腺病毒介导HCN4通道基因过度表达构建生物起搏器的实验研究

电子起搏器是窦房结功能障碍和重度房室传导阻滞的首选治疗。但是，目前使用的电子起搏器存在很多缺陷。最近的研究表明，介导起搏电流（If）的超极化激活环核苷酸门控通道基因（HCN4）在生理性起搏机制中扮演重要角色。在人类遗传性窦房结功能障碍家系中存在HCN4基因突变。而且，在HCN4基因敲除小鼠胚胎心脏记录不到具有4期自动除极特征的起搏细胞动作电位。最近，国外用HCN4腺病毒载体转染体外培养的心室肌细胞使其过度表达If电流，成功将其转变为“起搏”细胞并显增加了搏动频率。     

TBX18腺病毒载体体外诱导乳鼠心肌细胞向起搏样细胞分化

目的观察TBX18腺病毒载体在体外转染乳鼠心肌细胞,能否诱导其向起搏样细胞分化。方法胰酶和Ⅱ型胶原酶混合消化法分离培养乳鼠心肌细胞,光学显微镜下观察细胞形态,48h后用免疫荧光技术检测心肌细胞纯度。将心肌细胞随机分为实验组(TBX18组)、空病毒对照组(GFP组),转染时分别加入带TBX18转录因子和绿色荧光蛋白(GFP)的腺病毒,带GFP的腺病毒,采用实时荧光定量聚合酶链式反应,蛋白质免疫印迹和免疫荧光技术检测各组心肌细胞HCN4mRNA和HCN4蛋白的表达。结果培养24h后,心肌细胞几乎完全贴壁,可见梭形、菱形或多边形;48h后形成网状或放射状细胞簇。α-actin检测心肌细胞纯度高达96%。TBX18组心肌细胞中HCN4mRNA和HCN4蛋白的表达水平明显高于GFP组(28 943.997±5 019.682vs 1.000±0.000,n=9,P0.05;0.631±0.025vs 0.192±0.003,n=9,P0.05);倒置荧光显微镜下观察TBX18组因表达HCN4蛋白而发出红色荧光,GFP组几乎看不到HCN4蛋白的表达。结论 TBX18腺病毒载体体外转染乳鼠心肌细胞,能使乳鼠心肌细胞向起搏样细胞分化。     

腺病毒介导短发夹RNA沉默Nkx2.5基因对乳鼠心肌细胞的影响

目的探讨腺病毒介导短发夹RNA下调Nkx2.5基因表达对体外培养大鼠乳鼠心肌细胞(NRVMs)的影响。方法采用胰酶和Ⅱ型胶原酶混合消化法分离NRVMs,随机分为阴性对照组(NC组)和实验组。实验组转染携带靶向Nkx2.5的RNA干扰序列(短发夹RNA,shRNA)和绿色荧光蛋白(GFP)的腺病毒Ad-Nkx2.5-shRNA-GFP,NC组转染等量的仅携带GFP的对照组腺病毒Ad-GFP。以不同感染复数(MOI)转染细胞选取最适MOI,按最适MOI转染NRVMs 48h后,采用实时荧光聚合酶链式反应和蛋白质免疫印迹检测Nkx2.5沉默效果,保证沉默效果之后,检测起搏细胞发育相关转录因子(Tbx3、Tbx18、Shox2和Isl1)、起搏相关离子通道超极化激活环核苷酸门控通道4型(HCN4)和缝隙链接蛋白40(Cx40)mRNA和蛋白水平变化,采取免疫荧光法检测HCN4蛋白的表达。结果分离培养的原代NRVMs 48h呈现成簇搏动,α-actin检测心肌纯度达0.91±0.01,转染NRVMs的最适MOI=20,构建的病毒可有效下调Nkx2.5水平(P<0.05);下调心肌细胞Nkx2.5水平后,起搏细胞发育相关转录因子、HCN4表达水平升高(P<0.05),心室肌相关缝隙连接蛋白Cx40表达水平下降(P<0.05)。荧光显微镜观察实验组红色荧光即离子通道HCN4表达强于对照组。结论下调Nkx2.5可将NRVMs重编程为起搏样细胞。     

在体经皮微创注射TBX18构建生物起搏点

目的探讨经皮微创注射转录因子T-box 18(TBX18)对三度房室传导阻滞模型犬心率的影响。方法取两只比格犬,均植入起搏器(右室VVI起搏,45次/分)并经股静脉途径消融房室结构建三度房室传导阻滞模型。经导管(NOGA MyoStar)分别注射腺病毒-绿色荧光蛋白-TBX18(Ad-GFP-TBX18,TBX18犬)或Ad-GFP(GFP犬)至右室流出道靠近间隔处,观察14天后犬的心率变化及逸搏节律起源部位,并在荧光显微镜下观察注射部位心肌细胞荧光表达强度。结果房室结消融后两只犬均为起搏心律,频率45次/分,14天后TBX18犬心率64次/分,逸搏节律起源点位于注射部位,GFP犬心率48次/分,逸搏节律起源点远离注射部位。荧光检测显示注射部位心肌组织有绿色荧光表达。结论经皮微创注射TBX18可构建生物起搏点。     

心脏瓣膜病心房颤动患者心房肌超极化激活环化核苷酸门控通道基因表达的研究

目的研究心脏瓣膜病心房颤动（房颤）患者心房肌超极化激活环化核苷酸门控通道（HCN）各亚型及其调控因子环腺苷酸（cAMP）的基因转录,探讨房颤患者心房肌超极化激活电流（If）改变的分子机制。方法心外科心脏瓣膜病需开胸换瓣的病人45例,分为两组,其中房颤者27例,窦性心律者18例,术中取左心房组织,采用半定量逆转录-聚合酶链反应（RT—PCR）测定HCN1、HCN2、HCN4、cAMP的mRNA的含量。结果同窦性心律组相比,房颤组患者心房肌HCN2、14CN4的mRNA表达水平上调（P〈0．05）,HCN1、cAMP的mRNA表达水平在房颤组患者中亦有增高,但差异无统计学意义（P〉0．05）。HCN2的mRNA表达与左心房内径呈正相关（r=0．441,P=0．002）。结论心房肌HCN2、HCN4的mRNA表达水平上调可能是心脏瓣膜病房颤患者心房肌If电流改变的重要分子基础,通过If的改变进一步参与心房的电重构。     

胚胎心肌细胞移植治疗缓慢型心律失常的实验研究

目的探讨胚胎心肌细胞移植重建心脏优势起搏点治疗缓慢型心律失常的可行性.方法酶法分离引产男性胎儿心房组织(包括窦房结),获取单个心肌细胞,差速贴壁法纯化,4、6-二脒基-2-苯基吲哚(DAPl)标记后制备成5×106个/ml心肌细胞悬液,开胸直视下将1ml悬液注入Yorkshire猪左室游离壁(n=2),对照组(n=2)注入等体积培养基DMEM,移植前3天开始应用环孢素A(Ⅳ,5mg/kg/d)和泼尼松龙(Ⅳ,2.5mg/kg/d)抑制免疫排斥反应.移植后2～3周应用射频消融技术打断希氏束建立完全性房室传导阻滞动物模型,分别应用心电图、Holter、免疫荧光显像、心腔内起搏标测和激动标测进行组织学和电生理学评价,RT-PCR检测各组Y染色体SRYmRNA表达情况.结果希氏束消融后,两组动物均形成完全性房室传导阻滞,细胞移植组室性心律频率为75±30bpm,对照组为室性逸搏心律,频率为(35±10)次/min或交界心律,最后发生室颤死亡.心腔内起搏标测和激动标测证实细胞移植组室性心律起源于细胞注射表达.心脏组织冰冻切片可见DAPI标记的呈蓝色荧光的移植细胞核,移植细胞与宿主心肌细胞间有连结蛋白43(connexin43)和N型钙粘素(N-Cadherin)的表达,说明移植细胞存活并与宿主心肌细胞形成电一机械联系.RT-PCR检测到细胞移植组SRY基因片段区,对照组未扩增出SRY片段,说明胚胎心肌细胞在移植区存活.结论心肌细胞移植可能取代电子起搏器治疗缓慢型心律失常.     

同种异体心肌细胞移植治疗缓慢性心律失常的实验研究

探讨新生心肌细胞移植重建心脏优势起搏点治疗缓慢性心律失常的可行性。采用酶法分离新生Yorkshire猪右房组织(包括窦房结),获取单个心肌细胞,差速贴壁法纯化,4,6-二脒基-2-苯基吲哚(DAPI)标记后制备成5×106个/ml心肌细胞悬液,开胸直视下将1ml悬液注入细胞移植组幼年猪左室游离壁(n=5),对照组(n=5)注入等体积培养基,移植前3天开始应用环孢素A和泼尼松龙抑制免疫排斥反应。移植3周后应用射频消融技术打断His束造成Ⅲ度房室阻滞。分别应用心电图、Holter、心腔内起搏标测和免疫荧光显像进行电生理学评价和组织学观察。结果:His束消融后,两组动物均形成Ⅲ度房室阻滞。细胞移植组室性节律频率显著快于对照组(移植组平均为95次/分,对照组为32次/分)。心腔内起搏标测证实细胞移植组室性心律起源于细胞移植区。对照组均在24h内发生心室颤动死亡。心脏组织冰冻切片可见DAPI标记的呈蓝色荧光的移植细胞核,移植细胞与宿主心肌细胞间有连接蛋白43和N型钙粘素的表达。结论:移植的心肌细胞可在宿主心脏存活并与周围细胞发生电连接,并主导心室节律。     

起搏通道基因亚型HCN4重组腺病毒载体的构建及通道电流检测

目的旨在构建超极化激活环核苷酸门控阳离子通道基因亚型4(HCN4)重组腺病毒载体并鉴定其离子通道功能。方法全长人HCN4基因酶切后亚克隆到腺病毒穿梭载体pAdTrack-CMV,形成含目的基因和绿色荧光蛋白基因的穿梭载体。穿梭载体和病毒骨架载体pAdEasy-1经电穿孔法在BJ5183大肠杆菌中同源重组,重组后的腺病毒载体经PacⅠ酶切线性化后,利用脂质体介导转染到HEK293细胞进行病毒的包装和扩增。用多聚酶链反应(PCR)方法对病毒上清中的HCN4进行检测,并将重组腺病毒感染COS-7细胞,用免疫荧光染色检测HCN4蛋白质的表达,利用全细胞膜片钳方法测定转HCN4基因细胞的电生理功能。结果通过酶切、测序、PCR等证实HCN4通道基因重组腺病毒载体构建正确,免疫荧光检测证实转染AdHCN4的COS-7细胞中HCN4通道基因的表达,膜片钳实验也在转基因细胞中检测到超极化激活的非选择性内向阳离子电流(If)。结论HCN4通道基因重组腺病毒载体的构建成功为进一步研究该离子通道的电生理功能及在心律失常疾病基因治疗方面的潜在应用价值奠定了基础。     

慢性心力衰竭合并持续性心房颤动患者心脏再同步治疗术后房室结消融及药物控制心室率疗效观察

目的观察慢性心力衰竭合并持续性心房颤动（房颤）患者心脏再同步治疗（CRT）的疗效,比较房室结消融术及药物控制心室率两种方法疗效的差异。方法慢性心力衰竭合并持续性房颤患者,符合CRT植入适应证并接受CRT或心脏再同步治疗除颤器（CRT—D）植入术,术后随机分为两组,房室结消融组以及药物治疗组,术后随访观察患者临床症状及心功能改善等情况,比较两组的疗效。结果共人选了26例患者,其中房室结消融组14例,药物控制组12例。术前两组患者间心功能,左心室舒张末期内径（LVEDD）,左心室射血分数（LVEF）及用药等基本情况差异无统计学意义。CRT术后随访结果,房室结消融组双心室起搏比例100％,药物治疗组双心室起搏比例72．0％±9．7％。与药物治疗组相比,房室结消融组LVEDD略有缩小[（61．0±6．9）mm对（62．0±7．8）mm],但差异无统计学意义（P=0．08）,LVEF改善明显（0．41±0．06对0．35±0．04）,差异有统计学意义（P=0．04）,提示房室结消融组疗效更佳。结论对慢性心力衰竭合并持续性房颤患者,CRT可以改善患者心功能,CRT术后行房室结消融可以提高有效的双心室起搏比例,进一步提高CRT疗效。     

腺病毒介导的胶质细胞源性神经营养因子基因脑内转移对帕金森病大鼠模型的保护作用

目的 探讨腺病毒介导的胶质细胞源性神经营养因子（GDNF）基因直接转移对帕金森病（PD）的保护作用。方法 实验SD大鼠分重组GDNF腺病毒（Ad－GDNF）实验组、LacZ腺病毒（AdLacZ）对照组和磷酸缓冲液（PBS）对照组。将重组腺病毒及PBS定向注射至一侧黑质附近,1周后于同侧纹状体注射6－羟基多巴胺（6－OHDA）诱发多巴胺（DA）能神经元进行性变性。通过旋转行为观察和中脑酪氨酸羟化酶（TH）免疫组化染色及纹状体单胺类递质高压液相色谱－电化学仪（HPLC－ECD）检测评估其治疗效应;通过RT－PCR、ELISA检测Ad-GDNF在脑内的表达情况。结果 Ad-GDNF组阿扑吗啡诱发的旋转次数明显低于2个对照组;Ad-GDNF组约70％的黑质DA能神经元得以保存,而Ad-LacZ及PBS对照组令有30％左右;Ad－GDNF组纹状体DA含量也显著高于Ad-LacZ及PBS对照组;Ad－GDNF在脑内可有效表达,注射后5周黑质附近GDNF含量达1ng/10mg脑组织湿重,是对照组的16－20倍。结论 腺病毒介导的GDNF基因脑内直接转移可阻止6－OHDA诱发的大鼠DA能神经元进行性变性,提示这一手段在PD保护性治疗方面具有一定的应用价值。     

胰岛素瘤的解剖分布特点分析

目的胰岛素瘤是最常见的胰腺神经内分泌肿瘤，因其临床表现多样，导致诊断困难。影像学诊断尤其是超声内镜(EUS)在胰岛素瘤的诊断中起着重要作用，拥有较高的敏感性和特异性。本研究拟通过明确胰岛素瘤的解剖分布特点，以期有助于提高影像学的诊断准确率和降低漏诊率，尤其是在教育和培训实践中对于EUS的学习者更具有指导价值。 方法回顾性分析解放军总医院第一医学中心病案资料数据库1993年1月至2019年11月经外科手术、病理确诊为胰岛素瘤的患者的临床资料，检索方法采取搜索术后病理诊断为"胰岛素瘤"的病例，通过查阅病例的方法，提取出胰岛素瘤的大小和解剖分布等数据，进一步分析其特点。 结果共检索到确诊为胰岛素瘤的患者116例，其中，男45例、女71例，年龄13～76岁，平均年龄(44.4±14.85)岁。胰岛素瘤单发110例(94.8%)、多发6例(5.2%)。位置分布：头颈部46例(39.7%)，单发45例、多发1例；体尾部68例(58.6%)，单发65例、多发3例；全胰腺多发2例(1.7%)。病变大小特点：最大径0.4～3.4 cm，平均大小(1.53±0.58)cm。≤1 cm 29例、>1 cm而≤1.5 cm41例、>1.5 cm而≤2.0 cm28例，≤3 cm 15例，>3 cm 3例。年龄与肿瘤的大小相关，≤44岁患者肿瘤平均大小为(1.36±0.51)cm、>44岁患者肿瘤平均大小为(1.70±0.60)cm，P<0.05。头颈部的肿瘤大于体尾部的肿瘤，头颈部肿瘤平均大小(1.66±0.63)cm，体尾部(1.42±0.52)cm，P<0.05。 结论胰岛素瘤在胰腺体尾部较头颈部更好发；绝大多数单发，但可以全胰腺多发；多数小于1.5 cm，肿瘤的大小与患者年龄和肿瘤的解剖分布相关。     

Pathogenesis of carcinoma of the papilla of Vater

Most adenomas and carcinomas of the small intestine and extrahepatic bile ducts arise in the region of the papilla of Vater. In familial adenomatous polyposis (FAP) it is the main location for carcinomas after proctocolectomy. In many cases symptoms due to stenosis lead to diagnosis at an early tumor stage. In about 80%, curative intended resection is possible. Operability is the most relevant prognostic factor. Most ampullary carcinomas resp. carcinomas of the papilla of Vater develop from adenomatous or flat dysplastic precursor lesions. They can be sited in the ampulloduodenal part of the papilla of Vater, which is lined by intestinal mucosa. They also can develop in deeper parts of the ampulla, which are lined by pancreaticobiliary duct mucosa. Intestinal-type adenocarcinoma and pancreaticobiliary-type adenocarcinoma represent the main histological types of ampullary carcinoma. Furthermore, there exist unusual types and undifferentiated carcinomas. Many carcinomas of intestinal type express the immunohistochemical marker profile of intestinal mucosa (keratin 7?, keratin 20+, MUC2+). Carcinomas of pancreaticobiliary type usually show the immunohistochemical profile of pancreaticobiliary duct mucosa (keratin 7+, keratin 20?, MUC2?). Even poorly differentiated carcinomas, as well as unusual histological types, may conserve the marker profile of the mucosa they developed from. These findings underline the concept of histogenetically different carcinomas of the papilla of Vater which develop either from intestinal- or from pancreaticobiliary-type mucosa of the papilla of Vater. Molecular alterations in ampullary carcinomas are similar to those of colorectal as well as pancreatic carcinomas, although they appear at different frequencies. In future studies, molecular alterations in ampullary carcinomas should be correlated closely with the different histologic tumor types. Consequently, the histologic classification should reflect the histogenesis of ampullary tumors from the two different types of papillary mucosa.     

Lack of correlation of degree of villous atrophy with severity of clinical presentation of coeliac disease

BACKGROUND AND AIM: Both the clinical presentation and the degree of mucosal damage in coeliac disease vary greatly. In view of conflicting information as to whether the mode of presentation correlates with the degree of villous atrophy, we reviewed a large cohort of patients with coeliac disease. PATIENTS AND METHODS: We correlated mode of presentation (classical, diarrhoea predominant or atypical/silent) with histology of duodenal biopsies and examined their trends over time. RESULTS: The cohort consisted of 499 adults, mean age 44.1 years, 68% females. The majority had silent coeliac disease (56%) and total villous atrophy (65%). There was no correlation of mode of presentation with the degree of villous atrophy (p=0.25). Sixty-eight percent of females and 58% of males had a severe villous atrophy (p=0.052). There was a significant trend over time for a greater proportion of patients presenting as atypical/silent coeliac disease and having partial villous atrophy, though the majority still had total villous atrophy. CONCLUSIONS: Among our patients the degree of villous atrophy in duodenal biopsies did not correlate with the mode of presentation, indicating that factors other than the degree of villous atrophy must account for diarrhoea in coeliac disease.     

Demonstration of the mechanism of action of biguanides

Summary Palmitic acid oxidation in rat diaphragm homogenate is depressed by biguanide concentrations that are still incapable of inhibiting oxidative phosphorylation. Glucose oxidation is not directly effected by the same biguanide concentrations: however, the inhibitory effect of palmitic acid on glucose oxidation is partly removed by biguanides. Inhibition of fatty acid oxidation, which accounts for most of the metabolic effects caused by these drugs, can be regarded as the fundamental mechanism of action of biguanides. There is some evidence suggesting that these drugs might interact with carnitine, thus preventing long-chain fatty acids from being transported across the mitochondrial membrane to the site of oxidation. Traduzione a cura degli AA.     

血吸虫童虫生长发育及其机制的研究进展

血吸虫童虫是宿主免疫系统攻击的重要靶标,包括皮肤型、肺型和肝门型童虫。宿主分子对童虫生长发育具有重要作用。童虫生长发育机制包括免疫调节、信号转导、性别发育及凋亡等。肌动蛋白、组织蛋白酶、烯醇化酶和葡萄糖基转移酶等分子为血吸虫童虫生长发育的重要分子。本文对血吸虫童虫生长发育及其机制的研究进展做一综述。     

124例耐多药结核分枝杆菌基因突变特征分析

目的对临床分离的耐多药结核分枝杆菌相关基因的突变特征进行分析。方法对124例耐多药结核分枝杆菌以及50株敏感株的耐药相关基因(包括异烟肼inh A、kat G、oxyR-ahp C间隔区以及利福平rpo B)进行序列测定,分析其基因突变情况。结果异烟肼耐药inh A基因突变率为14.5%;kat G基因突变率为70.2%(87/124),主要位于315位;oxyR-ahp C间隔区突变率为15.3%;inh A、kat G两种基因同时突变率75.0%,三种基因同时突变率为89.5%。利福平rpo B基因突变的检出率高达95.2%,突变主要发生在531、526、516位点。结论我省耐多药菌异烟肼耐药相关基因最常见突变为kat G 315、inh A C-T(-15)、axyR-ahp C间隔区(-10)C-T,利福平为rpo B531、526、516。结合MDR-TB耐药相关基因的特征分析,可以建立一种快速、准确、特异的适合于我省的检测结核菌耐多药性的新方法。     

Assessment of quality of life of parents of children with juvenile chronic arthritis

The aim of the study was to assess the quality of life (QOL) and the psychological status of parents of children with juvenile chronic arthritis (JCA). The QOL, anxiety and depression of the parents of 28 children with JCA were evaluated and compared to those of the parents of 28 healthy children. Mothers of JCA children and mothers of healthy children reported similar QOL. The reported anxiety and depression levels were similar for mothers and fathers in both groups. The parents of children with pauciarticular-type JCA reported lower QOL and higher levels of anxiety and depression than the parents of children with other types, namely polyarticular and systemic JCA. These findings may be explained by the fact that the pauciarticular patients had shorter disease duration and were less frequently seen in the outpatient clinic. The QOL of mothers of children with JCA was found to be slightly impaired in the group of children with pauciarticular JCA. Future larger studies are needed to confirm these results, as the number of subjects in the three groups was rather low. Received: 26 September 2001 / Accepted: 8 February 2002     

氯硝柳胺悬浮剂的毒性评价

目的评价氯硝柳胺悬浮剂的毒性，为现场大规模应用灭螺提供依据。方法按照中华人民共和国国家标准GB 15670-1995《农药登记毒理学试验方法》和鱼类毒性试验方法进行。结果经口、经皮肤的LDso雌、雄性大鼠均>5 000 mg/kg，经呼吸道的LCso雌、雄性大鼠均>5 000mg/m3，该药经口、经皮肤、经呼吸道毒性均属微毒类药物；兔眼用药后，观察期内无不良反应，对眼无刺激性；皮肤用药后对皮肤无刺激性。与氯硝柳胺原药、氯硝柳胺乙醇胺盐原药和氯硝柳胺乙醇胺盐可湿性粉剂相比，氯硝柳胺悬浮剂对鱼急性毒性最低。结论氯硝柳胺悬浮剂属微毒类药物，对鱼的毒性低于其乙醇胺盐可湿性粉剂，适合于现场应用。     

Numerical Simulation of the Effect of Rate of Change of Glucose on Measurement Error of Continuous Glucose Monitors

Background

A 5-day in-patient study designed to assess the accuracy of the FreeStyle Navigator® Continuous Glucose Monitoring System revealed that the level of accuracy of the continuous sensor measurements was dependent on the rate of glucose change. When the absolute rate of change was less than 1 mg•dl⁻¹•min⁻¹ (75% of the time), the median absolute relative difference (ARD) was 8.5%, with 85% of all points falling within the A zone of the Clarke error grid. When the absolute rate of change was greater than 2 mg•dl⁻¹•min⁻¹ (8% of the time), the median ARD was 17.5%, with 59% of all points falling within the Clarke A zone.

Method

Numerical simulations were performed to investigate effects of the rate of change of glucose on sensor measurement error. This approach enabled physiologically relevant distributions of glucose values to be reordered to explore the effect of different glucose rate-of-change distributions on apparent sensor accuracy.

Results

The physiological lag between blood and interstitial fluid glucose levels is sufficient to account for the observed difference in sensor accuracy between periods of stable glucose and periods of rapidly changing glucose.

Conclusions

The role of physiological lag on the apparent decrease in sensor accuracy at high glucose rates of change has implications for clinical study design, regulatory review of continuous glucose sensors, and development of performance standards for this new technology. This work demonstrates the difficulty in comparing accuracy measures between different clinical studies and highlights the need for studies to include both relevant glucose distributions and relevant glucose rate-of-change distributions.     

治疗高血压药物的经济学评价

重视高血压治疗中的经济学评价,对利用我国有限的卫生资源来遏制高血压对人民群众的危害有着重要的现实意义。药物经济学对于药物治疗的成本和治疗的结果给予同样的关注。因为治疗高血压的费用,不仅涉及药物价格,还包括患者的危险水平,降压疗效和对临床终点事件的影响,以及治疗的依从性和安全性。因此药物经济学更强调整体成本和价-效比。低危病人,若非药价低廉,治疗的价-效比不够理想。而在高危的患者,价-效比越小越经济而不是药费越便宜越好。