模糊模式识别法在有机毒物系统鉴别中的应用

首先获得常见有机毒物的标准红外光谱，然后用模糊聚类分析方法存贮标准光谱，建立起常见有机毒物标准红外光谱库。鉴定未知有机毒物时，用模式识别的直接方法寻找图谱。以２０１种常见有机毒物为实例进行检索，证明该方法可以用于有机毒物的快速筛选和定性鉴别。     

一个分析药物吸收动力学的方法

本文提出一个分析药物吸收动力学的方法。它的数学推导简单且易推广到多室模型;其计算量比Loo-Riegelman法及其简化法都少,且因不含指数函数而完全适合手算;其计算结果与L-R法基本相同。     

口腔粘膜内酶对胰岛素口腔吸收的影响

目的　研究口腔粘膜内酶对胰岛素口腔吸收的影响。方法　用三氯醋酸沉淀法,考察胰岛素在仓鼠口腔粘膜匀浆物中不同条件下的降解情况。在胰岛素口腔喷雾剂中加入酶抑制剂(杆菌肽、屈来赛多)和去氧胆酸钠,考察了大鼠经口腔喷入胰岛素后的血糖降低情况。结果　小肠粘膜细胞内酶活性远高于口腔粘膜细胞中的酶的活性。杆菌肽、屈来赛多和去氧胆酸钠均能抑制口腔粘膜内胰岛素的降解。在相同浓度下,去氧胆酸钠的酶抑制作用比杆菌肽弱,但比屈来赛多强。胰岛素在正常仓鼠口腔内的降解显著大于糖尿病仓鼠。胰岛素溶液中加入杆菌肽、屈来赛多及去氧胆酸钠后,给正常大鼠口腔喷雾给药,药理相对生物利用度分别有不同程度的提高。只含胰岛素的喷雾液(胰岛素空白液) ,喷雾液中加入屈来赛多(0.1% ) ,加入杆菌肽(0.5% ) ,去氧胆酸钠(1% ) ,与sc胰岛素比较药理相对生物利用度分别为2.89% ,4.84% ,7.52 %和9.60%。结论　口腔粘膜中的酶可以限制胰岛素在口腔粘膜的吸收     

THE IMPORTANCE OF THE DILUENT FOR AIRWAY TRANSPORT OF TOLUENE DIISOCYANATE FOLLOWING INTRANASAL DOSING OF MICE

Uncertainty of the transport of reactive chemicals to the lung is a major concern when using intranasal dosing of animals. In a preliminary study using mice, intranasal instillation of the dyes methylene blue (in water) and Sudan black B (in 1:4 ethyl acetate:olive oil), indicated that the following conditions were necessary to achieve transport to the lung: (1) aqueous diluent, (2) light anesthesia prior to dosing, (3) holding the animal in a supine position during chemical application, and (4) maintaining the animal in the same position postdosing. Using these conditions, we investigated the distribution of toluene diisocyanate (TDI), a major industrial asthmogen, to the lung following intranasal administration. Female C57BL/6 mice received 20 mul of 1% TDI in ethyl acetate:olive oil (1:4). Group 1 received a single application on day 1; group 2, single applications on 2 consecutive days; group 3, single applications on 4 consecutive days; and group 4, a single application of the vehicle on 2 consecutive days. All mice were necropsied 24 h after the final application. The nasal passages, upper pharynx, trachea, lungs, and olfactory bulbs of each animal were examined with hematoxylin-eosin and immunohistochemical staining, the latter using a rabbit anti-TDI antiserum. Histopathology revealed desquamation of ciliated epithelial cells as well as inflammatory cell debris in the nasal cavity and upper pharynx of animals in groups 1-3. The intensity of these changes was dependent on the number of applications. No inflammation was observed in the trachea, lungs, or olfactory bulbs in any of the groups. Immunohistochemical examination revealed positive staining for the TDI moiety in epithelial cells of the nasal cavity and upper pharynx in animals of groups 1-3. No staining was observed in the trachea, lungs, or olfactory bulbs of any animal. These results suggest that TDI, when dissolved in olive oil:ethyl acetate and applied intranasally, does not reach the trachea and/or lower airways.     

常见有机毒物指纹UV图谱定性法

分别扫描有机毒物在不同pH溶液中和不同极性溶剂中的标准UV图谱,得到该化合物零阶UV光谱的较全面信息,作为定性依据.然后用模糊聚类分析方法分类存贮标准光谱,建立常见有机毒物多溶剂下UV图谱库。鉴定未知有机毒物时,用模式识别的直接法寻找图谱。以70种常见毒物为实例进行检索,证明该方法可以用于毒物的定性鉴别。     

A NEW MODEL FOR THE GENERATION OF SYMPATHETIC NERVE ACTIVITY

1. Sympathetic discharges from multifibre nerve recordings vary in their frequency of occurrence which displays both slow and fast rhythms and in their amplitude which reflects the number of activated fibres. It has been shown that the frequency of occurrence of these rhythms varies according to baroreceptor activity (via blood pressure and heart rate) while the number of activated fibres is independently affected by chemoreceptor activity. 2. A new model is proposed for the generation of sympathetic nerve activity by the central nervous system to account for these results. The upper layer of the model comprises two oscillators, a fast and a slow cycle frequency oscillator, with the balance and occurrence maintained by afferent inputs such as the baroreceptors. 3. It is hypothesized that two central oscillators impinge on a lower layer of the model influencing the number of activated fibres within each postganglionic sympathetic burst. This is independent of the frequency control and affected by separate afferent inputs such a chemoreceptors.     

EFFECT OF NITROGEN DIOXIDE ON OVALBUMIN-INDUCED ALLERGIC AIRWAY DISEASE IN A MURINE MODEL

The effect of exposure to irritant air pollutants on the development of allergic airway disease is poorly understood. This study examines the effects of the lower respiratory tract irritant, NO 2 , on the outcome of ovalbumin (OVA)-induced allergic airway disease. Male and female C57Bl/6 mice were sensitized by weekly intraperitoneal (ip) OVA injections for 3 wk followed by daily 1-h OVA aerosol inhalation challenge for 3 or 10 d. Initially, mice were exposed daily for 3 d to air or 0.7 or 5 ppm NO 2 for 2 h following each OVA aerosol challenge. OVA exposure resulted in pronounced lower airway inflammation, as evidenced by a significant increase in bronchoalveolar lavage (BAL) total cellularity and eosinophil levels. BAL eosinophil levels were significantly lower in OVA-NO 2 compared to OVA-air animals. The reduction was similar at both NO 2 exposure concentrations. In a subsequent study, sensitized animals were exposed for 3 or 10 d to aerosolized OVA followed by air or 0.7 ppm NO 2 . BAL eosinophils were again reduced at 3 d by OVA-NO 2 exposure compared to OVA-air mice. At 10 d the eosinophilia was virtually abolished. This reduction in OVA-induced cellular inflammation by NO 2 was confirmed by histopathological analysis. Contrary to expectations, exposure to NO 2 during the aerosol challenge to OVA dramatically diminished the outcome of allergic disease in lungs as measured by airway cellular inflammation.     

药物动力学的灰色系统建模方法

本文以给狗一次快速静脉注射常咯啉20mg/kg后所得c-t数据为依据,利用灰色系统(Grey Systems)理论建立不依赖于室分析的药物动力学模型,该模型的计算是用FORTRAN标准语言在IBM计算机上实现的。结果表明,用该模型计算的数据与实测数据之间的平均绝对误差为0.0267;而依据同样数据建立的室模型的平均绝对误差则为0.036。     

A HIERARCHICAL BINOMIAL-POISSON MODEL FOR THE ANALYSIS OF A CROSSOVER DESIGN FOR CORRELATED BINARY DATA WHEN THE NUMBER OF TRIALS IS DOSE-DEPENDENT

ABSTRACT

The differential reinforcement of a low-rate 72-seconds schedule (DRL-72) is a standard behavioral test procedure for screening a potential antidepressant compound. The data analyzed in the article are binary outcomes from a crossover design for such an experiment. Recently, Shkedy et al. (2004 Shkedy , Z. , Vandersmissen , V. , Molenberghs , G. , Van Craenendonck , H. , Aerts , N. , Steckler , T. , Bijnens , L. (2004). Behavioral testing of antidepressant compounds: an analysis of crossover design for correlated binary data. Submitted to the Biometrical Journal . [Google Scholar]) proposed to estimate the treatments effect using either generalized linear mixed models (GLMM) or generalized estimating equations (GEE) for clustered binary data. The models proposed by Shkedy et al. (2004 Shkedy , Z. , Vandersmissen , V. , Molenberghs , G. , Van Craenendonck , H. , Aerts , N. , Steckler , T. , Bijnens , L. (2004). Behavioral testing of antidepressant compounds: an analysis of crossover design for correlated binary data. Submitted to the Biometrical Journal . [Google Scholar]) assumed the number of responses at each binomial observation is fixed. This might be an unrealistic assumption for a behavioral experiment such as the DRL-72 because the number of responses (the number of trials in each binomial observation) is expected to be influenced by the administered dose level. In this article, we extend the model proposed by Shkedy et al. (2004 Shkedy , Z. , Vandersmissen , V. , Molenberghs , G. , Van Craenendonck , H. , Aerts , N. , Steckler , T. , Bijnens , L. (2004). Behavioral testing of antidepressant compounds: an analysis of crossover design for correlated binary data. Submitted to the Biometrical Journal . [Google Scholar]) and propose a hierarchical Bayesian binomial-Poisson model, which assumes the number of responses to be a Poisson random variable. The results obtained from the GLMM and the binomial-Poisson models are comparable. However, the latter model allows estimating the correlation between the number of successes and number of trials.     

THE EFFECT OF ADRIAMYCIN AGAINST A LIVER METASTATIC MODEL BY ENCAPSULATION IN LIPOSOMES

Antitumour activities of liposomes containing adriamycin (L-ADM) and their distribution process into tumour cells were analysed. The lipid composition of the liposomes was dimyristoylphosphatidylglycerol (DMPG)/egg phosphatidylcholine/cholesterol/adriamycin (ADM) in a molar ratio of 11·4 : 2 : 12 : 1·3. Liver-metastasizing murine tumour models, M5076 and L5178Y-ML, were used. In vivo antitumour effect against these tumour models was assessed from increase in life span (ILS). The survival prolongation effect of L-ADM in mice with liver failure caused by M5076 was significantly higher than that of F-ADM. In contrast, significant enhancement of the effects by encapsulation in liposomes was not observed in L5178Y-ML-bearing mice. In vitro cytostatic activities of L-ADM against M5076 cells as well as against other tumour cell lines were lower than those of F-ADM. The in vitro kinetic study of the distribution of L-ADM to the tumour cells revealed that ADM in L-ADM was taken up into the tumour cells mainly after it was released from the liposomes rather than taken up as the liposomal form. Among the cell lines tested, M5076 cells had the highest phagocytic activity and therefore the highest uptake activity of ADM during incubation with L-ADM. These findings suggest that the augmented antitumour activity of L-ADM in M5076-bearing mice was the result of phagocytosis of L-ADM by M5076 cells as well as the reduction of toxicity, prolonged retention of ADM in systemic circulation, and liver accumulation of ADM after administration of L-ADM.     

哮喘患者糖皮质激素吸入前后气道反应性变化

通过比较二丙酸倍氯米松及沙丁胺醇气雾剂吸入前后气道对乙酰甲胆碱的反应性，说明皮质激素吸入可降低气道反应性，且气道反应性的高低与体内膜白介素－２受体阳性（ＩＬ－２Ｒ＋）Ｔ细胞相关；而β２受体激动剂吸入不能改变气道反应性     

LACK OF DNA BINDING IN THE RAT NASAL MUCOSA AND OTHER TISSUES OF THE NASAL TOXICANTS ROFLUMILAST,A PHOSPHODIESTERASE 4 INHIBITOR,AND A METABOLITE, 4-AMINO-3,5-DICHLOROPYRIDINE,IN CONTRAST TO THE NASAL CARCINOGEN 2,6-DIMETHYLANILINE*

The phosphodiesterase 4 inhibitor Roflumilast (B9302-107) (RF) and its metabolite 4-amino-3,5-dichloropyridine (ADCP) produced nasal toxicity in preclinical safety studies with rats. The purpose of this study was to assess the possible formation of DNA adducts, by RF and ADCP, in the nasal mucosa, liver and testes of male rats using the ³²P-postlabeling assay. For comparison, rats were exposed to the DNA-reactive carcinogens 2,6-dimethylaniline (DMA), also known as 2,6-xylidine, a nasal carcinogen, and the aromatic amine carcinogens 4,4′-methylene-bis(2-chloroaniline) (MOCA), which yields monocyclic DNA adducts, and 2-acetylaminofluorene (2-AAF). In the case of RF, possible sources of DNA adducts include the parent molecule and its ADCP moiety by enzymatic N-hydroxylation and sulfation, reactions typical of carcinogenic aromatic amines. 4-Acetoxylamino-3,5-dichloropyridine (N-acetoxy-ADCP), a chemically activated derivative of ADCP, was prepared and used to modify DNA which was then used to establish the chromatographic conditions with which to reliably detect whether or not such adducts were formed metabolically from RF and ADCP. Similarly, a standard N-hydroxy-DMA was prepared, but the corresponding N-acetoxy derivative was unstable and decomposed during synthesis. Both N-hydroxy-DMA and N-acetoxy-ADCP were mutagenic in the Salmonella typhimurium Ames assay using strain TA100 without an exogenous bioactivation system, with the former being more potent. N-hydroxy-ADCP was essentially inactive in this assay. For the ³²P-postlabeling assay, male Wistar rats were exposed to the test substances and carrier control compounds by intragastric instillation at the selected dose levels for 7 days. Subsequently, the nasal mucosa, liver, and testes of the rats exposed to the test or control compounds were extirpated, the DNA extracted and the samples postlabeled. The patterns of adducts formed with the test compounds were compared to those formed in N-acetoxy-ADCP- and N-hydroxy-DMA-adducted DNA, which were assayed by both nuclease P₁ and butanol enhancement methods. Based upon the similarity of results from the two enhancement methods, only the former was used for the in vivo studies. No evidence was obtained for the formation of DNA adducts from RF or its metabolites, specifically ADCP, under the conditions of these assays despite the ability to detect adducts from DNA modified chemically with N-acetoxy-ADCP and DNA adducts from the other compounds in their target organs. In the absence of a pattern of compound-related spots, we conclude that RF does not form DNA adducts having the potential to initiate neoplasia in these three tissues.