mechanism remains unclear. Here, we studied the function of the DET on macrophage activation and investigated the anti-inflammatory effects of DET associated with interfering with glycolysis in macrophage. Our results first demonstrated that DET attenuates LPS-induced interleukin-1β (IL-1β) and high-mobility group box 1 (HMGB1) release in vitro and in vivo and protected mice against lethal endotoxemia. Furthermore, DET decreased the expression of pyruvate dehydrogenase kinase 1 (PDK1), glucose transporter 1(GLUT1), lactate dehydrogenase A (LDHA), and reduced lactate production dose-dependently in macrophages. Moreover, we further revealed that DET attenuates aerobic glycolysis in macrophages associated with regulating the nuclear localization of PKM2. Our results provided a novel mechanism for DET suppression of macrophages activation implicated in anti-inflammatory therapy.     

Timing of Direct Enteral Tube Placement and Outcomes after Acute Stroke

Background: Direct enteral feeding tube (DET) placement for dysphagia after stroke is associated with poor outcomes. However, the relationship between timing of DET placement and poststroke mortality and disability is unknown. We sought to determine the risk of mortality and severe disability in patients who receive DET at different times after stroke. Methods: We used the Ontario Stroke Registry and linked administrative databases to identify patients with acute ischemic stroke or intracerebral hemorrhage between 2003 and 2013 who received DET (gastrostomy or jejunostomy) during their hospital admission. We grouped patients by week of DET placement and evaluated mortality at 30 days and 6 months after DET insertion, and disability at discharge. We used Cox proportional hazard models and multiple logistic regression to determine the association between time from admission to DET placement and outcomes, adjusting for patient and hospital factors. Results: In the study sample of 1367 patients, the median time from admission to DET placement was 17 days. After adjustment, each week of delay to DET placement was associated with lower mortality at 30 days (adjusted hazard ratio [aHR] .88, 95% confidence interval [CI] .79-.98), but not at 6 months (aHR .98, 95% CI .91- 1.05), and a higher likelihood of severe disability at discharge (adjusted odds ratio 1.35, 95% CI 1.13- 1.60). Conclusions: Later DET placement after stroke was associated with lower 30-day mortality but higher severe disability at discharge. Further research is needed to understand the reasons for these observations and to optimize patient selection and timing of DET.     

The dilemma faced by patients who undergo single embryo transfer

Purpose  The aim of this study was to identify the factors that contribute to the decision to choose single embryo transfer (SET). Methods  Two hundred and nine patients who underwent ART treatment in our clinics between April 2006 and May 2007 were enrolled in this study. All patients had elected to undergo SET before the start of each treatment cycle; a questionnaire was administered to all patients prior to the SET procedure. Results  The mean age of the patients was 34.6 years old (range: 24–45 years). The mean number of redundant embryos was 3.7 (range: 1–17), and the pregnancy rate per embryo transfer was 25.7%. A total of 121 patients (57.9%) who underwent SET returned their questionnaires. Based on the results of questionnaire, 56.2% of patients who received SET waived their right to choose between single and double embryo transfer. Among patients who selected SET, 67.6% believed that the pregnancy rate resulting from double embryo transfer (DET) is significantly greater than that associated with SET, and 25% of patients wanted to have twins. The majority of patients (80.9%) who underwent SET understood that multi-fetal pregnancy increases the risk of complications during gestation and delivery. Among all patients who completed the questionnaire, 72.8% believed that the number of transferred embryos should not be controlled by law. Conclusions  The results of the present study show that greater than one-half of patients who underwent SET were faced with a dilemma––the difficult choice between their own desires and their clinician’s recommendation.     

In situ quantitative monitoring of polyplexes and polyplex micelles in the blood circulation using intravital real-time confocal laser scanning microscopy

Surface modification using poly(ethylene glycol) (PEG) is a widely used strategy to improve the biocompatibility of cationic polymer-based nonviral gene vectors (polyplexes). A novel method based on intravital real-time confocal laser scanning microscopy (IVRTCLSM) was applied to quantify the dynamic states of polyplexes in the bloodstream, thereby demonstrating the efficacy of PEGylation to prevent their agglomeration. Blood flow in the earlobe blood vessels of experimental animals was monitored in a noninvasive manner to directly observe polyplexes in the circulation. Polyplexes formed distinct aggregates immediately after intravenous injection, followed by interaction with platelets. To quantify aggregate formation and platelet interaction, the coefficient of variation and Pearson's correlation coefficient were adopted. In contrast, polyplex micelles prepared through self-assembly of plasmid DNA with PEG-based block catiomers had dense PEG palisades, revealing no formation of aggregates without visible interaction with platelets during circulation. This is the first report of in situ monitoring and quantification of the availability of PEGylation to prevent polyplexes from agglomeration over time in the blood circulation. This shows the high utility of IVRTCLSM in drug and gene delivery research.     

Biodegradable hybrid recombinant block copolymers for non-viral gene transfection

Thermal targeting of therapeutic genes can enhance local gene concentration to maximize their efficacy. However, lack of safe and efficient carriers has impeded the development of this delivery option. Herein, we report the preparation and evaluation of a hybrid recombinant material, p[Asp(DET)](53)ELP(1-90), that possess a thermo-responsive elastin-like polypeptide (ELP) segment and a diethylenetriamine (DET) modified poly-L-aspartic acid segment. The term, hybrid, indicates that the material was prepared by genetic engineering and synthetic chemistry. In summary, the thermal phase transition behavior and cytotoxicity of the biodegradable copolymer were studied. The polyplexes formed by the copolymer and pGL4 plasmid were characterized by dynamic light scattering and ζ-potential measurements. The polyplexes retained the thermal phase transition behavior conferred by the copolymer; however, they exhibited a two-step transition process not seen with the copolymer. The polyplexes also showed appreciable transfection efficiency with low cytotoxicity.     

体外受精供胚移植成功一例报道

本文报道了我国首例经体外受精供胚移植成功的病例。供、受者经应用促排卵药后使排卵周期同步。受者于月经周期第16天,接受供者经体外受精的4细胞、6细胞及两原核阶段胚胎各一个。移植后确定了妊娠,于1988年6月7日诞生了一体重3kg发育正常的男婴。对作为优生工程之一的供胚移植的历史、适应症、成功的因素和应注意事项进行了讨论。     

Clinical relevance of antimicrobial resistance in the management of pneumococcal community-acquired pneumonia

Streptococcus pneumoniae remains the most common bacterial cause of community-acquired pneumonia, and these infections are associated with significant morbidity and mortality worldwide. A major concern is the increasing incidence of antibiotic resistance among pneumococcal isolates, which, in the case of certain of the antibiotic classes, has been associated with treatment failure. Yet despite multiple reports of infections with penicillin-resistant pneumococcal isolates, no cases of bacteriologic failure have been documented with the use of penicillin or ampicillin in the treatment of pneumonia caused by penicillin-resistant pneumococci. Current prevalence and levels of penicillin resistance among pneumococal isolates in most areas of the world do not indicate a need for substantial treatment changes with regard to the use of the penicillins. For infections with penicillin-sensitive strains, penicillin or an aminopenicillin in a standard dosage will still be effective for treatment. In the cases of strains with intermediate resistance, beta-lactam agents are still considered appropriate treatment, although higher dosages are recommended. Infections with isolates of high-level penicillin resistance should be treated with alternative agents such as the third-generation cephalosporins or the new antipneumococcal fluoroquinolones. In the case of the cephalosporins, pharmacodynamic/pharmacokinetic parameters help predict which of those agents are likely to be successful, and the less active agents should not be used. Debate continues in the literature with regard to the impact of macrolide resistance on the outcome of pneumococcal pneumonia, with some investigators providing evidence of an "in vivo-in vitro paradox," referring to discordance between reported in vitro resistance and clinical success of macrolides/azalide in vivo. However, several cases of macrolide/azalide treatment failure have been documented, and many clinicians recommend that these agents not be used on their own in areas with a high prevalence and levels of macrolide/azalide resistance. However, evidence is emerging to show beneficial effects on outcome with combination therapy, especially that of a beta-lactam agent and a macrolide given together to sicker, hospitalized patients with pneumococcal pneumonia. In an attempt to prevent the emergence of resistance, it has been recommended by some that the new fluoroquinolones not be used routinely as first-line agents in the treatment of community-acquired pneumonia; instead, they say, these agents should be reserved for patients who are allergic to the commonly used beta-lactam agents, for infections known to be or suspected of being caused by highly resistant strains, and for patients in whom initial therapy has failed.     

胆甾醇修饰的PEG-P[Asp(DET)]/miRNA复合物的制备、理化性能及细胞摄取能力

目的：制备疏水基修饰的聚阳离子高分子基因载体PEG-P[Asp(DET)]-10chole,对其复合miRNA的理化能力和细胞摄取能力进行研究。方法：开环聚合合成PEG-P[Asp(DET)],再采用氯甲酸胆甾醇基进行疏水修饰,核磁验证其结构;使其与hsa-miR-15a形成胶束复合物,对该胶束复合物的粒径,Zeta电位,包封率以及细胞毒性进行考察;以白血病细胞K562细胞系为模型细胞进行体外细胞实验对其摄取进行考察。结果：合成的PEG113-P[Asp(DET)]94-10%chole具有良好的溶解性,可与miRNA形成稳定的胶束复合物）形成的胶束复合物,细胞对其摄取能力明显强于商品化试剂脂质体lipo2000组。结论：PEG113-P[Asp(DET)]94-10%chole是一种优良的高分子基因传递系统载体,在体外实验中可有效实现细胞对于miRNA 的稳定摄取。