桂枝茯苓丸加地龙治疗脑内微小病变的临床疗效及其危险因素分析闫振国1,曹贺2,陈婡3,王长德3,胡春梅1,王锋1,游毅3,刘笑迎3摘要目的:观察桂枝茯苓丸加地龙颗粒治疗脑内微小病变病人的临床疗效,并分析脑内微小病变的危险因素㊂方法:纳入2019年9月 2021年9月诊断为脑内微小病变的病人106例,随机分为试验组和对照组,每组53例㊂试验组予以桂枝茯苓丸加地龙颗粒,对照组予以阿司匹林肠溶片,两组均治疗6个月㊂在治疗前后记录脑内微小病变个数㊁糖化血红蛋白㊁总胆固醇㊁三酰甘油等生化指标,收集基础信息及血管危险因素相关病史,采用Logistic回归分析影响因素㊂结果:治疗前两组总胆固醇㊁三酰甘油㊁糖化血红蛋白水平比较差异无统计学意义(P>0.05),治疗后两组总胆固醇水平均下降,且试验组优于对照组,差异有统计学意义(P<0.05),糖化血红蛋白水平试验组下降,对照组未见明显改变,两组差异有统计学意义(P<0.05),两组三酰甘油水平差异无统计学意义(P> 0.05);治疗后两组脑内微小病变数量均较治疗前减少,且试验组优于对照组(P<0.05);试验组总有效率为88.46%,对照组总有效率为67.35%,差异有统计学意义(P<0.05)㊂经Logistic回归分析发现:性别㊁吸烟㊁高血压㊁糖尿病㊁高脂血症是脑内微小病变的危险因素(P<0.05)㊂结论:桂枝茯苓丸加地龙颗粒通过降低脑内微小病变病人的糖化血红蛋白和总胆固醇水平,减少脑内微小病变的发生;男性㊁吸烟㊁高血压㊁高脂血症㊁糖尿病是脑内微小病变发生的危险因素㊂关键词脑内微小病变;桂枝茯苓丸;地龙;危险因素;消癥通络d o i:10.12102/j.i s s n.1672-1349.2023.18.031Clinical Efficacy of Guizhi Poria Pills and Cadelorol on Intracerebral MicrolesionsYAN Zhenguo,CAO He,CHEN Lai,WANG Changde,HU Chunmei,WANG Feng,YOU Yi,LIU XiaoyingShanghai Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine,Shanghai201900,China Corresponding Author LIU Xiaoying,E-mail:***********************Abstract Objective:To observe the clinical effect of Guizhi Poria Pills and Cadelorol on patients with intracerebral microlesions and analyze the risk factors of intracerebral microlesions.Methods:A total of106patients diagnosed with intracerebral microlesions were included and randomly divided into experimental group and control group,with53cases in each group.The experimental group was given Guizhi Poria Pills and Cadelorol,and the control group was given aspirin enteric-coated tablets.Both groups were treated for6 months.The number of intracerebral microlesions,glycated hemoglobin,total cholesterol,triacylglycerol and other biochemical indicators were recorded before and after treatment,basic information and history related to vascular risk factors were collected,and variables were analyzed by Logistic regression.Results:There was no significant difference in the levels of total cholesterol,triacylglycerol,and glycated hemoglobin between two groups before treatment(P<0.05).The total cholesterol level of both groups decreased after treatment,and the experimental group was better than that in the control group,and the difference was statistically saignificant(P<0.05). The level of glycated hemoglobin in the experimental group decreased,but there was no significant change in the control group,and the difference between two groups was statistically significant(P<0.05).There was no significant difference in triglyceride level between two groups(P<0.05).After treatment,the intracerebral microlesions in both groups was reduced,and the experimental group was better than that in the control group(P<0.05).The total effective rate of the experimental group was88.46%,and that in the control group was67.35%,the difference was statistically significant(P<0.05).Logistic regression analysis showed that gender, smoking,history of hypertension,diabetes,and hyperlipidemia were risk factors for intracerebral microlesions(P<0.05).Conclusion: Guizhi Poria Pills and Cadelorol can reduce the occurrence of intracerebral microlesions by reducing the glycosylated hemoglobin and total cholesterol in patients with intracerebral microlesions.Male,smoking,hypertension,hyperlipidemia,and diabetes are the risk factors of intracerebral microlesions.Keywords eliminate mass to dredge collaterals;Guizhi Poria Pills;Cadelorol;risk factors;intracerebral microlesions脑内微小病变的概念源于扩大的血管周围间隙基金项目2020年度上海市虹口区卫生健康委员会中医药科研课题(No.HKQ-ZYY-2020-11);上海市科学技术委员会中医引导类课题(No. 16401931600);上海中医药大学科技发展基金(No.23KFKP09)作者单位 1.上海市宝山区中西医结合医院(上海201900);2.上海市杨浦区中医医院;3.上海中医药大学附属上海市中西医结合医院(上海200082)通讯作者刘笑迎,E-mail:***********************引用信息闫振国,曹贺,陈婡,等.桂枝茯苓丸加地龙治疗脑内微小病变的临床疗效及其危险因素分析[J].中西医结合心脑血管病杂志, 2023,21(18):3444-3448.(virchow-robin space,VRS),主要为头颅磁共振成像(magnetic resonance imaging,MRI)T2加权(T2WI)图像上直径小于3mm边缘整齐㊁境界清楚㊁不伴有周围信号改变的病灶,常见于基底节区㊁半卵圆中心和中脑[1],其数量与年龄㊁血管危险因素和其他的小血管疾病具有一定的相关性[2]㊂有文献表明,扩大的血管周围间隙能够增加缺血性脑卒中(腔隙性脑梗死㊁脑小血管病变等)㊁血管性痴呆和阿尔茨海默病的发病风险[3]㊂曲红等[4]通过129个月的随访发现:脑内微小病变主要分布在基底节上部(95.1%),与多项脑血管病危险因素相关,也是缺血性脑卒中的重要危险因素之一,临床上可以作为脑梗死的预测因子㊂因此,预防脑内微小病变的发生也是预防缺血性脑卒中的重要手段之一㊂本研究基于 消癥通络 理论采用桂枝茯苓丸加地龙治疗脑内微小病变病人,并采用Logistic回归分析探讨其危险因素,现报道如下㊂1资料与方法1.1研究对象入选2019年9月 2021年9月就诊于上海中医药大学附属上海市中西医结合医院脑病科诊断为脑内微小病变病人,依据公式计算样本量:N1=N2=(P1(1-P1)+P2(1-P2)) Z1-α+Z1-βP1-P2-δ{}2其中1-β=Φ(Z-Z1-α/2)+Φ(-Z-Z1-α/2),依据既往临床研究中对照组阿司匹林对脑内微小病变的有效率为94%,采用试验组优于对照组的优效性检验,确定α=0.025,β=0.1,效能1-β=0.9,界值Δδ=-0.15㊂代入公式计算出N1=N2=53例㊂其中有4例因联系信息不正确㊁死亡和其他疾病而退出临床试验,最终入组101例,试验组52例,对照组49例㊂本研究经上海中医药大学附属上海市中西医结合医院伦理委员会批准实施(伦理号:2020-060-1),所有入组病人或委托人均签署知情同意书,本研究内容符合世界医学协会‘赫尔辛基宣言“相关要求㊂1.2纳入与排除标准1.2.1纳入标准1)年龄18~80岁,尚未发生脑血管意外事件,磁共振检查发现微小病灶;2)影像学检查标准:选择基底节区呈Ⅱ型病变[T1WI低㊁T2WI高㊁液体衰减反转恢复等序列(FLAIR)信号]和Ⅲ型病变(T1WI低㊁T2WI 高㊁FLAIR低信号),且两侧基底节微小病变数合计ȡ6处[5]㊂1.2.2排除标准1)影像学提示发生过脑血管意外事件;2)病人治疗前或治疗中出现相应临床症状;3)脑内肿瘤病人;4)有药物(阿司匹林/中药地龙等)过敏不能耐受试验者;5)有出血风险者;6)孕期或哺乳期病人㊂1.2.3退出标准本试验观察期间,入选病人如出现不良事件或意外事件,或其他可能干预试验结果的情况,则退出试验㊂1.2.4脱落标准1)不能耐受本试验者;2)试验中因各种原因拒绝继续使用试验药物者;3)试验过程中因联系方式错误等原因失联者;4)试验过程中因其他疾病死亡者㊂1.3方法采用PHILIPS(1.5Testa)机拍摄,每例均行轴向常规T1WI㊁T2WI㊁FLAIR扫描㊂所有序列的切片厚度(slice)为5mm,间隙(gap)为1mm;矩阵(matrix)为256ˑ256,FOV(Field of View)为240ˑ240㊂使用PiView STAR软件,在底片阅读器上读取;由2名固定研究人员共同评估㊂按照脑内微小病变位置和分类计数,ɤ10个者按实际数目记录,>10个者按照分级程度记录>10个(2级)或ȡ25个(3级)㊂计数微小病变的数量,按0~9个㊁10~25个㊁>25个划分为低㊁中㊁重3个等级㊂1.4治疗方案试验组予以桂枝茯苓丸加地龙治疗,组方:地龙10g,茯苓10g,桂枝10g,牡丹皮10g,桃仁10g,芍药10g㊂经本课题组加工成颗粒剂,每次6g,每日2次,温水冲服㊂对照组予以口服阿司匹林肠溶片100 mg(国药准字:J20130078,拜耳医药保健有限公司生产),每日1次㊂两组均以6个月为1个疗程㊂观察期间保证病人基础疾病用药方案不变,如有不适及时干预处理㊂1.5观察指标及疗效评价治疗前记录病人基础信息(年龄㊁性别),生活习惯(吸烟史㊁饮酒史),血管危险因素(高血压病史㊁糖尿病病史㊁高血脂病史);治疗前后均进行头颅磁共振检查,观察脑微小病灶的变化(数量和形态);记录治疗前后病人总胆固醇㊁糖化血红蛋白㊁三酰甘油的变化㊂疗效评价:脑内微小病灶减少ȡ5个为显效;脑内微小病灶减少<5个,数量和形状不变为有效;数量或形状增加为无效㊂1.6统计学处理采用SPSS25.0数据分析软件分析㊂定量资料通过正态分布和方差齐性检验后选择采用独立样本t检验和配对样本t检验或校正t检验分析,以均数ʃ标准差(xʃs)表示;不符合正态分布且经校正后仍不符合正态分布和等级资料的数据,选用非参数Wilcoxon符号秩和检验;对于分类资料可采用皮尔逊χ2检验;对于二分类资料采用Logistic回归分析其影响因素㊂以P<0.05为差异有统计学意义㊂2结果2.1两组一般资料比较试验组,男26例,女26例,年龄(70.75ʃ10.24)岁;对照组,男26例,女23例,年龄(69.73ʃ10.43)岁㊂两组年龄㊁性别㊁吸烟㊁饮酒㊁高血压病史㊁糖尿病病史㊁高脂血症比较差异无统计学意义(P >0.05),具有可比性㊂详见表1㊂表1 两组临床资料比较单位:例(%)项目试验组(n =52)对照组(n =49)χ2值P 性别 男26(50.0)26(53.1)0.0950.843 女26(50.0)23(46.9)年龄 <65岁14(26.9)16(32.7)0.3970.664 ȡ65岁38(73.1)33(67.3)饮酒 是22(42.3)21(42.9)0.0030.995 否30(57.7)28(57.1)吸烟 是25(48.1)24(49.0)0.0080.928 否27(51.9)25(51.0)高脂血症 是25(51.9)26(53.1)0.2510.692 否27(48.4)23(46.9)高血压病史 是35(67.3)31(63.3)0.1820.682 否17(32.7)18(36.7)糖尿病史 是41(78.8)38(77.6)0.0250.875否11(21.2)11(22.4)2.2 两组总胆固醇㊁糖化血红蛋白㊁三酰甘油比较治疗前两组总胆固醇㊁三酰甘油㊁糖化血红蛋白水平比较差异无统计学意义(P >0.05);经过6个月的临床治疗后两组总胆固醇均有下降,且试验组优于对照组,差异有统计学意义(P <0.05);糖化血红蛋白水平试验组有下降,对照组未见明显改变,两组差异有统计学意义(P <0.05);三酰甘油治疗前后两组均差异有统计学意义(P >0.05)㊂桂枝茯苓丸加地龙治疗能够改善病人总胆固醇和糖化血红蛋白含量,且优于阿司匹林治疗㊂详见表2㊂表2 两组糖化血红蛋白㊁总胆固醇㊁三酰甘油水平比较(x ʃs )组别例数 总胆固醇(mmol/L ) 治疗前治疗后糖化血红蛋白(%) 治疗前治疗后三酰甘油(mmol/L ) 治疗前治疗后试验组52 6.08ʃ0.53 4.71ʃ0.99①②8.67ʃ1.277.98ʃ0.58①②1.48ʃ1.35 1.30ʃ0.86对照组496.14ʃ0.585.21ʃ1.00①8.67ʃ1.378.79ʃ0.431.82ʃ1.811.38ʃ1.26注:与同组治疗前比较,①P <0.05;与对照组治疗后比较,②P <0.05㊂2.3 两组脑内微小病变数量比较治疗前试验组脑内微小病变数量为(15.79ʃ5.89)个,对照组为(16.90ʃ6.30)个,治疗后试验组为(12.60ʃ4.04)个,对照组(14.94ʃ4.58)个,两组均较治疗前有减少,且试验组优于对照组(P <0.05)㊂两组治疗结束后,试验组脑内微小病变显效14例,有效32例,总有效率为88.46%;对照组脑内微小病变显效10例,有效23例,总有效率为67.35%㊂桂枝茯苓丸加地龙治疗对脑内微小病变的治疗效果优于阿司匹林治疗(P <0.05)㊂详见表3㊂ 表3 两组临床疗效比较单位:例(%)组别例数显效有效无效总有效试验组5214(26.92)32(61.54)6(11.54)46(88.46)对照组4910(20.41)23(46.94)16(32.65)33(67.35)注:两组总有效率比较,χ2=6.602,P =0.037㊂2.4 脑内微小病变的危险因素分析为进一步研究脑内微小病变发生的危险因素,对入组病人既往病史(血压㊁血脂㊁血糖),不良生活习惯(吸烟㊁饮酒)及高龄(以65岁分层)㊁性别等进一步分析㊂详见表4㊂表4 脑内微小病变发生情况分类观测 预测(例) 低级中重级敏感度(%)特异度(%)低级111396.145.8中重级374使用二分类Logistic 回归分析对脑内微小病变的危险因素进行分析,评估病人性别㊁年龄㊁吸烟㊁饮酒㊁血脂㊁血糖㊁血压等对脑内微小病变发生的影响㊂该模型解释了在中重级脑内微小病变发生的77例中,74例预测正确,敏感度为96.1%,特异度为45.8%㊂表明该模型对脑内微小病变数ȡ10个的预测效果较好㊂模型纳入7个危险因素,其中性别㊁吸烟㊁高脂血症㊁糖尿病㊁高血压5个变量差异有统计学意义(P<0.05),吸烟病人发生脑内微小病变的风险是未吸烟病人的4.972倍,高脂血症病人发生的脑内微小病变的风险是无高脂血症的8.940倍,糖尿病病人发生脑内微小病变的风险是无糖尿病的5.704倍,高血压病病人发生的脑内微小病变的风险是无高血压的 4.556倍,男性病人发生的脑内微小病变的风险是女性的3.705倍㊂详见表5㊂表5脑内微小病变危险因素的Logistic回归分析因素回归系数标准误Waldχ2值P OR值95%CI下限上限性别 1.3100.628 4.3570.037 3.705 1.08312.675年龄0.1560.6810.0530.819 1.1690.308 4.440吸烟 1.6040.658 5.9450.015 4.972 1.37018.046饮酒0.9510.629 2.2850.131 2.5880.7548.883高脂血症 2.1910.7259.1410.0028.940 2.16136.988糖尿病 1.7410.694 6.2870.012 5.704 1.46322.247高血压 1.5160.644 5.5510.018 4.556 1.29016.0882.5不良反应发生率本研究病人未发现有出血㊁皮下瘀斑瘀点等不良反应,无药物过敏等出现㊂3讨论脑内微小病变在中医学中并无对应病名明确记载,曲红等[6-7]根据脑内微小病变在头颅核磁共振上的表现,结合中医瘀血㊁痰饮㊁水湿等病理机制,将其归类为 有形之邪㊃癥瘕 范畴㊂桂枝茯苓丸源于‘金匮要略㊃妇人妊娠病脉证并治第二十“: 妇人宿有癥病,经断未及三月,而得漏下不止 所以血不止者,其癥不去故也,当下其癥,桂枝茯苓丸主之 ㊂现代常用于治疗子宫内膜炎㊁内膜异位症㊁痛经㊁子宫肌瘤㊁盆腔疾病等瘀血阻滞证的妇科疾病㊂近年来,有文献表明该方在治疗中风㊁痴呆等脑血管疾病具有良好的临床疗效㊂候娜娜等[8]运用桂枝茯苓丸加味辅助治疗急性脑梗死,研究发现桂枝茯苓丸具有保护病人神经功能,改善神经缺损症状,降低血浆神经元特异性烯醇化酶和内皮素-1水平,升高神经营养因子水平和改善凝血功能的作用㊂桂枝茯苓丸和黄芪建中汤合方可有效改善急性脑梗死病人神经功能缺损及残障程度,其疗效与丁苯酞软胶囊相当,具有改善侧支循环㊁挽救颅内缺血半暗带的功效[9]㊂本研究发现桂枝茯苓丸加地龙颗粒通过降低总胆固醇和糖化血红蛋白水平,可有效减少和延缓脑内微小病变的进展,进一步证实桂枝茯苓丸加地龙在脑血管病领域的预防价值㊂现代药理学表明桂枝茯苓丸具有降低血黏度㊁降低血脂㊁调节内分泌系统㊁控制血压,抑制大脑缺血后再灌注,抑制C-Fos基因表达,阻断脑组织水肿的发生,抑制氨基酸兴奋而造成的大脑损伤[10-12]㊂其中桂枝味甘性辛,通经络而开闭塞,入经络而达营解郁,具有温通血脉㊁助阳化气的功效,同时还具有扩血管㊁抗氧化㊁降血脂的作用[13];茯苓气平味甘,功擅消痰,利水渗湿,现代药理研究表明茯苓含有多糖类㊁三萜类等多种成分,具有抗炎㊁保肝降脂㊁抗氧化㊁改善细胞代谢的作用[14];桃仁味苦性辛,通经络而化瘀滞,破血瘀而消癥瘕,具有一定的抗血小板聚集㊁抗纤维化㊁保护神经等多重药理作用[15];牡丹皮味苦性辛,善化凝血而破癥,达木郁而清风,使风清热退而血行瘀消㊂现代药理表明,牡丹皮具有缓解及改善缺血性中风的作用[16]㊂芍药味酸苦性寒,能舒经通脉,除血痹破坚积消瘢瘕,能激活磷脂酰肌醇激酶-蛋白激酶B(PI3K-AKT)通路上调Bcl-2蛋白表达水平而抑制神经细胞凋亡和保护神经元[17-18]㊂地龙性寒味咸,功善循经入络,破瘀阻而开窍㊂现代药理研究表明,地龙具有调节血流速度㊁抑制血小板聚集㊁改善动脉硬化㊁调节微循环,调控血压㊁血糖㊁血脂等多种作用,广泛应用于脑血管病㊁惊厥㊁癫痫㊁哮喘等疾病治疗中[19]㊂本方桂枝温经通脉为君,桃仁㊁牡丹皮㊁茯苓化痰消癥㊁活血祛瘀为臣,芍药㊁地龙通经活络为佐使之品,诸药合用,发挥消癥通络之效,进而减少脑内微小病变,预防缺血性脑血管病的发生和复发㊂脑内微小病变与腔隙性脑梗死在头颅核磁共振上具有一定的差异,其发病机制可能与淋巴系统体液循环障碍有关,且与年龄㊁高血压㊁性别㊁睡眠障碍㊁脑外伤㊁炎症等因素有一定相关性[20-21]㊂资料显示脑内微小病变与脑卒中㊁脑小血管病变㊁认知功能障碍㊁淀粉样病变㊁脑微出血㊁神经退行性病变等疾病密切相关[22]㊂黄珊等[23]学者通过对278例脑梗死病人进行分析发现中重度的脑血管周围间隙扩大是脑梗死复发的独立危险因素㊂本研究通过采用Logistic回归分析对脑内微小病变的危险因素进一步分析表明糖尿病㊁高血压㊁高脂血症病人的发生率是正常病人的5.704倍㊁4.556倍和8.940倍;吸烟病人发生率是不吸烟的4.972倍,男性发生的概率是女性的3.705倍,这可能与男性吸烟的人数更多有关㊂高脂血症是脑内微小病变发生的一项重要危险因素,其发病机制可能与脂代谢紊乱引起血管内皮损伤有关,血浆中胆固醇㊁三酰甘油㊁类脂等脂类的升高能够增加血液黏度,降低血流速度,影响血管壁的通透性,促使血管硬化,大量的血浆脂蛋白通过内膜,引起巨噬细胞的吞噬功能,诱发平滑肌细胞增生而引起斑块形成和动脉粥样硬化,造成脑内微小病变的早期形成[24]㊂糖尿病导致脑内微小病变可能与胰岛素抵抗的形成具有一定的相关性,胰岛素抵抗与动脉粥样硬化具有相关性,是累及小血管病变的主要危险因素,通过改变血管分子水平和细胞水平的病理变化,能够增加糖尿病病人腔隙性梗死发生率[25]㊂高血压是脑微血管病变的一项重要危险因素,静态下24h动态血压变化与脑血管扩大的周围间隙具有一定相关性,可能与血管的变化导致血管通透性增加,引起纤维组织的变性,血管搏动的力度产生改变,最终抑制组织间液的回流,沉积,形成脑内微小病变[26-28]㊂本研究发现,通过减低总胆固醇㊁糖化血红蛋白水平,能够减少脑内微小病变的发生,与既往研究脑梗死的复发和糖尿病病史㊁高血压病史以及高脂血症相关,且与总胆固醇的含量密切相关[29]相一致㊂本研究显示,通过采用 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BRIEF COMMUNICATIONRheological behaviour of ethylene glycol-titanate nanotube nanofluidsHaisheng Chen ÆYulong Ding ÆAlexei Lapkin ÆXiaolei FanReceived:11July 2008/Accepted:4February 2009/Published online:26February 2009ÓSpringer Science+Business Media B.V.2009Abstract Experimental work has been performed on the rheological behaviour of ethylene glycol based nanofluids containing titanate nanotubes over 20–60°C and a particle mass concentration of 0–8%.It is found that the nanofluids show shear-thinning behaviour particularly at particle concentrations in excess of *2%.Temperature imposes a very strong effect on the rheological behaviour of the nanofluids with higher temperatures giving stronger shear thinning.For a given particle concentration,there exists a certain shear rate below which the viscosity increases with increasing temperature,whereas the reverse occurs above such a shear rate.The normalised high-shear viscosity with respect to the base liquid viscosity,however,is independent of temperature.Further analyses suggest that the temperature effects are due to the shear-dependence of the relative contributions to the viscosity of the Brownian diffusion and convection.The analyses also suggest that a combination of particle aggregation and particle shape effects is the mechanism for the observed high-shear rheological behaviour,which is also supported by the thermal conductivity measure-ments and analyses.Keywords Rheological behaviour ÁEthylene glycol ÁTitanate nanotube ÁNanofluid ÁThermal conductivityNanofluids are dilute suspensions of particles with at least one dimension smaller than about 100nm (Choi 1995).Such a type of materials can be regarded as functionalized colloids with special requirements of a low-particle loading,a high-thermal performance,favourable flow/rheolgocial behaviour,and a great physical and chemical stability over a wide range of process and solution chemistry conditions.Nano-fluids have been shown to be able to enhance heat transfer (Choi 1995;Wang and Mujumdar.2007),mass transfer (Krishnamurthy et al.2006),and wetting and spreading (Wasan and Nikolov 2003),and have been a hot topic of research over the past decade (Wang and Mujumdar 2007;Keblinski et al.2005).Most published studies have focused on the heat transfer behaviour including thermal conduction (Choi 1995;Wang et al.1999;Wang and Mujumdar 2007;Keblinski et al.2005;Eastman et al.2001;He et al.2007;Ding et al.2006),phase change (boiling)heat transfer (Das et al.2003;Pak and Cho 1998),and convective heat transfer (Wang and Mujumdar 2007;Keblinski et al.2005;He et al.2007;Ding et al.2006,Chen et al.2008;Prasher et al.2006a and Yang et al.2005).Only few studies have been devoted to the rheological behaviour ofH.Chen ÁY.Ding (&)Institute of Particle Science and Engineering,University of Leeds,Leeds,UK e-mail:y.ding@pkin ÁX.FanDepartment of Chemical Engineering,University of Bath,Bath,UKJ Nanopart Res (2009)11:1513–1520DOI 10.1007/s11051-009-9599-9nanofluids(He et al.2007;Chen et al.2008;Prasher et al.2006a,b;Kwak and Kim2005;Lee et al.2006), although there is a large body of literature on suspensions rheology;see for example,Russel et al. (1991);Chow(1993);Petrie(1999),Larson(1999); Goodwin et al.(2000)l;Mohraz et al.(2004);Larson (2005);Egres and Wagner(2005);Abdulagatov and Azizov(2006).Particularly,there is little in the literature on the effect of temperature on the rheo-logical behaviour of nanofluids.Clearly,there is a gap in the current rheological literature for this type offluids.Furthermore,recent work has shown that the thermal behaviour of nanofluids correlates well with their rheological behaviour(Prasher et al.2006a, b;Chen et al.2007a;Abdulagatov and Azizov2006). In a recent study,we investigated systemically the rheological behaviour of ethylene glycol(EG)based spherical TiO2nanofluids(Chen et al.2007b).The results show that the nanofluids are Newtonian over a shear rate range of0.5–104s-1and the shear viscosity is a strong function of temperature,particle concentration and aggregation microstructure.This work is concerned about the rheological behaviour of EG based nanofluids containing titanate nanotubes (TNT).The specific objectives of the work are to investigate the effects of particle shape,particle concentration and temperature on nanofluids viscosity, and to understand the relationship between the rheo-logical behaviour and the effective thermal conductivity of nanofluids.It is for thefirst time that the rheological behaviour of a highly viscous EG based TNT nanofluids is investigated in a systematic manner.As will be seen later,the results of this work provide further evidence that the rheological measure-ments could provide information of particle structuring for predicting the effective thermal conductivity of nanofluids.The EG-TNT nanofluids used in this work were formulated by using the so-called two-step method with EG purchased from Alfa Aesar and TNT synthesized in our labs using a method described elsewhere(Bavykin et al.2004).The details of nanofluids formulation can be found elsewhere(Wen and Ding2005;He et al.2007;Chen et al.2007b). The TNT particles have a diameter(b)of*10nm and a length(L)of*100nm,giving an aspect ratio of(r=L/b)of*10.To avoid complications in interpreting the experimental results,no dispersants/ surfactants were used in the formulation.The nanofluids formulated were found stable for over 2months.The rheological behaviour of the nano-fluids was measured by using a Bolin CVO rheometer (Malvern Instruments,UK)over a shear rate range of 0.03–3,000s-1,a nanoparticle mass concentration of w=0–8%,and a temperature range of20–60°C (293–333K).The nanofluids were characterised for their size by using a Malvern Nanosizer(Malvern Instruments,UK)and a scanning electron microscope (SEM).The average effective particle diameter was found to be*260nm for all nanofluids formulated. This size is much larger than the equivalent diameter of the primary nanoparticles due to aggregation;see later for more discussion.Note that the particle size characterisation was performed both before and after the rheological measurements and no detectable changes to particle size were found.Figure1shows the viscosity of pure EG and EG-TNT nanofluids as a function of shear rate at 40°C.The results at other temperatures are similar.It can be seen that the EG-TNT nanofluids exhibit highly shear-thinning behaviour particularly when the TNT concentration exceeds*2%.Such behaviour is different from the observed Newtonian behaviour of EG-TiO2nanofluids containing spherical nanoparti-cles over similar shear rate range(Chen et al.2007b) where the base liquid,EG,is the same as that used in the current wok.The behaviour is similar to the observations of carbon nanotube nanofluids(Ding et al.2006)and CuO nanorod nanofluids(Kwak and Kim2005),although there are important differencesbetween them such as temperature dependence as will be discussed later.The shear-thinning behaviour of well-dispersed suspensions can be interpreted by the structuring of interacting particles(Doi and Edwards1978a,b and Larson1999).In a quiescent state,a rod-like particle has three types of motion due to Brownian diffusion: rotational(end-over-end)motion around the mid-point and translational motion in parallel or perpendicular to the long axis.For dilute suspensions with a number density,c,ranging between0and1/L3or volume fraction,u,ranging between0and1/r2),the average spacing between the particles is larger than the longest dimension of the rod,and zero shear viscosity can be approximated by gð0Þ%g0ð1þAÁcL3Þwith g0the base liquid viscosity and A,a numerical constant(Doi and Edwards1978a).For suspensions with 1/L3\c\1/bL2or1/r2\f/\1/r,the rod-like particles start to interact.The rotational motion is severely restricted,as well as the translational motion perpendicular to the long axis,and the zero shear viscosity can be estimated by gð0Þ%g0ð1þðBcL3Þ3Þ; with B a numerical constant(Doi and Edwards1978b). As a consequence,the zero shear viscosity can be much greater than the base liquid viscosity.The large viscosity is due to the rod-like shape effect and the viscosity is very sensitive to shear,which tends to align particles and hence the shear-thinning behaviour as shown in Fig.1.Note that the above mechanism can give a qualitative explanation for the experimental observations at low-shear rates and the shear-thinning behaviour as shown in Fig.1,it does not explain the high-shear viscosity of the nanofluids,which will be discussed later.It should also be noted that the criteria for classifying nanofluids given above need to be modified due to the presence of aggregates;see later for more discussion.Figure2shows the shear viscosity of4.0%EG-TNT nanofluids as a function of shear rate at different temperatures.The results under other concentrations are similar.It can be seen that the temperature has a very strong effect on the rheological behaviour of nanofluids with higher temperatures giving stronger shear thinning.For shear rates below*10s-1,the shear viscosity increases with increasing temperature, whereas the trend is reversed when the shear rate is above*10s-1.As mentioned above,this behaviour was not observed for carbon nanotube(Ding et al. 2006)and CuO nanorod(Kwak and Kim2005)nanofluids and we have not seen reports on such behaviour for nanofluids in the literature;see later for more discussion on the underlying mechanisms. Figure2also shows that the strongest shear thinning occurs at40–60°C,whereas very weak-shear thinning takes places at20–30°C.It is also noted that the shear viscosity of nanofluids at all temperatures investigated approaches a constant at high-shear rates.If the high-shear viscosity is plotted against temperature,Fig.3is obtained where the shear rate corresponding to the high-shear viscosity is taken as *2,000s-1.An inspection of all the data indicates that theyfit the following equation very well:ln g¼AþBÂ1000=TþCðÞð1Þwhere g is the shear viscosity(mPaÁs),T is the absolute temperature(K),and A,B and C areconstants given in Table1.Equation(1)takes a similar format as that widely used for liquid viscosity (Bird et al.2002)and for EG based nanofluids containing spherical particles(Chen et al.2007b).If the measured high-shear viscosity is normalized with respect to the shear viscosity of the base liquid, the relative increaseðg i¼ðgÀg0Þ=g0Þof the high-shear viscosity is found to be only a function of concentration but independent of temperature over the temperature range investigated in this work.The relative increments in the shear viscosities of nano-fluids containing0.5%,1.0%,2.0%,4.0%and8.0% particles are 3.30%,7.00%,16.22%,26.34%and 70.96%,respectively.Similar temperature indepen-dence of the shear viscosity was also observed for EG-TiO2and water-TiO2nanofluids containing spherical nanoparticles(Chen et al.2007b).The experimentally observed temperature depen-dence can be interpreted as follows.Given the base liquid and nanoparticles,the functional dependence of viscosity on shear rate is determined by the relative importance of the Brownian diffusion and convection effects.At temperatures below*30°C,the contribu-tion from the Brownian diffusion is weak due to high-base liquid viscosity.As a consequence,the shear dependence of the suspension is weak(Fig.2).The contribution from the Brownian diffusion becomes increasingly important with increasing temperature particularly above40°C due to the exponential dependence of the base liquid viscosity on temperature (Fig.3).At very high-shear rates,the Brownian diffusion plays a negligible role in comparison with the convective contribution and hence independent of the high-shear viscosity on the temperature.We now start to examine if the classical theories for the high-shear viscosity predict the experimental measurements(note that there is a lack of adequate theories for predicting the low shear viscosity).Figure4shows the shear viscosity increment as a function of nanoparticle volume concentration together with the predictions by the following Brenner &Condiff Equation for dilute suspensions containing large aspect ratio rod-like particles(Brenner and Condiff1974):g¼g01þg½ uþO u2ÀÁÀÁð2Þwhere the intrinsic viscosity,½g ;for high-shear rates has the following form(Goodwin and Hughes2000):½g ¼0:312rln2rÀ1:5þ2À0:5ln2rÀ1:5À1:872rð3ÞAlso included in Fig.4are the data for EG-TiO2 nanofluids with spherical nanoparticles(Chen et al. 2007b)and predictions by the Einstein Equation (Einstein1906,1911)for dilute non-interacting suspensions of spherical particles,g¼g01þ2:5uðÞ: It can be seen that both the Einstein and Brenner& Condiff equations greatly underpredict the measured data for the EG-TNT nanofluids.The high-shear viscosity of EG-TNT nanofluids is much higher than that of the EG-TiO2nanofluids containing spherical nanoparticles,indicating a strong particle shape effect on the shear viscosity of nanofluids.Although the shear-thinning behaviour of the nanofluids could be partially attributed to the structuring of interacting rod-like particles,the large deviation between the measured high-shear viscosity and the predicted ones by the Brenner&Condiff equation cannot fully be interpreted.In the following,an attempt is made to explain the experimental observations from the viewpoint of aggregation of nanaoparticles,which have been shown to play a key role in thermal behaviour of nanofluids in recent studies(Wang et al. 2003;Xuan et al.2003;Nan et al.1997;Prasher et al. 2006a,b;Keblinski et al.2005).Such an approach is also supported by the SEM and dynamic lightTable1Empirical constants for Eq.(1)a Maximum discrepancies;b Minimum discrepancies Concentration(wt%)A B C MaxD a(%)MinD b(%)0.0-3.21140.86973-154.570.62-1.440.5-3.42790.94425-148.490.93-0.471.0-2.94780.81435-159.14 1.11-0.692.0-2.2930.65293-174.57 1.64-0.694.0-2.63750.7574-165.820.99-0.948.0-2.73140.93156-145.010.88-1.57scattering analyses,which,as mentioned before, show clear evidence of particle aggregation.According to the modified Krieger-Dougherty equation(Goodwin and Hughes2000;Wang et al. 2003;Xuan et al.2003;Nan et al.1997),the relative viscosity of nanofluids,g r,is given as:g r¼1Àu a=u mðÞÀ½g u mð4Þwhere u m is the maximum concentration at which the flow can occur and u a is the effective volume fraction of aggregates given by u a¼u=u ma with u ma the maximum packing fraction of aggregates.As aggre-gates do not have constant packing throughout the structure,the packing density is assumed to change with radial position according to the power law with a constant index(D).As a result,u a is given as u a¼uða a=aÞ3ÀD;with a a and a,the effective radii of aggregates and primary nanoparticles,respectively. The term D is also referred as the fractal index meaning the extent of changes in the packing fraction from the centre to the edge of the aggregates.Typical values of D are given in normal textbook as D= 1.8–2.5for diffusion limited aggregation(DLA)and D=2.0–2.2for reaction limited aggregation(RLA); see for example Goodwin and Hughes(2000).For nanofluids containing spherical nanoparticles,the value of D has been shown experimentally and numerically to be between1.6and1.8(Wang et al. 2003,Xuan et al.2003)and between1.8and2.3, respectively(Waite et al.2001).A typical value of 1.8is suggested for nanofluids made of spherical nanoparticles(Prasher et al.2006a,b).However,little research has been found on the fractal index for nanofluids containing rod-like nanoparticles.The colloid science literature suggests a fractal index of 1.5–2.45for colloidal suspensions depending on the type of aggregation,chemistry environment,particle size and shape and shearflow conditions(Haas et al. 1993;Mohraz et al.2004;Hobbie and Fry2006; Micali et al.2006;Lin et al.2007).In a recent study, Mohraz et al.(2004)investigated the effect of monomer geometry on the fractal structure of colloi-dal rod aggregates.They found that the fractal index is a non-linear function of the monomer aspect ratio with the D increasing from*1.80to*2.3when the aspect ratio of the rod-like nanoparticles increases from1.0to30.6.Based on the above,a value of D=2.1is taken for nanofluids used in this work (Mohraz et al.2004,Lin et al.2007).Although the fractal model may appear to simplify the complexity of microstructures in aggregating systems containing rod-like particles,excellent agreement between the model prediction and experimental measurements exists when a a/a=9.46;see Fig.4.Here the aggregates are assumed to formflow units of an ellipsoidal shape with an effective aspect ratio of r a¼L a=b a;where L a and b a are the effective length and diameter,respectively.In the calculation,a typical value of u m of0.3is taken(Barnes et al.1989),and the intrinsic viscosity[g]is calculated by Eq.(3).It is to be noted that the aggregate size thatfits well to the rheological data(Fig.4)is consistent with the particle size analyses using both the SEM and the Malvern Nanosizer.A comparison between the EG-TNT data (a a/a=9.46,D=2.1,u m=0.30)and the EG-TiO2 data(a a/a=3.34,D=1.8,u m=0.605)(Chen et al. 2007b)in Fig.4suggests that the larger aggregate size in TNT nanofluids be an important factor responsible for the stronger shear-thinning behaviour and higher shear viscosity of TNT nanofluids.An inspection of Eq.(4)indicates that the effec-tive volume fraction u a u a¼u a a=aðÞ3ÀDis much higher than the actual volume fraction(u).This leads to the experimentally observed high-shear viscosity even for very dilute nanofluids,according to the classification discussed before.As a consequence,the demarcations defining the dilute and semi-concen-trated dispersions should be changed by using the effective volume fraction.The model discussed above can also provide a macroscopic explanation for the temperature indepen-dence of the high-shear viscosity.From Eq.(4),one can see that the relative high-shear viscosity depends on three parameters,the maximum volume fraction, u m,the effective volume fraction,u a and the intrinsic viscosity,[g].For a given nanofluid at a temperature not far from the ambient temperature,the three parameters are independent of temperature and hence the little temperature dependence of the relative shear viscosity.Microscopically,as explained before,the temperature-independent behaviour is due to negligi-ble Brownian diffusion compared with convection in high-shearflows.To further illustrate if the proposed aggregation mechanism is adequate,it is used to predict the effective thermal conductivity of the nanofluids by using the following conventional Hamilton–Crosser model(H–C model)(Hamilton and Crosser1962):k=k0¼k pþðnÀ1Þk0ÀðnÀ1Þuðk0Àk pÞk pþðnÀ1Þk0þuðk0Àk pÞð5Þwhere k and k0are,respectively,the thermal conductivities of nanofluids and base liquid,n is the shape factor given by n=3/w with w the surface area based sphericity.For TNT used in this work,the sphericity w is estimated as0.6(Hamilton and Crosser1962).For suspensions of aggregates,the above equation takes the following form:k=k0¼k aþðnÀ1Þk0ÀðnÀ1Þu aðk0Àk aÞa0a0að6Þwhere k a is the thermal conductivity of aggregates.To calculate k a,Eq.(6)is combined with the following Nan’s model(Nan et al.2003)for randomly dispersed nanotube-based composites:k a=k0¼3þu in½2b xð1ÀL xÞþb zð1ÀL zÞ3Àu in½2b x L xþb z L zð7Þwhere/in is the solid volume fraction of aggregates, b x¼ðk xÀk0Þ=½k mþL xðk tÀk mÞ and b z¼ðk zÀk0Þ=½k mþL zðk tÀk mÞ with k x,k m and k t being the thermal conductivities of nanotubes along trans-verse and longitudinal directions and isotropic thermal conductivity of the nanotube,respectively. In this work,k x,k m and k t are taken the same value as k p for afirst order of approximation due to lack of experimental data,and L x and L z are geometrical factors dependent on the nanotube aspect ratio given by L x¼0:5r2=ðr2À1ÞÀ0:5r coshÀ1r=ðr2À1Þ3=2 and L z¼1À2L x:Figure5shows the experimental results together with predictions by the original H–C model(Eq.5) and revised H–C model(Eq.6).Here the experiment data were obtained using a KD2thermal property meter(Labcell,UK)(Murshed et al.2005;Chen et al. 2008).One can see that the measured thermal conductivity is much higher than the prediction by the conventional H–C model(Eq.5),whereas the modified H–C model taking into account the effect of aggregation(Eq.6)agrees very well with the exper-imental data.The above results suggest that nanoparticle aggregates play a key role in the enhancement of thermal conductivity of nanofluids. The results also suggest that one could use the rheology data,which contain information of particle structuring in suspensions,for the effective thermal conductivity prediction.In summary,we have shown that EG-TNT nano-fluids are non-Newtonian exhibiting shear-thinning behaviour over20–60°C and a particle mass concen-tration range of0–8%,in contrast to the Newtonian behaviour for EG-TiO2nanofluids containing spher-ical particles.The non-Newtonian shear-thinning behaviour becomes stronger at higher temperatures or higher concentrations.For a given particle concen-tration,there exists a certain shear rate(e.g.*10s-1 for4wt%)below which the viscosity increases with increasing temperature,whereas the reverse occurs above such a shear rate.The normalised high-shearviscosity with respect to the base liquid viscosity, however,is found to be independent of temperature. These observations have not been reported in the literature for nanofluids.Further analyses suggest that the temperature effects are due to the shear-depen-dence of the relative contributions to the viscosity of the Brownian diffusion and convection.The analyses also suggest that a combination of particle aggregation and particle shape effects is the mechanism for the observed high-shear rheological behaviour,which is supported not only by the particle size measurements but also by the thermal conductivity measurements and analyses using a combination of the H–C and Nan’s models.The results of this work also indicate that one could use the information of aggregation from the rheological experiments for predicting the effec-tive thermal conductivity of nanofluids. 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疯狂的贤妻疯狂的贤妻车明辙从县城里卖完鱼开车回来，天已经黑了。
妻子柳金莲已经把饭菜做好了，让车明辙很是吃惊的是柳金莲竟然做了满满一桌子菜；特别是那种他最爱喝的老白干，竟然放在桌子的中间。
车明辙怔怔地看着柳金莲，他实在想不明白，平常她压根就不让他喝酒，今天她怎么会一反常态，竟然给他酒喝？柳金莲见车明辙怔怔地看着自己，便用手指很是亲昵地点了一下车明辙的脑门，说道：“你傻啊，今天不是咱家老狗的生日嘛！”车明辙一下子想了起来，可不是嘛，今天是7月初七，是他的生日啊！吃饭时，柳金莲便对车明辙说道：“平常不让你喝酒，怕你开车不安全，今天是你的生日，你就放开量喝吧，今晚我去喂鱼！”车明辙嘿嘿一笑：“臭婆娘，我就是喝个晕晕乎乎，也不能让个妇人家黑灯瞎火去江里喂鱼啊！”车明辙其实并没有什么酒量，喝不上半斤八两就晕晕乎乎了。
车明辙有自己的养鱼场，每天晚上都要去江里喂鱼。
待车明辙喝完酒后，柳金莲便让他老老实实躺下睡觉，她去江边喂鱼。
车明辙很爱柳金莲，他不可能让她一个人黑灯瞎火去江里喂鱼。
车明辙一把把柳金莲按在床上，狠狠亲了一口，就趔趔趄趄朝外走去。
柳金莲赶忙爬起来，朝车明辙说道：“那咱俩一起去。
”柳金莲撵上车明辙，想搀扶他走，车明辙用手一推，说道：“你回去吧，我自个能行！”谁知他这么一推，柳金莲脚下被石头一绊，竟趔趔趄趄地摔倒在了路边的臭水沟里。
柳金莲的衣服全湿透了，柳金莲便冲车明辙骂道：“臭老狗，你先慢慢走，我回去换套衣服。
”柳金莲返回家，换了套衣服，便来到江边，江边一点动静也没有，专门用来喂鱼的小艚盆，也没泊在岸边，老狗肯定是摆着艚盆去江里喂鱼了。
柳金莲便用双手卷成喇叭状，朝江里喊道：“老狗，你在哪啦？”江面上很安静，没有任何回声。
柳金莲掏出手机，给车明辙打电话，手机竟然无法接通。
柳金莲有些慌神了，拔起腿就朝下游跑去，车明辙的舅舅在下游养鱼。
柳金莲跑到舅舅的鱼场时，已经累得说不出话来了。
舅舅赶紧将艚盆向上游划去。
