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。     

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.     

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.     

碱性成纤维细胞生长因子对体外培养大鼠胚胎脊髓神经细胞的作用

目的:适当的碱性成纤维细胞生长因子剂量能促进脂质过氧化活性,发挥保护脊髓神经细胞的功能。设立不同浓度的碱性成纤维细胞生长因子,比较其对大鼠胚胎脊髓神经细胞生长发育和脂质过氧化的影响,筛选出保护脊髓损伤的机会窗口。方法:实验于2006-08/10在江苏大学医学技术学院细胞培养室完成。①实验方法:健康成年妊娠16d的Wistar孕鼠1只,取出胚胎脱颈椎法处死,分离脊髓组织胰蛋白酶消化,制备细胞悬液,将脊髓神经细胞密度调整至4×105L-1。碱性成纤维细胞生长因子组分别向细胞悬液中加入1,10,50,100,200μg/L碱性成纤维细胞生长因子20μL,设立正常对照组。②实验评估:倒置相差显微镜下观察胚胎脊髓神经细胞形态,计数集落数,确定细胞分化的结果。检测超氧化物歧化酶活性、丙二醛含量及相对蛋白质含量。结果:①胚胎脊髓神经细胞的形态:刚接种的脊髓神经细胞为圆形,随着培养的时间延长胞体逐渐增大,伸出突起的脊髓神经细胞逐渐增多、突起伸长。培养5～8d的脊髓神经细胞胞体最丰满,周围晕光明显,随后大量脊髓神经细胞增殖形成细胞岛。②鼠胚胎脊髓神经细胞的生长分化:与正常对照组比较,碱性成纤维细胞生长因子10,50,100μg/L组细胞集落数明显增加(P<0.05);至200μg/L时细胞集落数减少(P<0.01),细胞存活率明显下降,甚至出现细胞死亡现象。③鼠胚胎脊髓神经细胞相对蛋白质含量:与正常对照组比较,碱性成纤维细胞生长因子10,50,100μg/L组可明显提高鼠胚胎脊髓神经细胞相对蛋白质含量(P<0.05);至200μg/L时则产生抑制作用(P<0.01)。④鼠胚胎脊髓神经细胞抗氧化指标检测:与正常对照组比较,碱性成纤维细胞生长因子10,50,100μg/L组超氧化物歧化酶活性升高,丙二醛含量降低(P<0.05);至200μg/L时丙二醛含量明显升高(P<0.01)。结论:10～100μg/L的碱性成纤维细胞生长因子能促进鼠胚胎脊髓神经细胞的生长发育,增加细胞突起长度,调节脂质过氧化水平,维持细胞内的自由基动态平衡。     

A prospective, randomized study of the use of platelet concentrates irradiated with ultraviolet-B light in patients with hematologic malignancy

BACKGROUND: Irradiation of platelet concentrates (PCs) with ultraviolet- B (UVB) light inactivates the contaminating white cells and might be an alternative to filtration for the prevention of alloimmunization to HLA antigens and subsequent refractoriness to further platelet transfusions in multiply transfused patients with bone marrow failure. STUDY DESIGN AND METHODS: Patients with hematologic malignancy, mainly acute myeloid leukemia, were prospectively assigned in a random manner to receive either UVB-irradiated or control, nonirradiated PCs. All patients were given red cells that were white cell reduced by filtration. Transfusion efficacy and alloimmunization were assessed by means of corrected count increments, requirement for red cells and PCs, and measurement of lymphocyte-reactive antibodies. RESULTS: UVB-irradiated PCs had a clinical efficacy similar to controls as judged by corrected count increments at 1 to 6 and 12 to 24 hours and by the median requirement for red cell and platelet transfusions. Alloimmunization determined by measurements of lymphocyte-reactive antibodies using both conventional and antiglobulin-augmented lymphocytotoxicity techniques was not abolished in recipients of UVB-irradiated PCs (4/30, 13%) but was less than that in controls (5/20, 25%; p = NS). The mean number of platelet transfusion episodes prior to the occurrence of alloimmunization was greater in the control group (27 vs. 10; p = 0.017). CONCLUSION: In this trial, UVB irradiation did not diminish the clinical efficacy of platelet transfusions. There was a small but nonsignificant reduction alloimmunization, but no difference in refractoriness of the two groups was observed. Larger prospective randomized studies are required to confirm these findings and to compare UVB irradiation with white cell reduction.     

Community acquired, nursing home acquired and hospital acquired pneumonia: A five-year review of the clinical, bacteriological and radiological characteristics

Purpose:

To assess the contemporary clinical, bacteriological and radiographic features of hospitalized patients with community acquired (ca), nursing home acquired (na) and hospital acquired pneumonia (ha) and to examine patient outcome.

Patients and Methods:

All hospital records of patients with pneumonia over a five-year period from April 1987 to March 1992 were reviewed retrospectively. Patients included in the study were all those with a diagnosis of pneumonia as identified by computer records of diagnostic codes at discharge; patients with a specific diagnosis of Pneumocystis carinii pneumonia were excluded. Of 74,435 discharges over the five-year period, 1782 patients met the inclusion criteria.

Results:

Charts of 1622 of the total 1782 cases were reviewed. Mean age was 64.4 years with 59.4% men and 40.6% women. Sixty-three per cent were ca, 28.5% were ha and 8.5% were na. A total of 1542 patients (95%) had at least one concomitant medical condition. Chest roentgenogram was abnormal in 97%. Common organisms isolated overall were Haemophilus influenzae (from 204 patients), Staphylococcus aureas (from 152 patients), Streptococcus pneumoniae (from 143 patients ), Escherichia coli (from 113 patients) and Pseudomonas aeruginosa (from 111 patients). H influenzae and S pneumoniae were most common in ca pneumonia, whereas S aureus and Gram-negative organisms were more common in the ha group and Gram-negative agents in the na group. One hundred and four patients developed complications. Fifteen per cent required intensive care unit admission. The average length of hospitalization in the ca and na groups was 17 days and in the ha group, 43 days. At time of discharge 1261 patients (78%) were cured or improved, and 361 patients (22%) died during the admission.

Conclusions:

These results suggest that hospitalization for pneumonia in the 1990s is primarily for elderly patients with significant co-morbidity. Although microbiology appears unchanged compared with earlier reports, the contemporary population is significantly sicker than previous cohorts. This may account for the persistently high morbidity and mortality despite better or newer antibiotics.     

A collaborative, double-blind randomized study of cetiedil citrate in sickle cell crisis

We have recently completed a double-blind, placebo-controlled, noncrossover study, the goal of which was to determine whether cetiedil citrate (cetiedil) could affect the course of vaso-occlusive crises in sickle cell disease. Patients, who presented to the emergency room at least 4 but no more than 24 hours after the onset of a painful vasoocclusive crisis severe enough to require hospitalization, were considered candidates for the study. Each patient received either placebo or cetiedil at one of the following three dosages: 0.2, 0.3, or 0.4 mg/kg body weight. The assigned drug dosage was given as a 30 minute intravenous infusion every 8 hours for 4 consecutive days. A total of 67 patients was enrolled in the study. Cetiedil, at its highest dosage (0.4 mg/kg body weight), was found to be significantly superior to placebo both in reducing the number of painful sites present on all 4 treatment days and in shortening the total time in crisis. No serious adverse reactions were observed during the course of the study. We conclude that cetiedil, given at a dosage of 0.4 mg/kg body weight, is therapeutically advantageous for sickle cell crisis.