心肌梗死大鼠非梗死区心肌细胞的凋亡及机制探讨

目的:探讨心肌梗死后不同阶段非梗死区心肌细胞凋亡的变化及其发生机制。方法:雌性Wistar大鼠,通过结扎左冠状动脉前降支制备心肌梗死模型。术后24h、1周、2周及4周随机从各组中各取10～12只大鼠,行病理组织学检查及非梗死区心肌组织的TNF-α、caspase-3、AngⅡ、凋亡细胞检测、透射电镜、Bcl-2及p53的mRNA检测。结果:大鼠梗死范围为24%～33%。术后1～4周,可见心梗组大鼠心肌组织凋亡细胞增多,凋亡细胞指数升高;AngⅡ水平逐渐升高;心肌间质可见明显TNF-α表达;p53mRNA上升,Bcl-2mRNA下降。术后2～4周,caspase-3阳性染色产物的心肌细胞数量增多。结论:(1)大鼠心梗2周后非梗死区心肌发生细胞凋亡改变。(2)局部肾素-血管紧张素-醛固酮系统(RAAS)激活、TNF-α上调及caspase-3活化可能与非梗死区细胞凋亡有关。(3)非梗死区细胞凋亡与凋亡基因p53及Bcl-2相关。     

红花黄色素对实验性肾间质纤维化大鼠肾小管上皮细胞凋亡的影响

目的观察红花黄色素注射液对肾间质纤维化大鼠肾小管上皮细胞凋亡的的影响,探讨其肾脏保护机制。方法45只雄性SD大鼠,随机分为假手术组（A组）、单侧输尿管梗阻（unilateral ureteral obstruction;UUO）组（B组）、UUO联合红花黄色素治疗组（C组）,各15只。C组红花黄色素5mg/（kg·d）,造模术前1d开始腹腔注射给药,各组术后10d处死大鼠,处死后取术侧肾组织行HE、Masson染色,TUNEL法检测肾小管上皮细胞凋亡。结果B组、C组可见明显肾间质纤维化的病理改变,可检测到凋亡细胞。C组与B组相比,肾间质纤维化病变程度较轻,凋亡细胞明显减少（P〈0.01）。结论注射用红花黄色素对大鼠肾间质纤维化有保护作用,这种作用可能通过抑制肾小管细胞过度凋亡实现。     

康脑液1号对大鼠脑缺血再灌注病理学改变及神经细胞凋亡的影响

目的观察康脑液1号对SD大鼠脑缺血再灌注后组织病理学改变及神经细胞凋亡的影响,探讨其对脑缺血再灌注保护作用的可能机制。方法采用栓线法复制SD大鼠大脑中动脉梗死模型（MCAO）,分别于缺血2h后再灌注6、24、72h。将150只大鼠随机分为5组,每组30只,假手术组、模型（缺血再灌注）组、盐酸法舒地尔组、康脑液1号A组、康脑液1号B组。观察康脑液1号对大鼠脑缺血再灌注神经功能、脑梗死面积和病理形态学的影响。采用TUNEL凋亡法检测分析脑缺血半暗带和灶中心区凋亡阳性细胞的数目。结果模型组与假手术组比较,凋亡细胞阳性数目增多;康脑液1号可不同程度地降低实验性脑缺血大鼠的神经功能评分、脑梗死面积及减轻脑组织病理形态改变（P〈0.05）;康脑液1号2组大鼠梗死灶面积减小,脑组织缺血半暗带凋亡细胞阳性数目减少,而梗死灶中心凋亡细胞阳性数目增多;康脑液1号A组与康脑液1号B组比较差异无统计学意义（P〉0.05）。结论康脑液1号可能通过调节脑缺血再灌注后神经细胞凋亡而促进脑损伤修复及重塑,从而发挥脑保护作用。     

NF-KBP65在心肌梗死大鼠心肌细胞凋亡中的表达及罗格列酮对其的影响

目的 观察罗格列酮对心肌梗死后大鼠心肌细胞凋亡过程中NF-KBP65表达的影响。方法45只雄性wistar大鼠随机分为假手术组（B组,n=15）和心肌梗死组（n=30）,通过结扎左冠状动脉前降支（LAD）制作急性心肌梗死模型。模型制作成功24h后,心肌梗死组再随机分为心肌梗死对照组（A组,n=15）和罗格列酮干预组（C组,n=15）。罗格列酮干预组每日给以罗格列酮灌胃（4mg／kg）,假手术组和心肌梗死对照组每日给以等量生理盐水灌胃,持续8周。利用免疫组化法检测非梗死区NF—KBP65（nuclear factor—KBP65）的含量。结果给药8周后,A组非梗死区心肌中NF—KBP65的表达,心肌细胞凋亡率,左心重量指数与B、C组相比显著升高,差异有统计学意义（P〈0．05）;C组与B组相比,非梗死区心肌中NF—KBP65的表达,心肌细胞凋亡率,左心室重量指数显著升高,差异有统计学意义（P〈0．05）。结论罗格列酮可能通过抑制NF—KBP65的表达来改善大鼠心肌梗死后心肌细胞凋亡。     

康脑液1号对大鼠脑缺血再灌注细胞凋亡及GFAP表达的影响

目的观察康脑液1号对SD大鼠脑缺血再灌注细胞凋亡及胶质纤维酸性蛋白（GFAP）表达的影响,探讨其对脑缺血再灌注保护作用的可能机制。方法采用栓线法复制SD大鼠大脑中动脉梗死模型（MCAO）,分别于缺血2h后再灌注1d、3d、7d。将180只大鼠随机分为5组（每组36只）：假手术组,模型（缺血再灌注）组,盐酸法舒地尔注射液组,康脑液1号A组,康脑液1号B组。观察康脑液1号对大鼠脑缺血再灌注神经功能、脑梗死面积和病理形态学的影响。采用TUNEL法检测缺血半暗带和灶中心区凋亡细胞,采用免疫组化法检测缺血半暗带和灶中心区GFAP表达的变化。结果模型组与假手术组相比,缺血半暗带凋亡细胞及GFAP阳性细胞数目增多（P〈0.05）。康脑液1号可不同程度地降低实验性脑缺血大鼠的神经功能评分、减小梗死灶面积并减轻脑组织病理形态改变（P〈0.05）;康脑液1号2组大鼠脑组织缺血半暗带凋亡细胞和GFAP表达减少,而梗死灶中心凋亡细胞和GFAP表达却增多。结论康脑液1号可能通过调节脑缺血再灌注细胞凋亡和GFAP表达而促进脑损伤修复及重塑,从而发挥脑保护作用。     

醛固酮阻滞对心肌梗死大鼠非梗死区心肌组织胶原重塑的影响

目的研究醛固酮阻滞对心肌梗死大鼠非梗死区心肌组织胶原重塑的影响。方法将心肌梗死后24h存活大鼠随机分为2组：盐水组（22只,5ml/d）,螺内酯组（23只,20mg/kg）;另设假手术组（15只）作对照。分别于心肌梗死后6周：导管法测定左室有创血流动力学;组织学方法检测胶原纤维沉积;化学比色法测定胶原含量;免疫组化法观察胶原Ⅰ/Ⅲ比值;RT-PCR检测Ⅰ型胶原及Ⅲ型胶原mRNA的表达。结果①所有心肌梗死大鼠均出现显著的心肌间质纤维沉积,左室重量指数增大,与假手术组相比差异有统计学意义（P〈0.01）。与盐水组相比,螺内酯组心肌间质纤维沉积减轻,左室重量指数降低,差异有统计学意义（P〈0.01）;②与假手术组相比,心肌梗死组非梗死区的胶原含量增加,胶原Ⅰ/Ⅲ比值升高,Ⅰ型、Ⅲ型胶原mRNA水平增加,差异具有统计学意义（P〈0.05,P〈0.01）。与盐水组相比,螺内酯组非梗死区胶原含量、非梗死区胶原Ⅰ/Ⅲ比值、Ⅰ型及Ⅲ型胶原mRNA水平均降低,差异具有统计学意义（P〈0.05,P〈0.01）;③与假手术组相比,所有心肌梗死大鼠6周后左室收缩压（LVSP）和左心室内压最大上升和下降速率（±dp/dtmax）均显著下降,LVEDP显著上升,差异有统计学意义（P〈0.01）;与盐水组相比,螺内酯组大鼠心功能显著改善,差异有统计学意义（P〈0.01）。结论心肌梗死后大鼠非梗死区心肌组织出现胶原重构;醛固酮阻滞能改善心肌的纤维化,改善心脏功能。     

Rofecoxib对肾间质纤维化大鼠TGF-及肾小管上皮细胞凋亡的影响

目的 探讨Rofecoxib对肾间质纤维化大鼠的肾脏保护机制。方法以UUO建立肾间质纤维化大鼠模型,随机分为假手术组、UUO组及Rofecoxib干预组,检测不同时间点肾脏COX-2、TGF-1及肾小管上皮细胞凋亡的表达。结果与假手术组相比,UUO组随着模型时间延长,TGF-β、COX-2蛋白表达明显增加,可检测到较多的凋亡细胞（P〈0．01）,用药组与UUO组平行相比TGF-β,、COX-2蛋白表达明显减少（P〈0．01）,凋亡细胞明显减少（P〈0．01）。结论特异性COX-2抑制剂Rofecoxib可能通过阻断UUO大鼠肾组织COX-2活性,下调TGF-的蛋白合成,减少肾小管细胞的过度凋亡,起到肾脏保护的作用。     

老年人脑梗死后抑郁症及影响因素的研究

应用Ｈａｍｉｌｔｏｎ抑郁量表对１０２例老年脑梗死患者的抑郁症进行研究,同时研究其与神经功能缺损程度、病变部位、病灶面积及数目的关系。结果显示：（１）老年人脑梗死后有５８％的患者出现抑郁症状。（２）抑郁症状与神经功能缺损程度成显著正相关（Ｐ〈０．００１）。（３）皮质下梗死,尤其是多发性腔隙梗死,与其他部位梗死相比,更易发生抑郁症。（４）梗死后抑郁症的发生率与腔隙梗死灶的数量及非腔隙梗死的面积有关。老     

重组人脑利钠肽后适应对兔急性缺血再灌注损伤心肌的保护作用

目的探讨重组人脑利钠肽（rhBNP）后适应对兔急性缺血／再灌注（I／R）心肌的保护作用及其机制。方法将36只健康日本大耳白兔按数字表法随机分为三组（每组12只）,即假手术组、I／R组（缺血40rain后再灌注180min）及BNP＋I／R组（I／R前5min以0．01μg／kg静脉给予rhBNP）。假手术组开胸于左冠回旋支只穿线但不结扎,观察180min结束;I／R组及BNP＋I／R组：缺血40min,分别再灌注180min后处死。进行心肌磷酸肌酸激同工酶（CK．MB）含量检测,观察心肌HE染色后病理形态变化及BCI-2、Bax表达的检测。结果与假手术组相比,I／R组和BNP＋I／R组CK—MB水平均显著增高（t=3．047、3．032,均P〈0．01）;与I／R组相比,BNP＋I／R组心肌酶明显升高（t=3．067,P〈0．01）。与假手术组相比,I／R组及BNP＋L／R组均可见到凋亡细胞,但BNP＋IYR组凋亡细胞明显减少,UR组Bax的表达增加,Bcl-2的表达降低。与I／R组相比,BNP＋I／R组Bax的表达明显升高,而Bcl-2的表达明显降低。结论rhBNP可减少梗死后心肌的损伤;可以增加梗死后心肌细胞抑制凋亡基因（Bcl-2）的表达,从而减少心肌细胞的凋亡。     

大鼠脑梗死早期星形细胞胶质化及其与神经营养因子的关系

目的 探讨星形南细胞（ＡＳ）在脑梗死早期的变化及与神经营养因子的关系。方法 运用免疫组织化学技术检测Ｍｉｄｋｉｎｅ（ＭＫ）、星形胶质纤维酸性蛋白（ＧＦＡＰ）的动态变化。结果 梗死后１天,梗死边缘开始表达ＧＦＡＦ。梗死后２天,ＧＦＡＰ表达达高峰。ＭＫ于梗死后１天表达,随后其阳性梗死后２￣４天表达逐步增强。结论 脑梗死早期星形胶质细胞增生可能与分泌神经营养因子及损伤后的修复有关。     

Interindividual variability in metabolic activation in humans in vivo

In assessing interindividual variability in metabolic activation, the toxic metabolite is often too unstable for conventional analysis. Possible alternatives include a stable product of the reactive metabolite e.g. cysteinyl derivatives of N-acetyl-4-benzoquinoneimine, the toxic metabolite of paracetamol, adducts with DNA or protein, and indirect measurement of the activity of the enzyme(s) producing the active metabolite. An example of the last approach is the use of furafylline, a highly specific inhibitor of human CYP1A2, to determine the extent of the metabolic activation of the cooked food mutagens PhIP and MeIQx. The extent of inhibition, determined from levels of unchanged amine in urine, is an indirect measure of the activity of the activation pathway. Further refinement of this approach, allied to improved measures of the biological process of interest should prove of value in evaluating interindividual variability and its role in the risk assessment process.     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg.kg) or i.p. (50 mg.kg) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) l.h. kg in the male rat and 10.6 (95% CI: 7.5, 15.0) l.h. kg in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p 0.001) in plasma obtained from the male (8.8 2.0%) compared with the female rat (11.7 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

Theophylline kinetics in peripheral tissues in vivo in humans

Several biochemical and cellular effects have been described for methylxanthines under in vitro conditions. However, it is unknown, whether threshold concentrations required to exert these effects are attained in target tissues in vivo. We therefore employed the microdialysis technique for measuring theophylline concentrations in peripheral tissues under in vivo conditions.Following in vitro and in vivo calibration, microdialysis probes were inserted into the medial vastus muscle and into the periumbilical subcutaneous adipose layer of healthy volunteers. Following single oral dose administration of 300 mg or i.v. infusion of 240 mg theophylline, in vivo time courses of theophylline concentrations were monitored in tissues and plasma. Major pharmacokinetic parameters (c_max, t_max, AUC) were calculated for plasma and tissue time courses. The mean AUC_tissue /AUC_plasma-ratio was 0.56 (p.o.) and 0.55 (i.v.) for muscle and 0.55 (p.o.) and 0.72 (i.v.) for subcutaneous adipose tissue.We conclude that microdialysis provides important information on the distribution and the tissue pharmacokinetics of theophylline.Abbreviations FPIA Fluorescence polarisation immuno assay - AUC Area under the curve - t_max Time to peak concentration - c_max Peak concentration     

休克时血中氧自由基的变化

本实验测定10名休克患者血浆和红细胞的丙二醛(MDA)、血浆总抗的氧化活性(AOA)的含量。结果表明:休克病人红细胞膜和血浆 MDA 含量(4.298±0.722;5.348±0.834)与对照组(3.235±0.682;4.356±1.081)比较明显增高(P<0.05);血浆 AOA(39.65±7.858)与对照组(48.21±10.81)比较明显降低(P<0.01)。提示:休克时,患者机体内自由基反应增强是引起组织细胞损伤的原因之一。     

Polymorphisms in genes involved in neurotransmission in relation to smoking

Smoking behavior is influenced by both genetic and environmental factors. The genetic contribution to smoking behavior is at least as great as its contribution to alcoholism. Much progress has been achieved in genomic research related to cigarette-smoking within recent years. Linkage studies indicate that there are several loci linked to smoking, and candidate genes that are related to neurotransmission have been examined. Possible associated genes include cytochrome P450 subfamily polypeptide 6 (CYP2A6), dopamine D₁, D₂, and D₄ receptors, dopamine transporter, and serotonin transporter genes. There are other important candidate genes but studies evaluating the link with smoking have not been reported. These include genes encoding the dopamine D₃ and D₅ receptors, serotonin receptors, tyrosine hydroxylase, trytophan 2,3-dioxygenase, opioid receptors, and cannabinoid receptors. Since smoking-related factors are extremely complex, studies of diverse populations and of many aspects of smoking behavior including initiation, maintenance, cessation, relapse, and influence of environmental factors are needed to identify smoking-associated genes. We now review genetic polymorphisms reported to be involved in neurotransmission in relation to smoking.     

Tramadol concentrations in blood and in cerebrospinal fluid in a neonate

Based on blood and cerebrospinal fluid samples collected in a full-term neonate, the penetration of tramadol in the central nervous system is described. Following intravenous administration of tramadol, a lag time of about 4 h was observed until full blood–brain equilibration was achieved. This pharmacokinetic observation is in line with a recent pharmacodynamic evaluation of the central opioid effects of tramadol in adults.     

Disease control in asthmatic children seen in private practice in Switzerland

ABSTRACT

Background: Asthma is the most common chronic childhood disease in Switzerland with a prevalence of 10%. Asthma has a high economic burden accounting for high medical costs. Assessment of disease control is likely to be of help in the implementation of strategies to improve asthma. Therefore, we aimed to evaluate asthma control and therapy regimens among children in private practice.

Methods: We assessed asthma control as well as therapy regimens in 575 asthmatic children in an experience programme in Switzerland by using an abbreviated questionnaire based on the asthma control questionnaire and the child health questionnaire on Visit 1 and Visit 2.

Results: Good asthma control at Visit 1 was only present in 25.7% of asthmatic children. Occasional asthma symptoms, limitation of physical activity, nocturnal awakening and anxiety of the parent was present in 80.5%, 41.2%, 46.8% and 57% of the children, respectively. After adjustment of therapy regimens at Visit 1, mainly by adding a leukotriene receptor antagonist, asthma control was reported to be much better in 53.4% of the children at Visit 2.

Conclusions: As asthma control is inadequately achieved within a major portion of asthmatic children, it is imperative to find measures to improve asthma control and hence, to reduce the burden of disease.