干细胞移植治疗缺血性心脏病的进展及其作用机制

学术背景：心肌梗死后，尽管现有的内外科治疗手段可以改善冠状动脉供血、挽救缺血心肌，但对已坏死的心肌或无功能心肌尚无良好治疗措施。细胞作为构成心脏结构、执行心脏功能的物质基础，尽管存在争议，但大量研究资料表明干细胞移植治疗是安全有效的。 目的：文章试图就目前成体干细胞在缺血，陛心脏病治疗的临床研究进展做一综述，客观评价成体干细胞治疗缺血性心脏病的安全性、有效性，阐述成体干细胞改善心功能的可能机制，介绍当今临床研究方向。 检索策略：由该论文的研究人员应用计算机检索Pubmed数据库1996／2007成体干细胞与缺血性心脏病方面的文献，检索词“adult stem cells,ischemial heart disease，cardiomyocytes”，并限定文章语言种类为English。同时计算机检索中国期刊全文数据库1996／2007的相关文献，检索词“成年干细胞，心肌细胞，缺血性心脏病”，并限定文章语言种类为中文。共检索到1303篇文献，对资料进行初审，纳入标准：①文章所述内容应与缺血性心脏病干细胞移植密切相关。②同一领域选择近期发表或在权威杂志上发表的文章。排除标准：①重复性研究。②Meta分析。 文献评价：文献的来源主要是通过对干细胞移植治疗缺血，陛心脏病现状及其作用机制进行汇总分析。1303篇文献中，动物实验和在体、离体、细胞学实验626篇，综述、述评、讲座类文献345篇，临床研究45篇，选用其中的46篇作为本文参考文献。 资料综合：①干细胞为一群具有自我更新、多向分化潜能的原始细胞，分为胚胎干细胞和成体干细胞。虽然研究表明胚胎干细胞较成体干细胞具有更强的增殖和分化潜能，但由于其涉及伦理道德、来源困难等原因，限制了它的使用。②就目前已完成的包括不同类型的成体细胞（如骨髓单个核细胞、内皮祖细胞、CD133^＋细胞、骨髓间充质干细胞、成肌细胞等）移植治疗缺血性心脏病的早期临床试验来看，尽管存在样本小、缺乏随机对照等不足，但均显示一个公认的事实，即无论采用何种方法移植成体干细胞治疗缺血性心脏病均是安全有效的。这对于正在进行的较大规模的临床研究是十分重要的，为其提供了更充分的临床资料。③多数研究认为干细胞改善心功能的作用机制包括直接与间接效应，如移植细胞横向分化为再生心肌与血管、移植细胞的旁分泌作用促进血管再生、抑制心肌细胞凋亡及心室重构等。近来研究认为外源前体移植心肌可以刺激机体内源心肌存留的干细胞增殖，从而改善心功能。 结论：尽管目前成体干细胞改善心功能的确切机制仍不清楚，但多数早期临床研究表明成体干细胞移植治疗缺血性心脏病是安全有效的。当前的研究方向是需要随机、双盲、安慰剂对照的多中心临床试验。     

Antigen-matched donor blood in the transfusion management of patients with sickle cell disease

BACKGROUND: Alloimmunization to red cell antigens is a significant risk in chronically transfused patients with sickle cell disease. Antigen matching, by decreasing the likelihood of alloantibody development, may significantly facilitate long-term management while decreasing morbidity. STUDY DESIGN AND METHODS: The transfusion records of 86 patients who underwent chronic transfusion for sickle cell disease at a tertiary-care medical center were reviewed retrospectively to determine the efficacy of an antigen-matching program in the prevention of alloimmunization to clinically significant red cell antigens. Recipients were phenotyped and given units matched for the K, C, E, S, and Fya or Fyb antigens. RESULTS: None (0%) of the 40 patients who received antigen-matched transfusions showed any evidence of alloimmunization, while 16 (34.8%) of the 46 patients who received both antigen-matched and non-antigen-matched transfusions developed clinically significant alloantibodies. The cost was 1.8 to 1.5 times that for a standard transfusion protocol. CONCLUSION: On the basis of this experience, it is recommended that transfusion centers engaged in the management of chronically transfused sickle cell anemia patients consider providing antigen-matched units for such patients. This is recommended not only because it prevents alloimmunization but also because such a program provides additional clinical benefits to the patient that may outweigh the higher costs of the process.     

Pharmacodynamic activity of telithromycin against macrolide-susceptible and macrolide-resistant Streptococcus pneumoniae simulating clinically achievable free serum and epithelial lining fluid concentrations

BACKGROUND: The association between macrolide resistance mechanisms and ketolide bacteriological eradication of Streptococcus pneumoniae remains poorly studied. The present study, using an in vitro model, assessed telithromycin pharmacodynamic activity against macrolide-susceptible and macrolide-resistant S. pneumoniae simulating clinically achievable free serum and epithelial lining fluid (ELF) concentrations. MATERIALS AND METHODS: Two macrolide-susceptible [PCR-negative for both mef(A) and erm(B)] and six macrolide-resistant [five mef(A)-positive/erm(B)-negative displaying various degrees of macrolide resistance and one mef(A)-negative/erm(B)-positive] S. pneumoniae were tested. Telithromycin was modelled simulating a dosage of 800 mg by mouth once daily [free serum: maximum concentration (C(max)) 0.7 mg/L, t(1/2) 10 h; and free ELF: C(max) 6.0 mg/L, t(1/2) 10 h]. Starting inocula were 1 x 10(6) cfu/mL in Mueller-Hinton broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24 and 48 h assessed the extent of bacterial killing (decrease in log(10) cfu/mL versus initial inoculum). RESULTS: Telithromycin free serum concentrations achieved in the model were: C(max) 0.9+/-0.08 mg/L, AUC(0-24) 6.4+/-1.5 mg.h/L and t(1/2) of 10.6+/-1.6 h. Telithromycin free ELF concentrations achieved in the model were: C(max) 6.6+/-0.8 mg/L, AUC(0-24) 45.5+/-5.5 mg.h/L and t(1/2) of 10.5+/-1.7 h. At 2 h, free serum telithromycin concentrations achieved a 1.0-1.9 log(10) reduction in inoculum compared with a 3.0-3.3 log(10) reduction with free ELF versus macrolide-susceptible and macrolide-resistant S. pneumoniae. Free telithromycin serum and ELF concentrations simulating C(max)/MIC > or =14.1 and area under the curve to MIC (AUC(0-24)/MIC) > or =100 [time above the MIC (t > MIC) of 100%], were bactericidal (> or =3 log(10) killing) at 4, 6, 12, 24 and 48 h versus macrolide-susceptible and macrolide-resistant S. pneumoniae. CONCLUSION: Telithromycin serum and ELF concentrations rapidly eradicated macrolide-susceptible and macrolide-resistant S. pneumoniae regardless of resistance phenotype. Achieving C(max)/MIC > or =14.1 and AUC(0-24)/MIC > or =100 resulted in bactericidal activity at 4 h with no regrowth over 48 h.