细胞色素P450及其与脑内胆红素的氧化代谢的研究进展

细胞色素P450(CYP)是混合功能氧化酶超家族中含有血红素的膜蛋白,可对各种外源性物质包括药物、致癌物和其他化合物及内源性底物(如类固醇、脂肪酸、前列腺素和胆红素等)进行生物转化。非结合胆红素能通过血脑屏障,当脑内胆红素水平过高,就会产生神经毒性。正常情况下,胆红素在肝内代谢,CYP是主要代谢酶之一。CYP在脑内同样存在,并且能够代谢胆红素,减轻胆红素引起的神经元的损伤。     

保留足趾的自体复合第2足趾关节移植治疗手指关节炎

目的 探讨保留足趾的自体复合第2足趾关节移植治疗手指关节炎的临床疗效.方法 2016年2月至2018年6月,共收治创伤性手指关节炎9例,其中男7例,女2例;年龄19~53岁,平均31.7岁;示指3例,中指6例;掌指关节(MP)关节炎4例,近侧指骨间关节(PIP)关节炎5例;均为创伤后继发的手指关节炎.采用游离带血供的自体复合第2足趾跖趾或趾骨间关节移植进行治疗,同时将受区废弃关节(7例)或切取自体髂骨移植(2例)修复供区骨缺损保留足趾长度,供区创面均直接关闭.术后观察手指和足趾骨折愈合情况、外形、移植关节活动度(ROM)、术后供区愈合情况和行走功能及相关并发症.结果 本组术后9例移植关节全部成活,1例足部供区行髂骨植骨微型钢板固定,术后1周伤口不愈合,考虑为内固定物排异反应,予拆除钢板改克氏针交叉固定,2周后创口顺利愈合.术后随访6~30个月,平均16.3个月.手指骨折平均愈合时间7~10周,平均8.3周,手指外观及功能良好.移植后的MP活动度为50°~75°,平均65.3°,PIP活动度为10°~85°,平均60.6°.根据中华医学会手外科学分会上肢部分功能评定试用标准评价手指功能:优5例,良3例,可1例,优良率为88.9%.足趾骨折平均愈合时间9~12周,平均10.2周,所有患者足趾外形良好,行走功能正常.2例取髂骨患者供区仅残留一条线形瘢痕,无疼痛、麻木等不适.结论 游离带血供的自体复合第2足趾关节移植治疗手指关节炎,同时应用受区废弃关节或切取自体髂骨移植修复供区骨缺损保留足趾,不仅能恢复手指关节的正常结构,使关节具有良好的功能,而且能保留足趾外形与功能,减少供区损伤,具有良好的治疗效果.     

丹蛭降糖胶囊通过mTOR/S6K1信号通路对糖尿病肾病大鼠的干预作用研究

目的研究丹蛭降糖胶囊对糖尿病肾病大鼠的肾脏病理改变和足细胞自噬水平的影响,初步探讨其相应的作用机制。方法选取GK大鼠40只,采用醋酸脱氧皮质酮-盐皮下注射联合高脂饲料喂养诱导糖尿病肾病模型。造模成功后随机分为模型组、丹蛭降糖胶囊低剂量组[0.54 g/(kg·d)]、高剂量组[1.08 g/(kg·d)]、缬沙坦组[10 mg/(kg·d)],每组10只。另选取10只同周龄正常Wistar大鼠作为正常组。模型组和正常组给予等容积生理盐水。连续灌胃10周后检测空腹血糖(FBG)、血肌酐(SCr)、尿素氮(BUN)和尿微量蛋白(U-mAlb)。Western Blot检测肾小球p-mTOR、p-S6K1、Beclin-1、LC3和Nephrin蛋白的表达,HE染色和PAS染色后于光镜下观察肾脏病理变化,电镜下观察各组亚细胞形态结构变化。结果与正常组比较,模型组FBG、SCr、BUN、U-mAlb水平升高(P<0.01);与模型组比较,丹蛭降糖胶囊低、高剂量组和缬沙坦组U-mAlb水平降低(P<0.01)。模型组可见肾小球基底膜增厚,系膜基质沉积,足细胞损伤,各用药组均有不同程度改善,丹蛭降糖胶囊高剂量组足细胞内有较多自噬体形成。与正常组比较,模型组p-mTOR、p-S6K1的表达增高,Nephrin、Beclin-1和LC3的表达水平降低(P<0.01);与模型组比较,各用药组p-mTOR、p-S6K1的表达下降,Nephrin、Beclin-1和LC3的表达增高(P<0.01)。丹蛭降糖胶囊高剂量组和缬沙坦组Beclin1、LC3Ⅱ/LC3Ⅰ水平较丹蛭降糖胶囊低剂量组升高(P<0.05)。结论丹蛭降糖胶囊具有减轻糖尿病肾病大鼠U-mAIb、足细胞损伤及相关肾脏病理改变的作用,其机制可能与抑制mTOR/S6K1信号通路进而提高足细胞的自噬活性有关。     

Sequential Therapy Based on Evolvement of Patterns: A New Model for Treatment of Alzheimer’s Disease

In order to solve the problem of long-term (>9 months) efficacy in the treatment of Alzheimer''s disease (AD) by conventional therapy (CT), a staged and multiply-targeted sequential therapy based on the evolvement of patterns (STEP) was developed. Its main innovations include: (1) the time order of evolution of patterns defined by Chinese medicine (CM) in AD was found, that is, "the orderly pattern evolution starting from Shen (Kidney) deficiency, progressing to phlegm, stasis and fire, and worsening to severe toxin as well as functional collapse"; (2) the cascade hypothesis of Shen deficiency in AD and its sequential therapy based on Shen-reinforcing was proposed, that is, "reinforcing Shen in the early stage and throughout the whole process, resolving phlegm, activating blood and purging fire in the middle stage, detoxifying and replenishing vitality to stop the collapse in the advanced stage", and through meta-analysis, clinical drug use was optimized, thus the leap from "inferential selection" to "evidence-based selection" was realized; (3) the STEP regimen combined with CT maintained cognitive and behavioral stability in AD patients for at least 12 months, with cognitive enhancement and behavioral synergy after 9 months, and cognitive benefit was superior to CT at 9, 12, 15, 18, 21, and 24 months, respectively. The 2-year cognitive improvement rate was increased by 25.64% (P=0.020) and the cognitive deterioration rate was decreased by 48.71% (P=0.000). Among them, the cognitive and functional benefits of Shen-reinforcing therapy for very early AD (350 cases) for 1 year were better than the placebo (P<0.001), and the dementia conversion rate was reduced by 8.85% (P=0.002). The behavioral symptomatic relief of patients with vascular dementia received fire-purging therapy (540 cases) was superior to those received CT (P=0.016). These data suggested that the STEP regimen has synergistic effects on CTs at least in terms of cognitive benefit, and the earlier the use, the greater the benefit will have. Therefore, the STEP regimen should be considered as one of the clinical options, particularly for the dearth of effective pharmaceutical or immunological interventions that are currently available for AD.     

生长抑素及其类似物联合质子泵抑制剂应用于急性非静脉曲张性上消化道出血的循证分析

目的 系统评价生长抑素及其类似物联合质子泵抑制剂（proton pump inhibitor，PPI）治疗急性非静脉曲张性上消化道出血（acute non-variceal upper gastrointestinal bleeding，ANVUGIB）的有效性和安全性，并分析其用药经济性。方法 采用循证医学方法搜集生长抑素及其类似物联合PPI治疗ANVUGIB的RCT、队列研究进行meta分析，得到相应的有效性及安全性分析结果，并进行成本-效果分析。结果 最终纳入6个RCT均未接受内镜治疗，共610例受试者。Meta分析结果显示，生长抑素及其类似物联合高、中、低剂量PPI治疗在以下方面均优于单用高、中、低剂量PPI治疗，差异有统计学意义，总有效率[OR=3.34，95%CI（2.03，5.47），P<0.000 01]、止血时间[MD=-9.04，95%CI（-11.69，-6.38），P<0.000 01]、输血量[MD=-1.10，95%CI（-1.46，-0.74），P<0.000 01]；在不良反应发生率方面，2组差异无统计学意义[OR=0.49，95%CI（0.11，2.12），P=0.34]。ANVUGIB患者予生长抑素联合高、中、低剂量奥美拉唑与单用高、中、低剂量奥美拉唑进行成本-效果分析，增量成本效果比分别为172.28，217.26，330.37，敏感性分析后显示结果稳定。而接受内镜治疗后应用生长抑素及其类似物联合PPI治疗仅1个队列研究，研究结果显示内镜治疗成功后联合治疗并不优于PPI单药治疗。结论 现有证据表明，生长抑素及其类似物联合PPI治疗未经内镜治疗的ANVUGIB患者为较有效的方案，两者安全性相当、耐受性较好，从药品直接成本考虑，高剂量PPI组联合治疗较中、低剂量PPI组联合治疗更具有成本效果性。而对于经内镜下止血治疗的患者两者疗效相当，可考虑单用PPI。