Hay et al 2008 IJA Evidence of IC and CG impact on audit fees
急性心肌梗死患者血清超敏C反应蛋白、肌红蛋白、肌钙蛋白水平动态监测的临床意义
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急性心肌梗死患者血清超敏C-反应蛋白、肌红蛋白、肌钙蛋白水平动态监测的临床意义【摘要】目的探讨急性心肌梗死患者血清超敏C反应蛋白(CRPhs)、心肌肌钙蛋白I(cTnI)、肌红蛋白(Mb)动态变化与病情发展的关系。
方法采用胶乳增强的免疫透射比浊法对35例初发AMI 患者血清CRPhs、cTnI、Mb水平进行动态监测。
结果 CRPhs在发病后不断上升,在48 h 前后达到高峰(13.20±6.69)mg/L,1周后CRPhs 基本降至正常水平;Mb在12 h 前后达到高峰(203.5±92.6)μg/L,48 h 基本降至正常;cTnI在24 h 达到高峰(10.56±4.65)μg/L,1周后检测仍然较正常水平偏高。
结论动态监测CRPhs、Mb、cTnI血清水平对判断病情及评估预后有重要临床价值和意义。
【关键词】超敏C反应蛋白;心肌肌钙蛋白I;肌红蛋白;急性心肌梗死急性心肌梗死(AMI)发病率和死亡率均较高,欲降低死亡率,早期诊断和早期治疗十分重要。
为探讨代表血管硬化斑块炎症反应和心肌损伤两个不同方面的典型标记物C反应蛋白(CRP)与心肌肌钙蛋白Ⅰ(cTnI)、肌红蛋白(Mb)在AMI的诊断、治疗及预后判断中的应用价值。
我们检测了35例初发急性心肌梗死,现将结果报告如下。
1 材料与方法1. 1 研究对象 35例初发急性心肌梗死患者,均为2007年1月—2008年1月本院心内科住院患者。
以上诊断均符合国际心脏病协会和世界卫生组织(WHO) 缺血性心脏病的诊断和命名标准,经病史、临床心电图、冠状动脉造影、超声心电图等检查确诊。
1.2 标本处理 35例AMI初发患者分别在发病后1 h、发病后6、12、24、48 h、1周各抽1次血。
置于干燥洁净试管中,37 ℃水浴30 min 后,3 000 r/min,离心15 min,分离出500 μl 血清于洁净带盖的试管后置于-20 ℃冰箱冰冻保存待测。
2008年诺贝尔生理或医学奖
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2008年诺贝尔生理学或医学奖揭晓作者:佚名来源:生物秀时间:2008-10-8北京时间10月6日下午5点30分,2008年诺贝尔生理学或医学奖揭晓,德法三科学家分享该奖项。
德国癌症研究中心的科学家Harald zur Hausen 因发现人类乳突淋瘤病毒(HPV)导致子宫颈癌而获奖;法国两位科学家,巴斯德研究所病毒学系逆转录病毒感染调控小组的FrançoiseBarré-Sinoussi 和巴黎世界艾滋病研究与预防基金会的Luc Montagnier 因发现人类免疫缺陷病毒(HIV)而获奖。
今年的诺贝尔生理学或医学奖奖励的是导致严重人类疾病的两类病毒的发现。
Harald zur Hausen一反传统教条,假定瘤原性人类乳突淋瘤病毒(HPV)导致了宫颈癌——女性第二常见的癌症。
他认识到,HPV-DNA能够存在于肿瘤非生长性状态中,而且应该能够通过对病毒DNA的特定搜寻发现。
他发现,HPV是病毒的一种异质家族。
只有一些HPV种类会导致癌症。
他的发现引发了对HPV感染自然史的描述,以及对于HPV诱导致癌作用机制和抗HPV获得性预防疫苗发展的理解。
Françoise Barré-Sinoussi 和Luc Montagnier发现了人类免疫缺陷病毒(HIV)。
病毒产生分别在淋巴(来自在获得性免疫缺陷早期阶段带有增大淋巴结病人)和血液(来自晚期患者)中得到鉴别。
根据这一病毒的形态、生化及免疫学特性,他们将它确定为第一个已知的人类慢病毒。
HIV损伤免疫系统,因为病毒大量复制,对淋巴细胞造成损伤。
这一发现对于当前的艾滋病生物学及它的抗逆转录病毒治疗来说是一个先决条件。
德国科学家Harald zur Hausen 法国科学家Françoise Barré-Sinoussi法国科学家Luc Montagnier发现人类乳突淋瘤病毒导致宫颈癌与20世纪70年代流行的观点不同,Harald zur Hausen假定人类乳突淋瘤病毒在宫颈癌中扮演了一个角色。
Huang_et_al-2008-Journal_of_Pharmaceutical_Sciences
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Drug–Polymer Interaction and Its Significance on the Physical Stability of Nifedipine Amorphous Dispersion in Microparticles of an Ammonio Methacrylate Copolymer and Ethylcellulose Binary BlendJINGJUN HUANG,1RODNEY J.WIGENT,1,2JOSEPH B.SCHWARTZ11Department of Pharmaceutical Sciences,University of the Sciences in Philadelphia,600S43rd Street,Philadelphia, Pennsylvania191042Department of Chemistry,University of the Sciences in Philadelphia,600S43rd Street,Philadelphia,Pennsylvania19104Received18December2006;revised24January2007;accepted25January2007Published online in Wiley InterScience().DOI10.1002/jps.21072ABSTRACT:Using spectroscopic and thermal analysis,this study investigated drug–polymer interaction and its significance on the physical stability of drug amorphousdispersion in microparticles of an ammonio polymethacrylate copolymer(Eudragit RL1)(RL)and ethylcellulose(EC)binary blend(RL/EC¼2:1w/w)prepared for use incontrolled release of poorly water-soluble drugs.Solid dispersion of the model drug,nifedipine in the microparticles could be described as an ideal amorphous mixture fordrug loadings up to11%w/w.The antiplasticizing effect of the polymer blend wasindicated by a significant increase in the glass transition point from$508C for theamorphous nifedipine to$1158C for its solid solution.Moreover,shifts in infraredvibration wavenumber of nifedipine carbonyl and amine groups suggested that thehydrogen bonds(H-bonds)originally formed among nifedipine molecules were brokenand replaced by those formed between nifedipine and polymers in the microparticles.Further infrared analysis on nifedipine amorphous dispersions with a single polymer,namely RL or EC,confirmed the proposed hydrogen-bonding interactions;and theirstability study results suggested that both antiplasticizing effects and hydrogen bondingof EC and RL with nifedipine might be responsible for the physical stability of themicroparticles of nifedipine amorphous dispersion with a RL/EC binary blend.ß2007Wiley-Liss,Inc.and the American Pharmacists Association J Pharm Sci97:251–262,2008Keywords:nifedipine;solid dispersion;microparticles;ethylcellulose;Eudragit RL;poorly water-soluble drug;controlled release;solid-state stabilityINTRODUCTIONControlled release of poorly water-soluble drugs constitutes challenges for pharmaceutical scien-tists.Not only does the dissolution rate of drug have to be improved to avoid bioavailability problem,but also technologies are needed to obtain a desired release rate.Belonging to the class of calcium-channel blockers,a high perme-able,but practically water-insoluble drug,nifedi-pine(aqueous solubility of5.6m g/mL)is one of the examples.1The slow dissolution rate of its stable crystalline form had been reported as the cause of low drug bioavailability.2,3Furthermore,due to its short body half-life,nifedipine immediate-release dosage forms,requiring a dosing regimen of three times a day,result in a significantfluc-Jingjun Huang’s present address is Pharmaceutical and Analytical R&D,L-0071,AstraZeneca Pharmaceuticals LP, 1800Concord Pike,Wilmington,DE19850-5437.Correspondence to:Jingjun Huang(Telephone:1-302-885-4645,Fax:1-302-886-7470;E-mail:jingjun.huang@)Journal of Pharmaceutical Sciences,Vol.97,251–262(2008)Pharmacists AssociationJOURNAL OF PHARMACEUTICAL SCIENCES,VOL.97,NO.1,JANUARY2008251tuation of plasma drug concentration that causes toxic side effects.4Consequently,nifedipine con-trolled-release dosage forms have become the practical approach to achieve its therapeutic efficacy through reducing side effects and improv-ing patient compliance.Having potential advantages in achieving a reproducible drug-release rate5and in improving drug bioavailability,6,7microparticle or nanopar-ticle multiparticulate dosage forms may offer a solution to meet the challenges in controlled release of poorly water-soluble drugs.Especially, the matrix-type microparticles containing mole-cularly dispersed drug in water-insoluble poly-meric matrix could potentially improve the dissolution rate of poorly water-soluble drugs and modulate the drug-release rate simulta-neously.Based on this concept,amorphous dis-persion-containing microparticles of hydrophilic and hydrophobic polymer binary blends were pre-viously developed using phase-separation meth-odology for application in controlled delivery of the poorly water-soluble model drug,nifedipine.8,9 Drug-release mechanism and preliminary char-acterization studies on those microparticles indi-cated that due to the formation of an amorphous dispersion,nifedipine release was no longer con-trolled by drug dissolution;but rather it was controlled by the drug diffusion in the matrix.As a result,different combinations of two pharmaceu-tical-grade,insoluble polymers of different hydro-philicity,namely ethylcellulose(EC)and ammonio methacrylate copolymer(Eudragit1RL)(RL), had been demonstrated to be capable to control nifedipine-release rate by changing the drug matrix permeability and microparticle size.More-over,in contrary to the general knowledge that amorphous solid dispersion is inherently ins-table,10it was surprisingly observed that the microparticles,containing$10%of amorphously dispersed nifedipine in a binary blend of RL/ EC¼2:1and1:2w/w,appeared to be stable upon long-term storage.8No significant changes in the drug physical form and drug-release rate were observed on those microparticle samples stored in a closed container after12-month storage at ambient room temperature plus3-month acceler-ated stability at408C/75%relative humidity.In view of those earlier observations,it was of interest to fully characterize the nifedipine solid dispersions formed inside of those microparticles, especially the drug–polymer interactions at the molecular level.An in-depth understanding of the amorphous molecular association between drug and polymers may provide useful informa-tion in understanding how crystallization could be possibly prevented or slowed down by the matrix polymers of this study.Since Fourier-transform infrared spectroscopy(FTIR)has been demonstrated to be capable to detect changes in hydrogen-bonding interactions between func-tional groups as a result of physical form modi-fications,11–13with support of other solid-state characterization techniques including differential scanning calorimeter(DSC)and X-ray powder diffraction spectroscopy(XRPD),infrared spectro-scopy was primarily utilized to investigate the drug–polymer interactions in the microparticles of an RL/EC binary blend.To aid the under-standing of specific drug–polymer interactions, the amorphous dispersions of nifedipine with EC or RL polymer and their physical stability were also evaluated by FTIR.MATERIALSMicronized crystalline nifedipine of stable poly-morph A(NIF)was purchased from Sigma(St. Louis,MO).EC of N7viscosity grade(containing 48.0–49.5w/w of ethoxyl group)was kindly pro-vided by Hercules(Wilmington,DE).Ammonio methacrylate copolymer,Eudragit RL1100(RL) granules(containing6%of molar substitution by the positive-charged quaternary ammonium functional group)were donated by Rohm America (Piscataway,NJ).Acetone and methanol were purchased from Sigma-Aldrich(St.Louis,MO). All other materials were at least of analytical grade.Due to photosensitivity of nifedipine,the storage and handling of drug samples was con-ducted under yellow light.METHODSPreparation of Solid Dispersion-Containing Microparticles by Phase Separation Method Following a phase separation method developed from previous study,8different amounts of nife-dipine(0–3.3g)were dissolved in a50-mL acetone solution containing7.5g of RL and EC polymer blend of a weight ratio of2:1.While the mixture was stirred at600rpm throughout the experi-ment,a volume of100mL purified water(non-solvent)was added dropwise into the drug and polymer solution at a rate1mL/min.In the courseJOURNAL OF PHARMACEUTICAL SCIENCES,VOL.97,NO.1,JANUARY2008DOI10.1002/jps 252HUANG,WIGENT,AND SCHWARTZof the water addition,the drug and polymers were coprecipitated out to form microparticles.At the end of water addition,the solidified micro-particle suspension was then vacuumfiltered with a Whatman#5filter disk,and vacuum dried at room temperature for72h.The dried micropar-ticles were then stored in a desiccator at room temperature and protected from light until use. Preparation of Nifedipine Solid Dispersion With Polymer by Hot-Melt MethodAt a ratio of1:9w/w,nifedipine was mixed with RL or EC polymer to homogeneity in a stainless vessel using a spatula.With nitrogen blanketing over the powder blend inside the vessel,the mixture was heated on a hot plate with tempera-ture controlled at$1768C by a thermostat.After the powder was melted,the vessel was removed from the heat and cooled to room temperature to solidify the comelt;gently ground the comelt with a mortar and pestle for$10–20s;stored the samples in a desiccator at room temperature and protected from light until use.Analysis of Nifedipine ContentFor nifedipine loading determination,micropar-ticles were dissolved in methanol to obtain a theoretical nifedipine concentration of20mg/L. The drug concentration was then analyzed using a UV-VIS spectrophotometer at236nm with a standard curve of bracketed concentrations of nifedipine methanol solution.No interference from the polymers or SDS on the nifedipine assay was found at236nm.Light Microscopic Characterization Microparticles were dispersed in mineral oil on a glass slide and covered with a cover glass.The microparticles were observed under an Olympus polarized light microscope equipped with a digital camera and image analysis software(Image-Pro1 Plus4.5software for Windows TM,San Diego,CA). X-ray Powder Diffraction(XRPD)XRPD2was carried out with a Philips X’Pert powder diffractometer.A CuK a source operation (40kV,50mA)was employed.The diffraction patterns were recorded over a2u angular range of2–408with a step size of0.028in2u and a6s counting per step at room temperature. Differential Scanning Calorimetry(DSC)Thermal analysis was carried out using DSC (Model:DSC2910,TA Instruments Inc.,New Castle,DE).At a heating rate of108C/min,sam-ples of2–5mg were heated from room tempera-ture to2008C in an open aluminum pan under a 10mL/min stream of nitrogen purge.Universal Analysis(Version 2.5)software was used for analysis.Fourier-Transform Infrared(FTIR)The FTIR spectra of samples were obtained,using an FTIR spectrophotometer(Nicolet Magna560, Nicolet Instrument,Madison,WI).About2mg of the samples were mixed with dried potassium bromide of equal weight and compressed to form a KBr disc.The samples were scanned64times from400to4000cmÀ1.RESULTSUsing a phase separation method developed from previous study,8nifedipine microparticles with various drug loading levels,which possessed desired physical properties,such as nearly sphe-rical shape,a narrow size distribution,and a median particle size of$10–20m m,were prepared using the polymer ratio of RL/EC¼2:1w/w.Those microparticles were later used for the character-ization studies.An image of representative micro-particles under a polarized light microscopy is shown in Figure1.Drug and Polymer Crystallinity in Microparticles by XRPDXRPD had been used to identify crystalline phase and to determine drug maximum amorphous drug loading in polymeric matrix at room tempera-ture.14To aid the analysis of drug–polymer interactions of this study,XRPD was used to evaluate the crystallinity of nifedipine,EC,and RL polymers,and to identify possible formation of other nifedipine polymorphs in the microparticles. The X-ray diffractograms of drug-loaded micro-particles together with those of crystalline nife-dipine(stable polymorph A),untreated EC and RL polymers,and plain microparticles without drugDOI10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES,VOL.97,NO.1,JANUARY2008DRUG–POLYMER INTERACTION253loading were shown in Figure 2.As indicated by the X-ray diffractograms,RL polymer was an amorphous material in nature,whereas partial crystallinity was observed on untreated EC pow-der.The halo shape of X-ray diffractograms of the plain microparticles indicated that EC lost its partial crystallinity and was completely converted into the amorphous form after microparticle pre-paration.For nifedipine-loaded microparticles with up to21%(w/w)of drug loading,the characteristic peaks of crystalline nifedipine were not detected in the X-ray diffractograms,indicating that nife-dipine was mainly in the amorphous state in those microparticle.When the drug loadings weregreater than or equal to32%w/w,those characteristic peaks of crystalline nifedipine of stable form were observed in the diffractograms. No other nifedipine crystalline polymorphs were observed.Nifedipine–Polymer Interactions in Microparticles by Thermal AnalysisThe melting point of crystalline nifedipine(poly-morph form A)was observed at$1758C(Fig.3). No significant depressing of crystalline nifedipine melting point was observed on the physical mix-ture of crystalline nifedipine and the plain micro-particles of(10%w/w of nifedipine),which showed a melting point of nifedipine at$1748C.The amorphous nifedipine sample prepared using the melting and chilling method described by Forster et al.15was observed to have a glass transition with an enthalpy recovery endotherm at$40–508C,exothermic recrystallization peaks at$88–1308C,and an endothermic melting peak at $1728C.16,17For nifedipine solid dispersion-containing micro-particles,when drug loading was less than or equal to11%(w/w),other than the ECexothermal Figure2.Evaluation of microparticle crystallinity byX-ray powder diffraction.EC,untreated ethylcelluloseN7powder;RL,untreated Eudragit RL powder;%,drugloading(w/w),NIF,crystallinenifedipine.Figure1.Nifedipine microparticles(RL/EC¼2:1w/w)with14%w/w of drug loading by polarized lightmicroscopy(magnification:40Â).Scale bar equals to20mm.Figure3.DSC thermal analysis of nifedipine of dif-ferent physical forms.ANIF,amorphous nifedipine;NIF,crystalline nifedipine;NIFþplain microparticles,the physical mixture of plain microparticles with10%w/w of crystalline nifedipine.JOURNAL OF PHARMACEUTICAL SCIENCES,VOL.97,NO.1,JANUARY2008DOI10.1002/jps 254HUANG,WIGENT,AND SCHWARTZdegradation peak at $160–1808C,18neither amor-phous nifedipine glass transition nor the melting peak of crystalline nifedipine was displayed in the DSC thermograms (Fig.4A).Instead,a weak glass transition attributed to the drug–polymer solid solution was observed,decreasing from $125to $1158C with increasing drug loading from 0%to 11%w/w.The measured T g values of the drug–polymer solid solution were in an agreement with the values estimated by the modified Gordon–Taylor equation developed from an ideal amor-phous solid solution system 19,20(Eq.(1))(Fig.4B).The study result suggested that nifedipine,interacting with polymers as a plasticizer,wasmiscible with polymers in microparticle as an amorphous solid solution.21The significant increase in the glass transition point from $508C for nifedipine amorphous state to $1158C for its solid solution state indicated the antiplas-ticizing effect of the polymer blend on the amorphous dispersed drug:T g12¼w 1T g1þw 2K T g2w 1þK w 2(1)where w 1and w 2are the weight fraction of each component,and T g1and T g2are the corresponding glass transition temperature of each component.For this study,the components 1and 2repre-sented the polymer blend (RL/EC ¼2:1w/w)and amorphous nifedipine,ing Simha–Boyer rule,22the constant K was esti-mated from the glass transition temperature and density of the two components:K ffir 1T g1r 2T g2(2)where T g1and T g2were defined previously,and r 1and r 2are the density of each component.For this study,the T g values of the polymer blend (1258C)and the amorphous nifedipine (508C)were mea-sured by DSC.The density of amorphous nifedi-pine (1.36g/cm 3)was obtained from literature by Forster et al.23;and the density of the polymer blend (0.93g/cm 3)is a weight-averaged value calculated from that of EC (1.13g/cm 3)and RL (0.83g/cm 3).24When the nifedipine loading was increased to 21%(w/w)and above,the glass transition of the drug–polymer solid solution became very weak and no further change in the glass transition of the solid solution was observed.Instead,a ther-mal transition at $508C attributed to the glass transition and enthalpy recovery of the amor-phous nifedipine and a new endothermic peak at $153–1578C were displayed in the DSC thermo-grams (Fig.4A).This deviation of the solid dispersion from ideal amorphous mixture with an appearance of the amorphous nifedipine glass transition may suggest phase separation 20of the amorphous nifedipine from the drug–polymer solid solution at those loading levels (Fig.4B).The endothermic thermal transition at $153–1578C (T m1)was attributed to the melting of solid nifedipine domains that were in close contact with polymers inside of the microparticles;the interactions between drug and polymers may have resulted in this endothermic peak at $153–1578C.16,25,26Figure 4.DSC thermal analysis of nifedipine micro-particles with different drug loadings.(A)DSC thermo-grams of microparticles.(B)Phase diagrams of microparticles estimated from the DSC thermal analy-sis;solid line in the phase diagrams (B)represents the glass transition point (T g )of drug–polymer solid solu-tion predicted by the Gordon–Taylor equation (Eq.(1));ANIF,amorphous nifedipine;NIF,crystalline nifedi-pine;T m1,melting temperature of solid nifedipine domains in microparticles;T m2,melting temperature of crystalline nifedipine outside of microparticles.DOI 10.1002/jpsJOURNAL OF PHARMACEUTICAL SCIENCES,VOL.97,NO.1,JANUARY 2008DRUG–POLYMER INTERACTION 255When nifedipine loading levels were further increased to32%w/w or higher,the amorphous nifedipine glass transition with enthalpy recovery endotherm at$508C,a weak exothermic transi-tion attributed to amorphous nifedipine recrys-tallization at$1008C,16,17and two endothermic peaks at$153–1578C(T m1)and$167–1738C (T m2)were observed in one DSC heating cycle. Since the nifedipine crystals of stable polymorph (form A)outside of microparticles were visually observed and confirmed by X-ray powder diffrac-tograms(Fig.2)for the drug loading levels,the endothermic peak at$167–1738C(T m2)was attributed to the melting of crystalline nifedipine form A outside of the microparticles that had less surface contact with polymers.The depres-sion of drug melting point(T m2)from that of pure crystalline nifedipine(1758C)was attributed to the drug–polymer interactions or the impurity effect by polymers.With increasing drug loading, the melting point(T m2)was elevated to1738C at45%w/w of drug loading(Fig.4)and was similar to that of physical mixture of crystalline nifedipine and plain microparticles(1748C)(Fig.3). Drug–Polymer Interactions in Microparticlesby FTIRBecause the frequency of vibrations within a che-mical structure is very sensitive to how the atomsare arranged and how the atoms interact with neighboring functional groups,not only can FTIR provide a detailedfingerprint of pharmaceutical substances of different physical forms,17but also it can detect changes in hydrogen-bonding pattern of amorphous materials11–13,27that cannot be monitored by DSC and X-ray.The strong infrared absorption of the nifedipine hydrogen-bonding groups,namely the amine and carbonyl groups, makes FTIR especially useful in the detection of the specific drug–polymer hydrogen bond (H-bond)interactions in the microparticles of this study.Illustrated in Figure5are the chemical struc-ture and potential H-bond binding sites of nife-dipine,RL,and EC.The structure of nifedipine illustrates that nifedipine can potentially act as either proton acceptor(through the carbonyl groups,–C–O)or proton donor(through the amine group,–NH).13An X-ray diffraction study conducted on crystalline nifedipine28indicated that the H-bonds are formed via the amine group and one of the carbonyl groups,and the nitro group(–NO2)is not involved in the H-bond interactions.RL polymer monomer has one proton acceptor(carbonyl group,–C–O),whereas EC has hydroxyl groups(–OH)functioning as the proton donor or acceptor.The stretching vibration wavenumbers of the carbonyl group of RL and the hydroxide group of EC were found at$1736 and$3484cmÀ1,respectively(Fig.6B).Both bands located at the same regions were also observed in the spectra of the plain microparticles of RL/EC binary blend(Fig.6A,0%of loading). For nifedipine,shifts in stretching vibration wavenumber of the carbonyl and amine groups as a result of changes in hydrogen-bonding pattern caused by physico-chemical modifications1,13,17,29 are summarized in Table 1.Consistent with literaturefindings,1for both nifedipine crystalline polymorph A and its physical mixture with the plain microparticles8(10%w/w of nifedipine), the hydrogen-bonded nifedipine amine and car-bonyl groups were observed to have strong stretc-hing vibration bands at3332cmÀ1(–NH),and at 1679cmÀ1and1689cmÀ1(–C––O),respectively. Figure5.Chemical structure and proposed hydro-gen-bonding sites between(A)nifedipine and nifedipine;(B)Eudragit RL(R1––CH3,H;R2––CH3,CH2CH3;R3––CH2CH2Nþ(CH3)4ClÀ;R2:R3ffi3:0.2mole/mole)and nifedipine;(C)ethylcellulose and nifedipine;---repre-sents hydrogen bonding between functional groups.JOURNAL OF PHARMACEUTICAL SCIENCES,VOL.97,NO.1,JANUARY2008DOI10.1002/jps 256HUANG,WIGENT,AND SCHWARTZFor amorphous nifedipine prepared using the melting and chilling method described by Forster et al.,15due to irregularity and weakening in hydrogen bonding,13,17,20the stretching vibrationbands of the carbonyl and amine groups became broader and less defined (Fig.6A),reflecting an increase in irregularity of ‘‘long-range order of molecular packing’’of the amorphous substance.30Felodipine,a nifedipine analog belonging to the same dihydropyridine calcium-channel blocker class,was reported to have a nonhydrogen-bonded,‘‘free’’amine vibration band at 3420cm À1.13Nitro-derivative of nifedipine,the dehydrogenated form,was found to have a stretching vibration peak of nonhydrogen-bonded,‘‘free’’carbonyl at 1728cm À1.29Completely replacing the two strong bands caused by the carbonyl groups of crystalline nifedipine at 1679cm À1and 1689cm À1,a new sharp stretching vibration band at 1705cm À1was detected on the nifedipine amorphous dispersion-containing microparticles and its relative inten-sity increased with drug loading for up to 21%w/w (Fig.6A).Since this new stretching vibration band was located between that of the carbonyl group of amorphous nifedipine (1701cm À1)17and that of ‘‘free,’’nonhydrogen-bonded carbonyl group (1728cm À1)29(Tab.1),this peak at 1705cm À1was attributed to the nifedipine carbonyl group that formed H-bonds with polymers.A similar literature value of 1707cm À1had been reported for the stretching vibration of hydrogen-bonded carbonyl group.31As the drug loading level was increased to 21%w/w,the development of a shoulder at the lower wavenumber region of the peak at 1705cm À1suggested the presence of a separate nifedipine phase.Eventually,when drug loading was further increased to 32%w/w,the strong bands characteristic of crystalline nifedi-pine (1679and 1689cm À1)dominated and over-lapped other peaks,indicating the presence of nifedipine crystalline phase.Similarly,as a result of breakage of H-bonds between nifedipine amine and carbonyl groups by molecular dispersion,the changes in nifedi-pine hydrogen-bonding pattern in microparticles were also reflected by concomitant shifts in nife-dipine amine stretching vibration wavenumber (Fig.6A).As the nifedipine loading increased,a new broad band at the higher wavenumber region of $3364cm À1developed in the spectra of nife-dipine amorphous dispersion-containing micro-particles.This peak was most apparent for the microparticles containing 11%w/w of drug load-ing.Since this peak was also located in the region between that of the amine group of amorphous nifedipine (3346cm À1)17and the ‘‘free,’’nonhy-drogen-bonded amine groups (3420cm À1),13thisFigure 6.Investigation of drug–polymer interactions by FTIR.(A)Microparticles of nifedipine solid disper-sion with an EC and RL binary blend (RL/EC ¼2:1)at different drug loadings.(B)Solid dispersion of nifedi-pine with a single polymer RL or EC (10%w/w).NIF,crystalline nifedipine;ANIF,amorphous nifedipine;NIFRL,solid dispersion of nifedipine with RL;NIFEC,solid dispersion of nifedipine with EC;EC,untreated ethylcellulose N7;RL,untreated Eudragit RL.DOI 10.1002/jpsJOURNAL OF PHARMACEUTICAL SCIENCES,VOL.97,NO.1,JANUARY 2008DRUG–POLYMER INTERACTION 257stretching vibration at$3364cmÀ1was postu-lated to be the nifedipine amine group associating with polymers via H-bonds.Illustration of Specific Drug–Polymer Interaction of Nifedipine With EC or RLTo assess the specific interactions between nifedipine and polymers,nifedipine amorphous dispersion with a single polymer,namely EC or RL(10%w/w of nifedipine),were prepared and characterized by FTIR(Fig.6B).To ensure that no solvent or water would interfere the FTIR analysis,these two solid dispersions were pre-pared by hot-melt method.Similar to the nifedipine amorphous dispersion-containing microparticles of RL/EC¼2:1with 11%w/w of drug loading,the stretching vibration bands characteristic of the amine and carbonyl groups of crystalline nifedipine at3332,1689, and1679cmÀ1completely disappeared from the spectra of NIF–RL solid dispersion(Fig.6B), indicating that nifedipine was in an amorphous state in the solid dispersion.The infrared spectra of the NIF–RL solid dispersion also displayed a new broad band at$3374cmÀ1,which,based on the band location(Tab.1),was attributed to the stretching vibration of nifedipine amine groups that formed H-bonds with RL carbonyl groups. However,a difference from that of the nifedipine amorphous dispersion-containing microparticles was observed on the spectra of the NIF–RL solid dispersion.The sharp stretching vibration peak at 1705cmÀ1previously observed on those micro-particles was not found.Instead,only a hump was shown at the lower wavenumber region adjacent to the free RL carbonyl band at$1736cmÀ1.Given the structure of nifedipine and RL polymer (Fig.5B),the abovefindings suggested that the H-bonds formed between the amine and carbonyl groups of crystalline nifedipine may have been disrupted by solid dispersion and been replaced by the H-bonds formed between nifedipine amine and RL carbonyl groups.As a result,the nife-dipine carbonyl groups became‘‘free,’’and its stretching vibration moved a higher wavenumber region($1728cmÀ1),29which,however,was over-lapped by the broad band caused by the free RL carbonyl groups at$1736cmÀ1.On the other hand,since some of the RL carbonyl group formed H-bonds with the nifedipine amine group,the stretching vibration wavenumber of those hydro-gen-bonded RL carbonyl was moved to a lower wavenumber region and was shown as a hump adjacent to the stretching band caused by the ‘‘free’’RL carbonyl group.Similar to the NIF–RL amorphous dispersion and nifedipine amorphous dispersion-containing microparticles,the stretching vibration bands of the amine and carbonyl groups of crystalline nifedipine at3332,1689,and1679cmÀ1were alsoTable1.Shifts of the Stretching Vibration Wavenumber of Carbonyl and Amine Groups at Different FormsFormulations Carbonyl,–C––O(cmÀ1)Amine,–N–H(cmÀ1)Assignment of HydrogenBondingCrystalline nifedipine1679,1679a3331a NIF–C––O---HN–NIF e Physical mixture of microparticles(RL/EC¼2:1)with crystalline NIF(10%w/w of NIF)1679,1689b3332b NIF–C––O---HN–NIF e Amorphous nifedipine1701c3346c NIF–C––O---HN–NIF e Microparticles of RL/EC¼2:1(11%w/w of NIF)1705d3364d NIF–C––O---HO–ECNIF–NH---O––C–RLNIF–NH---O(H)–ECNIF solid dispersion with RL(10%w/w of NIF)—3374NIF–NH---O––C–RLNIF solid dispersion with EC(10%w/w of NIF)17063354NIF–C––O---HO–ECNIF–NH---O(H)–EC‘‘Free’’amine(NIF analog,felodipine e)—3420e Non-H-bonded–NH e‘‘Free’’carbonyl(nifedipine nitro derivative f)1728f—Non-H-bonded–C––ONIF,nifedipine;EC,ethylcellulose;RL,Eudragit1RL;---indicates hydrogen bond interaction.a Ali,1989.1b Huang et al.,2006.8c Burger and Koller,1996.17d Huang et al.,2006.9e Tang et al.,2002.13f Teraoka et al.,1999.29JOURNAL OF PHARMACEUTICAL SCIENCES,VOL.97,NO.1,JANUARY2008DOI10.1002/jps 258HUANG,WIGENT,AND SCHWARTZ。
小胶质细胞及其在阿尔茨海默病中的作用_邓小华
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第27卷第4期2007年8月国际病理科学与临床杂志In ternati onal Journal ofPat h ol ogy and C li n i calM ed ici neVo.l27N o.4Aug.2007¹小胶质细胞及其在阿尔茨海默病中的作用邓小华综述罗学港审校(中南大学湘雅医学院人体解剖学与神经生物学系,长沙410013)[摘要]阿尔茨海默病(AD)是一种常见的老年神经变性疾病,病因十分复杂。
目前多数学者认为:B2淀粉样蛋白沉积使得神经胶质细胞活化引起脑内慢性炎症反应可能是AD发病的核心病理机制之一。
在AD炎症过程中,渉及到诸多细胞如小胶质细胞、星形胶质细胞及神经元参与,小胶质细胞则是其最主要的炎症细胞,小胶质细胞被B2淀粉样蛋白(A B)激活,产生大量致炎性细胞因子和神经元毒性介质,从而诱发脑内炎症反应,导致神经元损伤、死亡。
A B的持续存在,小胶质细胞被持续激活,形成炎症发生和持续的恶性循环,最后导致AD的发生发展。
[关键词]阿尔茨海默病;小胶质细胞;炎症;老化;B2淀粉样蛋白[中图分类号]R741[文献标识码]A[文章编号]167322588(2007)0420332204M icrogli a and its rol es i n A lzhei m er.s d isea seDENG X i a o2hua,L UO Xue2gang(D e part m ent of Ana t o m y and N eurobi ology,Xiangya Sc h ool of M e d ici n e,Centra l Sou t h Un i versit y,Changs ha410013,Ch ina)[Ab stract]A lz hei m er.s disease(AD)is the most co mmon neurodegenerati o n d isease of ol d age, the cause ofwhich is ver y co mp licated.A t presen,t most of scholars t h i n k that the deposit of B2a myloi d make the acti v ation of neuroglial ce lls,wh ich trigger the chronic infla mmator y reacti v ity in AD bra i n.A lot of cells such asm icroglia,astr ocyte and neuron are involved i n the process ofAD,m icroglial cells are the most i m portant cells i n AD brain.M icroglia can be acti v ated by B2a myloid protein.Th i s acti v ation can produce f u rther release of pro2i n fla mma tory cytokines and toxic mediators thatm i g h t i n duce i n fla mm a2 tor y responses i n AD brai n and m i g ht contri b u te to neur ona l i n j u ry and death.A B and acti v ated m icroglia persist and thus i n itiate a vicious c ircle of i n fla mmatory pr ocesses,wh ich fina ll y leads to the developmen t and progression of AD.[K ey w ord s]A lz hei m er.s d isease;m icroglia;i n fla mmati o n;aging;B2a myloi d[Int J Pathol ClinM ed,2007,27(4):0332204]1小胶质细胞1.1小胶质细胞的个体发生及形态特征小胶质细胞广泛分布于中枢神经系统,占胶质细胞总数的5%220%,在整个脑实质区均可见,在灰质中分布比白质多5倍。
非酒精性脂肪性肝病代谢组学研究进展
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机制尚未完全明确,1998 年Day 等[12]提出“二次打击”学说。 开。同时NAFLD 肝硬化患者与酒精性肝硬化患者也可有效区
随后Tilg 等[13 -14]提出“多重平行打击”理论,包括遗传因素、 分开(AUC =0. 83)。他们认为此方法可作为区分NAFLD 纤维
IR、氧化应激、脂毒性、慢性炎症、纤维化、免疫和肠道菌群等, 化程度及诊断的无创生物标志物,且可以显著减少对肝活检的
黄酯和13 - cisRA 呈正相关。他们在人类组织中首次检测到 验证;单不饱和TAG 的增加可能是NAFLD 和CHB 患者NASH
atRA 的活性代谢物4 - oxo - atRA,表明这种类维生素A 可能 的特异性标志物。
有助于人体类维生素A 的信号传导。肝脏维生素A 的稳态平 2. 3 代谢组学对NAFLD 药物作用与疗效研究的推动作用
录组学、蛋白质组学为代表的系统生物学技术提供了新的技术 展的新学科,代谢组学较为全面的展示了机体的代谢结果,为
与思路。区别于其他组学技术,以内源性小分子代谢物为研究 临床医学提供了新的技术和方法。
对象的代谢组学可以很好的揭示机体变化的最终代谢结果。因 2 非酒精性脂肪性肝病(NAFLD)
收 基 作DO稿 金 者I:日 项 简10期 目 介. 3:::912上 栾研6709)2海究雨/0j.中婷-is医1s(n1药.1-19大090006学1—;修-附)5回,属2女5日第6,.期七主20:人2要210民.2从00医4事-.院01慢42人7-性才1肝7培病养计的划基(础XX与20临19床- 通信作者:顼志兵,xzb6160@ 163. com
和遗传易感密切相关的代谢应激性肝损伤,包括非酒精性单纯 1 代谢组学概述
性肝脂肪变(NAFL)、非酒精性脂肪性肝炎(NASH)、肝硬化和 1. 1 代谢组学含义 代谢组学最初于1999 年由Nicholson
律复康胶囊对哇巴因致豚鼠心律失常模型的作用
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【 摘要】目的 : 观察 律复 康胶 囊对 哇 巴因致 豚 鼠心律 失பைடு நூலகம் 模 型的 对抗作 用 , 为临床 用 药提 供依 据 。方 法 : 实验 豚 鼠 取
5 只 , 分为 模型 对照 组 ( 0 均 等容 量蒸 馏水 ) 阳性对 照组 (.8 ag 、 、 41 5g ) 律复 康胶 囊小 剂 量组 ( . 9g生药/g 、 1 3 5 k ) 中剂量
d i diom e cn o gop ( sldw t esl o m )psi otl op (. 5g g,o o g id t o l ot l ru d t e a r fh al vl e oi ecn o g u 41 ) l ds e v e n d r ii l eot T e u , t v r r a 8 w a gop(5 9 ue r / )mdl ds e ru 3 7 rd r g adhg oae r p( 16g rd rg r u 1 3 c d u k , i e oa op(0 8gc ed g ) n i ds o 6 5 ued / . gr dgg d g g . u u a h g gu . c u k ) f iu agC pue ep c vl. l ted sg ru sw r ie u c si dc t nfr3d y, r y mi m - g o i k n a sls set ey A lh oa ego p eegvnsces eme ia o as ar t c o Lf r i v i o h h d
长期照护机构老年人综合评估工具研究进展及系统评价
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长期照护机构老年人综合评估工具研究进展及系统评价张沁;桂前;王燕君;陈宇婧;徐桂华【摘要】背景目前国内外的老年人综合评估工具较多,但我国养老机构的照护服务质量参差不齐,尚缺乏统一的老年人能力评估工具.目的系统评价国内外老年人综合评估工具的信效度并结合我国国情进行分析,以选择适合我国长期照护机构老年人综合评估的工具.方法于2018年1—6月,计算机检索中国知网、万方数据知识服务平台以及Scopus、PubMed、Usearch、CINAHL、PsycINFO、Medline数据库中与老年人综合评估有关的文献(发表时间为2008—2018年),以获取老年人综合评估工具及相关资料.采用\"基于共识选择健康测量工具的标准\"(COSMIN)评估合格文献中老年人综合评估工具的方法学质量.结果最终纳入合格文献21篇,涉及老年人综合评估工具9种,仅5种工具被汇报了信效度相关信息.根据COSMIN:国际居民长期照护评估工具(interRAI-LTCF)的内部一致性等级评定为一般,3篇文献中汇报的重测信度等级分别评定为差、一般、一般;诺丁汉健康量表(NHP)的内部一致性、重测信度等级评定为差;重庆市医院-养老机构-社区通用老年人健康综合评估量表(BGA)的效度和信度等级均被评定为差;老年人能力评估问卷的内部一致性等级评定为一般;老年人健康功能综合评价量表的内部一致性、内部效度、结构效度等级评定为差.结论 interRAI-LTCF和老年人能力评估问卷是未来值得在我国长期照护机构中进行推广的老年人综合评估工具,但仍需更多高质量的将评估工具应用于长期照护机构的研究来测量其信效度和可行性.【期刊名称】《中国全科医学》【年(卷),期】2019(022)004【总页数】6页(P462-467)【关键词】老年人;长期照护机构;能力等级;评估工具【作者】张沁;桂前;王燕君;陈宇婧;徐桂华【作者单位】210023江苏省南京市,南京中医药大学护理学院;210023江苏省南京市,南京中医药大学护理学院;210023江苏省南京市,南京中医药大学护理学院;210023江苏省南京市,南京中医药大学护理学院;210023江苏省南京市,南京中医药大学护理学院【正文语种】中文【中图分类】R161.7我国的养老问题日益突出,预计2012—2050年,我国老年人口将由1.94亿增长到4.83亿,老龄化水平由14.3%提高到34.1%[1]。
“R-TA生物调序平衡疗法”,彻底击碎自闭症的那堵坚冰
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“R-TA生物调序平衡疗法”,彻底击碎自闭症的那堵坚冰2007年12月联合国大会通过决议:从2008年起,将每年的4月2日定为“世界自闭症日”,以提高人们对自闭症和相关研究与诊断以及自闭症患者的关注。
自闭症的概念由美国约翰斯.霍普金斯大学专家莱奥·坎纳于1943年首次提出。
自闭症是什么,到底有哪些危害?自闭症是一个医学名词,又称孤独症,被归类为一种由于神经系统失调导致的发育障碍,其病征包括不正常的社交能力、沟通能力、兴趣和行为模式。
儿童自闭症是广泛性发育障碍的一种亚型,以男性多见,起病于婴幼儿期,主要表现为不同程度的言语发育障碍、人际交往障碍、兴趣狭窄和行为方式刻板。
约有3/4的患者伴有明显的精神发育迟滞,部分患儿在一般性智力落后的背景下某方面具有较好的能力。
从1943年世界上发现第一个自闭症病例至今已70年,目前,全球约有6700万自闭症患儿,且以每年10%-14%的速度递增。
今年4月份,美国疾控中心(Centers for Disease Control and Prevention )最新研究数据表明,每88个人中就有一个是自闭症患者,全球每20分钟就有一个孩子被诊断为自闭症,男女患病比例大约为4:1。
他们由于发育受到阻碍,缺乏正常的语言沟通和社会交往能力,已经成为全世界必须正视的社会难题。
自闭症已经成为医学界最为之头痛的疑难杂症。
随着临床生物技术的应用,医学界对于自闭症的认知、诊疗再次迈上了新的台阶。
在安徽长征医院儿童医学中心的李万顺教授倡议下,数十位医疗精英组成自闭症研究小组,医院联合国外知名医疗机构共同探究自闭症治疗方法。
“R-TA生物调序平衡疗法”便是众位专家的劳动成果,也是对医学界的重大贡献。
安徽长征“R-TA生物调序平衡疗法”,让孩子回到阳光中来“R-TA生物调序平衡疗法”是根据生物基因调控原理,借助精密数字化导航仪器,对受损部位进行数字模拟,然后应用尖端的磁极超声精确定位,使生物蛋白基因作用于自闭症孩子体内,通过血液、淋巴细胞循环,改善脑内血液循环,营养、修复受损脑细胞,平衡脑神经递质功能,全新脑神经通路,唤醒孩子的感知能力,增强对信息反馈功能,使孩子走出自闭。
内脏脂肪相关指数与急性胰腺炎严重程度的关系
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*+,内脏脂肪相关指数与急性胰腺炎严重程度的关系黄河铭,杨慧莹,覃颖颖,唐国都广西医科大学第一附属医院消化内科,南宁530021摘要:目的 探讨内脏脂肪相关指数与急性胰腺炎(AP)严重程度之间的关系。
方法 选取2014年9月—2021年10月于广西医科大学第一附属医院住院的308例诊断为AP的患者作为研究对象,按AP分级诊断标准将其分为轻症急性胰腺炎(MAP)(n=186)、中度重症急性胰腺炎(MSAP)(n=60)和重症急性胰腺炎(SAP)(n=62),通过收集腰围、身高、体质量、血脂、生化等指标对比它们在年龄、住院费用及天数、评分系统和人体测量学指标等方面的差异。
符合正态分布且方差齐性的计量资料组间比较采用单因素方差分析,方差不齐的组间及组内两两比较均采用Kruskal-WallisH检验检验;不符合正态分布的计量资料组间及组内两两比较均采用Kruskal-WallisH检验。
分类资料和计数资料组间比较采用Kruskal-WallisH检验。
采用Spearman秩相关分析方法对各指标与AP的严重程度进行相关性分析;对各指标构建受试者工作特征曲线,并计算曲线下面积(AUC),比较AUC大小;用单因素及多因素Logistic回归分析方法找出MSAP和SAP发生的独立危险因素。
结果 住院费用及天数、TG、HDL-C、NLR、WBC、Alb、Cr、BUN、SIRS、BISAP、MEWS、Glasgow、PANC-3在3组间的差异均有统计学意义(P值均<0.05)。
进一步两两比较发现,与MAP组相比,MSAP和SAP组的CMI、LAP、WTI、CVAI明显升高,差异均有统计学意义(P值均<0.05)。
在相关性分析中,CMI与AP严重程度之间有一定相关性(r=0.352,P<0.001)。
通过对各AUC大小的比较发现,CMI对预测MSAP和SAP发生的效能最大(AUC=0.708,95%CI:0.651~0.765,P<0.001)。
他汀类药物在临床应用中的不良反应及产生机制
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他汀类药物在临床应用中的不良反应及产生机制宋媛媛;杜丽萍;王蕴怡;李翔;梁洋【摘要】他汀类药物作为胆固醇合成早期阶段的竞争性抑制剂,抑制3-羟基-3-甲基戊二酰辅酶A(3-hydroxy-3-methyl glutaryl coenzyme A reductase,HMG-CoA)还原酶的活性,使HMG-CoA向甲羟戊酸的转化途径受阻,阻碍肝脏合成内源性胆固醇,代偿性地增加肝细胞膜上低密度脂蛋白受体,从而降低血浆中低密度脂蛋白(LDL)水平,达到治疗和预防心脑血管疾病的目的.本文对他汀类药物使用过程中副作用的细胞代谢途径、产生机制以及临床表现进行了综述,探讨了他汀类药物调脂过程中,在肌肉、肝脏等方面引起的副作用表现及其分子机制.【期刊名称】《中国生化药物杂志》【年(卷),期】2016(000)001【总页数】5页(P174-177,182)【关键词】他汀类药物;不良反应;致病机理;细胞代谢;分子机制【作者】宋媛媛;杜丽萍;王蕴怡;李翔;梁洋【作者单位】东北林业大学生命科学学院,黑龙江哈尔滨150040;东北林业大学生命科学学院,黑龙江哈尔滨150040;东北林业大学生命科学学院,黑龙江哈尔滨150040;东北林业大学生命科学学院,黑龙江哈尔滨150040;东北林业大学生命科学学院,黑龙江哈尔滨150040【正文语种】中文【中图分类】R96他汀类药物是一类具有萘酯环骨架结构的3-羟基-3-甲基戊二酰辅酶A(3-hydroxy-3-methyl glutaryl coenzyme A reductase,HMG-CoA)还原酶抑制剂,是目前唯一降低心脑血管疾病死亡率的调脂药。
代表性药物有:普伐他汀(pravastatin)、辛伐他汀(simvastatin)、氟伐他汀(fluvastatin)、阿托伐他汀(atorvastatin)和瑞舒伐他汀(rosuvastatin)等。
自1987年洛伐他汀应用于临床始,他汀类药物迅速成为临床上的首选降血脂药。
教师发展379篇国内外期刊文献 - 副本
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Procedia - Social and Behavioral Sciences 2(2): 4672-4676.borda, J. G. (2010). ―Book review: Anne Burns and Jack Richards (Eds.) (2009). The Cambridge guide to second language teacher education. New York: Cambridge University Press.‖ Language Teaching Research, 14(3), 341-344.zăr, A. (2013). "Learner Autonomy and its Implementation for Language Teacher Training."Procedia - Social and Behavioral Sciences 76: 460-464.158.Lee, I. (2010). "Writing teacher education and teacher learning: Testimonies of four EFL teachers." Journal of Second Language Writing 19(3): 143-157.159.Lee, I. (2012). ―Becoming a writing teacher: Using ―identity‖ as an analytic lens to understand EFL writing teachers‘ development.‖ Journal of Second Language Writing.160.Lee, I. (2013). "Becoming a writing teacher: Using ―identity‖ as an analytic lens to understand EFL writing teachers‘ development." Journal of Second Language Writing 22(3): 330-345.161.Lee, J. F. K. (2009). 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2008 “ACCORD”研究 美国 解读
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著名的美国“ACCORD”研究简介Action to Control Cardiovascular Risk in Diabetes (ACCORD)(2011-05-25 22:09:24)转载▼分类:糖尿病理论资料标签:美国心血管疾病accordadvancevadt美国“ACCORD”研究的结果可以说是糖尿病研究领域的里程碑式的事件,其震撼力不亚于上世纪八十年代美国内分泌专家Reaven提出的Ⅱ型糖尿病及胰岛素抵抗理论。
ACCORD的研究结论与以往的研究(如1998年英国UKPDS研究以及与ACCORD同时发表的ADVANCE研究)最大的不同在于宣布了“严控血糖有害”的结论。
该研究结果公布后,我国医学界一片“震惊”“意外”“困惑”“失望”“出乎预料”等(真不太理解);从这些用词可见,医学界的震惊是如何强大,医学界的某些传统理念是如何根深蒂固!但医学界也同时指出:与那些“意料之中”的试验相比,这些“出乎意料”的研究结果对科学的发展可能具有更大的意义。
ACCORD研究是怎么回事呢?2008年,第68届美国糖尿病学会(ADA)的年会上发布了关于ACCORD(控制糖尿病大血管风险行动)与ADVANCE(糖尿病和心血管行动,注1)的研究结果,引起医学界一片争鸣。
ACCORD研究结果显示:强化治疗组(严控血糖及血压)的全因死亡率和心血管病死亡率明显高于常规治疗组。
这提醒医疗界不能一味追求血糖达标而疏忽病人整体状况!“ACCORD”研究简介:ACCORD(Action to Control Cardiovascular Risk in Diabetes,控制糖尿病心血管危险行动)试验是由美国国家心脏、肺和血液研究所(NHLBI)、国立卫生研究院(NIH)资助,国立糖尿病、消化和肾脏疾病研究所(NIDDK)提供研究附加支持的一项大型临床研究,分为降压支、降脂支与降糖支三部分。
其降糖支试验旨在评估对Ⅱ型糖尿病患者强化血糖控制(糖化血红蛋白<6%)是否比标准血糖控制(7.0-7.9%)更大程度的减少心血管终点事件的发生。
NMDA受体介导了加兰他敏对阿尔茨海默病大鼠认知功能的改善_曹续政
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文章编号:1003-2754(2006)06-0678-03NM DA 受体介导了加兰他敏对阿尔茨海默病大鼠认知功能的改善曹续政1, 张黎明1, 沈月娥1, 周珊珊1, 姜国华2收稿日期:2006-06-09;修订日期:2006-10-17作者单位:(1.哈尔滨医科大学第一附属医院神经内科,黑龙江哈尔滨150001;2.黑龙江中医药大学解剖学教研室,黑龙江哈尔滨150030;张黎明,通信作者) 摘 要: 目的 研究加兰他敏对阿尔茨海默病(A D )大鼠认知功能的影响及N M DA 受体在其中的作用。
方法 雄性SD 大鼠65只,随机分为假手术、链脲菌素(ST Z )组,加兰他敏、M K -801和犬尿烯酸3个治疗组。
侧脑室注射ST Z 制备大鼠AD 模型,水迷宫试验测定大鼠的学习记忆能力。
3个治疗组分别给予加兰他敏、M K -801+加兰他敏、犬尿烯酸+加兰他敏,共6周。
结果 术后第10天各组潜伏期明显延长,过平台次数明显减少,差异均无统计学意义。
治疗6周后加兰他敏组潜伏期缩短,过平台次数增加,与ST Z 组比较,有显著差异,而M K -801和犬尿烯酸组潜伏期和过平台次数与ST Z 组比较,无明显差异。
结论 加兰他敏对A D 大鼠的认知功能具有明显的改善作用,而应用N M DA 受体阻断剂后其治疗作用消失。
说明N M DA 受体介导了加兰他敏对A D 大鼠认知功能的改善。
关键词: 加兰他敏; 阿尔茨海默病; 痴呆; N M DA 受体中图分类号:R 742 文献标识码:A NMDA receptors mediate the eff ect of galantamin on the cognitive function of Alzheimer 's disease in rats CA O X u -z heng ,ZH A N G L i -ming ,S H EN Y ue -e ,et al .(D ep ar tment of N eur ology ,the Fir st A f f iliated H osp ital ofH ar bin M edical U nivers ity ,H arbin 150001,China )Abstract : Objective T o study the effect of g alantam in on the co gnit ive functio n o f Alzheimer 's disease and N M DA receptor s'ro le in ra ts .Methods 65male SD r ats w ere divided into sham o per ated ,st repto zo tocin (ST Z ),ga lantamin (GT ),M K -801a nd cynurenic acid (CA )g ro ups ,randomly .T he models o f A lzheimer 's disease w ere cr e-ated by intracer ebro ventr icular injectio n of strepto zo to cin ,and a M or ris maze w as used to test the r ats'lear ning and memor y ability .GT ,M K -801a nd CA w ere administer ed t o the thr ee tr eating g ro ups for six w eeks ,respect ively .Results Of t he three tr eating g ro ups ,t he latency 10d after the o per ation w as 48.64±8.41,52.09±11.35,50.06±10.37seco nds ,r espectively ,and the t imes o f passing thr ough the platfo rm w ere 0.74±0.40,0.81±0.35,0.79±0.27,r espectiv ely .N o statistic differ ences w er e fo und .Six w eeks later ,the latency and passing t hro ug h platfor m times o f GT gr oup wer e 26.33±9.51and 3.33±1.51,respectively ,all had statistic differences co mpa red with theST Z g r oup .A nd the latency and passing thro ug h platfor m times of the M K -801and CA g ro ups had no sta tistic dif-ferences co mpared with the ST Z g ro up .Conclusion Galantamin could impr ov e t he lear ning and memo ry ability of ra ts with A lzheimer 's disease ,and it s t reat ing effect disappear ed under the use of N M D A receptor antag on ,which sug g ests that NM DA receptor s may m ediat e the effect of galantamin o n t he co gnitiv e functio n of A lzheimer's dis-ease in rats .Key words : Galantamin ; A lzheimer 's disease ; D ement ia ; N M D A r ecept or s 阿尔茨海默病(Alzheim er 's disease ,AD )已成为老龄化社会一个日益突出的社会问题,严重威胁着人们的健康和生命安全。
卡巴拉汀治疗路易体痴呆的疗效——一项随机双盲安慰剂对照的国际研究
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性 和 安 全性 。
新新贸易理论的贡献与发展
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78
空间经济学
西南民族大学学报 ( 人文社科版 ) 2009 / 12总第 220期
本刊网址: www xuebao net 79
3. 开放经济中的企业行为和均衡
由于封闭经济中的市 场规模一定, 均衡 条件
表明, 一旦加权企业平均 生产率确定, 企业数量、
价格水平和人均财富都被确定, 因此行业 总生产
率只能通过其他途径得以提高, 尤其依靠 企业技
术水平的提高。而梅里兹模型的关键之处在于,
条件则变为 ∃( #* ) = ∃d ( #* ) + n∃x ( #* ) = 0。 值得注意的是, 企业进入国际业务面临 的成
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核酸适配体ppt课件
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核酸适配体的应用
核酸适配体在分析化学中的应用 核酸适配体与疾病诊断和新药研发
核酸适配体在分析化学中的应用
靶物质的分析与检测
该方面应用的基本思路是将各种报告基团,如荧光试剂,定点标 记在aptamer核苷酸上,然后在一定条件下,使aptamer与靶物质 发生相互作用,再通过对报告基团的信号检测实现对靶物质的定 性检测或定量分析。
核酸适配体的筛选策略
核 酸 适 配 体 的 体 外 筛 选 是 利 用 SELEX 技 术 ( Systematic Evolution of Ligands by Exponential Enrichment) )来完成的, SELEX是指数富集配体系统进化的简称,它的基本原理就 是就是利用分子生物基(aptamer) ,经反复扩增、筛选数个循环,即可使与该 靶分子特异结合的寡核苷酸序列得到富集。
Aptamer巨大的应用前景
APTAMERS: AN EMERGING CLASS OF THERAPEUTICS(.Annu. Rev. Med. 2005. 56:555–83)
Analytical Applications of Aptamers(Andrew D. Ellington .Annual Review of Analytical Chemistry (2008). Volume 1, Jul 2008)
基于适配体的生物传感器是用适配体作为识别元件来特异 性地检测其相应的靶物质。
目前适配体生物传感器(Aptasensors)尚处于起步阶段。 Chunyan Yao等将IgE适配体固定在石英晶体微平衡生物传 感器阵列,建立了适配体压电石英生物传感器模型,用于 特异性检测标准溶液和人血清中的IgE。该方法最低可在标 准和人血清溶液中分别检测出2.5-200 ug/L的IgE,整个检 测时间只需15 min,而且固定在金膜表面的适配子在反复 洗脱后并不影响其灵敏度。
细菌人工染色体的修饰及其转基因应用研究
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现代生物医学进展Ⅵ唧.biomed.net.饥Progress in Mode rn Biome dic in e 2008 V01.8 No.6 ·1 11生细菌人工染色体的修饰及其转基因应用研究吴宏梅1 刘长青1。
刘帅-’3陆涛峰- 包阿东-’3关伟军△1马月辉△1 (1中国农业科学院北京畜牧兽医研究所北京100094;2中国海洋大学生命与技术学部山东青岛266003;3内蒙古农业大学动物科学与医学学院内蒙古呼和浩特010018)摘要:细菌人工染色体(BacterialArtificial Chromosome,BAC)是一种新发展起来的DNA载体系统,它具有容量大、遗传特性稳定、易于操作等优点。
广泛的应用于基因组文库构建、基因功能分析等方面。
随着基因组测序工程的实施与完成,如何对包含完整基因信息的特定细菌人工染色体进行有目的修饰已成为功能基因组学研究的一个重要环节。
BAC载体转基因技术可能成为避开基因打靶获得高效表达的转基因生物的另一途径。
本文介绍了BAC作为转基因栽体的几种修饰方法及其在转基因研究上的应用。
关键词:细菌人工染色体;BAC修饰;BAC转基因;中图分类号:Q782文献标识码:A文章编号:1673-6273(2008)06-1149-03Study on Modification Methods of BAC and the Application ofBAC in Transgene+WUH on g-mei,L IU Cha ng-q in g,L1U Sh ua i,L U Tao-feng,B AOA-dong,GU AN Wei-jun",MA Yu e-h ui(Institute ofAn imal Science,Chi nes e Academy of Ag r ic u l tu r al Science,Beijing,100094,China)A B S T R A C T:A s n e w l y dev elo ped v e c t o r s yst em,th e bacterial artificial chromosome(BAC)has several a d v a n ta g e s,i n c l u di n g l a r g ecapacity,stable h eritage and easy handling.It is utilized e x t e n si v e l y in libraries const ruc ti on,ge no me research andanalysis o f ge ne f un c-tion.With the c om p l e ti o n of ge no me—s eq ue nc in g projects,i ntentio nal modification o f definite bacterial artificial ch r om o s om e s,w h i c h c ar r y en ti r e components ofmost eukaryotic genes,is becoming mor e i m po r t an t for t h e s u b se q u e nt f u n ct i o n al g en om ic s s t ud ie s.B AC v e c-t o r s may be another approac h to obtain transgenic bi ol og y w i th high efficie ncy a n d high expression without gene targeting.Some m od i f i-cation metho ds o f B A C and th e application o f B A C in tr a ns g en e research wer e re vie wed in present article.K ey wo r d s:B a c te r i a l artificial chromosome(BAC);BAC m od if ic at io n;B AC tra ns ge n eChin esc Library Cla ssification:Q782Docu men t code:AArticle ID:1673-6273(2008)06-1149-03100~350kb的大片段DNA。
绿色荧光蛋白
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荧光蛋白的应用
细胞分裂和骨架 细胞器动力学和泡囊运输 发育生物学 分子标记 药物筛选 光伏发电
细胞分裂和骨架
GFP较小,与其它蛋白质融 合后不影响自身的发光性能, 利用这一特性可以加深我们 对细胞内一些过程的了解, 如细胞分裂、染色体复制和 分裂,发育和信号转导等 。 如研究脑神经细胞的发展 或者癌症细胞是如何扩散的 等。
绿色荧光蛋白
2008年诺贝尔化学奖 获得者:马丁· 查尔菲(Martin Chalfie)、钱永健 (Roger Y. Tsien)和下村修(Osamu Shimomura) 小组成员:张艳嫡 邱丹丹 郎平 肖欢 颜旭 张忠丽 黄春林 刘凯 郭高尚 曾万强
绿色荧光蛋白(green fluorescence protein; GFP)
科学使用绿色荧光蛋白跟踪大脑细胞的活动
药物筛选
由于GFP分子量小,在活细胞内可溶且对细胞 毒性较小,因而常用作荧光探针。 将一荧光蛋白与信号分子相偶联,根据荧光蛋 白的分布情况即可推断信号分子的迁移状况, 并推断该分子在迁移中的功能。利用这一原理, 已经成功构建了一个筛选模型,用于研究药物 介导的糖皮质激素受体(hGR)的迁移过程。
绿色荧光蛋白分子的形 状呈圆柱形,就像一个 桶,负责发光的基团位 于桶中央。装在“桶” 中的发光基团对蓝色光 照特别敏感。当它受到 蓝光照射时,会吸收蓝 光的部分能量,然后发 射出绿色的荧光 。
特性决定广泛用途
GFP是无毒的,它可在不同的有机体中, 高水平地予以表达,而对有机体的生理学 则仅有很小的影响.可用于在时间和空间 上监视越来越多的活细胞中的现象和机制, 如基因表达、蛋白质的定位和动态学等.因 此可以说,绿色荧光蛋白质的发现是联系到 生物科学上的一次技术革命.
人类免疫缺陷病毒的发现——2008年度诺贝尔生理学或医学奖成果简介
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人类免疫缺陷病毒的发现——2008年度诺贝尔生理学或医学
奖成果简介
李敬云
【期刊名称】《科技导报》
【年(卷),期】2008(26)24
【摘要】艾滋病是近20多年来新发生的人类传染病,分离并鉴定导致艾滋病的病原体是艾滋病防治进程中具有里程碑意义的重大成果,为艾滋病致病机理、诊断试剂、药物和疫苗研制奠定了基础。
两位法国科学家吕克·蒙塔尼(Luc Montagnier)和弗朗索瓦丝·巴尔-西诺西(Fran oise Barré-Sinoussi)"因发现人类免疫缺陷病毒"而与德国科学家哈拉尔德·楚尔豪森(Harald zur Hausen)共享2008年度诺贝尔生理学或医学奖。
【总页数】6页(P37-42)
【关键词】艾滋病;人类免疫缺陷病毒;分离和鉴定
【作者】李敬云
【作者单位】军事医学科学院微生物流行病研究所
【正文语种】中文
【中图分类】R512.91
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Evidence on the Impact of Internal Control and Corporate Governance on Audit FeesDavid Hay,1W.Robert Knechel 2and Helen Ling 11University of Auckland,New Zealand 2University of Florida,USAPrevious studies generally suggest that internal control and external auditing can substitute for each other,so that better internal control will be associated with lower audit fees.However,their empirical results do not support this view.In contrast,previous studies of the interaction between corporate governance and external audit services often assume that they are complementary,and that improved governance is associated with higher audit fees,although the evidence about this issue is also mixed.We examine whether the ‘substitution’or ‘complementary controls’views apply.We find that measures of internal auditing,corporate governance,and concentration of ownership are all positively related to audit fees,consistent with the explanation that controls are complementary.The study makes a contribution by assisting regulators in understanding the effects of regulation of corporate governance,and by showing auditors and auditing standard setters that the view that internal controls can substitute for external auditing may not be helpful.We also find that these relationships hold only in a relatively less-regulated environment.Key words:Corporate governance,internal control,audit feesSUMMARYMost previous research that examined relationships among external audits and other sources of control (e.g.,internal auditing)is based on an assumption that decisions about risk reduction reflect the potential substitution of one control for another.In contrast,previous studies ofthe interaction between corporate governance and external audit services often suggest that they are complementary,although the evidence on this issue is also mixed.We present arguments that controls,governance and auditing are complements,not substitutes,and that an increase in one will lead to an increase in the others.Our results are consistent with these propositions.This issue of the relationship between internal control and audit fees is of interest because there are two contrary views expressed in the literature regarding internal control on the one hand andCorrespondence to David Hay,Department of Accounting and Finance,The University of Auckland Business School,Commerce C Building,18Symonds St,Private Bag 92019,Auckland,New Zealand.Email:d.hay@ International Journal of AuditingInt.J.Audit.12:9–24(2008)ISSN 1090-6738©2008The Author(s)Journal compilation ©2008Blackwell Publishing Ltd,9600Garsington Rd,Oxford OX42DQ,UK and Main St.,Malden,MA 01248,USA.corporate governance on the other,namely(1)that better control will lead to lower audit fees and(2) that better governance will lead to more auditing and thus higher audit fees.We use a New Zealand setting in1995and2005. New Zealand in1995was an interesting setting in which there were wide variations in the corporate governance mechanisms used,and we found support for our hypotheses.By contrast,in the more recent period,stock exchange listing requirements allow little variation in corporate governance arrangements so there are few differences among companies,and as a result the associations between control mechanisms and auditing can no longer be observed.1.PRIOR RESEARCH AND HYPOTHESISDEVELOPMENTPrior researchSeveral prior internal control studies have argued that better internal control will allow reduced external audit work,i.e.,control mechanisms in an organization can be substituted one for another(e.g.,Simunic,1980,1984;Wallace,1984). Furthermore,a basic tenet of auditing is that better internal control reduces the need for substantive audit work by external auditors.Simunic(1980, 1984)argued that auditees can substitute internal control for external auditing if there is monopoly pricing,or substitute external auditing for internal control when knowledge spillovers reduce the cost of external auditing.Since the quality of internal control is not usually observable to researchers, several studies have used internal auditing as a proxy for internal control.Wallace(1984)reported that the relationship between internal audit expenditures and audit fee was negative in a study of32large US companies.However,other studies have not found this predicted result.Anderson and Zéghal(1994)found a significant positive relationship between the ratio of the auditees’internal audit costs to total assets and audit fees for large auditees(and no relationship for small auditees).Anderson and Zéghal(1994)suggest that there are certain firm characteristics which are not captured by size and complexity measures that result in high demand for both internal auditing and external auditing.Gerrard et al.(1994)suggest that internal auditing will have little effect,and they find no significant relationship.Gist(1995)found no relationship between internal audit payroll and external audit fees;Johnson et al.(1995)found no relationship between assistance provided by the internal audit function and external audit fees;and Walker and Casterella(2000)found a positive relationship between external audit fees and the presence of an internal audit department.Other studies have found that the expected reduction in the quantity of substantive audit work does not occur when auditors are able to rely on internal control(O’Keefe et al.,1994;Hackenbrack& Knechel,1997;Mock&Wright,1999).An exception occurs when the contribution of the internal auditors to the external audit is the issue examined (rather than the existence or extent of the internal audit).Felix et al.(2001)suggest that internal audit’s contribution to external audit work will reduce audit fees,and they find a significant negative relation.Goodwin-Stewart and Kent(2006)predict that audit fees will be positively related to the use of an internal audit function on the basis of the previous research and because‘firms that are more committed to strong corporate governance are likely to engage in greater levels of internal auditing as well as being prepared to pay for a higher quality external audit’.They find a positive relation.In contrast to the substitution view applied to internal control,the literature usually argues that the relationship between external auditing and corporate governance mechanisms such as outside directors and audit committees is complementary. Directors have an investment in reputation capital (Fama,1980),are concerned about possible liability (Eichenseher&Shields,1985)and do not themselves pay for improved internal control or external auditing(Carcello et al.,2002).As a result independent directors are expected to demand more auditing and better governance to protect themselves from damage to reputation or personal liability arising from financial report misstatements.Research results have generally been consistent with this view.Eichenseher and Shields(1985)and Pincus et al.(1989)found that companies switching to Big8auditors were more likely to voluntarily form an audit committee. Collier and Gregory(1996)found some support for higher audit fees when companies in the UK had an audit committee,although Goddard and Masters (2000)did not find this result in a later period. O’Sullivan(2000)found that audit fees were positively associated with the percentage of equity owned by executive directors.In the US,Carcello et al.(2002)found that board of director10 D.Hay et al.Int.J.Audit.12:9–24(2008)©2008The Author(s)Journal compilation©Blackwell Publishing Ltd.2008independence,diligence,and expertise were associated with higher audit fees,and Abbott et al. (2003)found that audit committee independence and financial expertise were associated with higher audit fees.Knechel and Willekens(2006)argue that this occurs because‘external auditing will increase in situations where there are multiple stakeholders with individual risk profiles who can shift some of the cost of monitoring to other stakeholders’–that is,that the external directors will demand additional assurance that helps to protect their reputation,especially when the cost is borne by the shareholders,not the directors themselves. Another mechanism available for corporate governance includes the existence of a major shareholder(Shleifer&Vishny,1997).Jensen (1993)describes active investors who hold large investments in a company and participate in its strategic direction as important to good governance and effective internal control.The existence of such a major shareholder may also lead to further demand for increased external auditing,both as a means for the major investor to monitor its investment,and for other shareholders to protect themselves from the major shareholder. Hypothesis developmentThe substitution view,that more of one source of control leads to less of another,and so there will be a negative relationship between control or governance and external audit,is initially appealing.However,this relationship is not what is usually found in previous research,and positive relationships are more commonly found.It does not take account of the separate interests of individual stakeholders,as discussed above,nor of the circumstance that greater need for controls is usually met by investing in a number of forms of control,not one control to the exclusion of another. The substitution view implies that alternative sources of control will have a negative relationship with external auditing.This viewpoint is implicitly based on a scenario comprising a single decision-maker minimizing risk to the entire system and having the ability to control all relevant decisions.In that case,the single decision-maker can indeed adjust the portfolio of control mechanisms,and if one becomes stronger,then another can be reduced in strength.In contrast,the perspective in the previous corporate governance research suggests there may be a complementary relationship among controls due to the multiple stakeholders in the process and the externalities of costs and benefits of their individual decisions.For instance,a company whose stakeholders wish to improve its control and governance might start by appointing higher-quality independent directors.While these directors will help to look after the interests of other stakeholders,they also have an interest in protecting their own reputations,and therefore have reason to demand better external auditing, more use of audit committees,and better internal audit functions.1In addition,it seems unreasonable that a company that is in need of greater controls would achieve this by utilizing just one control dimension–it is more likely to make a broader investment in a range of mechanisms for control. These arguments show that it is quite reasonable to suggest that controls could be complementary,and that they are not necessarily substitutes for each other.If the substitution view holds,controls can be offset against each other and there will be negative relationships between control mechanisms;if control mechanisms are complementary,the relationship will be positive.On the basis of the balance of arguments presented in previous studies,and the empirical results of those studies, positive relationships are predicted in our study. Internal controlIf a company’s control and governance decisions were made by a single stakeholder minimizing the total costs of control and audit,then internal auditing and external auditing could be perceived as substitutes.However,there are usually several stakeholders involved.The direct decision about how much to invest in internal auditing generally resides with management,while outside directors and audit committee members may be able to exert some influence over implementing internal auditing.Consequently,directors and audit committee members may choose to increase investment in both internal and external auditing, in order to protect their reputations(Knechel& Willekens,2006),or because they see a need to invest in all forms of control(Goodwin-Stewart& Kent,2006),or because of some other firm characteristic which we cannot observe(Anderson &Zéghal,1994).If the personal risks and agency costs of managers or directors are reduced by higher internal and external auditing,but some of the costs are borne by the company as a whole andEvidence on the Impact of Internal Control and Corporate Governance on Audit Fees11Int.J.Audit.12:9–24(2008)©2008The Author(s)Journal compilation©Blackwell Publishing Ltd.2008so passed on to other stakeholders(such as shareholders),we could expect to see a positive relationship between internal and external auditing (Knechel et al.,2007).Therefore,our first hypothesis is based on the argument that internal auditing and external auditing are complements rather than substitutes:H1:The greater the extent of internal auditing, the higher will be the demand for external auditing services.Corporate governanceOrganizations are also subject to external forms of control and oversight,many of which are considered to be part of the overall control environment of the organization.Three forms of governance and control are of interest in this study:involvement by major shareholders,outside directors and audit committees.A major shareholder that is actively involved in operations and decision-making may have such a broad span of control over activities and internal control that the need for external auditing may be reduced.On the other hand,a major outside shareholder may use this influence to increase external auditing to compensate for a lack of control over other internal decisions.An alternative explanation that would also support an increase of external auditing associated with a major shareholder is that minority shareholders demand increased external assurance as a balance against the power of the major shareholder.Different types of major shareholders may also have differing effects–for example multinational corporations based in another country will not have the same effect on corporate governance as active investors based in the same country.These arguments indicate that the existence of a dominant shareholder could lead to an increased demand for external auditing,leading to our second hypothesis:H2:The existence of major shareholders will be associated with greater demand for external auditing services.Corporate governance is typically implemented through the board of directors.Outside directors, being independent of management,bear the primary responsibility for monitoring management’s performance.As a component of the control environment,the board’s responsibilities include monitoring the quality of financial reporting and developing controls related to key strategic risks.In the substitution view,a large number of outside directors,and the existence of an audit committee,may reduce the need for external auditing because of improved oversight by the board itself.Alternatively,board members’professional and legal responsibilities,combined with their lack of direct interaction with the internal environment,may lead to an increase in the demand for external auditing as they will wish to protect their reputations.Carcello et al.(2002) found a positive relationship between outside directors and fees paid to auditors in the US,while Collier and Gregory(1996)and O’Sullivan(2000) found similar results in the UK.2This discussion leads to our third and fourth hypotheses:H3:The existence of an audit committee will be associated with greater demand for external auditing services.H4:Greater oversight by outside directors will be associated with greater demand for external auditing services.2.RESEARCH METHODThe empirical portion of this study seeks to determine how alternative control mechanisms interact with audit fees.In order to control for the riskiness of a specific organization and to establish a baseline model for audit fees based on prior literature,we use seven variables to reflect factors/ risks that have been shown in prior research to be related to audit fees:31.Size(LNASSETS):Larger companies arelikely to face more and varied risks from their environment.Furthermore,it is well documented that audit fees are significantly associated with the size of an organization(e.g., see Bell et al.,1994among others).We measure size as the natural log of total assets.plexity(SQSUB):Organizations that aremore diverse and widespread can also face incrementally more risks,and experience higher fees.We measure complexity as the square root of the number of subsidiaries, consistent with many previous studies.3.Inherent Risk(INVREC):Certain assets areperceived as being riskier to audit,resulting in higher audit fees.Prior research has noteda relationship between increased levels ofreceivables and inventory and audit failures12 D.Hay et al.Int.J.Audit.12:9–24(2008)©2008The Author(s)Journal compilation©Blackwell Publishing Ltd.2008(Stice,1991).Furthermore,Simunic(1980) and Newton and Ashton(1989)suggest that inventory and receivables are more difficult to audit than other accounts.We use the ratio of inventory plus receivables to total assets as a measure of inherent risk.4.Financial condition(CASCLS):Organizationsthat are suffering from fiscal distress and/or are unprofitable are often perceived as being riskier and more challenging to audit(Simunic, 1980).We use the current ratio as a measure of potential fiscal distress.5.Big audit firm premium(BIG):The Big Six,(Five or Four)audit firms are regarded as having higher audit quality,and are expected to be able to earn higher audit fees as a result.We use a dummy variable to indicate a Big firm audit.6.Foreign assets(FOR):Foreign assets are anindicator of a more complex company,and a more complex audit,and are expected to be associated with higher fees(Simunic,1980).We use the proportion of overseas assets to total assets.7.A recent change of audit firm(SWITCH):Client companies that have changed auditor in the last three years might have lower audit fees, if lowballing takes place.We use a dummy variable to indicate whether the company switched auditors in the current year or the two previous years.To test our first hypothesis(H1),we examine the relationship of the existence of an internal audit (IA)department to audit fees.We define IA as the number of internal audit professionals that the organization has listed in the Member’s Handbook published by the Institute of Internal Auditors(IIA) in New Zealand4(where available)or the existence of an internal audit department(in a later period when data about the number of audit professionals is not available).A limitation of the proposed measurement is that it may not sufficiently capture the effect of internal auditing since not all practising internal auditors are members of IIA.However,it may overcome some problems encountered by previous studies such as:(1) the inclusion of clerical work;(2)different organizations may have different definitions for internal audit costs;and(3)voluntary disclosure through questionnaires generally results in low response rates.To test the second,third and fourth hypotheses (H2,H3and H4),we examine three variables that reflect the hypothesized relationships among forms of corporate governance and audit fees:1.Existence of an audit committee(COM):Audit committees are charged with exercising oversight regarding an organization’s financial reporting and internal control and provide a conduit for both internal and external auditors to report important findings to stakeholders.We set COM equal to1if a company has an audit committee,0otherwise.2.Number of outside directors(OUT):Directorswho are independent of management can exercise significant oversight of a company but require independent information about the organization’s operations and controls,which is usually obtained via the external auditor.We measure OUT as the number of directors who are independent of management.3.Existence of a major outside shareholder(MAJ):A major shareholder often has the ability to directly intervene in the operations and controls of an organization and impose an audit requirement on the organization.We define MAJ to be1if there is a single shareholder who controls20%or more of the company’s stock,0otherwise.Under either the substitution or complementary controls views,the relationship among control mechanisms may be endogenous–better controls might lead to more(or less)demand for auditing, but equally,better auditing might lead the organization to increase(or reduce)other forms of control.To control for this endogeneity we use three categories of variables in our study:1.Predetermined explanatory variables to controlfor factors known to affect audit fees: LNASSETS,SQSUB,INVREC,CASCLS,BIG, FOR and SWITCH,as previously discussed.2.V ariables for control or governance variablesthat are considered to be predetermined as part of the structure of the organization and are unaffected by internal controls and auditing, namely major shareholdings(MAJ)and external directors(OUT).53.V ariables for control or governance that areendogenous,namely internal audit(IA)and audit committee(COM).There is expected to be a two-way relationship between external auditing and control.It has been argued in many‘substitution view’papers(e.g.,Simunic 1980,1984)that an organization can choose to trade off more or less internal auditing against external auditing;and it has also been arguedEvidence on the Impact of Internal Control and Corporate Governance on Audit Fees13Int.J.Audit.12:9–24(2008)©2008The Author(s)Journal compilation©Blackwell Publishing Ltd.2008that external auditing may have an impact on voluntarily forming an audit committee (Eichenseher&Shields,1985;Pincus et al., 1989).Alternatively,using the complementary controls arguments presented earlier,the relationship between control and auditing is expected to be endogenous,but complementary.Increased external auditing could lead to increases in control and governance,for example if auditors identify weaknesses in internal controls or recommend formation of an audit committee.In these circumstances,use of OLS regression could lead to biased and inconsistent results.We therefore use two-stage least squares(2SLS)to estimate the relationship between audit fees and the dependent variables.This procedure can be used when variables in the model are reciprocally related and thus not independent of the error term (Berry,1984).In order to carry out this regression,it was necessary to employ instrumental variables which are correlated with the variables for control mechanisms.The instrumental variables were used to obtain revised estimates of the endogenous variables that are unrelated to the residuals in the model.They do not form part of the audit fee models reported.The appropriate set of instrumental variables to use has not been explored in the previous literature.We considered that the following instrumental variables were reasonable in the circumstances:•Debt to assets,as lenders could exert some influence over control and governance mechanisms(DEBTTOA).While debt is sometimes used in audit fee models as a measure of risk,it is often not significant(Hay et al.,2006)and appears to be more directly related to governance.•Regulated industry(UTILITY),a dummy variable for whether the company is in the utility industry,as the existence of regulators is expected to increase the demand for control.(Financial services companies are also considered to be regulated,but were excluded from our study as they differ from other companies in too many other ways.)•Following by share market analysts(ANFOLL), as higher profile in the market is likely to induce directors to demand more control mechanisms in order to protect their reputation.•The number of chartered accountants employed by the company(ACCOUNT)as professionalaccountants is likely to influence implementation of control mechanisms.The instrumental variables are variables that are related to the variables for control and governance but that do not have a reciprocal relationship with them.In its general form,the2SLS model we use can be expressed as:LNFEE a a ENDOGENOUSa PREDETERMINEDTESTa SIZEETC=+()+()+()+1234e(1)where ENDOGENOUS represents the predicted values of the endogenous variables IA and COM derived from this equation:ENDOGENOUS b b INSTRUMENTALb PREDETERMINEDTESTb SIZ=+()+()+1234E ETC u()+(2)and PREDETERMINEDTEST is the set of predetermined test variables for internal control and governance(MAJ and OUT),SIZEETC is the set of predetermined control variables for other factors that affect the audit(LNASSETS,SQSUB, INVREC,CASCLS,FOR,BIG,SWITCH)and INSTRUMENTAL is the set of instrumental variables.IA and COM are treated as endogenous as there is a two-way relationship with other forms of control and auditing whereby these variables might change depending on audit fees or MAJ and OUT.On the other hand,it seems unlikely that changes in audit fees or IA and COM could change the ownership of the company(MAJ)or the number of outside directors(OUT).We examine this issue using data from1995, when little public attention was paid to corporate governance and companies had considerable freedom to make arrangements that suited them, and again with data from2005,after there was considerable attention to corporate governance and changes to listing regulations requiring outside directors and an audit committee.There were142 companies listed on the New Zealand Stock Exchange in1994/95,as shown in The New Zealand Company Register1994/95.Thirteen companies are excluded from the final sample as two companies were delisted during1995,five companies had missing data,one company was involved in a merger and four companies were financial institutions.The final sample consists of130 companies.Data relating to audit fees,total assets, number of segments,accounts receivable, inventories,return on assets and the existence of14 D.Hay et al.Int.J.Audit.12:9–24(2008)©2008The Author(s)Journal compilation©Blackwell Publishing Ltd.2008an audit committee were obtained from the annual reports of the companies.The number of internal auditors employed by each company who were members of the Institute of Internal Auditors was obtained from The Members Handbook1994/95 published by The Institute of Internal Auditors of New Zealand.The number of outside directors and the existence of a major overseas shareholder were collected from The New Zealand Company Register 1995.According to the New Zealand Company Register2004/2005,there were130companies listed on the New Zealand Stock Exchange in 2004/2005.We excluded5financial institutions and companies with missing data We obtained83 observations in the final sample.3.RESULTSDescriptive resultsDescriptive statistics are presented in Table1.The descriptive statistics show that the sample covers a wide range of companies,some very small,some relatively large.The companies also range from simple,with no subsidiaries,to more complex.The mean is10subsidiaries in1995(and10in2005). On average,the companies in our sample had inventory and receivables comprising27%of assets in1995(25%in2005).Most of the companies(86%) were audited by Big5firms in1995(88%in2005). The number of internal auditors is small,with the average company having less than one internal auditor listed in the IIA’s membership guide in 1995(and60%having an internal audit function in 2005).This is to be expected in New Zealand,where internal auditing has been established relatively recently and it is not as widespread as in other countries such as the US.Corporate governance changed considerably between1995and2005as a result of changes to listing requirements.6Audit committees were voluntary in1995,and at that time only45%of the companies had such committees.By2005,audit committees were a requirement of the New Zealand Stock Exchange listing requirements,and95%of companies now have them.There was no regulation requiring outside directors in1995,but this too had become a listing requirement by2005.The minimum number of outside directors increased as a result: companies had from zero to11outside directors in 1995and from two to11in2005.The average stayed about the same,at approximately five outside directors in both1995and2005.The proportion of companies with a major shareholder is high. Listed companies(87%)frequently have a major shareholder,and Shleifer and Vishny(1997) observe that this is the norm for countries other than the US and the UK.This had declined to47% in2005,probably due to changes in takeover regulations which from2001require an acquirer of more than20%of a company’s shares to make an offer for the remainder(King,2002).Table2reports the correlation matrix for the variables in the regression model.Audit fee is significantly related to all of the explanatory variables with two exceptions,SWITCH and MAJSH(in both periods).Internal auditing is significantly related to the corporate governance variables COM and OUT(both periods),and to the size and complexity of the company represented by LNASSETS and SQSUB(in1995only).COM and OUT are also significantly correlated in1995. In2005,COM is no longer significantly related, presumably because almost all companies have an audit committee and so little variation occurs. The remaining corporate governance variable MAJ is not related to most of the other governance variables(except negatively to COM in1995only), and not related to any other variable in the study. This result suggests that MAJ is not directly related by itself to governance,control or audit,but it could nevertheless be related in the multiple regression models when other variables are controlled for. There are some indications of multicollinearity–for example,larger companies also have more subsidiaries and are more likely to have Big5 auditors–and we report tests of this issue later in the paper under the heading‘Supplementary Analysis’.Primary tests of hypothesesTable3presents the first part of our regression results,using OLS models where only the predetermined control and governance variables MAJ and OUT and the other explanatory variables are included.All the OLS models are statistically significant at p<0.0001with adjusted R2s higher than0.7.Most of the variables representing size, complexity,risk and factors we control for have significant coefficients in the predicted direction. The exceptions are CASCLS in some models,BIG and SWITCH.Previous New Zealand research by Johnson et al.(1995)also found large firm premiums applied only to some categories ofEvidence on the Impact of Internal Control and Corporate Governance on Audit Fees15Int.J.Audit.12:9–24(2008)©2008The Author(s)Journal compilation©Blackwell Publishing Ltd.2008。