Use of recombinant human erythropoietin in allogeneic bone marrow transplant donor/recipient pairs

In an attempt to reduce or eliminate homologous red blood cell transfusion requirements during allogeneic bone marrow transplantation (BMT), we instituted a novel program whereby recombinant human erythropoietin was administered to pairs of BMT donors and recipients. Eleven recipients and their HLA-matched donors were enrolled. Donors treated with recombinant human erythropoietin (rHuEPO) were phlebotomized a median of 6 U (range, 4 to 11 U) of blood over a 5-week period. This donor-derived blood was available to the BMT donor or recipient as needed. Transplant recipients were also treated with rHuEPO post-BMT to hasten erythropoiesis. Five of 11 BMT recipients underwent transplant receiving only donor-derived red blood cell transfusion, compared with 0 of 11 concomitant control recipients (P = .04). In addition, the time to absolute reticulocyte count > or = 10(4)/microL was statistically shorter in the rHuEPO-treated recipient group. This study serves as a paradigm for hematopoietic growth factor use in allogeneic BMT to decrease or eliminate homologous transfusion exposures and to possibly hasten hematopoietic engraftment.     

CD8+ T Cell Recognition of Epitopes Within the Capsid of Adeno-associated Virus 8–based Gene Transfer Vectors Depends on Vectors' Genome

Self-complementary adeno-associated viral (AAV) vectors expressing human factor IX (hF.IX) have achieved transient or sustained correction of hemophilia B in human volunteers. High doses of AAV2 or AAV8 vectors delivered to the liver caused in several patients an increase in transaminases accompanied by a rise in AAV capsid-specific T cells and a decrease in circulating hF.IX levels suggesting immune-mediated destruction of vector-transduced cells. Kinetics of these adverse events differed in patients receiving AAV2 or AAV8 vectors causing rise in transaminases at 3 versus 8 weeks after vector injection, respectively. To test if CD8⁺ T cells to AAV8 vectors, which are similar to AAV2 vectors are fully-gutted vectors and thereby fail to encode structural viral proteins, could cause damage at this late time point, we tested in a series of mouse studies how long major histocompatibility (MHC) class I epitopes within AAV8 capsid can be presented to CD8⁺ T cells. Our results clearly show that depending on the vectors'' genome, CD8⁺ T cells can detect such epitopes on AAV8''s capsid for up to 6 months indicating that the capsid of AAV8 degrades slowly in mice.     

精神分裂症患者的社交技能训练小组活动方案

目的:通过社交技能训练让精神分裂症患者明确正确的沟通方式,锻炼自己的交谈能力,学会社会交往技巧,体会人与人之间的关系,学会分析解决社交过程中出现的问题,从而掌握社会交往的技能,防止或延缓发生严重的社会功能衰退。方法:选择早期精神分裂症患者(5年内),在住院治疗达到临床治愈出院后立即开始训练。活动以小组为单位(10人1组)进行,小组成员相对固定。前3个月每个月1次,以后每3个月1次,持续1年。活动过程中以游戏为主导,让组员在游戏中领会人际交往过程中的要领。具体训练方案包括6个方面:①训练一:语言表达能力,正确的沟通方式。②训练二:如何寻找帮助。③训练三:指导患者学习人际交往的基本技巧。④训练四:如何与人打交道。⑤训练五:合作。⑥训练六:社交问题的解决。结果:通过增加对社交时恐惧的暴露及社交技巧训练,对精神分裂症伴发社交恐惧症有效;但对精神分裂症意志活动减退所致社交时主动性不足效果较差。结论:对精神分裂症患者的社交训练应尽早进行,同时在设计精神分裂症社交训练时应加强对患者主动性不足的针对性。     

肺纤维化鼠Ⅰ型前胶原和Ⅲ型前胶原mRNA表达及芪丹颗粒剂的干预效应

目的:观察芪丹颗粒对博莱霉素致肺纤维化鼠的Ⅰ型前胶原和Ⅲ型前胶原mRNA表达的影响,探讨其作用机制。方法:实验于2004-10/2006-10在山东省医学科学院基础所病理实验室完成。实验材料:清洁级雄性SD大鼠160只,体质量180～210g。氢化可的松琥珀酸钠50mg/支;芪丹(颗粒剂)是由黄芪、丹参、川芎等中草药加工提纯后的粗提取物制成的颗粒剂,10g/包(1g干粉相当于原生药8g)。实验分组:160只SD大鼠按随机区组设计分为正常组20只、模型组40只、芪丹颗粒剂50只、氢化可的松50只。实验干预:正常组20只气管内灌注和灌胃均用生理盐水。其余大鼠经气管内一次性灌注博莱霉素A5按0.25mL左右(5mg/kg体质量)诱导大鼠肺间质纤维化。随机取40只为模型组。取芪丹颗粒剂组和氢化可地松组大鼠各30只,分别从造模后第2天灌注芪丹颗粒剂(3125mg/kg)和腹腔注射氢化可的松(25mg/kg),药物干预后第7,14,28天麻醉下处死动物。两组各余20只分别从造模14d后灌注芪丹颗粒剂和腹腔注射氢化可的松(用量同前),于第28、42天分别处死动物。实验评估:用苏木精-伊红评价肺组织病理学变化和原位杂交方法检测各组大鼠肺Ⅰ型和Ⅲ型前胶原mRNA表达。结果:160只大鼠全部进入结果分析。①大鼠肺脏大体标本观察:对照组肺组织各观察时间点无明显改变,模型组肺组织表面凸凹不平,部分肺叶体积缩小,表面见灰白色结节。氢化可的松组与模型组相似。芪丹颗粒剂组见部分肺叶表面不光滑及大小不等结节。②肺组织病理学观察:模型组7d肺泡腔内大量巨噬细胞淋巴细胞中性粒细胞浸润,肺间质成纤维细胞增殖,28d肺泡结构破坏肺泡内见大量胶原纤维和成纤维细胞。芪丹颗粒剂组肺泡炎及肺纤维化程度均明显轻于模型组和氢化可的松组(P<0.05)。③肺间质纤维化形成中Ⅰ型、Ⅲ型前胶原mRNA表达:原位杂交显示两种前胶原mRNA表达呈动态变化,早期肺泡炎以Ⅲ型前胶原mRNA大量增生为主,晚期纤维化期以Ⅰ型前胶原mRNA增生为主。芪丹颗粒剂组Ⅲ型前胶原mRNA的表达在第14天处于最高,至28d仍维持较高的水平,芪丹颗粒剂组Ⅲ型前胶原mRNA的表达高于模型组和氢化可的松组(P<0.05)。28d,Ⅰ型前胶原mRNA的表达在第二天给药芪丹颗粒剂组和氢化可地松组及第14天给药芪丹颗粒剂组和氢化可的松组组间差异均有显著性(P<0.05)。结论:大鼠肺纤维化的早期以Ⅲ型前胶原mRNA的表达为主,晚期纤维化期以Ⅰ型前胶原mRNA的大量表达为主。芪丹颗粒可减轻博莱霉素诱导的大鼠肺泡炎及肺纤维化的程度,其机制可能通过影响了Ⅰ型和Ⅲ型前胶原mRNA的代谢和表达,从而减慢肺间质纤维化的进程。芪丹颗粒对肺间质纤维化有治疗作用,且优于氢化可的松。     

The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen

BACKGROUND: Tamoxifen is biotransformed to the potent anti-estrogen, endoxifen, by the cytochrome P450 (CYP) 2D6 enzyme. CYP2D6 genetic variation and inhibitors of the enzyme markedly reduce endoxifen plasma concentrations in tamoxifen-treated patients. Using a North Central Cancer Treatment Group adjuvant tamoxifen trial, we performed a comprehensive evaluation of CYP2D6 metabolism by assessing the combined effect of genetic variation and inhibition of the enzyme system on breast cancer recurrence and death. METHODS: Medical records were reviewed at each randomizing site to determine whether CYP2D6 inhibitors were co-prescribed with tamoxifen. Extensive metabolizers were defined as patients without a *4 allele (i.e., wt/wt) who were not co-prescribed a CYP2D6 inhibitor. Patients with decreased CYP2D6 metabolism were classified as intermediate or poor metabolizers (PM) based on the presence of one or two CYP2D6*4 alleles or the co-administration of a moderate or potent CYP2D6 inhibitor. The association between CYP2D6 metabolism and clinical outcome was assessed using Cox modeling. RESULTS: Medication history was available in 225/256 eligible patients and CYP2D6*4 genotype in 190 patients. Thirteen patients (6%) were co-prescribed a CYP2D6 inhibitor [potent (n = 3), moderate (n = 10)], resulting in the following CYP2D6 metabolism: extensive (n = 115) and decreased (n = 65). In the multivariate analysis, patients with decreased metabolism had significantly shorter time to recurrence (p = 0.034; adj HR = 1.91; 95% CI 1.05-3.45) and worse relapse-free survival (RFS) (p = 0.017; adj HR = 1.74; 1.10-2.74); relative to patients with extensive metabolism. Cox' modeling demonstrated that compared to extensive metabolizers, PM had the most significant risk of breast cancer relapse (HR 3.12, p = 0.007). CONCLUSION: CYP2D6 metabolism, as measured by genetic variation and enzyme inhibition, is an independent predictor of breast cancer outcome in post-menopausal women receiving tamoxifen for early breast cancer. Determination of CYP2D6 genotype may be of value in selecting adjuvant hormonal therapy and it appears CYP2D6 inhibitors should be avoided in tamoxifen-treated women.