Effects of cellular pharmacology on drug distribution in tissues

The efficacy of targeted therapeutics such as immunotoxins is directly related to both the extent of distribution achievable and the degree of drug internalization by individual cells in the tissue of interest. The factors that influence the tissue distribution of such drugs include drug transport; receptor/drug binding; and cellular pharmacology, the processing and routing of the drug within cells. To examine the importance of cellular pharmacology, previously treated only superficially, we have developed a mathematical model for drug transport in tissues that includes drug and receptor internalization, recycling, and degradation, as well as drug diffusion in the extracellular space and binding to cell surface receptors. We have applied this "cellular pharmacology model" to a model drug/cell system, specifically, transferrin and the well-defined transferrin cycle in CHO cells. We compare simulation results to models with extracellular diffusion only or diffusion with binding to cell surface receptors and present a parameter sensitivity analysis. The comparison of models illustrates that inclusion of intracellular trafficking significantly increases the total transferrin concentration throughout much of the tissue while decreasing the penetration depth. Increasing receptor affinity or tissue receptor density reduces permeation of extracellular drug while increasing the peak value of the intracellular drug concentration, resulting in "internal trapping" of transferrin near the source; this could account for heterogeneity of drug distributions observed in experimental systems. Other results indicate that the degree of drug internalization is not predicted by the total drug profile. Hence, when intracellular drug is required for a therapeutic effect, the optimal treatment may not result from conditions that produce the maximal total drug distribution. Examination of models that include cellular pharmacology may help guide rational drug design and provide useful information for whole body pharmacokinetic studies.     

Injection techniques to anesthetize the difficult tooth

Failure to achieve anesthesia can be a significant problem in the day-to-day practice of dentistry. The usual strategy following an anesthetic failure is to reinject. Therefore, a good understanding of conventional anesthetic techniques is important. But the practitioner also needs to have a broad armamentarium of injection strategies available for the "difficult-to-anesthetize cases". These strategies include the use of 5 percent lidocaine, intrapulpal injection, periodontal ligament injection and intraosseous injection. This paper will be a brief discussion of those techniques with an emphasis on the intraosseous injection.     

Resting respiratory tract dendritic cells preferentially stimulate T helper cell type 2 (Th2) responses and require obligatory cytokine signals for induction of Th1 immunity

Consistent with their role in host defense, mature dendritic cells (DCs) from central lymphoid organs preferentially prime for T helper cell type 1 (Th1)-polarized immunity. However, the "default" T helper response at mucosal surfaces demonstrates Th2 polarity, which is reflected in the cytokine profiles of activated T cells from mucosal lymph nodes. This study on rat respiratory tract DCs (RTDCs) provides an explanation for this paradox. We demonstrate that freshly isolated RTDCs are functionally immature as defined in vitro, being surface major histocompatibility complex (MHC) II lo, endocytosishi, and mixed lymphocyte reactionlo, and these cells produce mRNA encoding interleukin (IL)-10. After ovalbumin (OVA)-pulsing and adoptive transfer, freshly isolated RTDCs preferentially stimulated Th2-dependent OVA-specific immunoglobulin (Ig)G1 responses, and antigen-stimulated splenocytes from recipient animals produced IL-4 in vitro. However, preculture with granulocyte/macrophage colony stimulating factor increased their in vivo IgG priming capacity by 2-3 logs, inducing production of both Th1- and Th2-dependent IgG subclasses and high levels of IFN-gamma by antigen-stimulated splenocytes. Associated phenotypic changes included upregulation of surface MHC II and B7 expression and IL-12 p35 mRNA, and downregulation of endocytosis, MHC II processing- associated genes, and IL-10 mRNA expression. Full expression of IL-12 p40 required additional signals, such as tumor necrosis factor alpha or CD40 ligand. These results suggest that the observed Th2 polarity of the resting mucosal immune system may be an inherent property of the resident DC population, and furthermore that mobilization of Th1 immunity relies absolutely on the provision of appropriate microenvironmental costimuli.     

Dynamics of glucose-induced insulin release from mouse islets transplanted under the kidney capsule

Mouse pancreatic islet grafts under the kidney capsule of syngeneic hosts were removed and perifused in vitro 1-40 weeks after the transplantation. In comparison with fresh islets, 12- to 40-week-old grafts exhibited an attenuated first phase of glucose-stimulated insulin release. In grafts 1, 12, 28, or 40 weeks old, but not in fresh islets, the mean secretory rate during the initial 10 min of stimulation was significantly lower than that during the subsequent 15 min. When expressed in relation to insulin content, the insulin output in response to 11 mmol/L glucose was no less from grafts than from fresh islets; in grafts 12 or 40 weeks old at 16.7 mmol/L glucose, the fractional output above baseline was significantly diminished during the initial 10 min, but not subsequently. Immediately on switching from basal to stimulatory glucose concentration, there was a transient drop in insulin secretion from the grafts, especially after more than 12 weeks of transplantation and in response to 16.7, as compared with 11, mmol/L glucose. When glucose was switched back from stimulatory to basal concentration, grafts also frequently exhibited a transient increase in the insulin secretory rate. Neither initial drops nor "off responses" were seen in untransplanted islets. The modifications of the secretory dynamics in islet grafts suggest that transplantation influences the balance between the stimulatory and inhibitory influences of glucose on the beta-cell's secretory machinery.     

基于STC单片机的机场车辆超速报警系统

采用STC89C52单片机结合LM2596-5.0开关电压调节器、DS12C887时钟芯片、AT24C64串行存储器、74HC595移位寄存器以及接触式IC卡等器件,实现了对机场车辆速度的实时显示以及超速后的自行报警,并将超速情况以数据的形式存储到存储器中,可用IC卡对数据进行读取.该系统通过超速报警来提醒司机减速,从而减少车辆刮碰飞机等事件的发生.     

The influence of collaboration styles to children’s cognitive performance in digital problem-solving game “William Adventure”: A comparative case study

Since a large variety of digital games have been used in many fields for educational purposes, their real functions in learning have caught much attention as well. This study first defines learning characteristics of problem-solving digital games and their corresponding cognitive levels, then designs and develops a problem-solving game in accordance to the criteria. Tasks in the game context are inter-related to each other so that players need to critically and creatively think about problem solutions. Learners’ task analyses are performed to observe four elementary learners’ gaming paths, behaviors and cognitive activities, individually and collaboratively. System documentation, video recording, researcher observation, and interviews are conducted to analyze learners’ learning strategies and their cognitive performance during the gaming process.     

从软件角度谈机房的日常维护和管理

随着教学信息化程度的不断提高,如何对计算机机房进行科学、高效的维护和管理,在保障正常的教学和科研任务的同时,减轻机房管理员的负担,是一个重要的课题。文章从软件角度出发,分别对系统的安装和分发、硬盘还原以及四种常见的系统安全设置进行了详细探讨。     

Work fatigue and physiological symptoms in different occupations of high-elevation construction workers

The objective of this study is to investigate whether work fatigue and physiological symptoms that high-elevation construction workers experience would be affected by the occupations. Questionnaires of demographic data and subjective fatigue symptoms as well as some physiological measurements were carried out, pre- and post-shift, on scaffolders, steel fixers, formworkers, electrician-plumbers, concreters and miscellaneous workers at a high-rise building construction site. This study found that some subjective fatigue symptoms coincide with the life style of some workers and that the extent of fatigue symptoms and physiological strains varies among different occupations of construction workers. Scaffolders, steel fixers and formworkers are categorized as physically demanding fatigue type of workers, while concreters, electrician-plumbers and miscellaneous workers as general type. The prevalence and occurrence of subjective fatigue symptoms indicate high-elevation workers have more complaints of “projection of physical impairment” than “drowsiness and dullness” and “difficulty in concentration”. Some unexpected changes (i.e., post-shift measurements are greater than pre-shift ones) in some strength tests in scaffolders and concreters were consistent with the observations of how they exercised their bodies during work shift. Considerable variation of average heart rate among occupations was found, with scaffolders the highest and concreters the lowest. This study concludes that questionnaires of subjective fatigue symptoms and some physiological measurements can be used as indicators to predict the extent of strains or hazards which construction workers encounter. In terms of management program of safety and health, more attention should be paid to those physically demanding workers, such as scaffolders, workers with lower sense of safety and health, such as miscellaneous workers, and workers with older age, such as concreters.     

A novel user identification scheme with key distribution preserving user anonymity for distributed computer networks

Recently, Yang et al. proposed an efficient user identification scheme with key distribution, in which it is possible for the user to anonymously log into a system and establish a secret key shared with the system. Mangipudi and Katti later demonstrated a Deniable-of-Service (DoS) attack on the Yang et al. scheme and then proposed an improvement to withstand such an attack. However, this paper demonstrates an identity disclosure attack to show that neither schemes’ claimed user anonymity requirement can be achieved. We further propose a novel user identification scheme with key distribution preserving user anonymity for distributed computer networks. The proposed scheme not only withstands the attacks mentioned above, but also achieves the following: (i) user anonymity, (ii) key distribution, (iii) mutual authentication, and (iv) key confirmation. The performance of our scheme is of greater efficiency than that of previously proposed schemes in terms of communication costs and computational complexities.