Once- versus twice-daily dosing of eliglustat in adults with Gaucher disease type 1: The Phase 3, randomized,double-blind EDGE trial

Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) with compatible CYP2D6-metabolizer phenotypes (> 90% of patients). The randomized, double-blind EDGE trial (NCT01074944, Sanofi Genzyme) evaluated once-daily eliglustat dosing compared with the approved twice-daily regimen at the same total daily dose in adults with GD1. Subjects received twice-daily dosing during a 6- to 18-month lead-in period. Only subjects who attained prespecified treatment goals for hemoglobin, platelet count, spleen and liver volumes, and bone symptoms during the lead-in period were randomized to once- or twice-daily dosing. Of 170 enrolled patients, 156 completed the lead-in period and 131 met all requirements to enter the double-blind treatment period. To achieve the composite primary endpoint in the double-blind period, patients had to maintain clinical stability relative to baseline on all five endpoints (hemoglobin, platelet count, spleen and liver volumes, and bone symptoms) and meet pharmacokinetic and other tolerability requirements as determined by the investigator after 1 year of eliglustat treatment. After 1 year, 80.4% (95% CI: 67.6, 89.8) of once-daily patients were stable compared with 83.1% (95% CI: 71.0, 91.6) of twice-daily patients. The 95% CI for the mean difference of ? 2.7% between groups was ? 17.7, 11.9. Because the lower bound of the CI exceeded the pre-defined non-inferiority margin of ? 15%, once-daily dosing could not be declared non-inferior to twice-daily dosing. Both once-daily and twice-daily patients maintained mean values for hematologic and visceral measures within established therapeutic goals during the double-blind treatment and long-term extension periods. Eliglustat was generally well-tolerated during this long-term trial (mean treatment duration: 3.3 years), with just four withdrawals (2%) for related adverse events (AE), and similar AE profiles for both dosing regimens. Patients on twice-daily eliglustat showed more stability overall, and this dose regimen was better tolerated, confirming the dosing regimen for most patients specified in the drug label.     

鞍区病变3D打印模型的临床应用观察

目的 探讨根据薄层增强扫描数据制作的鞍区占位性病变3D打印模型在术前制订手术计划和术中指导手术操作中的应用价值。方法 采用前瞻性研究方法,纳入2015年3月—2017年6月解放军福州总医院神经外科15例鞍区病变患者,其中男6例、女9例,年龄40~75岁;垂体腺瘤13例,鞍结节脑膜瘤和颈内动脉床突上段动脉瘤各1例。将CTA、MRI薄层扫描数据输入Mimic软件,建立数字模型,通过3D打印机制作模型。在3D打印模型上分析病变与周围结构的解剖关系、模拟建立手术入路并进行模拟手术操作,确定手术方案。临床采用经单侧鼻孔-蝶窦入路显微手术切除垂体腺瘤13例、开颅手术切除鞍结节脑膜瘤1例、开颅手术夹闭左侧颈内动脉床突上段大型动脉瘤1例,并在手术中进一步参考和验证模型的模拟结果。结果 3D打印模型上,13例垂体腺瘤在经鼻蝶入路视角下,可清晰显示鞍底隆突的形态、蝶窦的大小、气化分型、蝶窦分隔情况和蝶窦后壁形态,还可观察侧壁的骨性隆突;根据影像和3D模型观察结果进行适当地鞍底开窗,外侧缘不累及颈内动脉,上缘达到前海绵间窦,下方显露充分。1例鞍结节脑膜瘤及1例动脉瘤患者病变均与前床突关系密切,术中所见与3D打印模型所见一致。15例患者临床手术均顺利完成,术中、术后无血管及重要脑组织结构损伤、脑脊液漏、感染等并发症发生。结论 3D打印模型可清晰显示鞍区病变与周围骨质、血管的关系,为术前手术方案设计提供了良好、直观的立体解剖结构观察,并可用于模拟手术操作,进而提高手术安全性和成功率。     

hs-CRP和髓样细胞触发受体-1在肺炎细菌感染检测中的应用

目的 考察超敏C反应蛋白(hs-CRP)和髓样细胞触发受体-1(myeloid cell trigger receptor-1 TREM-1)在肺炎细菌感染检测中的应用效果.方法 收集健康体检者50例,非细菌感染性肺炎患者50例,细菌感染性肺炎患者100例,比较三组间患者hs-CRP和髓样细胞触发受体-1表达水平.结果 方差分析显示,三组间血清hs-CRP和TREM-1水平差异均具有统计学差异(P＜0.05),其中感染组患者血清hs-CRP显著高于健康组,细菌感染组患者血清TREM-1水平显著高于健康组和非细菌感染组(P＜0.05).进一步比较不同病情患者血清hs-CRP和TREM-l水平可知,随着疾病严重程度增加,患者血清hs-CRP和TREM-1水平也随之增高,两者均有显著相关性(P＜0.05).两指标联合应用对细菌性感染肺炎的诊断灵敏度为97％、特异性99％.结论 血清hs-CRP和TREM-1水平可以有效反应细菌性感染肺炎患者病情并且是良好的潜在诊断指标.     

输注器具铅镉含量能力验证

目的通过输注器具铅镉含量能力验证计划评价医疗器械检验机构,为提高实验室检测能力提供指导。方法依据CNAS-CL03:2010《能力验证提供者认可准则》策划并实施本次能力验证。采用模拟输注器具溶出液作为样品,根据随机原则发放给参加者,要求参加者按照作业指导书规定的步骤采用原子吸收分光光度法测定样品中铅镉含量。通过计算专家实验室公仪值获得指定值,计算上一轮次结果的散度作为能力评定标准差。结果全国共有30个省的58家实验室参加,其中39家结果满意,18家不满意,1家退出。通过结果分析参加者应在3个方面提高检验能力,一是设备核心部分加强维护保养,二是按照SOP进行试验操作,三是加强环境监控避免干扰。结论客观准确地评价了全国医疗器械检验机构铅镉含量项目的检验能力,发现并分析了问题,为实验室提高检验能力提供指导。     

c-Kit mutation reduce intestinal epithelial cell proliferation and migration,but not influence intestinal permeability stimulated by lipopolysaccharide

The proto-oncogene c-kit, as a marker of interstitial cells of Cajal (ICCs) in the gastrointestinal tract, plays an important role in the ICCs. Although limited evidences showed c-kit is present in the colonic epithelium but its roles remain unclear. In the present study, we aimed to investigate the expression, location and function of c-kit in the intestinal epithelium. Immunofluorescence, western blotting, and RT-PCR were performed to detect the expression and location of c-kit in the intestinal mucosa of WT mice. We investigated intestinal epithelial proliferation and migration in vivo by performing 5-Bromodeoxyuridine (BrdU) incorporation and Ki-67 staining in WT and Wads ^m/m mice. An Ussing chamber with fluorescein-isothiocyanate dextran 4000 was used to detect the transepithelial electric resistance (TER), short circuit current (ISC) and permeability across ex vivo colon segments under control and endotoxaemia conditions. We demonstrated that c-kit was located and expressed in the gut crypt compartment in WT mice, which was demonstrated in the c-kit mutant mice (Wads ^m/m). In addition, both the number of proliferating cells and the percentage of the distance migrated were lower in the Wads ^m/m mice than those in the WT mice. Moreover, the intestinal permeability, TER and tight junction were unaltered in the Wads ^m/m mice under endotoxic conditions compared with those in both the control condition and the WT mice. Altogether, these observations imply that the expression of c-kit in the colonic epithelium is involved in the proliferation and permeability of the colonic epithelium.     

CFTR氯通道在硫化氢诱导的心肌保护及细胞增殖中的作用

目的： 探讨囊性纤维化跨膜传导调节因子（CFTR）氯通道在硫化氢（H2S）诱导的心肌保护及细胞增殖中的作用。方法：应用氯化钴（CoCl2）在大鼠H9c2心肌细胞建立化学性缺氧损伤心肌细胞实验模型;CCK-8试剂盒检测心肌细胞存活率;Hoechst 33342核染色法检测心肌细胞凋亡。结果：在400-2 000 μmol/L浓度范围内,CoCl2呈剂量依赖性地抑制H9c2心肌细胞的存活率,600 μmol/L CoCl2 能诱导H9c2心肌细胞产生明显的凋亡;在100-800 μmol/L浓度范围内,硫氢化钠（NaHS）呈剂量依赖性地促进H9c2心肌细胞增殖;NaHS能保护H9c2心肌细胞对抗CoCl2引起的细胞损伤作用,使细胞存活率升高,凋亡率降低;100 μmol/L CFTR氯通道拮抗剂5-硝基-2-（3-苯丙胺）-苯甲酸（NPPB)能明显地阻断NaHS对CoCl2的细胞毒性的抑制作用,但不能阻断NaHS抗心肌细胞凋亡作用及促进心肌细胞增殖作用。结论：CFTR氯通道可能参与H2S的抗CoCl2引起的心肌细胞毒性作用。     

免疫酶法与ELISA法检测EB病毒VCA-IgA的比较

为探讨免疫酶法与ELISA在鼻咽癌诊断中的临床价值,检测鼻咽癌组患者与健康对照组血清EB病毒壳抗原抗体,并对两种检测方法的结果进行分析。结果表明：177例鼻咽癌患者中,免疫酶法检测EB-VCA-IgA阳性率高92．1％（163／177）,而国产试剂和进口试剂ELISA法检测结果阳性率都较低,分别为65．0％（115／177）和67．2％（119／177）,有显著性差异（P〈0．005）;在90名对照组血清EB-VCA-IgA,免疫酶法的阴性率为100％（90／90）,ELISA法中的国产和进口试剂的阴性率分别为：98．9％（89／90）和95．6％（86／90）,无显著性差异（P〉0．05）。为此免疫酶法检测EB-VCA-IgA的灵敏度较高,更适合用于鼻咽癌的普查、协助诊断等,具有实际临床意义。     

重组腺病毒载体vAd-tat的构建及其在细胞中的表达

目的 构建含HIV-1 tat基因重组腺病毒,观察在不同细胞中外源蛋白Tat的表达,作为DC抗HIV疫苗的基础.方法 通过PCR扩增,获得HXB2 tat的cDNA片段,定向克隆入腺病毒转移载体pTrack-CMV,线性化后转化含有腺病毒骨架pAd-easy-1的大肠杆菌BJ5183,获得同源重组的质粒prAd-tat,Pac Ⅰ酶切纯化后转染293细胞,包装成具有感染力的复制缺陷型重组腺病毒vAd-tat.结果 经PCR、酶切及DNA序列测定,插入片段大小、方向正确,获得具有感染力的含有HIV-1 tat基因的重组腺病毒;通过Western blot方法 检测,重组腺病毒在293细胞中表达出Mr,为15 000的蛋白.结论 成功构建了含有HIV-1 tat基因的腺病毒,并观察到该基冈在细胞中的表达.