Ranolazine—Treatment of Ventricular Tachycardia and Symptomatic Ventricular Premature Beats in Ischemic Cardiomyopathy

Premature ventricular complexes (PVCs) are a frequent occurrence in the presence of ischemic heart disease. A very high PVC load can be symptomatic or occasionally result in a cardiomyopathy (CMP). Treatment options include pharmacologic agents and radiofrequency ablation (RFA). RFA has been successful in treating PVCs in symptomatic patients or in the presence of unexplained CMP. Ranolazine is a piperazine derivative used for treating chronic stable angina. It also has antiarrhythmic properties. We report a patient with ischemic CMP, symptomatic PVCs, and monomorphic ventricular tachycardia (VT) despite attempts to control symptoms with two antiarrhythmic drugs. Initiation of ranolazine led to marked reduction in PVCs along with control of VT and symptoms. (PACE 2010; 33:e119–e120)     

缺血性心肌病与扩张型心肌病的超声比较研究

目的 研究二维多普勒超声心动图对缺血性心肌病（ＩＣＭ）及扩张型心肌病（ＤＣＭ）的诊断价值。方法 应用二维多普勒超声心动图对６８例ＩＣＭ,５６例ＤＣＭ及５０例正常人（ＮＣ）从心脏形态学、血流动力学及房室功能方面进行比较。结果 ＩＣＭ组与ＤＣＭ组各项超声指标间均有显著性差异（Ｐ〈０．０５或Ｐ〈０．０１）。其特点为：①ＤＣＭ组心脏多个房室腔护大呈球形结构,室壁变薄及弥温性动度减弱。ＩＣＭ组心脏以左房室扩     

Clinical Protocols for the Isolation and Expansion of Mesenchymal Stromal Cells

SUMMARY: Multipotent mesenchymal stromal cells (MSCs) are currently exploited in numerous clinical trials to investigate their potential in immune regulation, hematopoiesis, and tissue regeneration. The low frequency of MSCs necessitates cell expansion to achieve transplantable numbers. The challenge is to assure safe and high-quality cell production. GMP(Good Manufacturing Practice)-graded cell processing such as cell preparation, culture, and manipulation is mandatory for the progress of such advanced cell therapy. This review summarizes protocols to isolate MSCs from bone marrow and adipose tissue and to expand MSCs for clinical use focussing on culture media composition as well as culture devices and assays to ensure and control quality of the final product.     

Current Regulations for the Production of Multipotent Mesenchymal Stromal Cells for Clinical Application

SUMMARY: In this review, the appropriate legislation on the expansion of multipotent mesenchymal stromal cells (MSCs) in Europe is described. The collection of cells and the manufacturing of MSCs are being regulated by European Directives (EUDs). Recently, the Regulation on Advanced Therapies Medicinal Products (ATMPs) is being published, which is of importance for the production of MSCs in Europe, and this legislation is not yet ready, but it is in its final stage. MSCs are currently being used in clinical trials, mostly in academic hospitals, for patients suffering from a wide variety of diseases. Companies (small and medium-sized enterprises) are becoming more and more involved in the production of MSCs for human use, and since marketing authorisation is the scope of the Regulation it was decided to install a Committee on Advanced Therapies (CAT) within European Medicines Agency (EMEA). This CAT will formulate a draft opinion on quality, safety and efficacy of ATMPs and will have an advisory and scientific role for the Committee for Medicinal Products for human use. The aim of this review is to outline the current legislation which is important for the manufacturing of MSCs.     

间充质干细胞治疗缺血性脑卒中的荟萃分析

目的:收集间充质干细胞治疗缺血性脑卒中的临床对照研究,并对其疗效进行系统评价。方法:计算机检索Pub Med、Embase、Cochrane library、中国知网(CNKI)、万方数据知识服务平台、中文科技期刊数据库(维普期刊)等数据库。筛选纳入间充质干细胞治疗缺血性脑卒中的临床对照研究进行荟萃分析。结果:最终纳入文献13篇,共计患者686例。Meta分析结果显示,美国国立卫生院卒中量表结果中,间充质干细胞优于常规治疗[SMD=-1.022,95%CI(-1.312,-0.732),P=0.000];Fugl-Meyer量表结果中,间充质干细胞同样优于常规治疗[SMD=1.009,95%CI(0.107,1.911),P=0.028]。而巴氏指数、改良Rankin量表评分及功能独立性评分结果中,间充质干细胞未显示出治疗优势。亚组分析及Meta回归分析显示,是否通过静脉输注以及输注细胞数量可能是造成结果异质性的原因。结论:间充质干细胞对缺血性脑卒中患者的神经功能恢复具有一定的治疗作用,但是对于患者的日常生活能力恢复效果有限。此外,不同的细胞输注途径、不同的细胞注射剂量以及选用的细胞类型可能会造成结果的差异。     

Noninvasive Monitoring of the Mitochondrial Function in Mesenchymal Stromal Cells

Purpose

Mitochondria are a gatekeeper of cell survival and mitochondrial function can be used to monitor cell stress. Here we validate a pathway-specific reporter gene to noninvasively image the mitochondrial function of stem cells.

Procedures

We constructed a mitochondrial sensor with the firefly luciferase (Fluc) reporter gene driven by the NQO1 enzyme promoter. The sensor was introduced in stem cells and validated in vitro and in vivo, in a mouse model of myocardial ischemia/reperfusion (IR).

Results

The sensor activity showed an inverse relationship with mitochondrial function (R ²?=??0.975, p?=?0.025) and showed specificity and sensitivity for mitochondrial dysfunction. In vivo, NQO1-Fluc activity was significantly higher in IR animals vs. controls, indicative of mitochondrial dysfunction, and was corroborated by ex vivo luminometry.

Conclusions

Reporter gene imaging allows assessment of the biology of transplanted mesenchymal stromal cells (MSCs), providing important information that can be used to improve the phenotype and survival of transplanted stem cells.

     

缺血性心肌病顽固性心力衰竭PCI治疗的有效性及安全性探讨

目的探讨对缺血性心肌病顽固性心力衰竭(ICM)患者实施经皮冠状动脉介入治疗(PCI)的有效性与安全性进行分析。方法选取100例接受治疗的ICM患者,以随机方式平均分为对照组与观察组,对所有患者实施规范化药物治疗,在规范化药物治疗基础上,对观察组开展PCI治疗。比较两组ICM患者行PCI手术前与手术后2个月实施超声心电图检查LVEDD(左室舒张末内径)、LVEF(左室射血分数)、NYHA心功能分级、X线心胸比例及步行6min的距离,从而对PCI影响ICM患者心功能的程度进行分析与评价。结果观察组均通过PCI顺利完成血运重建。相比于手术前,两组患者症状都有所减轻,均改善了NYHA心功能,且增加了患者步行6min的距离,LVEF有所提升,LVEDD与X线心胸比例有所缩小,对于以上指标,观察组改善比较明显(P<0.05),而对照组改善不明显(P>0.05)。观察组治疗有效率为96.0%,对照组为76.0%,观察组治疗有效率明显高于对照组(P<0.05)。对两组患者进行2个月的随访观察发现,观察组死亡1例,再发心肌梗死2例,脑栓塞1例,心律失常4例,死亡率为2.0%,并发症发生率为16.0%;对照组死亡3例,再发心肌梗死4例,脑栓塞3例,心律失常5例,死亡率为30.0%,并发症发生率为6.0%。结论PCI能够有效改善ICM患者心功能,有利于患者生活质量的提升,具有较好的近期疗效,在PCI时,应该对最佳血运重建方案进行选择,合理掌握手术操作时间,由此才能保证手术治疗的有效与安全。     

多巴酚丁胺负荷超声在缺血性心肌病患者中的应用研究

目的 :本研究应用多巴酚丁胺负荷超声 (DSE)检测缺血性心肌病患者的心肌存活性 ,预测冠状动脉旁路移植 (CABG)术后心功能的恢复。方法 :左室射血分数≤ 40 %的多支冠状动脉病变患者于 CABG术前一周内接受 DSE检查 ,术后 3个月随诊检查。结果 :入选患者 2 6例 ,经 DSE无严重并发症 ,识别存活心肌敏感性 73 .9% ,特异性 81.5% ,准确性 78.2 % ,预测 CABG术后室壁功能恢复的敏感性 85.7% ,特异性 83 % ,准确性 85% ,5例患者 2 8个节段出现双向反应。结论 :对于缺血性心肌病的患者 ,小剂量 DSE可以安全、有效地检测存活心肌并预测 CABG术后的效果     

In Vitro and In Vivo Efficacy of Florfenicol for Treatment of Francisella asiatica Infection in Tilapia

Francisella asiatica is a recently described, Gram-negative, facultative intracellular fish pathogen, known to be the causative agent of francisellosis in warm-water fish. Francisellosis outbreaks have increased in frequency among commercial aquaculture operations and have caused severe economic losses in every case reported. The lack of effective treatments for piscine francisellosis led us to investigate the potential efficacy of florfenicol for inhibition of F. asiatica in vitro and as an oral therapeutic agent in vivo. The MIC of florfenicol for F. asiatica, as determined by the broth dilution method, was 2 μg/ml, which indicates its potential efficacy as a therapeutic agent for treatment of francisellosis. The intracellular susceptibility of the bacterium to florfenicol in tilapia head kidney-derived macrophages (THKDM) was also investigated. Addition of florfenicol to the medium at 10 μg/ml was sufficient to significantly reduce bacterial loads in the THKDM in vitro. Cytotoxicity assays done in infected THKDM also demonstrated drug efficacy in vivo, as determined by lactate dehydrogenase (LDH) release. Levels of LDH released from infected THKDM were significantly lower in macrophages treated with florfenicol (P < 0.001) than in untreated cells. In medicated-feed trials, fish were fed 15 mg of florfenicol/kg of fish body weight for 10 days, and the feeding was initiated at either 1, 3, or 6 days postchallenge. Immersion challenges resulted in 30% mean percent survival in nontreated fish, and fish receiving medicated feed administered at 1 and 3 days postinfection showed higher mean percent survival (100% and 86.7%, respectively). A significant decrease (P < 0.001) in bacterial numbers (number of CFU/g of spleen tissue) was observed in treated groups compared to nontreated infected fish at both 1 and 3 days postchallenge. There were no differences in bacterial burden in the spleens between fish treated 6 days postchallenge and untreated controls. In conclusion, if florfenicol is administered during early stages of infection, it has the potential for effectively treating piscine francisellosis, including the capacity for intracellular penetration and bacterial clearance.Members of the genus Francisella are small, pleomorphic, Gram-negative bacteria belonging to the Gammaproteobacteria (3, 7, 28). Many Francisella spp. are facultative intracellular pathogens, capable of replicating in macrophages and other various cell types in humans, rabbits, rodents, nonhuman primates, and fish. The bacteria may also exist as endosymbionts of amoebae and arthropods (1, 2, 7, 26, 31, 34). Francisella asiatica and Francisella noatunensis are two recently described members of the genus that causes piscine francisellosis in a wide variety of fish species (19).During the past 5 years F. asiatica has been implicated as the causative agent of mortality in tilapia (Oreochromis sp.) and other important warm-water species cultured in the United States (including Hawaii), Taiwan, Latin America (particularly Costa Rica), and Japan (13, 14, 15, 17, 19, 20, 29, 33). Due to its increase in incidence, high infectivity rates, and wide range of fish hosts, francisellosis is now considered one of the most important emergent diseases in aquaculture (13, 14, 15, 17, 19, 20, 29, 33). In tilapia the disease can present as an acute syndrome with few nonspecific clinical signs and high mortality rates or as a subacute to chronic syndrome with nonspecific clinical signs like anorexia, exophthalmia, and anemia. The bacterium has a high infectivity rate in tilapia fingerlings. Low numbers (1 to 10 CFU) of the bacterium injected intraperitoneally can cause colonization and significant damage to the head kidney and spleen, with a dose as low as 23 bacteria resulting in mortality (30). Macroscopic and microscopic examination often reveals enlarged internal organs containing widespread multifocal white nodules (13, 14, 15, 17, 19, 20, 29). Moreover, F. asiatica has been found to be resistant to serum killing and can penetrate, replicate, and survive in tilapia head kidney-derived macrophages (THKDM) (31).Very limited data on fish pathogen susceptibility to antibiotics have been published. Only recently have guidelines been published for broth microdilution testing of fish pathogens (8); however, methods for fastidious organisms such as F. asiatica are not included in this publication. Clinical breakpoints are not available for this class of fish pathogens either. Currently, only three antibiotics have been approved by the U.S. Food and Drug Administration for use in U.S. aquaculture: oxytetracycline (Terramycin 200 for fish; Phibro Animal Health, Fairfield, NJ), ormetoprim-sulfadimethoxine (Romet-30 type A medicated article; Pharmaq AS, Oslo, Norway), and florfenicol (Aquaflor type A medicated article; Intervet/Schering-Plough Animal Health, Roseland, NJ). Florfenicol is a fluorinated derivative of thiamphenicol that blocks the peptidyltransferase at the 50S ribosome subunit and acts against a wide variety of both Gram-positive and Gram-negative bacteria (5). As a medicated feed, florfenicol has been used to treat a wide variety of fish diseases in various warm- and cold-water cultured fish species, including Vibrio anguillarum, Aeromonas salmonicida, Streptococcus iniae, Listonella anguillarum, and Edwardsiella ictaluri, among others (9, 11, 23, 24, 27).Due to the emergent nature of francisellosis in fish and the fastidious characteristics of the bacteria, there is currently very little published data regarding antibiotic susceptibility of F. asiatica in vivo or in vitro, and at present there are no known efficacious chemotherapeutics or vaccines available (17, 20, 29, 30, 31, 32). Additionally, antimicrobial therapy in facultative intracellular bacteria is more complex than in extracellular bacteria since the efficacy of the drug depends on its ability to penetrate and accumulate within the cell, cellular metabolism, subcellular disposition, and bioavailability of the drug (25). For F. noatunensis, in vitro data were presented that indicated that strain GM2212T was resistant to trimethoprim-sulfamethoxazole, penicillin, ampicillin, cefuroxime, and erythromycin yet susceptible to ceftazidime, tetracycline, gentamicin, and ciprofloxacin (21). No further research has been published to demonstrate the potential use of any of these drugs in medicated feed for the treatment of francisellosis in fish. Moreover, at this point it is unknown if the antimicrobial susceptibilities of F. noatunensis and F. asiatica are the same.The goal of the present study was to determine the ability of florfenicol-medicated feed to control experimentally induced F. asiatica infection in tilapia. Additionally, we evaluated the capacity of florfenicol to eliminate intracellular F. asiatica from THKDM in vitro.     

自体骨髓基质细胞移植于缺血心肌的实验研究

目的 观察骨髓基质细胞自体移植到缺血坏死心肌局部细胞分化、血管新生和心功能改善状况。方法 30只日本大耳兔分成损伤对照组、心肌梗死组和细胞移植组。结扎梗死组和移植组兔冠状动脉左前降支，复制心肌梗死模型后梗死组心内注射培养基，移植组进行骨髓基质细胞移植。于移植后4周检测移植组抗Brdu染色、抗心肌特异性肌钙蛋白T(troponin T)染色和抗Ⅶ因子抗体的染色结果，比较毛细血管密度。分别于结扎前、结扎后和移植后4周测量3组实验兔的心脏形态大小和心功能。结果 移植组在移植区可检测到大量Brdu阳性标记的细胞，抗troponin T染色和抗Ⅶ因子染色阳性，毛细血管密度较梗死组显著增高，左室腔径则明显减小，心功能各项指标明显改善。结论 骨髓基质细胞移植入缺血坏死心肌能在局部分化成为类心肌细胞，促使血管新生，有效改善心功能。     

多普勒超声心动图检查对缺血性心肌病左室重构的研究

本文应用多普勒超声心动图对５１例缺血性心肌病（ＩＣＭ）患者的左室重构进行研究。结果显示。ＩＣＭ组的各项指标与正常组比较均有显著差异（Ｐ＜０．０１）。ＩＣＭ组的ＬＶＤｄ、ＬＶＤｓ、ＰＣＷＰ和ＥＳＳ显著增大，ＳＶ、ＣＩ、ＥＦ、ＭＶＣＦ明显降低。结论，ＩＣＭ的左室重构与缺血性心肌损伤（包括冠脉闭塞和冠脉狭窄）引起的左室扩张、肺毛细血管楔压和室壁应力增加有关。多普勒超声心动图对ＩＣＭ左室重构的研究具有重要临床价值。     

In Vivo Transfer of Intracellular Labels from Locally Implanted Bone Marrow Stromal Cells to Resident Tissue Macrophages

Intracellular labels such as dextran coated superparamagnetic iron oxide nanoparticles (SPION), bromodeoxyuridine (BrdU) or green fluorescent protein (GFP) are frequently used to study the fate of transplanted cells by in vivo magnetic resonance imaging or fluorescent microscopy. Bystander uptake of labeled cells by resident tissue macrophages (TM) can confound the interpretation of the presence of intracellular labels especially during direct implantation of cells, which can result in more than 70% cell death. In this study we determined the percentages of TM that took up SPION, BrdU or GFP from labeled bone marrow stromal cells (BMSCs) that were placed into areas of angiogenesis and inflammation in a mouse model known as Matrigel™ plaque perfusion assay. Cells recovered from digested plaques at various time points were analyzed by fluorescence microscopy and flow cytometry. The analysis of harvested plaques revealed 5% of BrdU⁺, 5–10% of GFP⁺ and 5–15% of dextran⁺ macrophages. The transfer of the label was not dependent on cell dose or viability. Collectively, this study suggests that care should be taken to validate donor origin of cells using an independent marker by histology and to assess transplanted cells for TM markers prior to drawing conclusions about the in vivo behavior of transplanted cells.     

急性脑梗死行动脉溶栓术患者的围术期护理

目的探讨急性脑梗死行动脉溶栓术患者的围术期护理方法。方法回顾分析并总结2009年1月至2013年6月苏州市立医院收治的31例急性脑梗死行动脉溶栓术患者的临床资料。结果本组患者使用阿替普酶15~35 mg,平均(24.4±15.9)mg;所有患者无围术期伤口血肿、假性动脉瘤等穿刺相关并发症发生;溶栓结束后有14例患者(45.16%)血管完全再通,11例(35.48%)部分再通,6例未通(19.36%),有效率达80.64%。结论精心细致的围术期护理有利于保证动脉溶栓治疗急性脑梗死患者的效果。     

曲美他嗪治疗酒精性心肌病的Meta分析

【目的】采用Meta分析评价联用曲美他嗪（TMZ）治疗酒精性心肌病（ACM ）的有效性。【方法】检索PubMed、MedLine、Clinical Trials、Cochrane临床对照试验中心数据库、CNKI全文数据库、万方医学数据库、维普全文数据库建库至今公开发表的与TMZ治疗ACM 相关的临床试验文献。按照纳入和排除原则进行文献筛选及进行方法学质量评估。采用RevM an 5．2软件进行M eta分析。【结果】共纳入5项研究,288例患者。Meta分析显示：与β受体阻滞剂、血管紧张素转换酶抑制剂（ACEI）、利尿剂、维生素等常规治疗相比,联用TMZ治疗可明显增加6分钟步行距离（WMD＝74．53,95％ CI 25．55～123．50）,明显提高左室射血分数（W M D＝5．15,95％ C I 2．82～7．49）,具有更好的治疗有效性（O R＝8．94,95％ C I 2．44～32．80）。【结论】联用TMZ可明显改善ACM患者的心功能指标,改善患者生活质量。     

从缺血性肾病的治疗困惑展望间充质干细胞治疗愿景

慢性肾动脉狭窄引起的缺血性肾脏疾病可能导致肾功能不可逆转的丧失,因其发病率和病死率呈上升趋势,有关临床和基础研究日益受到重视。慢性缺血性肾病的病理生理学是多方面的,涉及复杂的激素免疫和细胞的相互作用,并导致肾脏多种细胞类型损害,而且往往抵抗常规疗法。近年来多中心临床研究证明血管内支架治疗动脉粥样硬化引起的慢性肾动脉狭窄对血压控制,肾功能和预后均无显著益处。因此,有必要寻找新颖的方法来修复肾实质和保护肾脏功能。间充质干细胞(mesenchymal stem cells,MSC)通过旁分泌或内分泌作用赋予肾脏保护,并在一定程度上可直接转化为肾脏细胞,其抗炎和免疫调节性能作用于缺血性肾脏病致病机理的多个环节。本文就利用MSC预防治疗缺血性肾损伤的最新进展作一述评。