肾移植受者CYP3A5基因多态性对术后他克莫司药物代谢的影响

目的 研究肾移植受者细胞色素P450 3A(CMP3A)酶系中的CYP3A5基因多态性对术后他克莫司(Tac)药物代谢的影响,并探讨测定CYP3A5基因型的方法 .方法 选取97例肾移植术后常规使用Tac+吗替麦考酚酯+泼尼松三联免疫抑制方案的受者.用焦磷酸测序法测定受者CYP3A5基因型;用均相酶扩大免疫分析法(EMIT)测定受者全血Tac浓度谷值(C0);比较不同基因型的受者肾移植术后第7天、第14天、1个月、3个月和6个月时的Tac C0,与Tac校正剂量的比值(Tac G0/Tac校正剂量).结果 焦磷酸测序法能够快速准确的测定肾移植受者CYP3A5基因型;97例肾移植受者CYP3A5基因型分别为:CYP3A5+1/*1型17例(17.5%),CYP3A5* 1/*3型35例(36.1%),CYP3A5*3/*3型45例(46.4%).CYP3A5*1/*1型和CYP3A5*1/*3型受者肾移植术后Tac G0/Tac校正剂量均显著低于CYP3A5*3/*3型受者.结论 肾移植受者CYP3A5基因型对Tac药物代谢具有显著的影响.采用焦磷酸法测定肾移植受者CYP3A5基因多态性,有助于确定不同个体移植术后理想的Tac起始剂量,实现Tac个体化用药.     

胸腺肽α1治疗高龄患者消化系统肿瘤的临床疗效分析

目的观察及评价胸腺肽α1(Tα1)对高龄消化系统恶性肿瘤患者细胞免疫功能的影响和临床疗效。方法96例高龄消化系统恶性肿瘤患者,随机分为对照组(化疗)和治疗组(化疗 Tα1),每组48例。治疗组在化疗的同时给予1.6mg Tα1皮下注射,隔日1次,连续应用8周,对照组则在化疗的同时给予等剂量生理盐水,用法与治疗组相同。在化疗前1周和化疗第2、4、8周分别检测患者T淋巴细胞亚群及NK淋巴细胞活性,并记录患者Karnofsky体力评分。结果治疗后治疗组患者的Karnofsky评分明显高于对照组(P<0.05)。治疗组机体免疫能力相关指标CD4 、CD4 /CD8 和NK细胞活性在治疗后明显高于治疗前,差异有显著性(P<0.05)。治疗后治疗组CD4 、CD4 /CD8 和NK细胞活性明显高于对照组,差异有显著性(P<0.05)。结论胸腺肽α1可提高高龄消化系统恶性肿瘤患者的细胞免疫功能,改善患者生活质量,对消化系统恶性肿瘤有一定的辅助治疗作用。     

Relation between regional and global systolic function in patients with ischemic cardiomyopathy after β-Blocker therapy or revascularization

Background

To assess the relationship between improved regional and global myocardial function in patients with ischemic cardiomyopathy in response to β-blocker therapy or revascularization.

Materials and methods

Cardiovascular Magnetic Resonance (CMR) was performed in 32 patients with ischemic cardiomyopathy before and 8 ± 2 months after therapy. Patients were assigned clinically to β-blocker therapy (n = 20) or revascularization (n = 12). CMR at baseline was performed to assess regional and global LV function at rest and under low-dose dobutamine. Wall thickening was analyzed in dysfunctional, adjacent, and remote segments. Follow-up CMR included rest function evaluation.

Results

Augmentation of wall thickening during dobutamine at baseline was similar in dysfunctional, adjacent and remote segments in both patient groups. Therefore, baseline characteristics were similar for both patient groups. In both patient groups resting LV ejection fraction and end-systolic volume improved significantly (p < 0.05) at follow-up. Stepwise multivariate analysis revealed that improvement in global LV ejection fraction in the β-blocker treated patients was significantly related to improved function of remote myocardium (p < 0.05), whereas in the revascularized patients improved function in dysfunctional and adjacent segments was more pronounced (p < 0.05).

Conclusion

In patients with chronic ischemic LV dysfunction, β-Blocker therapy or revascularization resulted in a similar improvement of global systolic LV function. However, after β-blocker therapy, improved global systolic function was mainly related to improved contraction of remote myocardium, whereas after revascularization the dysfunctional and adjacent regions contributed predominantly to the improved global systolic function.     

A Randomized,Placebo-Controlled,Active-Reference,Double-Blind,Flexible-Dose Study of the Efficacy of Vortioxetine on Cognitive Function in Major Depressive Disorder

This multicenter, randomized, double-blind, placebo-controlled, active-referenced (duloxetine 60 mg), parallel-group study evaluated the short-term efficacy and safety of vortioxetine (10–20 mg) on cognitive function in adults (aged 18–65 years) diagnosed with major depressive disorder (MDD) who self-reported cognitive dysfunction. Efficacy was evaluated using ANCOVA for the change from baseline to week 8 in the digit symbol substitution test (DSST)–number of correct symbols as the prespecified primary end point. The patient-reported perceived deficits questionnaire (PDQ) and physician-assessed clinical global impression (CGI) were analyzed in a prespecified hierarchical testing sequence as key secondary end points. Additional predefined end points included the objective performance-based University of San Diego performance-based skills assessment (UPSA) (ANCOVA) to measure functionality, MADRS (MMRM) to assess efficacy in depression, and a prespecified multiple regression analysis (path analysis) to calculate direct vs indirect effects of vortioxetine on cognitive function. Safety and tolerability were assessed at all visits. Vortioxetine was statistically superior to placebo on the DSST (P<0.05), PDQ (P<0.01), CGI-I (P<0.001), MADRS (P<0.05), and UPSA (P<0.001). Path analysis indicated that vortioxetine''s cognitive benefit was primarily a direct treatment effect rather than due to alleviation of depressive symptoms. Duloxetine was not significantly different from placebo on the DSST or UPSA, but was superior to placebo on the PDQ, CGI-I, and MADRS. Common adverse events (incidence ⩾5%) for vortioxetine were nausea, headache, and diarrhea. In this study of MDD adults who self-reported cognitive dysfunction, vortioxetine significantly improved cognitive function, depression, and functionality and was generally well tolerated.     

Cervista和MALDI-TOF-MS HPV法用于子宫颈癌筛查效果评价检测

目的：中美合作深圳万例子宫颈癌筛查项目（SHENCCASTⅡ）,主要研究目的就是评价人类乳头状瘤病毒（HPV）作为子宫颈癌初筛方法的可行性。笔者报道研究项目中期评估数据,以HybridCaptureII（HC-II）法HPV检测为对照,评价新的CervistaHPV检测方法和MALDI-TOF-MSHPV基因分型检测技术（MALDI-TOF-MS）在宫颈癌筛查中的效果。方法：本研究拟募集深圳市区、郊区及周边农村地区1万名年龄25岁至59岁、至少3年未参加过子宫颈癌筛查、未接受过子宫切除术及放疗、有过性生活的非孕期女性为筛查对象。宫颈细胞由医生取样,收集在PreservCyt细胞保存液中,首先液基细胞学制片,然后进行HC-Ⅱ、Cervista和MALDI-TOF-MS3种方法的HPV检测。细胞学≥ASCUS及任一方法HPV检测结果阳性者均进一步行阴道镜下四象限多点活检及ECC病理诊断。结果：5316例参加筛查女性中,5043例数据齐全。HC-Ⅱ、Cervist、MALDI-TOF-MS3种HPV检测方法HPV阳性率分别是：14.6%,12.2%,14%。发现CIN2以上病变150例,CIN3以上病变97例,宫颈癌5例。对于发现CIN2及以上病变,HC-Ⅱ、Cervista、MALDI-TOF-MS3种HPV检测的敏感性、特异性、阳性预测值、阴性预测值分别是：94.7%、87.9%、19.3%、99.8%;90.7%、90.2%、22%、99.7%和92.7%、88.4%、19.7%、99.8%。对于检出CIN3及以上病变,HC-Ⅱ、Cervista、MALDI-TOF-MS的敏感性、特异性、阳性预测值、阴性预测值分别是：97%、87%、12.8%、99.9%;91.8%、89.3%、14.4%、99.8%和94.9%、87.6%、13.1%、99.9%。Cervista和HC-Ⅱ、MALDI-TOF-MS的敏感性、特异性比较有统计学差异（P〈0.01）,但MALDI-TOF-MS和HC-Ⅱ比较没有显著差异。结论：HPV检测作为人群为基础的子宫颈癌筛查的初筛方法是可行的,MALDI-TOF-MSHPV检测的敏感性、特异性可与目前公认的金标准HC-Ⅱ法HPV检测相媲美,同时又因其检测的高通量、相对较低的价格,以及可行基因分型而更具应用前景。     

电针对单纯性肥胖大鼠下丘脑组织中瘦素和神经肽Y表达的影响

目的:观察电针对单纯性肥胖大鼠下丘脑瘦素和神经肽Y表达的影响,探索电针减肥的机制。方法:实验于2005-12/2006-06在中南大学湘雅医院中西医结合研究所实验室完成。①取1月龄刚断乳SD雄性大鼠,随机取6只饲以普通饲料为正常对照组,其他大鼠饲以高脂饲料,喂养3个月后,选择体质量超过正常对照组20%的单纯性肥胖大鼠12只,随机分为模型组和电针组2组,每组6只。②电针组大鼠电针双侧足三里、天枢、三阴交穴,采用疏密波,电流强度0.3～0.6mA,留针20min,1次/d,共20次;其他2组不电针。实验期间均饲以普通饲料。③观察实验大鼠体质量、体长、Lee's指数及体脂,采用Western-blot技术检测下丘脑组织中瘦素、神经肽Y表达的变化。结果:18只大鼠进入结果分析。①模型组大鼠体质量和Lee’s指数高于正常对照组[(451.8±14.8),(323.6±6.8)g;324.25±1.4,305.14±1.5;P均<0.01];电针组电针后体质量和Lee’s指数低于电针前[(372.2±20.4),(454.7±19.7)g;307.71±1.5,323.56±1.6;P均<0.01]。②模型组大鼠心包、肾周和附睾脂肪量均高于正常对照组(P<0.01);电针组电针后心包、肾周和附睾脂肪量低于电针前(P<0.01)。③模型组下丘脑组织中瘦素蛋白表达低于正常对照组(0.62±0.11,0.88±0.15,P<0.01),电针组高于模型组(0.85±0.13,P<0.01);模型组下丘脑组织中神经肽蛋白表达高于正常对照组(2.42±0.27,1.75±0.24,P<0.01),电针组高于模型组(1.87±0.21,P<0.01)。结论:电针有良好的减肥效果,其作用可能与电针增强下丘脑组织瘦素蛋白的表达、同时抑制下丘脑组织中的神经肽Y蛋白表达有关。     

P-glycoprotein expression in human plasma cell myeloma: correlation with prior chemotherapy

Multidrug-resistant (MDR) myeloma patients failing chemotherapy may express P-glycoprotein (PGP), which serves as an efflux pump protecting the neoplastic cells. Unknown is whether PGP expression might relate to prior cytotoxic drug exposure. To address this question, we studied 106 consecutive bone marrow samples from 104 myeloma patients with samples studied either before or after therapy and at the time of relapse. We performed an established immunocytochemical assay of PGP using an MDR-1- specific monoclonal antibody and correlated PGP status with prior chemotherapy dosage. Myeloma patients with no prior therapy had a low incidence of PGP expression (6%, 3/47), whereas those receiving chemotherapy had a significantly higher incidence (43%, 21/49) (P < .0001). A substantially higher incidence of PGP expression (50%, 83%, respectively) occurred when the total vincristine dose exceeded 20 mg and when doxorubicin exceeded 340 mg. In the 11 patients who received both high vincristine and doxorubicin dosages (> 20 mg, > 340 mg total dose) there was 100% incidence of PGP expression in the tumor cells. These data provided the basis for a predictive mathematical model from which dose-related PGP expression normograms were generated. Time with myeloma for PGP-negative patients (mean 33 months) had overlapping confidence limits with PGP-positive patients (mean 42 months), suggesting that disease duration was not a significant variable. PGP expression did not correlate with other clinical factors or immunophenotypic factors. Our findings indicate a strong correlation between PGP expression in myeloma and past chemotherapy in myeloma, in particular, related to prior exposure to the natural product agents vincristine and doxorubicin. Additionally, the proportion of PGP- positive plasma cells was significantly higher in the doxorubicin- treated patients than the nondoxorubicin-treated patients (87.7% v 65.17%; P = .013). Combined high vincristine and doxorubicin total dosage appear highly predictive of PGP expression.     

Kaposi's sarcoma (KS)-associated herpesvirus-like DNA sequences in peripheral blood mononuclear cells: association with KS and persistence in patients receiving anti-herpesvirus drugs

Herpesvirus-like DNA sequences (KSHV/HHV-8) have recently been described in AIDS-associated Kaposi's sarcoma (KS) lesions. Many questions remain regarding the role of this virus in KS and the therapeutic implications of this finding. In the current study, KSHV/HHV-8 DNA was detected in peripheral blood mononuclear cells (PBMCs) from human immunodeficiency virus (HIV)-infected patients with KS (34/98) more often than in HIV-infected individuals without KS (12/64, P = .03). The detection of KSHV/HHV-8 DNA did not correlate with the CD4 lymphocyte count. Five patients demonstrated KSHV/HHV-8 DNA in their PBMCs during administration of intravenous foscarnet and/or ganciclovir. The continued detection of KSHV/HHV-8 DNA in the PBMCs of patients receiving these anti-herpesvirus drugs has potential implications regarding the virus-cell relationship of KSHV/HHV-8, as well as for the value of these drugs in treating or preventing KS, but additional studies are needed.