The aim of this study is to assess the impact of Tianxiangdan (TXD) on lipophagy in foam cells and its underlying mechanism in treating atherosclerosis, particularly focusing on its efficacy in lowering blood lipids. In vivo, ApoE-/- atherosclerosis mouse models were established for group intervention. Blood lipid levels of the mice were measured, lipid deposition and autophagy levels in atherosclerotic plaques were assessed, and co-localization of lipid droplets and autophagosomes was examined. In vitro, human THP-1 cells were induced into macrophages and then transformed into foam cells using ox-LDL induction. Different intervention groups were established. Total cellular cholesterol (TC), free cholesterol (FC), and autophagy levels were assessed, while the morphology and distribution of lipid droplets and autophagosomes in cells were observed using transmission electron microscopy. Western blot analysis was performed to evaluate the expression levels of PI3K, Akt, mTOR, TFEB, LC3II/I, ULK1, ABCA1, and p62. TXD effectively lowers blood lipid levels in ApoE-/- atherosclerotic mice, enhances lipophagy, and reduces lipid accumulation in foam cells and arterial lipid plaques. It achieves this by suppressing the expression of p85, Akt, and mTOR, while activating downstream autophagy signals such as TFEB, LC3II/I, and ULK1. Additionally, TXD reduces the expression of p62 and enhances the expression of the cholesterol transport molecule ABCA1. Our findings indicate that TXD activates lipophagy via the PI3K/Akt/mTOR pathway, leading to a reduction in lipid deposition within foam cells and plaques, thereby mitigating atherosclerosis.

Background and Aims: Chronic coronary syndrome (CCS) has always been controversial in its therapeutic strategy. Although invasive treatment and optimal medication therapy (OMT) are the most commonly used treatments, doctors continue to debate the best strategy. However, traditional Chinese medicine (TCM) for CCS is effective clinically.Methods: To identify potentially eligible observational and experimental studies, we searched Pubmed, the Web of Science, and the China National Knowledge Internet. To be eligible, studies had to report with end-of treatment outcomes, such as major adverse cardiac events (MACE), deaths from myocardial infarctions (MI), all-cause mortality, angina, cardiac mortality, the effectiveness rate of electrocardiographs, and the reduction rate of the Nitroglycerin tablets. Risk differences (RDs) and 95% confidence intervals (95% CIs) were calculated based on random-effects models or fixed-effects models. Citation screening, data abstraction, risk assessment, and strength-of-evidence grading were completed by 2 independent reviewers.Results: In Section 1 (13 studies, involving 17,287 patients), showed no significant difference between invasive treatment and medication treatment in MACE (RD = -0.04, 95 % CI = -0.08 to 0.00, I2 = 76.4%), all-cause mortality (RD = -0.01, 95 %CI = -0.022 to 0.01, I2 = 73.44%), MI (RD = 0.00, 95 %CI = -0.00 to 0.01, I2 = 0.00%) and cardiac mortality (RD = 0.00, 95% CI = -0.01 to 0.01, I2 = 34.9%). In Section 2 (21 studies, including 1820 patients), compared with WM treatment, TCM + WM treatment increased ECG effectiveness by 18%, angina effectiveness by 20%, and stopping or reducing Nitroglycerin tablets by 20%. In Section 3 (25 studies, including 2859 patients) showed that TCM revealed a better electrocardiogram effective rate (RD = 0.10, 95 %CI = 0.05 to 0.14, I2 = 44.7%) and angina effective rate (RD = 0.12, 95 %CI = 0.09 to 0.15, I2 = 44.9%). We identified that TCM treatment properties of "Circulating blood and transforming stasis" and application of warm/heat-properties medicines were frequently used in CCS treatment.Conclusions: TCM treatment has shown superior beneficial cardioprotective in CCS therapy strategy, among which "Circulating blood and transforming stasis" and the application of warm/heat-properties medicine are its characteristics.

经皮冠状动脉介入治疗术(PCI)是现在临床上对急性冠脉综合征(ACS)患者救治最重要措施之一,极大地降低了ACS患者死亡率.但随着PCI的普遍使用,术后仍有部分患者存在不良事件的发生,应对PCI术后伴随不良事件及不适症状的情况,中医药治疗可发挥独特优势,该文对近些年来PCI术后的中医药治疗进行综述,以期为PCI术后的患者临床预后改善及相关治疗提供参考.

目的 通过观察天香丹对动脉粥样硬化(Atherosclerosis,AS)小鼠不对称二甲基精氨酸(Asymmetric dimethylarginine,ADMA)及沉默信息调节因子 1(Sirtuin1,SIRT1)的影响,探讨天香丹对AS疾病血管内皮功能的调控作用.方法 采用 ApoE-/-小鼠(高脂饲料喂养)建立动脉粥样硬化模型,同时设C57 BL/6J 小鼠(普通饲料喂养)10 只为空白组作为对照.造模成功后将ApoE-/-小鼠按照随机数字表法分为模型组、他汀组、天香丹组,每组 10 只.天香丹组、他汀组分别给予天香丹 2.7 g·kg-1·d-1、阿托伐他汀 3 mg·kg-1·d-1 灌胃,模型组给予 0.5 mL蒸馏水灌胃,每日 1 次,连续 8 周.取小鼠血清用于检测总胆固醇(Total cholesterol,TC)、甘油三酯(Tri-glyceride,TG)、低密度脂蛋白(Low-density lipoprotein cholesterol,LDL-C)、高密度脂蛋白(High-density lipoprotein cholesterol,HDL-C)、一氧化氮(Nitrous oxide,NO)及 ADMA 含量,主动脉用于观察主动脉病理变化情况及检测 SIRT1 表达情况.结果 与空白组相比,模型组可见明显斑块形成及血管结构紊乱,斑块面积增加,脂质沉积明显,TC、TG、LDL-C、ADMA、SIRT1 升高,HDL-C、NO 下降,差异均有统计学意义(P<0.05);与模型组比较,他汀组可见少量斑块、内膜结构紊乱及少量内膜下脂质沉积,TC、TG、LDL-C降低,HDL-C、NO、SIRT1 升高,天香丹组仅有少量斑块及内膜增厚,斑块面积及脂质沉积情况明显改善,TG、LDL-C、ADMA 降低,HDL-C、NO、SIRT1 升高,差异均有统计学意义(P<0.05);与他汀组对比,天香丹组 NO 升高,ADMA降低,差异有统计学意义(P<0.05).结论 天香丹可以降低 AS 小鼠 ADMA 水平,提高 SIRT1 表达,升高NO 水平以改善内皮细胞功能障碍抗动脉粥样硬化.

Diabetic cardiomyopathy (DC) is a serious heart disease caused by diabetes. It is unrelated to hypertension and coronary artery disease and can lead to heart insufficiency, heart failure and even death. Currently, the pathogenesis of DC is unclear, and clinical intervention is mainly symptomatic therapy and lacks effective intervention objectives. Iron overdose mediated cell death, also known as ferroptosis, is widely present in the physiological and pathological processes of diabetes and DC. Iron is a key trace element in the human body, regulating the metabolism of glucose and lipids, oxidative stress and inflammation, and other biological processes. Excessive iron accumulation can lead to the imbalance of the antioxidant system in DC and activate and aggravate pathological processes such as excessive autophagy and mitochondrial dysfunction, resulting in a chain reaction and accelerating myocardial and microvascular damage. In-depth understanding of the regulating mechanisms of iron metabolism and ferroptosis in cardiovascular vessels can help improve DC management. Therefore, in this review, we summarize the relationship between ferroptosis and the pathogenesis of DC, as well as potential intervention targets, and discuss and analyze the limitations and future development prospects of these targets.

目的 通过研究天香丹对动脉粥样硬化(AS)模型小鼠Toll样受体-4(TLR4)/核因子-κB(NF-κB)信号通路及相关炎症因子的影响,探讨天香丹防治AS的可能机制.方法 选取8周龄ApoE-/-小鼠30只予以高脂饲料喂养12周,造模成功后随机分为模型组、他汀组、天香丹组,每组10只;另取10只C57BL/6J小鼠予以普通饲料喂养作为空白对照组.他汀组、天香丹组分别以相应药液3mg/kg、2.7g/kg灌胃干预,空白组、模型组以0.5mL蒸馏水灌胃,每日1次,连续12周.取小鼠血清用于检测血脂水平及TLR4、NF-κB、肿瘤坏死因子-α(TNF-α)含量,取主动脉用于观察主动脉病理变化情况.结果 1)HE染色结果显示:他汀组、天香丹组病理改变较模型组轻,斑块稳定性提高,模型组主动脉斑块面积(PA)与管腔面积(LA)比值显著大于空白组(P＜0.01),他汀组、天香丹组PA/LA比值则小于模型组(P＜0.01).2)血脂检测结果显示:较空白组,模型组三酰甘油(TAG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)明显升高,高密度脂蛋白胆固醇(HDL-C)明显降低(P＜0.01);与模型组比较,他汀组、天香丹组TAG及TC降低明显(P＜0.01),天香丹组HDL-C升高(P＜0.01)、LDL-C降低(P＜0.01).3)ELISA结果显示:模型组血清中TLR4、NF-κB、TNF-α含量均高于空白组(P＜0.01),他汀组、天香丹组血清中TLR4、NF-κB、TNF-α含量均低于模型组(P＜0.01).结论 天香丹具有防治AS的作用,其机制可能与调控TLR4/NF-κB信号通路、抑制炎症反应有关.

We investigated the mechanisms underlying the effects of Ziziphora clinopodioides Lam. (ZCL) on atherosclerosis (AS) using network pharmacology and in vitro validation.We collected the active components of ZCL and predicted their targets in AS. We constructed the protein-protein interaction, compound-target, and target-compound-pathway networks, and performed GO and KEGG analyses. Molecular docking of the active components and key targets was constructed with Autodock and Pymol software. Validation was performed with qRT-PCR, ELISA, and Western blot.We obtained 80 components of ZCL. The network analysis identified that 14 components and 37 genes were involved in AS. Then, 10 key nodes in the PPI network were identified as the key targets of ZCL because of their importance in network topology. The binding energy of 8 components (Cynaroside, α-Spinasterol, Linarin, Kaempferide, Acacetin, Genkwanin, Chrysin, and Apiin) to 4 targets (MMP9, TP53, AKT1, SRC) was strong and <−1 kJ/mol. In addition, 13 of the 14 components were flavonoids and thus total flavonoids of Ziziphora clinopodioides Lam. (ZCF) were used for in vitro validation. We found that ZCF reduced eNOS, P22 phox , gp91 phox , and PCSK9 at mRNA and protein levels, as well as the levels of IL-1β, TNF-α, and IL-6 proteins in vitro ( P < 0.05).We successfully predicted the active components, targets, and mechanisms of ZCL in treating AS using network pharmacology. We confirmed that ZCF may play a role in AS by modulating oxidative stress, lipid metabolism, and inflammatory response via Cynaroside, Linarin, Kaempferide, Acacetin, Genkwanin, Chrysin, and Apiin.

心房颤动(atrial fibrillation AF)简称房颤,是一种常见的快速性室上性心律失常,以快速、无序心房电活动导致心房机械功能恶化为特征的心律失常;房颤的发病率和患病率极高,可诱发血栓,使卒中风险增加,严重影响患者健康,并造成家庭、社会经济负担.本篇综述总结现阶段有关房颤中医研究,包括历史沿革、病因病机、辨证分型、中医药治疗.为后续进一步对房颤的研究做准备.

本文通过对稳定型心绞痛的中西医结合诊治现况进行研究分析,从而归纳聚类出该病中西医诊治相关性特点规律及其用药研究,以期为中医学结合西医诊治该病提供新思路新指导,为中医药治疗心血管疾病理论提供参考,发挥中医药在疾病防治中的优势,为临床工作提供诊疗依据.

IntroductionBody mass index (BMI) trajectories, such as non-linear time trends and nonlinear changes in BMI with age, can provide information on the underlying temporal health patterns. The relationship between BMI trajectories and the risk of hypertension remains controversial.MethodsPubMed, Embase, Cochrane, Scopus, and Web of Science databases were searched from their inception to January 31, 2022. We categorized BMI trajectories as “Stable high,” “table normal,” “Stable low,” “Fluctuated (sharp increase),” and “Fluctuated (elevated-decrease).” The main outcome was the relative risk for the prevalence of hypertension in the different BMI trajectories. Potential sources of heterogeneity were examined using meta-regression and subgroup analysis. A publication bias test and Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach were also used.ResultsThe 18 cohort studies included 89,094 participants. Compared with the “Stable normal” trajectory, “Stable high,” “Fluctuated (sharp increase),” and “Fluctuated (elevated-decrease)” trajectories were associated with an increased relative risk of hypertension: [RR (95% CI)]: 1.80 (1.29 2.50), p < 0.001; 1.53 (1.27 1.83), p < 0.001; 1.30 (1.24 1.37), p = 0.001, respectively. The “Stable low” trajectory was associated with a reduced risk of hypertension [0.83 (0.79 0.83), p < 0.001]. The “Stable high” trajectory (surface under the cumulative ranking curve = 88.1%) had the highest probability of developing hypertension in the population. The certainty of the evidence for direct comparisons of the incidence of hypertension between various BMI trajectories was generally very low.ConclusionOur findings suggested that “Stable high,” “Fluctuated (sharp increase),” and “Fluctuated (elevated-decrease)” trajectories were associated with an increased relative risk of hypertension, with the “Stable high” trajectory most likely associated with hypertension.Systematic review registration[https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=308575], identifier [CRD42022308575].

中医药在治疗临床心系疾病上一直有着独特的优势,其中善于运用膏方调治心系疾病更是体现了我国传统中医学理论框架"治未病"的基本思想,完善了我国中医学基本特点理论.膏方历史悠久,是一种具有良好的营养滋补及其预防健康保健功能的中成药,因此选择膏方进行调补已经成为了现代临床治疗手段的主要方式之一,也备受人们青睐和熟知.兹从近年来对于膏方及膏方在常见心系疾病治疗中的临床运用及其现状情况的角度立项研究,分析其治疗效果及优点,总结临床膏方治疗心系疾病的方法,对其研究进展予以综述,为临床心系疾病的治疗提供一种有效的途径和方法.

目的 探讨天香丹对冠状动脉微循环障碍(CMD)大鼠微血管结构变化及内皮功能的影响.方法 选取雄性Sprague-Dawley(SD)大鼠48只,随机分为假手术组、模型组、天香丹低剂量组、天香丹中剂量组、天香丹高剂量组及尼可地尔组,每组8只.建立大鼠CMD模型,造模完成后,按照体表面积法,假手术组给予生理盐水灌胃,每日2 mL;模型组给予生理盐水灌胃,每日2 mL;天香丹低剂量组给予天香丹灌胃,每日0.81 g/kg;天香丹中剂量组予天香丹灌胃,每日1.62 g/kg;天香丹高剂量组给予天香丹灌胃,每日3.24 g/kg;尼可地尔组给予尼可地尔灌胃,每日1.35 mg/kg,连续给药28 d.观察大鼠心肌微血管超微结构;测定大鼠心肌微血管密度;检测血清一氧化氮(NO)、内皮素-1(ET-1)水平及心肌组织内皮型一氧化氮合酶(eNOS)蛋白表达水平.采用脂多糖(LPS)诱导心肌微血管内皮细胞(CMECs)建立CMECs损伤模型,分为对照组、脂多糖组、天香丹组、脂多糖+天香丹组,检测各组细胞eNOS蛋白的表达水平及上清液NO水平.结果 在动物水平上,与模型组比较,天香丹可减轻冠状动脉微血管内皮肿胀、减少微血栓、增加微血管密度(P<0.05),天香丹中剂量组、天香丹高剂量组血清NO水平及NO/ET-1的比值明显升高(P<0.05),心肌组织eNOS蛋白表达水平升高(P<0.05或P<0.01).在细胞水平上,与脂多糖组比较,脂多糖+天香丹组CMECs内eNOS蛋白表达水平及上清液NO水平增加(P<0.01).结论 天香丹对CMD大鼠心肌微血管结构及内皮功能具有改善作用.

目的:探讨天香丹对tBHP诱导损伤的人脐静脉内皮细胞的保护作用.方法:将HUVECs分为对照组、模型组、阳性对照药(维生素C)组和天香丹剂量组(30、60、90μg/mL).MTT法筛选tBHP最佳造模浓度,并评价天香丹对内皮细胞氧化损伤的保护作用;微板法和WST法检测各组细胞乳酸脱氢酶(LDH)、还原型谷胱甘肽(GSH)和超氧化物歧化酶(SOD)表达情况;显微镜下观察各组细胞形态学变化,Hoechst 33258荧光染色法检测各组细胞凋亡情况.结果:经tBHP诱导24 h后,模型组细胞存活率、SOD活性和GSH含量较对照组显著降低(P<0.01),LDH释放量和细胞凋亡率明显增加(P<0.01);经维生素C和不同浓度天香丹预处理后,与模型组相比较,各组细胞存活率、SOD活性和GSH含量显著增加,LDH的释放和细胞凋亡率得到减轻(P<0.01).结论:天香丹具有保护HUVECs免于氧化损伤的作用,其机制可能与抗氧化通路的激活,抗氧化能力的增强及逆转细胞凋亡有关.

目的 采用三氯化铁(FeCl3)诱导小鼠颈动脉血栓模型,研究天香丹对颈动脉血栓形成的抑制作用.方法 取40只SPF级健康雄性C57BL/6小鼠,随机分为假手术组(蒸馏水)、模型组(蒸馏水)、天香丹组(2.7 g·kg-1·d-1)、阿司匹林组(11.4 mg·kg-1·d-1),预防性给药21 d后,用20％FeCl3溶液损伤小鼠左颈总动脉,建立颈动脉血栓模型.采用小动物超声影像系统检测各组造模前后血管管径变化;剪尾实验检测天香丹对小鼠尾出血时间、出血量的影响;取血浆采用酶标仪比浊法测定天香丹对二磷酸腺苷(ADP)刺激血小板后聚集率的影响;取左颈总动脉HE染色观察天香丹对颈动脉血栓形成的病理状态.结果 与模型组比较,天香丹组造模后血管管径增大、ADP诱导的血小板聚集率降低,差异均有统计学意义(P<0.05);与阿司匹林组比较,天香丹组小鼠尾出血时间和出血量都有所降低,且差异有统计学意义(P<0.05);HE染色显示天香丹可改善FeCl3诱导的左颈总动脉病理状态.结论 天香丹可抑制血小板聚集率,改善颈动脉血栓形成,并且对出血时间和出血量影响较小,为临床防治血栓性疾病提供实验依据.

心血管性胸痛为临床常见疾病,其中以冠脉相关性胸痛最为常见,病死率高,严重危害着人类的生命健康,本文将从其发病机制、诊断手段、病情及预后评估、西医的临床治疗和中医的辨证论治进行论述.

由2019年欧洲心脏病学会(European Society of Cardiology,ESC)的最新指南——《2019 ESC慢性冠状动脉(冠脉)综合征(chronic coronary syndrome,CCS)的诊断和管理指南》中可见:结合最新临床研究证据,在原稳定性冠心病诊断指南基础上,将冠心病分类为急性冠状动脉(冠脉)综合征(acute coronary syndromes,ACS)和慢性冠状动脉(冠脉)综合征(chronic coronary syndrome,CCS),更强调全过和循证程管理和识别冠心病不同人群.在过去几十年中,心血管死亡率稳步下降,这不仅仅与治疗手段的改善有关,其中预防干预冠心病危险因素是处理方案中必不可少的环节.近年来关于中医药干预治疗冠心病和冠心病中医证候与危险因素的文献见诸于报道,总结不可逆与可逆危险因素在冠心病中不同阶段与证候关系,以期中医预防干预本病全发病进程的对证处理提供参照.

目的 系统评价天香丹对冠心病(Coronary heart disease,CHD)患者血管生成因子的影响,为天香丹治疗冠心病提供药理学依据.方法 计算机检索中外文献数据库,检索时间为从建库至2021年9月30日,纳入有关天香丹治疗冠心病的随机对照试验,文献数据的提取及质量评价依据co-chrane系统评价.采用RevMan5.3软件进行数据统计分析.结果 共纳入符合要求的文献5篇,总计1345名研究对象.Meta分析结果显示:采用天香丹治疗的冠心病患者较对照组患者的血管内皮生长因子(Vascular endothelial growth factor,VEGF)水平[SMD=17.43,95％CI(2.14,32.72)]、一氧化氮(Nitric oxide,NO)水平[SMD=9.84,95％CI(5.31,14.37)]均显著提高(P<0.05),而一氧化氮合酶(Ni-tricoxide synthase,NOS)水平[SMD=0.17,95％CI(-0.02,0.37)]差异无统计学意义(P>0.05).结论 天香丹可有效提高冠心病患者血管生成因子VEGF及NO水平,从而改善冠心病相关临床症状.

目的 通过对古籍医案的研究,总结历代医家对心系疾病的辨证论治,并通过数据挖掘的方法,探索历代医家应用桂枝汤加减治疗心系疾病的用药规律,为临床提供借鉴.方法 飞熊软件科技出品的《中华医典》为本课题文献的来源,按照时间顺序总结历代医家对心系疾病的辨证论治,加以整理叙述.同时,对医案部分进行人工检索,收集桂枝汤加减治疗心系疾病的医案,运用古今医案云平台对医案进行频数分析、关联规则分析、聚类分析,探索古籍医案中桂枝汤加减治疗心系疾病的用药规律.结果 收集符合标准的医案105则,涉及中药156味,总用药频次894次.频数分析结果显示,心系疾病常见症状有胸痛、心悸、胸闷、胸痛彻肩背、水肿、喘息、不能平卧、咳喘、小便不利、气短、不寐、腹胀,桂枝汤加减治疗心系疾病用药频次≥10次的中药有19味,以辛温药物为主;中药归经主要为肺、脾、胃、心;主要功效为燥湿化痰、助阳化气、温通经脉、平冲降气、发汗解肌、降逆止呕、消痞散结、利水渗湿、宁心、健脾.关联规则分析显示,桂枝汤加减治疗心系疾病的常用药物组合有桂枝-茯苓-半夏、桂枝-薤白-半夏、瓜蒌-桂枝-半夏、白芍-桂枝-甘草.结论 数据挖掘结果显示,历代医家使用桂枝汤加减治疗心系疾病用药以辛温为主,多归肺、脾、胃、心经,以调和营卫为主,辅以助阳化气、温通经脉、平冲降气、利水渗湿、宁心、健脾等,用药灵活变通.

目的 本文选取安冬青教授论治胸痹、心悸、不寐验案三则,分析其运用桂枝汤合方加减治疗心系疾病的经验,为研究桂枝汤合方加减治疗心系疾病提供更多依据,为临床提供参考借鉴.方法 总结安冬青教授门诊使用桂枝汤合方加减治疗心系疾病的医案,通过列举个案的方法分析医案中的用药规律,讨论桂枝汤合方加减治疗心系疾病的临床应用.结果 桂枝汤合方加减治疗胸痹、心悸、不寐在临床应用中,以调和营卫的基本方法,调整机体气血阴阳,取得良好的治疗效果.结论 安冬青教授通过调和营卫的方法,以桂枝汤为基础方,根据患者的症状、体征进行加减用药,在治疗心系疾病方面取得良好的临床效果.

目的 系统评价益气养阴、活血通络法治疗糖尿病合并心律失常的临床疗效.方法 计算机检索MedLine、中国知网、万方、维普、中国生物医学文献数据库等近10年公开发表的益气养阴、活血通络法治疗糖尿病合并心律失常的随机对照试验或半随机对照试验,并用Jadad评分评价纳入研究的质量,采用Cochrane协作网专用软件RevMan 5.3进行Meta分析.结果 共纳入8篇文献,涉及816例病人.两组症状疗效比较:Meta分析结果显示,治疗组显效率高于对照组[RR=1.36,95％CI(1.15,1.61)];治疗组与对照组有效率比较差异无统计学意义[RR=1.19,95％CI(0.99,1.43)];治疗组无效率低于对照组[RR=0.45,95％CI(0.34,0.58)];治疗组总有效率高于对照组[RR=1.28,95％CI(1.18,1.38)].心电图疗效比较:Meta分析结果显示,治疗组显效率高于对照组[RR=1.48,95％CI(1.17,1.87)];治疗组与对照组有效率比较差异无统计学意义[RR=1.08,95％CI(0.83,1.40)];治疗组无效率低于对照组[RR=0.48,95％CI(0.34,0.67)];治疗组总有效率高于对照组[RR=1.28,95％CI(1.14,1.44)].结论 现有证据表明,益气养阴、活血通络法治疗糖尿病合并心律失常是有效的,但由于目前相关研究较少,尚需多中心、大样本、更加规范的随机对照试验来进一步加以佐证.