电针百会穴对APP/PS1双转基因小鼠学习记忆及脑源性神经营养因子表达的影响

目的观察电针百会穴对APP/PS1双转基因小鼠学习记忆功能及脑源性神经营养因子(BDNF)表达的影响,探讨电针治疗阿尔茨海默病的作用机制。方法将30只4月龄雌性APP/PS1双转基因小鼠随机分为模型组、百会组和非穴组,每组10只,另取10只同窝阴性野生小鼠为野生组。百会组电针百会穴,非穴组电针非穴,干预28 d,野生组和模型组不干预。采用Morris水迷宫实验观察小鼠学习记忆能力;免疫组化技术观察小鼠大脑皮质β-淀粉样蛋白的沉积;Western blotting和RT-PCR法检测小鼠皮质脑源性神经营养因子(BDNF)蛋白和基因的表达情况。结果与模型组相比,百会组小鼠逃避潜伏期缩短(P0.05),跨越平台次数明显增加(P0.01);β-淀粉样蛋白的沉积减少(P0.05);BDNF蛋白和基因的表达明显增多(P0.01)。非穴组与模型组相比无显著性差异(P0.05)。结论电针百会穴可改善APP/PS1双转基因小鼠的学习记忆功能,其作用机制可能与增加大脑皮质BDNF蛋白和基因的表达,降低β-淀粉样蛋白的沉积有关。     

电针百会穴对APP/PS1双转基因痴呆模型小鼠18F-FDGPET/CT成像及学习记忆的影响

目的:观察电针百会穴对APP/PS1双转基因小鼠葡萄糖代谢水平以及学习记忆的影响,探讨电针治疗阿尔茨海默病的作用机制。方法:将30只雌性12月龄APP/PS1双转基因小鼠随机分为模型组、百会组和非穴组,每组10只,另取10只同窝阴性野生小鼠为野生组。百会组电针百会穴,非穴组电针非穴,每次30min,每天1次,每周5天,共治疗4周,野生组和模型组不干预。采用正电子发射断层扫描技术(PET)观察各组小鼠大脑18F-FDG摄取率的水平;Morris水迷宫实验观察小鼠学习记忆。结果:与模型组相比,百会组小鼠逃避潜伏期缩短(P0.05),跨越平台次数增加(P0.01);非穴组小鼠逃避潜伏期与模型组相比无显著性差异(P0.05);百会组小鼠18F-FDG摄取率高于野生组、模型组以及非穴组。结论:电针百会穴可改善APP/PS1双转基因小鼠的学习记忆功能,其作用机制可能是通过改善小鼠脑内葡萄糖代谢从而发挥神经保护作用。     

电针对APP/PS1小鼠学习记忆及β位淀粉样前体蛋白裂解酶1表达的影响

目的探讨电针治疗阿尔茨海默病的效果和作用机制。方法雄性8月龄APP/PS1小鼠24只随机分为模型组、电针组和非穴组,各8只。8只野生型小鼠为野生组。电针组电针百会、神庭,非穴组电针双侧肋下非穴区,野生组和模型组予相同抓取和固定,共28 d。干预后,Morris水迷宫测试小鼠学习记忆能力,分别采用免疫荧光和免疫组化技术检测小鼠大脑皮质β淀粉样蛋白(Aβ)和β位淀粉样前体蛋白裂解酶1 (BACE1)含量,RT-PCR检测BACE1 m RNA水平。结果与模型组比较,电针组小鼠Morris水迷宫逃避潜伏期显著下降(P 0.001),穿越平台次数显著增加(P 0.001),BACE1表达和Aβ水平显著减少(P 0.001)。结论电针百会、神庭可能通过抑制APP/PS1小鼠大脑皮质BACE1表达,降低Aβ水平,改善小鼠学习记忆能力。     

电针百会穴对次声暴露大鼠学习记忆能力及其钙调素依赖性蛋白激酶Ⅱ-Tau蛋白信号通路的影响

目的 观察电针百会穴对次声暴露大鼠学习记忆能力及CaMKⅡ-Tau蛋白信号通路的影响,探讨电针百会穴防护次声性脑损害的作用机制。 方法 选取SD大鼠48只,采用随机数字表法将其分为空白组、次声组、百会组和非穴组,每组12只大鼠。空白组大鼠每日放置于无次声作用的次声仓中2 h,百会组、非穴组和次声组大鼠每日暴露于8 Hz、130 dB次声仓中2 h,连续7 d。百会组和非穴组大鼠在次声暴露结束后2 h内给予电针干预,其中百会组电针百会穴,非穴组电针非经非穴点,均每日1次,连续电针干预7 d;空白组和次声组给予与百会组和非穴组同样的方法抓取和固定,但不进行电针干预,亦为每日1次,每次7 d。干预6、7 d后,分别采用Morris水迷宫定位航行实验和空间探索实验检测4组大鼠的空间学习记忆能力。Morris水迷宫实验结束后,每组按随机数字表法选取6只大鼠,采用尼氏染色法观察4组大鼠海马区神经细胞的形态学改变;将4组剩余6只大鼠采用蛋白免疫印迹法（Western blot）检测其海马区磷酸化钙调依赖性蛋白激酶Ⅱ（P-CaMKⅡ）和磷酸化Tau蛋白（P-Tau）的表达,并进行组间比较。 结果 干预6 d和7 d后,次声组大鼠逃避潜伏期较空白组显著延长,平台象限时间比、平台象限路程比显著下降,穿越平台区域次数显著减少（P＜0.05）;与次声组比较,百会组大鼠逃避潜伏期显著缩短,平台象限时间比、平台象限路程比显著上升,穿越平台区域次数显著增多（P＜0.05）。干预7 d后,次声组大鼠海马区神经元损伤程度较空白组显著加重、神经元数量较空白组显著减少;与次声组比较,百会组大鼠海马区神经元损伤程度显著减轻、神经元数量显著增多。干预7 d后,次声组大鼠海马区P-CaMKⅡ和P-Tau蛋白水平分别为（0.735±0.094）和（0.873±0.089）较空白组显著增加（P＜0.05）;与次声组比较,百会组大鼠海马区P-CaMKⅡ和P-Tau蛋白水平显著下降（P＜0.05）。 结论 电针百会穴可以提高次声暴露大鼠的学习记忆能力,对次声性脑损害具有一定的防护作用,其机制可能与电针百会穴可通过降低海马区CaMKⅡ活性（磷酸化水平）抑制海马区Tau蛋白过度磷酸化,从而保护海马神经元有关。     

电针百会穴改善APP/PS1转基因小鼠空间学习记忆能力及对磁共振波谱的影响

目的:探讨电针百会穴对APP/PS1转基因小鼠空间学习记忆能力及氢质子磁共振波谱(1H-MRS)的影响。方法:雄性APP/PS1转基因小鼠及雌性阴性小鼠育种后代,经PCR鉴定后将育种后代中15只转基因小鼠根据随机数字表分为模型组7只和电针组8只,8只同窝阴性小鼠作为正常组。电针百会穴干预4周,正常组及模型组同等条件抓取。Morris水迷宫观察小鼠空间学习记忆能力,1H-MRS检测小鼠脑内海马区N-乙酰天门冬氨酸(NAA)、谷氨酸(Glu)水平。结果:Morris水迷宫试验显示,电针组小鼠逃避潜伏期较模型组显著缩短(P0.05),穿越平台次数增加(P0.05);与模型组小鼠比较,电针组小鼠海马区NAA、Glu水平均较高,差异具有统计学意义(P0.05)。结论:电针百会穴可改善APP/PS1转基因小鼠空间学习记忆能力,其作用机制可能与脑内海马区NAA、Glu含量增加有关。     

五味子酮对APP转基因鼠神经干细胞分化中Tau蛋白过磷酸化水平的影响

背景：华中五味子酮有强的抗氧化活性,可高效清除羟自由基和超氧阴离子,对处于活性氧应激状态下的细胞具有保护作用。神经元内神经原纤维缠结主要是由异常磷酸化的Tau蛋白组成,与阿尔茨海默病的严重程度呈正相关。 目的：探讨五味子酮在APP转基因小鼠神经干细胞诱导分化成神经细胞的过程中对Tau蛋白磷酸化的作用。 设计、时间及地点：细胞学体外对照观察,于2006-07／2008—10在郑州大学医学实验中心完成。 材料：自中国协和医科大学遗传动物中心购得APP基因突变小鼠30只,五味子酮由河南省中医研究院药物所提供。方法：剪取新生APP转基因小鼠尾尖,常规提取DNA,采用PCR法检测动物是否携带有APP基因。APP转基因阳性鼠记为“APP＋”,APP转基因阴性鼠记为“APP＋”。分别取APP＋鼠和APP＋鼠海马部位脑组织,体外分离培养神经干细胞,并将纯化的神经于细胞向神经细胞方向诱导分化。将从APP＋鼠来源的细胞分为五味子酮组、APP＋细胞对照组,将APP-鼠来源的细胞设为APP-细胞对照组。五昧子酮组向细胞培养液中加入终浓度为50umol／L的五咪子酮溶液,余2组加入相同容积的PBS,培养24h。主要观察指标：免疫荧光化学和免疫印迹分析测定APP＋、APP-细胞Tau蛋白在262、396位点的磷酸化水平。结果：与APP＋细胞对照组比较,五味子酮组细胞荧光强度减轻,Tau[Ps262]、Tau[Ps396]的磷酸化水平均降低,且Tau[Ps396]位点的磷酸化水平降低尤为明显。APP＋细胞对照组Tau[Ps262]、Tau[Ps396]磷酸化水平均较低。结论：在APP转基因小鼠神经干细胞诱导分化过程中,五味子酮可以明显降低Tau蛋白在396、262位点的磷酸化水平,减轻神经元损伤,但其磷酸化程度并未达到阴性细胞水平。     

电针对APP/PS1小鼠脑功能活动影响的功能性磁共振成像研究

目的探讨电针百会(DU20)、神庭(DU24)对APP/PS1小鼠的脑功能活动的影响。方法同窝4月龄APP/PS1双转基因小鼠16只随机分为模型组(n=8)和电针组(n=8);同窝转基因阴性小鼠(n=8)为对照组。电针组电针百会、神庭,共16周。干预前后进行新物体识别实验;小动物功能磁共振成像(fMRI)局部一致性(ReHo)分析法观察脑功能活动。结果干预后,与对照组相比,模型组新物体识别指数降低(P<0.05);与模型组相比,电针组新物体识别指数增高(P<0.05)。干预前,与对照组相比,模型组右侧基底前脑、左侧海马ReHo降低。干预后,与对照组相比,模型组双侧海马ReHo降低,压后皮质ReHo升高;与模型组相比,电针组双侧海马、运动皮质ReHo升高,前扣带回ReHo下降。结论电针百会、神庭可延缓APP/PS1小鼠学习记忆功能减退,可能与调节海马区的功能活动有关。     

电针调控L1CAM表达在阿尔茨海默病神经保护中的作用

目的 观察电针干预对阿尔茨海默病小鼠学习记忆能力及神经细胞粘附分子L1（L1CAM）表达的影响。 方法 采用随机数字表法将30只雄性APP/PS1小鼠分为模型组、电针组及非穴组,每组10只小鼠,另取10只C57BL/6小鼠纳入对照组。电针组小鼠给予电针刺激百会、肾俞穴,电刺激频率50 Hz,连续波,电流强度1 mA,每天刺激1次,连续干预14 d;非穴组小鼠在百会、肾俞穴附近给予电针刺激,其它操作均与电针组相同;模型组、对照组小鼠均继续常规饲养,未给予电针等特殊处理。于干预后采用Morris水迷宫实验检测各组小鼠行为学改变,选用Western blot技术检测各组小鼠海马组织中L1CAM、PTEN及p53蛋白表达水平。 结果 与对照组Morris水迷宫定位航行实验结果比较,模型组在第1,2,3,4,5天时的逃避潜伏期均显著延长（P＜0.05）。与模型组结果比较,电针组在第2,3,4,5天时逃避潜伏期均显著缩短（P＜0.05）。与模型组比较,电针组L1CAM蛋白表达量明显上调（P＜0.05）,PTEN及p53蛋白表达量均显著下调（P＜0.05）。与电针组比较,非穴组在第2,3,4,5天时逃避潜伏期均明显延长（P＜0.05）,L1CAM蛋白表达量下调（P＜0.05）,PTEN及p53蛋白表达量均显著上调（P＜0.05）。通过相关性分析发现,实验小鼠逃避潜伏期与L1CAM表达水平呈负相关性（P＜0.05）,与p53、PTEN表达水平呈正相关性（P＜0.05）。 结论 L1CAM参与实验小鼠学习记忆过程,电针穴位可改善AD小鼠学习记忆功能,其作用机制可能与促进海马组织中L1CAM蛋白表达、抑制PTEN及p53蛋白表达有关。     

电针百会、大椎、肾俞穴对SAMP8小鼠学习记忆与海马CA1区神经元突触的影响北大核心CSCD

目的观察电针百会、大椎、肾俞穴对SAMP8小鼠学习记忆与海马CA1区神经元突触的影响,探讨电针治疗阿尔茨海默病(AD)的机制。方法 7月龄SAMP8小鼠24只随机分为模型组和电针组,同龄正常老化SAMR1小鼠12只为对照组。电针组电针百会、大椎、肾俞穴30 d。Morris水迷宫检测小鼠学习记忆能力,免疫组织化学观察小鼠海马CA1区突触素(SYN)及突触后致密区蛋白95(PSD95)的表达,透射电镜观察小鼠海马CA1区突触超微结构的变化。结果与模型组相比,电针组逃避潜伏期缩短(P<0.05),原平台象限停留时间延长(P<0.05),穿越原平台次数增加(P<0.05),海马CA1区SYN与PSD95表达显著提高(P<0.001),突触结构较完整,数量增加。结论电针能提高小鼠海马CA1区神经元突触蛋白的表达,改善突触的超微结构,从而有效改善SAMP8小鼠的学习记忆能力。     

电针百会、大椎、肾俞穴对SAMP8小鼠学习记忆与海马CA1区神经元突触的影响

目的观察电针百会、大椎、肾俞穴对SAMP8小鼠学习记忆与海马CA1区神经元突触的影响,探讨电针治疗阿尔茨海默病(AD)的机制。方法 7月龄SAMP8小鼠24只随机分为模型组和电针组,同龄正常老化SAMR1小鼠12只为对照组。电针组电针百会、大椎、肾俞穴30 d。Morris水迷宫检测小鼠学习记忆能力,免疫组织化学观察小鼠海马CA1区突触素(SYN)及突触后致密区蛋白95(PSD95)的表达,透射电镜观察小鼠海马CA1区突触超微结构的变化。结果与模型组相比,电针组逃避潜伏期缩短(P0.05),原平台象限停留时间延长(P0.05),穿越原平台次数增加(P0.05),海马CA1区SYN与PSD95表达显著提高(P0.001),突触结构较完整,数量增加。结论电针能提高小鼠海马CA1区神经元突触蛋白的表达,改善突触的超微结构,从而有效改善SAMP8小鼠的学习记忆能力。     

创伤高血糖与感染和MODS早期诊断和干预

本文详细介绍了创伤后血糖应激适度理论,以及高血糖与感染和多器官功能不全综合征的关系;提出涉及胰岛B细胞功能不全的MODS实验诊断新方案和极化液个体化干预新措施,可早期发现创伤MODS、降低感染率及MODS发生率和病死率。     

腹膜后纤维化与肾积水发生关系的临床研究

目的：探讨腹膜后纤维化（RPF）导致肾积水的原因及诊治经验。方法：回顾分析2004年1月—2010年12月24例腹膜后纤维化致肾积水患者的诊治资料。结果：（1）RPF患者常见首发症状为腰背痛或腹痛（69.2%）;（2）红细胞沉降率（ESR）增快和血清IgG4升高最常见。超声检查仅提示上尿路积水。RPF的静脉肾盂造影（IVP）和CT尿路成像（CTU）表现具有特征性。IVP肾盂输尿管显影不良时,CTU能较清晰的显示上尿路影像。CT扫描发现腹膜后软组织肿块9例（37.5%）,优于超声检查;（3）输尿管松解和腹腔化手术治疗22例;行肾切除术1例;行输尿管置双J管术1例。最终确诊为继发性RPF8例,其中4例为术前诊断,3例为术中腹膜后软组织肿块冷冻活检证实,1例为术后病理证实;（4）特发性RPF手术后肾积水均获长期缓解,而继发性RPF的预后取决于原发疾病及其治疗方案。结论：影像学检查是诊断RPF的重要手段,CTU优于超声检查和IVP。输尿管松解和腹腔化手术可以使特发性RPF输尿管梗阻得到长期的缓解,术中对肿块进行冷冻活检有助于鉴别特发性和继发性RPF,及时调整治疗方案。     

Migraine and genetic and acquired vasculopathies

It is remarkable that migraine is a prominent part of the phenotype of several genetic vasculopathies, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and hereditary infantile hemiparessis, retinal arteriolar tortuosity and leukoencephalopahty (HIHRATL). The mechanisms by which these genetic vasculopathies give rise to migraine are still unclear. Common genetic susceptibility, increased susceptibility to cortical spreading depression (CSD) and vascular endothelial dysfunction are among the possible explanations. The relation between migraine and acquired vasculopathies such as ischaemic stroke and coronary heart disease has long been established, further supporting a role of the (cerebral) blood vessels in migraine. This review focuses on genetic and acquired vasculopathies associated with migraine. We speculate how genetic and acquired vascular mechanisms might be involved in migraine.     

Fibrinogen and fibrin structure and functions

Fibrinogen molecules are comprised of two sets of disulfide-bridged Aalpha-, Bbeta-, and gamma-chains. Each molecule contains two outer D domains connected to a central E domain by a coiled-coil segment. Fibrin is formed after thrombin cleavage of fibrinopeptide A (FPA) from fibrinogen Aalpha-chains, thus initiating fibrin polymerization. Double-stranded fibrils form through end-to-middle domain (D:E) associations, and concomitant lateral fibril associations and branching create a clot network. Fibrin assembly facilitates intermolecular antiparallel C-terminal alignment of gamma-chain pairs, which are then covalently 'cross-linked' by factor XIII ('plasma protransglutaminase') or XIIIa to form 'gamma-dimers'. In addition to its primary role of providing scaffolding for the intravascular thrombus and also accounting for important clot viscoelastic properties, fibrin(ogen) participates in other biologic functions involving unique binding sites, some of which become exposed as a consequence of fibrin formation. This review provides details about fibrinogen and fibrin structure, and correlates this information with biological functions that include: (i) suppression of plasma factor XIII-mediated cross-linking activity in blood by binding the factor XIII A2B2 complex. (ii) Non-substrate thrombin binding to fibrin, termed antithrombin I (AT-I), which down-regulates thrombin generation in clotting blood. (iii) Tissue-type plasminogen activator (tPA)-stimulated plasminogen activation by fibrin that results from formation of a ternary tPA-plasminogen-fibrin complex. Binding of inhibitors such as alpha2-antiplasmin, plasminogen activator inhibitor-2, lipoprotein(a), or histidine-rich glycoprotein, impairs plasminogen activation. (iv) Enhanced interactions with the extracellular matrix by binding of fibronectin to fibrin(ogen). (v) Molecular and cellular interactions of fibrin beta15-42. This sequence binds to heparin and mediates platelet and endothelial cell spreading, fibroblast proliferation, and capillary tube formation. Interactions between beta15-42 and vascular endothelial (VE)-cadherin, an endothelial cell receptor, also promote capillary tube formation and angiogenesis. These activities are enhanced by binding of growth factors like fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF), and cytokines like interleukin (IL)-1. (vi) Fibrinogen binding to the platelet alpha(IIb)beta3 receptor, which is important for incorporating platelets into a developing thrombus. (vii) Leukocyte binding to fibrin(ogen) via integrin alpha(M)beta2 (Mac-1), which is a high affinity receptor on stimulated monocytes and neutrophils.     

Telemedicine and teleradiology technologies and applications

Summary. Telemedicine and teleradiology hold the key for improving future health care delivery. In this paper we first review current communication and computer technologies used in telemedicine and teleradiology. Five examples in teleradiology applications are given including hospital-integrated picture archiving and communication systems, tele-neuro-imaging, telemammography, university consortium teleradiology service, and teleradiology for second opinion. Parameters important to teleradiology applications like costs, image quality, system reliability, and turn around time are considered. Data security is discussed, including patient confidentiality and image authenticity-which will be a major issue in future teleradiology applications.     

探讨儿童慢性顽固性咳嗽与支原体感染的关系及临床治疗观察

目的探讨儿童慢性顽固性咳嗽与肺炎支原体（MP）感染的关系及临床疗效观察。方法采用回顾性研究方法对于现将2005年3月至2008年3月在我院的55例确诊慢性顽固性咳嗽患儿,主要表现为肺炎支原体感染为临床特点进行分析,并进一步临床治疗研究。结果①临床特点：在55例确诊慢性咳嗽的患儿中,以慢性顽固性咳嗽为主要症状。58％（32／55）的病例无肺部体征;②外周血：85％（47／55）的病例外周血变化不大,WBC（4—10）×10 9／L之间,嗜酸性粒细胞增多;③特别检查：47．27％（26／55）肺炎支原体IgM（MP—IgM）抗体阳性,83．64％（46／55）PeR技术检测肺炎支原体特异性DNA;④X光报告为多种形式。结论肺炎支原体（MP）感染是引起儿童慢性顽固性咳嗽的病因之一,对儿童慢性咳嗽,特别是顽固性咳嗽的诊治中应更加重视。     

Physician and Nurse Practitioner Teamwork and Job Satisfaction: Gender and Profession

Designing interprofessional primary care teams composed of physicians and nurse practitioners (NPs) is a national priority. We assessed how profession and gender affect teamwork and job satisfaction among primary care physicians and NPs by using survey data from 186 physicians and 398 NPs practicing in New York State. Our regression models show profession (NP vs physician) moderates the associations of gender with teamwork and job satisfaction. Among NPs, men had higher job satisfaction than women. Among physicians, women had higher job satisfaction than men. Our results can benefit interprofessional primary care teams to optimize their professional and gender mix.     

VEGF和NSE在良恶性嗜铬细胞瘤中的表达及意义

目的探讨肿瘤标志物血管内皮生长因子（VEGF）和神经元特异性烯醇化酶（NSE）在良、恶性嗜铬细胞瘤组织中的表达,分析其可能的临床价值及病理学意义,为临床鉴别良、恶性嗜铬细胞瘤提供辅助依据。方法应用免疫组化（SP法）检测16例恶性嗜铬细胞瘤、18例良性嗜铬细胞瘤及17例正常肾上腺髓质组织中细胞因子VEGF和NSE表达情况,显微镜下判断组织切片的染色结果。结果①恶性嗜铬细胞瘤VEGF表达明显强于正常肾上腺髓质和良性嗜铬细胞瘤（P〈0.01）。良性肿瘤和正常肾上腺髓质的VEGF表达差异无统计学意义（P〉0.05）。恶性嗜铬细胞瘤强阳性率明显高于良性嗜铬细胞瘤（P〈0.01）。②良、恶性嗜铬细胞瘤NSE表达差异有统计学意义（P〈0.05）,良性嗜铬细胞瘤NSE的表达高于正常肾上腺髓质的NSE表达（P〈0.05）。恶性嗜铬细胞瘤强阳性率高于良性嗜铬细胞瘤（P〈0.05）。③VEGF和NSE共同阳性表达在良、恶性嗜铬细胞瘤之间差异有统计学意义（P=〈0.01）。结论临床上检测VEGF和NSE可能为鉴别良、恶性嗜铬细胞瘤提供辅助依据,共同检测VEGF和NSE可能提高良、恶性嗜铬细胞瘤鉴别的敏感性。     

Acetaminophen and acetylcysteine dose and duration: Past,present and future

Abstract

Acetylcysteine has been utilized successfully in the treatment of acetaminophen overdose since the 1970s. Although prospective trials as to efficacy and safety of acetylcysteine were conducted, there were no randomized controlled trials. This commentary addresses the reasons for this, and the background to choice of dose of acetylcysteine utilized in the oral and IV dosing regimens. Nomograms to predict possible hepatotoxicity based upon time of ingestion of acetaminophen were developed from a relatively arbitrary definition of toxicity as an aspartate aminotransferase/alanine aminotransferase (ALT/AST) greater than 1000 IU/L. While these have proved generally useful, patients still continue to develop hepatic damage after acetaminophen overdose, particularly if they present late after ingestion. The optimum management of these patients remains unclear, and one area of uncertainty is the dose and duration of acetylcysteine in various circumstances. This article discusses the issues that need to be elucidated to better target changes in acetylcysteine dose. The potential for measurements of other markers to improve treatment selection is the subject of further research.