Modeling the pharmacokinetics and pharmacodynamics of dexamethasone in depressed patients

Summary Changes in time course effected by cortisol suppression and the relationship of these changes to the plasma dexamethasone concentration of suppressor and non-suppressor patients are described in this report on a combined pharmacokinetic-pharmacodynamic model.Thirteen depressed patients (8 suppressors and 5 non-suppressors) received an intravenous dose (1.5 mg) of dexamethasone. The drug-induced effect changes are found to lag behind, in time, the plasma drug level changes. To accurately relate the temporal relationship of effect changes to plasma dexamethasone levels, a pharmacodynamic model (sigmoid-Emax) was combined with a pharmacokinetic model that incorporated an effect compartment. The magnitude of the time-lag was quantified by the half-time of equilibration between concentrations in the hypothetical effect compartment and the plasma dexamethasone levels (t_&frac;k_eo).The t_&frac;k_eo of the nonsuppressing group was about 50 of that of the suppressing group, indicating that for a given plasma level the onset and termination of effect for the nonsuppressing group is about two times more rapid than for the suppressing group. Moreover, the model can estimate the effect-site concentration that causes one-half of the maximal predicted effect (EC₅₀), a measure of an individual's sensitivity to dexamethasone. The receptor sensitivity (as determined from the EC₅₀ ratio) of the suppressing group was about twice that of the nonsuppressing group.     

解放军医学图书馆电子阅览室的技术特点

从阅览室网络拓扑结构、硬盘保护、网络控制、网址限制及视频点播等几个方面对电子阅览室采用技术的特点逐一做了简要介绍,并以此阐明通过综合管理,使阅览室各计算机能够正常、安全的运行,从而达到既可为读者提供优质服务又可保证系统安全的目的.     

垃圾处置场填埋作业区整体布局的完善设计

目的：完善上海市老港垃圾处置场，有效地缓解“垃圾包围城市”的局面和城市垃圾出路难的问题。方法：对老港场的整体布局进行完善设计．结果：在老港场完成1期工程的基础上，2期工程的设计相应增加了填埋区的供电、供水，修筑隔堤、道路、污水处理等土建设施和运输车辆、填埋作业机械配套等，并增加了环境保护措施，如污水收集和处理系统，沼气导排，营造绿化隔离带等．     

hnRNPU过表达抑制PIM1诱导的细胞衰老的机制研究

目的:探讨人前病毒整合位点1（PIM1）诱导细胞衰老的分子机制。方法:构建过表达PIM1的2BS细胞系,通过Western印迹法和衰老相关β-半乳糖苷酶染色实验测定过表达PIM1是否诱导细胞衰老。免疫沉淀联合质谱分析测定PIM1是否能有效免疫沉淀核异质核糖核蛋白U（hnRNPU）蛋白。运用Real-timePCR和Western印迹法测定PIM1是否影响hnRNPUmRNA和蛋白表达水平。构建同时过表达PIM1和hnRNPU的2BS细胞系,运用Western印迹法和衰老相关β-半乳糖苷酶染色实验检测hnNRPU过表达对PIM1诱导的细胞衰老的影响。结果:与空载对照组相比,过表达PIM1组中衰老信号通路关键基因p53、p21和p16的表达显著增加（p53,t=4.36,P<0.05;p21,t=3.814,P<0.05;p16,t=4.72,P<0.01）,衰老细胞的比例增加（t=6.831,P<0.01）。免疫沉淀联合质谱分析结果显示PIM1能有效免疫沉淀hnRNPU蛋白。PIM1过表达对hnRNPU的mRNA表达水平没有影响（t=0.295,P=0.783）,但是能抑制hnRNPU蛋白的表达（t=33.85,P<0.001）。与只过表达PIM1细胞相比,同时过表达PIM1和hnRNPU细胞,衰老信号通路关键基因p53、p21和p16的表达下降（p53,t=15.317,P<0.001;p21,t=8.012,P<0.01;p16,t=14.08,P<0.001）,衰老细胞的比例降低（t=10.38,P<0.01）。结论:hnRNPU过表达抑制PIM1诱导的细胞衰老。     

Drug Binding to α1-Acid Glycoprotein Studied by Circular Dichroism

The interactions of acidic and basic drugs with ₁-acid glycoprotein (₁-AGP) were investigated using circular dichroism (CD) measurements. Extrinsic Cotton effects were generated by the binding of drugs to ₁-AGP. The CD data suggested the presence of a single binding site on the ₁-AGP molecule. The induced ellipticities of the acidic drug–₁-AGP system decreased with increasing pH, while the ellipticities for the basic drugs increased with pH. The ellipticities for all drugs were reduced by the addition of fatty acids. Furthermore, the induced ellipticities decreased in the presence of cesium chloride for basic drugs bound to ₁-AGP. The extrinsic Cotton effects therefore appear to result from hydrophobic interaction with ₁-AGP for the acidic drugs and from hydrophobic and electrostatic interactions for the basic drugs.     

Preservation and redirection of HPV16E7-specific T cell receptors for immunotherapy of cervical cancer

Human papilloma virus (HPV) type 16 infections of the genital tract are associated with the development of cervical cancer (CxCa) in women. HPV16-derived oncoproteins E6 and E7 are expressed constitutively in these lesions and might therefore be attractive candidates for T-cell-mediated adoptive immunotherapy. However, the low precursor frequency of HPV16E7-specific T cells in patients and healthy donors hampers routine isolation of these cells for adoptive transfer. To overcome this problem, we have isolated T cell receptor (TCR) genes from four different HPV16E7-specific healthy donor and patient-derived human cytotoxic T lymphocyte (CTL) clones. We examined whether genetic engineering of peripheral blood-derived CD8+ T cells in order to express HPV16E711-20-specific TCRs is feasible for adoptive transfer purposes. Reporter cells (Jurkat/MA) carrying a transgenic TCR were shown to bind relevant but not irrelevant tetramers. Moreover, these TCR-transgenic Jurkat/MA cells showed reactivity towards relevant target cells, indicating proper functional activity of the TCRs isolated from already available T cell clones. We next introduced an HPV16E711-20-specific TCR into blood-derived, CD8+ recipient T cells. Transgenic CTL clones stained positive for tetramers presenting the relevant HPV16E711-20 epitope and biological activity of the TCR in transduced CTL was confirmed by lytic activity and by interferon (IFN)-gamma secretion upon antigen-specific stimulation. Importantly, we show recognition of the endogenously processed and HLA-A2 presented HPV16E711-20 CTL epitope by A9-TCR-transgenic T cells. Collectively, our data indicate that HPV16E7 TCR gene transfer is feasible as an alternative strategy to generate human HPV16E7-specific T cells for the treatment of patients suffering from cervical cancer and other HPV16-induced malignancies.     

Mapping location of excitation during magnetic stimulation: Effects of coil position

We determined the location of excitation for different positions of a round and butterfly coil duringin vitro magnetic stimulation of cut peripheral nerves. We analyzed the conditions under which excitation occurs, either at the termination or at the peak of the field gradients (first spatial derivative of the electric field). These results were then compared to predictions about the location of excitation sites from a theoretical model of magnetic stimulation of finite neuronal structures. Excitation along a straight nerve occurred at terminations when 1) a coil was positioned close to the end of a nerve (at least one diameter length from the end), 2) a nerve ended in a finite terminating impedance much greater than the axial resistance of the nerve, 3) the induced electric field was of sufficient magnitude, pointing in a direction away from the axis of a nerve. Excitation occurred at the negative peak of the field gradients along a nerve when 1) a coil was positioned far away from the ends of a nerve, 2) there were no geometric or volume conductor inhomogeneities around a nerve, and 3) it was of sufficient magnitude. Threshold strengths for excitation at terminations were significantly lower than that for field gradient excitation and comparable to that due to geometric and volume conductor inhomogeneities.     

Recognition of an extensive range of IgE-reactive proteins in cod extract

Allergy to fish is one of the most common food allergies. Gad c 1 is the only fish allergen which has been purified and characterized. Other allergens have been detected by Western blot in cod extracts. We have now improved the Western-blot procedure in order to characterize fish IgE-reactive proteins from extracts prepared under different conditions: pre-rigor mortis and postrigor mortis. EDTA addition or not. and DEAE ion-exchange chromatography. Several IgE-reactive protein bands have been identified over a wide molecular-weight range. In particular, the 104- and 130-kDa IgEreactive protein bands were detected. These new bands may correspond to aggregates, as EDTA increased the relative amount of the 60-, 67-, 104-, and 130-kDa IgE-reactive protein bands in Western blot. All these bands were also detected by an antiparvalbumin monoclonal antibody, specific to the first calcium-binding site. The longer period of storage increased the relative amounts of the 41-, 80-, 104-. and 130-kDa IgE-reactive protein bands. The 18-kDa band was detected only in fish stored for several days. In conclusion, we have described IgE-reactive protein bands over a wide molecular-weight range (12–130 kDa) in Western blot of cod extract, and shown that EDTA and storage conditions may influence the relative distribution of IgE-reactive protein bands.     

Periovulatory increase in temperature difference within the rabbit oviduct

BACKGROUND: Earlier studies demonstrated a small temperature difference between the sperm storage and fertilization sites within the oviducts of rabbits and pigs. Our aim was to reveal the time dependence of this temperature difference relative to ovulation, and to determine how this difference is generated-by temperature elevation at one of these sites or by temperature decrease at the other site. METHODS: The temperature at the sperm storage site (at the isthmus near the uterotubal junction) and at the fertilization site (the isthmic-ampullary junction) of rabbit oviducts were measured before, during, and after ovulation by two probes, connected to digital thermometers. Rectal temperature was constantly measured and served as a control for body temperature. RESULTS: The temperature difference between the fertilization site and the storage site was 0.8+/-0.2 degrees C before ovulation. This difference increased at ovulation, reaching 1.6+/-0.1 degrees C after ovulation (P<0.03). This increased difference was mainly due to temperature decrease in the sperm storage site. CONCLUSION: The temperature-difference increase within the rabbit oviduct is generated at ovulation by a reduced temperature at the sperm storage site. This temperature gradient may play a role in mammalian reproduction via sperm thermotaxis.