Guidelines for the diagnosis,treatment, prevention and control of infections caused by carbapenem-resistant gram-negative bacilli

The dissemination of carbapenem-resistant Gram-negative bacilli (CRGNB) is a global public health issue. CRGNB isolates are usually extensively drug-resistant or pandrug-resistant, resulting in limited antimicrobial treatment options and high mortality. A multidisciplinary guideline development group covering clinical infectious diseases, clinical microbiology, clinical pharmacology, infection control, and guideline methodology experts jointly developed the present clinical practice guidelines based on best available scientific evidence to address the clinical issues regarding laboratory testing, antimicrobial therapy, and prevention of CRGNB infections. This guideline focuses on carbapenem-resistant Enterobacteriales (CRE), carbapenem-resistant Acinetobacter baumannii (CRAB), and carbapenem-resistant Pseudomonas aeruginosa (CRPA). Sixteen clinical questions were proposed from the perspective of current clinical practice and translated into research questions using PICO (population, intervention, comparator, and outcomes) format to collect and synthesize relevant evidence to inform corresponding recommendations. The grading of recommendations, assessment, development and evaluation (GRADE) approach was used to evaluate the quality of evidence, benefit and risk profile of corresponding interventions and formulate recommendations or suggestions. Evidence extracted from systematic reviews and randomized controlled trials (RCTs) was considered preferentially for treatment-related clinical questions. Observational studies, non-controlled studies, and expert opinions were considered as supplementary evidence in the absence of RCTs. The strength of recommendations was classified as strong or conditional (weak). The evidence informing recommendations derives from studies worldwide, while the implementation suggestions combined the Chinese experience. The target audience of this guideline is clinician and related professionals involved in management of infectious diseases.     

感染性疾病病原学诊断新技术与临床应用策略

感染性疾病仍是威胁人类健康的主要疾病,传统诊断技术已无法满足临床需求,病原学诊断技术的发展对感染性疾病的诊断治疗至关重要。近年来,非培养的新型诊断技术正在迅速发展,特别是基于侧流免疫层析法和实时聚合酶链式反应为基础的即时检验,以及基于蛋白质组学质谱和高通量测序技术不断应用于临床,使感染性疾病的临床诊断向着更便捷、快速、准确的方向发展。但仍需正确对待新型诊断技术在临床应用中的问题,从循证医学角度评估诊断试验,关注应用人群,以最佳证据应用于合适人群以达到最佳效果,让病原学诊断新技术的应用真正解决临床诊断问题,最终为临床感染性疾病诊疗的科学决策提供依据。     

Docetaxel-loaded nanoparticles based on star-shaped mannitol-core PLGA-TPGS diblock copolymer for breast cancer therapy

A star-shaped biodegradable polymer, mannitol-core poly(d,l-lactide-co-glycolide)-d-α-tocopheryl polyethylene glycol 1000 succinate (M-PLGA-TPGS), was synthesized in order to provide a novel nanoformulation for breast cancer chemotherapy. This novel copolymer was prepared by a core-first approach via three stages of chemical reaction, and was characterized by nuclear magnetic resonance, gel permeation chromatography and thermogravimetric analysis. The docetaxel-loaded M-PLGA-TPGS nanoparticles (NPs), prepared by a modified nanoprecipitation method, were observed to be near-spherical shape with narrow size distribution. Confocal laser scanning microscopy showed that the uptake level of M-PLGA-TPGS NPs was higher than that of PLGA NPs and PLGA-TPGS NPs in MCF-7 cells. A significantly higher level of cytotoxicity was achieved with docetaxel-loaded M-PLGA-TPGS NPs than with commercial Taxotere®, docetaxel-loaded PLGA-TPGS and PLGA NPs. Examination of the drug loading and encapsulation efficiency proved that star-shaped M-PLGA-TPGS could carry higher levels of drug than linear polymer. The in vivo experiment showed docetaxel-loaded M-PLGA-TPGS NPs to have the highest anti-tumor efficacy. In conclusion, the star-like M-PLGA-TPGS copolymer shows potential as a promising drug-loaded biomaterial that can be applied in developing novel nanoformulations for breast cancer therapy.     

放射性球囊治疗冠状动脉再狭窄时导管内核素对正常血管的剂量分布计算

目的：计算放射性球囊治疗冠状动脉再狭窄时导管内核素对正常血管的剂量分布。方法：用Loevinger公式计算球囊、导管周围组织的剂量分布。结果：导管周围组织与球囊周围组织的剂量之比在整个经向距离范围内接近于1／10。正常治疗时，导管周围血液受到的平均剂量达到5．36Gy，血管壁受到的平均剂量达到1．62Gy。结论：用放射性球囊治疗冠状动脉再狭窄时，正常血管短期和长期辐射效应应该被考虑。     

Sonochemically prepared BSA microspheres containing Gemcitabine,and their potential application in renal cancer therapeutics

This report demonstrates the formation and characterization of sonochemically prepared bovine serum albumin (BSA)–Gemzar (Gemcitabine) microspheres and shows their increased anticancer activity compared to pristine Gemzar. The amount of loaded Gemzar was determined by light absorption measurements. The BSA–Gemzar composite was analyzed and characterized by optical microscopy and scanning electron microscopy. The release kinetics of Gemzar from the proteinaceous microspheres was tested. The BSA–Gemzar composite was examined for its anticancer activity (in vitro) in renal cancer cells (RCC, 786-O cells) using [³H]thymidine incorporation assays. It was found that the influence of the Gemzar-loaded microspheres on the cancer cells was significantly greater than that of an equimolar concentration of pristine Gemzar.     

Inhibition of phosphodiesterase-4 suppresses HMGB1/RAGE signaling pathway and NLRP3 inflammasome activation in mice exposed to chronic unpredictable mild stress

Inhibition of phosphodiesterase-4 (PDE4) produces robust anti-inflammatory and antidepressant-like effects in multiple animal models. However, the detailed mechanisms have not been well studied. Receptor for advanced glycation endproducts (RAGE) and inflammasome activation are implicated in the etiology of depression. Here, we aimed to investigate the involvement of RAGE and nucleotide-binding domain (NOD)–like receptor protein 3 (NLRP3) inflammasome in the antidepressant-like effects of PDE4 inhibition in mice. We found that inhibition of PDE4 by roflupram (ROF, 0.5, and 1.0 mg/kg, i.g.) exerted antidepressant-like effects in mice subjected to chronic unpredictable mild stress (CUMS). Simultaneously, ROF inhibited CUMS-induced microglial activation and restored the morphology of microglial cells in the hippocampus, as evidenced by reduced total process length, area, volume, number of branching points, number of terminal points and total sholl intersections of microglia. ROF also decreased the expression of ionized calcium-binding adapter molecule-1 and the level of interleukin-1β. Western blot analysis showed that PDE4 inhibition suppressed the high-mobility group box 1 protein (HMGB1)/RAGE signaling pathway, as the levels of HMGB1, RAGE, toll-like receptor 4, phosphorylated p38 mitogen-activated protein kinase, and nuclear factor κ-B were decreased in both hippocampus and cortex in mice after treatment with ROF. Moreover, ROF also attenuated the protein levels of NLRP3, the apoptosis-associated speck-like protein containing (ASC), and cysteine-requiring aspartate protease-1 (Caspase-1), which are key proteins in the NLRP3-mediated inflammasome signaling pathway. In summary, these results demonstrate that the down-regulation of HMGB1/RAGE signaling pathway and inflammasome suppression possibly contribute to the antidepressant-like effects of PDE4 inhibitors. And, ROF has potential as a candidate drug in the treatment of depression.     

失效模式与效应分析在低能X线术中放疗的应用

目的 探讨失效模式与效应分析(FMEA)在低能X线术中放疗(IORT)中的应用,分析其在IORT中的潜在风险,初步探讨FMEA优化IORT管理、减少潜在风险发生的可行性。方法 由IORT团队(1名放疗科医生、1名放疗科物理师、2名外科医生、2名护士)成立FMEA工作小组,应用FMEA方法开展系统风险评估。确立流程模块,对每项模块分析潜在失效模式和原因,对失效模式进行严重程度(SR)、发生频度(OR)和失效检验难度(DR)的评分,计算风险优先指数(RPN=SR×OR×DR)。前瞻性地分析并理解放疗过程中的各个环节可能的错误及潜在临床影响,对每项失效模式均进行原因分析和现行措施分析,提出预防措施并采取相应的风险管理措施。结果 IORT流程分为8个模块,14项失效模式。OR值最高为靶区确认不满意(7分),SR值最高为设备故障无法出束(10分),DR值最高为剂量计算后按键输入错误(7分),RPN值最高为靶区确认不满意(210分)和危及器官未有效保护(180分)。按照优先级对薄弱环节进行修正,优化工作流程和制定出更有效地管理方法。结论 FMEA是一种有效的IORT管理方法,有助于减少潜在风险发生。     

The effects of modified versus unmodified wheat gluten administration in patients with celiac disease

Celiac disease (CD) treatment requires a gluten-free diet (GFD), although alternative approaches have been proposed. Modification of gliadin peptides using microbial transglutaminase (mTG) inhibits their ability to induce immune response in vitro. Our aim was to evaluate the safety of mTG-modified wheat flour ingestion in CD patients. Twenty-one CD patients in remission were randomized to receive mTG-modified (n = 11) or unmodified (n = 10) wheat flour rusks, in double-blind fashion. Monthly, patients completed a symptom questionnaire. Serum anti-tTG, EMA and creatinine levels were monitored. At baseline and after 90 days, serum anti-actin antibodies (AAA) were measured and upper endoscopy was performed. Data were analyzed by non-parametric tests. 7/11 patients eating modified rusks and 7/10 patients receiving unmodified rusks completed the study. At baseline, all patients showed negative serum anti-tTG and EMA results. At the end, 2/7 (28.6%) patients ingesting modified and 4/7 (57.1%) patients taking unmodified rusks presented positive serum anti-tTG and EMA results. Creatinine results were unmodified. Moreover, 1/7 (14.3%) patients ingesting modified and 4/7 (57.1%) patients taking unmodified rusks presented villous atrophy. In patients who received unmodified rusks, the AAA levels increased significantly and duodenal anti-tTG levels appeared higher than those measured in patients who ate modified rusks. Abdominal swelling, bloating and nausea were more severe in patients ingesting unmodified rusks than those taking modified rusks. Our results may support larger clinical trials to confirm the enzymatic treatment of wheat flour as an alternative to GFD.Clinicaltrials.gov registration no: NCT02472119.     

Bone-derived MSCs encapsulated in alginate hydrogel prevent collagen-induced arthritis in mice through the activation of adenosine A2A/2B receptors in tolerogenic dendritic cells

Tolerogenic dendritic cells (tolDCs) facilitate the suppression of autoimmune responses by differentiating regulatory T cells (Treg). The dysfunction of immunotolerance results in the development of autoimmune diseases, such as rheumatoid arthritis (RA). As multipotent progenitor cells, mesenchymal stem cells (MSCs), can regulate dendritic cells (DCs) to restore their immunosuppressive function and prevent disease development. However, the underlying mechanisms of MSCs in regulating DCs still need to be better defined. Simultaneously, the delivery system for MSCs also influences their function. Herein, MSCs are encapsulated in alginate hydrogel to improve cell survival and retention in situ, maximizing efficacy in vivo. The three-dimensional co-culture of encapsulated MSCs with DCs demonstrates that MSCs can inhibit the maturation of DCs and the secretion of pro-inflammatory cytokines. In the collagen-induced arthritis (CIA) mice model, alginate hydrogel encapsulated MSCs induce a significantly higher expression of CD39⁺CD73⁺ on MSCs. These enzymes hydrolyze ATP to adenosine and activate A_2A/2B receptors on immature DCs, further promoting the phenotypic transformation of DCs to tolDCs and regulating naïve T cells to Tregs. Therefore, encapsulated MSCs obviously alleviate the inflammatory response and prevent CIA progression. This finding clarifies the mechanism of MSCs-DCs crosstalk in eliciting the immunosuppression effect and provides insights into hydrogel-promoted stem cell therapy for autoimmune diseases.