ering and ApplicationsComputer Engineering and ApplicationsCo

椎-基动脉供血不足(vertebrobasifarinsufficiency,V BI)是指椎-基动脉由于各种原因引起的形态、机能的异常,产生相应灌流区供血不足,引起眩晕、头晕、复视、共济失调、偏瘫、视力及视野改变等临床症状,而眩晕、头晕为其主要症状。我们采用盐酸倍司汀联用参麦注射液治疗椎-基动     

Golimumab and immunogenicity? 2010 and beyond

Immunogenicity is a frequent adverse event observed with biological agents' therapy. Challenges of management in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis treated with golimumab, an anti-TNF-alpha blocker, include limited generation of antibodies like anti-nuclear, anti-golimumab, and anti-double stranded DNA antibodies. We conducted here a meta-analysis study in order to evaluate and compare the newly generated antibody levels after golimumab therapy. The examination of original clinical trials revealed that their levels were neither higher nor significant. Moreover, no evident associations between the induced-antibodies and lupus-like syndromes and/or infusion site reaction were reported. The reduced patients cohort and the absence of systematic newly generated antibodies follow-up might be implicated in the difficulty to evaluate their risk in delaying diseases therapy, and/or predicting for their worse prognosis. Hence, further studies are required to ascertain the real impact of the induced antibodies after golimumab's therapy.     

Biomolecular structure and dynamics—experiment and theory

Biological macromolecules are complex systems and in order to understand their inner workings we need information from many sources. In this review we present some of the underlying principles for current methods of choice for structural and dynamical studies of biological macromolecules. Interplay between these disciplines—X-ray diffraction, nuclear magnetic resonance spectroscopy and theoretical calculations—has been extremely fruitful and our knowledge in this area of bioscience is rapidly increasing due to this cross-fertilization. While structural aspects of proteins are increasingly well studied and understood we do however still need to put more emphasis on their dynamical properties.     

Toxicology and Genetic Susceptibility of Drugs and Pollutant

S21Possibleinvolvementofhereditaryfactors intheriskmodulationofarseniasisintwoethnic clansexposedtoindoorcombustionofhigharse niccoal LINGuo Fang1,DUHui2,CHENJi Gang3,LU Hong Chao2,GUOWei Chao1,ZHANGXin Jiang4,SHENJian Hua1(1.ShanghaiInstituteforBiologicalSciences,Institute ofPlantPhysiologyandEcology,ChineseAcademyof Sciences,Shanghai200032,China;2.Prefecture CenterforDiseasePreventionandControl,Guiyang562400,China;3.MunicipalCenterforDiseasePre ventionandControl,Shang…     

Immunotoxicity and Neurotoxicity of Pharmaceuticals and Environmental Toxic Substances

W31ICHS8Guideline:immunotoxicitystud iesforhumanpharmaceuticals JSAWADA(NationalInstituteofHealthSciences,Tokyo,Japan)Toxicitytotheimmunesystemencompassessup pressionorenhancementoftheimmuneresponse.Sup pressionoftheimmuneresponsecanleadtodecreased hostresistancetoinfectiousagentsortumorcells.En hancingtheimmuneresponsecanexaggerateautoim munediseasesorhypersensitivity.Therfore,evaluationofpotentialadverseeffectsofhumanpharmaceuticals ontheimmunesystemshouldbeincorporatedinto standardd…     

The ethics and practice of authorship and peer review

Ｏｎｃｅａｃｌｉｎｉｃａｌｔｒｉａｌｉｓｃｏｍｐｌｅｔｅｄ，ｉｔｍｕｓｔｂｅｐｕｂｌｉｓｈｅｄｉｎｏｒｄｅｒｆｏｒｏｔｈｅｒｓｔｏｋｎｏｗｏｆｉｔｓｒｅｓｕｌｔｓ．Ｐｒｉｍａｒｙｓｏｕｒｃｅ，ｐｅｒｒｅｖｉｅｗｅｄｍｅｄｉｃａｌｊｏｕｒｎａｌｓａｒ...     

Toxicogenomics and Proteomics

W1:ToxicogenomicsandProteomics W11Differentialgeneexpressionprofilesofacuteandchronicinjuryandrecoveryinratliv ersteatosis fibrosis/cirrhosismodel HeekyoungCHUNG(KST)W12SNPsinCYP450s:apreliminaryphar macogenomicstudyinaChinesepopulation WENSi Yuan1,CHENKun2,XULi1,LIJian2,WANGRui2,WANGSheng Qi1(1.BeijingInstituteofRadiationMedicine,2.Beijing301GeneralHospital,Beijing100039,China)Pharmacogenomicswasestablishedonthefactthat certaingeneticpolymorphismsmaycausesignificantly di…     

Cl~-通道在内皮素-1引起的血管平滑肌细胞增殖中的作用

目的　研究Cl-通道在内皮素 1(endothelin 1,ET 1)引起的血管平滑肌细胞增殖中的作用 ,并探讨其可能的作用机制。方法　通过细胞计数和3H TdR参入实验 ,并结合fura 2 /AM荧光测定胞浆游离Ca2 + 浓度 ([Ca2 + ]i)等技术 ,观察了Cl-通道阻断剂对ET 1引起的 [Ca2 + ]i 变化及血管平滑肌细胞增殖的影响。结果　Cl-通道阻断剂DIDS可呈浓度依赖性地抑制 10nmol·L-1ET 1引起的血管平滑肌细胞增殖 ,其它Cl-通道阻断剂如IAA 94、NPPB、SITS、DPC和速尿均无此作用 ,DIDS也能抑制 10nmol·L-1ET 1引起的内流相 [Ca2 + ]i 升高 ,而对ET 1引起的Ca2 + 释放无影响 ;预先将细胞与 1μmol·L-1nifedipine作用后 ,3μmol·L-1DIDS对 10nmol·L-1ET 1引起的内流相 [Ca2 + ]i 升高及血管平滑肌细胞增殖不再有效 ,将细胞与 10 μmol·L-1SK&F96 36 5预孵后 ,DIDS却能进一步抑制ET 1的上述作用 ;3μmol·L-1DIDS对 30mmol·L-1KCl引起的胞浆[Ca2 + ]i升高无影响。结论　DIDS可通过阻断Cl-通道来抑制ET 1因促发Cl-通道开放经电压依赖性钙通道的Ca2 +内流及细胞增殖 ,DIDS敏感的Cl-通道可能在ET 1促发的Ca2 + 内流及血管平滑肌细胞增殖的调控上都起着重要的作用     

Pharmacological characterization of Ca2+ entry channels in endothelin-1-induced contraction of rat aorta using LOE 908 and SK&F 96365.

We have recently shown that endothelin-1 (ET-1) activates two types of Ca2+-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) and store-operated Ca2+ channel (SOCC). These channels can be pharmacologically discriminated using Ca2+ channel blockers such as SK&F 96365 and LOE 908. Here we characterized Ca2+ entry channels involved in ET-1-induced contractions of rat thoracic aortic rings and increases in the intracellular free Ca2+ concentration ([Ca2+]i) of single smooth muscle cells using these blockers. LOE 908 or a blocker of voltage-operated Ca2+ channel nifedipine had no effect on the contractions and increases in [Ca2+]i induced by thapsigargin or ionomycin, whereas SK&F 96365 abolished them. The contractions and increases in [Ca2+]i induced by ET-1 depended on extracellular Ca2+ but were resistant to nifedipine. The responses to lower concentrations (< or =0.1 nM) of ET-1 were abolished by either SK&F 96365 or LOE 908. The responses to higher concentrations (> or = 1 nM) were abolished by SK&F 96365, but were partially resistant to LOE 908. SK&F 96365 inhibited the LOE 908-resistant contractions induced by higher concentrations of ET-1 with IC50 values similar to those for contractions induced by thapsigargin or ionomycin. These results show that the contractions and increases in [Ca2+]i of rat aortic smooth muscles at lower concentrations of ET-1 involve only one Ca2+ entry channel which is sensitive to SK&F 96365 and LOE 908 (NSCC-2), whereas those at higher concentrations of ET-1 involve another Ca2+ entry channel which is sensitive to SK&F 96365 but resistant to LOE 908 (SOCC) in addition to the former channel.     

Analysis of Ca2+ entry channels in endothelin-1-induced contraction of rat aorta using new blockers

1) We have recently shown that endothelin-1 (ET-1) activates two types of Ca(2+)-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) and store-operated Ca2+ channel (SOCC). These channels can be pharmacologically discriminated using Ca2+ channel blockers such as SK&F 96365 and LOE 908. Here we characterized Ca2+ entry channels involved in ET-1-induced contractions of rat thoracic aortic rings and increases in the intracellular free Ca2+ concentration ([Ca2+]i) of single smooth muscle cells using these blockers. 2) LOE 908 or a blocker of voltage-operated Ca2+ channel nifedipine had no effect on the contractions and increases in [Ca2+]i induced by thapsigargin, whereas SK&F 96365 abolished them. 3) The contractions and increases in [Ca2+]i induced by ET-1 depended on extracellular Ca2+ but were resistant to nifedipine. The responses to lower concentrations (< or = 0.1 nM) of ET-1 were abolished by either SK&F 96365 or LOE 908. The responses to higher concentrations (> or = 1 nM) were abolished by SK&F 96365, but were partially resistant to LOE 908. 4) These results show that the contractions and increases in [Ca2+]i of rat aortic smooth muscles at lower concentrations of ET-1 involve only one Ca2+ entry channel which is sensitive to SK&F 96365 and LOE 908 (NSCC-2), whereas those at higher concentrations of ET-1 involve another Ca2+ entry channel which is sensitive to SK&F 96365 but resistant to LOE 908 (SOCC) in addition to the former channel.     

Cl~-通道阻断剂对5-HT和CPA引起的兔脑椎基底动脉平滑肌细胞Ca~(2+)内流的影响

目的　在培养的兔脑椎基底动脉平滑肌细胞上观察5 HT和CPA诱导的Ca2 + 内流的特性 ,电压依赖性Ca2 + 通道 (VDC)抑制药尼莫地平 ,非电压依赖性Ca2 + 通道抑制药SK&F963 65及Cl-通道阻断剂DIDS、NPPB对两种激动剂引起 [Ca2 + ]i 反应的影响 ,以探讨脑血管平滑肌细胞中 5 HT引起Ca2 + 内流的特性、Cl-通道与Ca2 + 内流的关系。方法　采用生物荧光双波长影像分析系统瞬即测定单细胞胞质[Ca2 + ]i 技术。结果　① 5 HT和CPA均能诱导平滑肌细胞[Ca2 + ]i 呈双相升高 ,并且 5 HT诱导的Ca2 + 释放是环匹阿尼酸 (CPA)敏感Ca2 + 池的一部分 ;②尼莫地平对 5 HT和CPA触发的Ca2 + 内流无明显影响 ,而SK&F963 65可阻止二者触发的Ca2 + 内流 ;③Cl-通道阻断剂DIDS、NPPB呈浓度依赖性抑制Ca2 + 内流 ,在SK&F963 65最大限度抑制Ca2 + 内流后 ,DIDS、NPPB可进一步抑制Ca2 + 内流 ;而Ca2 +内流被DIDS、NPPB分别最大抑制后 ,SK&F963 65也可进一步抑制Ca2 + 内流。结论　 5 HT引起的Ca2 + 内流是经SK&F963 65敏感的非VDC ,其中包含Ca2 + 释放引起的Ca2 + 内流 (CRAC)成分与非CRAC成分 ,并且这两部分Ca2 +内流均与DIDS、NPPB敏感的Cl-通道开放有关     

Ca2+ entry channels involved in contractions of rat aorta induced by endothelin-1, noradrenaline,and vasopressin

Endothelin-1 (ET-1) has been shown to activate three types of Ca2+ channel, namely two Ca2+-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) and a store-operated Ca2+ channel (SOCC), and that these channels can be discriminated by Ca2+ channel blockers such as LOE 908 (a blocker of NSCC-1 and NSCC-2) and SK&F 96365 (a blocker of NSCC-2 and SOCC). This study pharmacologically compared Ca2+ entry channels involved in contractions of rat thoracic aorta without endothelium induced by ET-1, noradrenaline (NA), or arginine-vasopressin (AVP). These agonists-induced contractions of aortic rings without endothelium and increases in the intracellular free Ca2+ concentration ([Ca2+]i) of cultured aortic smooth muscle cells were abolished by removal of extracellular Ca2+. A blocker of L-type voltage-operated Ca2+ channel (VOCC), nifedipine had no effect on the responses to ET-1, but it suppressed the responses to NA and AVP to 70% and 65% of control responses, respectively. LOE 908 partially suppressed the nifedipine-resistant responses to ET-1 and AVP, but not those to NA. SK&F 96365 also partially suppressed the nifedipine-resistant responses to ET-1 and AVP, whereas it abolished the responses to NA. LOE 908 in combination with SK&F 96365 abolished the nifedipine-resistant responses to either of the agonists. These results show that the contraction of rat aorta involves different Ca2+ entry channel depending on agonists: (a) NSCC-1, NSCC-2, and SOCC for ET-1; (b) VOCC and SOCC for NA; and (c) VOCC, NSCC-1, NSCC-2, and SOCC for AVP.     

Ca~(2+)运动对α_1-肾上腺素受体引起内源性ClC-3氯通道表达的作用

目的　研究Ca2 +运动对α1 肾上腺素受体引起ClC 3氯通道表达的作用。方法　在A10细胞上 ,用RT PCR和Westernblot检测ClC 3mRNA和蛋白质表达情况。结果　苯肾上腺素 ( 10 μmol·L-1)和thapsigargin( 0 1μmol·L-1)可促进ClC 3mRNA和蛋白质的表达 ;SK&F963 65 ( 10 μmol·L-1)和genistein( 10 μmol·L-1)可抑制苯肾上腺素引起的ClC 3的表达 ,nifedipine( 10 μmol·L-1)无此作用。结论　在A10细胞上 ,通过钙池操纵性Ca2 +通道 (SOCC)的Ca2 +内流参与了α1 肾上腺素受体引起的内源性ClC 3氯通道的表达 ,而通过电压依赖性Ca2 +通道 (VDCC)的Ca2 +内流可能与此无关。蛋白酪氨酸激酶参与了ClC 3氯通道的表达     

Ca2+ entry channels in rat thoracic aortic smooth muscle cells activated by endothelin-1.

The contraction of the rat aorta induced by endothelin-1 (ET-1) requires entry of extracellular Ca2+, but involvement of voltage-operated Ca2+ channel is minor. Using whole-cell recordings of patch-clamp and monitoring of the intracellular free Ca2+ concentration ([Ca2+]i), we characterized Ca2+ entry channels in A7r5 cells activated by ET-1. ET-1 activates three types of voltage-independent Ca2+ entry channels: two types of Ca2+-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) and a store-operated Ca2+ channel (SOCC). Furthermore, it was found that these channels can be pharmacologically discriminated using Ca2+ channel blockers such as SK&F 96365 and LOE 908. NSCC-1 is resistant to SK&F 96365, but sensitive to LOE 908, whereas NSCC-2 is sensitive to both SK&F 96365 and LOE 908. SOCC is sensitive to SK&F 96365, but resistant to LOE 908. Using these channel blockers, we analyzed Ca2+ entry channels involved in the ET-1-induced contractions of rat thoracic aorta and increases in [Ca2+]i of single smooth muscle cells. The responses to lower concentrations of ET-1 (< or = 0.1 nM) were abolished by either SK&F 96365 or LOE 908 alone. In contrast, the responses to higher concentrations of ET-1 (> or = 1 nM) were suppressed by SK&F 96365 or LOE 908 to about 10% and 35% of controls, respectively, and abolished by combined treatment with SK&F 96365 and LOE 908. These results show that the responses of rat aorta to lower concentrations of ET-1 involve only one Ca2+ channel that is sensitive to SK&F 96365 and LOE 908 (NSCC-2), whereas those to higher concentrations of ET-1 involve NSCC-1, NSCC-2 and SOCC, contributing 10%, 55% and 35%, respectively, to total Ca2+ entry.     

Inhibition by SK&F96365 of NO-mediated relaxation induced by Ca2(+) -ATPase inhibitors in rat thoracic aorta.

1. We investigated the effect of SK&F96365, a putative inhibitor of receptor-operated Ca2+ entry, on the endothelium-dependent, NO-mediated relaxation and cyclic GMP formation induced by Ca2(+)-ATPase inhibitors in rat thoracic aorta. 2. SK&F96365 inhibited cyclopiazonic acid or thapsigargin-induced relaxation and cyclic GMP formation mediated by a constitutive NO synthase, which is known to be activated by the Ca2+ that enters into the endothelial cells via plasma membrane Ca2+ channels subsequent to depletion of stored Ca2+ by Ca2(+)-ATPase inhibitors. 3. SK&F96365 also inhibited relaxation and cyclic GMP formation induced by acetylcholine, without affecting those induced by nitroprusside and A23187. 4. Ni2+ attenuated relaxation and cyclic GMP formation induced by cyclopiazonic acid and acetylcholine. 5. In contrast, the voltage-dependent Ca2+ channel blocker, nifedipine, did not affect the relaxation caused by Ca2(+)-ATPase inhibitors. 6. These results suggest that endothelium-dependent, NO-mediated relaxation of the arteries induced by Ca2(+)-ATPase inhibitors is triggered by the Ca2+ that enters into endothelial cells via receptor-operated channels (SK&F96365-sensitive channels) subsequent to depletion of stored Ca2+ as a result of inhibition of the Ca2(+)-ATPase (Ca2+ pump) of the stores.     

Characterization of Ca2+ channels involved in endothelin-1-induced contraction of rabbit basilar artery

This study attempted to characterize Ca2+ channels involved in endothelin-1-induced contraction of rabbit basilar artery using whole-cell patch-clamp and measurement of intracellular free Ca2+ concentration. Endothelin-1 activates two types of Ca2+-permeable nonselective cation channels (NSCC-1 and NSCC-2) and a store-operated Ca2+ channel (SOCC) in addition to the voltage-operated Ca2+ channel (VOCC). These channels can be discriminated using Ca2+ channel blockers, SK&F 96365 and LOE 908. Tension study was conducted to clarify the Ca2+ channels involved in endothelin-1-induced contraction of basilar artery. Endothelin-1-induced basilar artery contraction is fully dependent on extracellular Ca2+ influx. Based on sensitivity to nifedipine, an L-type VOCC blocker, VOCCs have a minor role in endothelin-1-induced contraction. Both LOE 908 and SK&F 96365 inhibit endothelin-1-induced contraction in a concentration-dependent manner, and their combination abolished it. The median inhibitory concentrations of these blockers for endothelin-1-induced contraction correlated well with those of the endothelin-1-induced [Ca2+]i responses. Thus, the inhibitory action of these blockers on endothelin-1-induced contraction may be mediated by blockade of NSCC-1, NSCC-2, and the SOCC. Extracellular Ca2+ influx through NSCC-1, NSCC-2, and SOCC may be essential for endothelin-1-induced basilar artery contraction.     

Potentiation of stretch-induced tone in the rabbit facial vein by an isoquinoline derivative, LOE 908

The rabbit facial vein exhibits extracellular Ca2+- and temperature-dependent spontaneous myogenic tone in response to stretch. The present study aimed to elucidate pharmacological characteristics of Ca2+ entry mechanisms responsible for the stretch-induced tension development of the rabbit facial vein. Ca2+- and temperature-sensitive vascular tone in response to stretch was refractory to L-type Ca2+ channel blockers such as nifedipine and diltiazem but was abolished by papaverine or SK&F 96365 which blocks both receptor- and store-operated Ca2+ channels. Interestingly, LOE 908, another type of voltage-independent Ca2+-permeable channel blocker, showed augmentation of the stretch-induced vascular tone instead of inhibition. Potentiation by LOE 908 of stretch-induced vascular tone was also extracellular Ca2+-dependent and counteracted by SK&F 96365. Membrane stretch-activated Ca2+ channels in the rabbit facial vein smooth muscle cells may have a unique characteristic that their opening is stimulated by LOE 908 and thus is distinguishable from other voltage-independent Ca2+-permeable channels.