Evaluation of Prediction Accuracy for Volume of Distribution in Rat and Human Using In Vitro,In Vivo,PBPK and QSAR Methods

Volume of distribution at steady state (V_ss) is an important pharmacokinetic parameter of a drug candidate. In this study, V_ss prediction accuracy was evaluated by using: (1) seven methods for rat with 56 compounds, (2) four methods for human with 1276 compounds, and (3) four in vivo methods and three Kp (partition coefficient) scalar methods from scaling of three preclinical species with 125 compounds. The results showed that the global QSAR models outperformed the PBPK methods. Tissue fraction unbound (f_u,t) method with adipose and muscle also provided high V_ss prediction accuracy. Overall, the high performing methods for human V_ss prediction are the global QSAR models, Øie-Tozer and equivalency methods from scaling of preclinical species, as well as PBPK methods with Kp scalar from preclinical species. Certain input parameter ranges rendered PBPK models inaccurate due to mass balance issues. These were addressed using appropriate theoretical limit checks. Prediction accuracy of tissue Kp were also examined. The f_u,t method predicted Kp values more accurately than the PBPK methods for adipose, heart and muscle. All the methods overpredicted brain Kp and underpredicted liver Kp due to transporter effects. Successful V_ss prediction involves strategic integration of in silico, in vitro and in vivo approaches.     

Uranium content in porcelain denture teeth and in porcelain powders for ceramic crowns

Some porcelain denture teeth and porcelain powders marketed in Sweden have been analyzed for the content of uranium. The fission track method and the delayed neutron technique were the methods used.

Compared to results published previously the content of uranium was generally found to be lower in the brands analyzed. The denture teeth contained 23–186 ppm for Anatoform. 35–137 ppm for Myerson. 15—15 ppm for Candu-lor G and 20–53 ppm for Vivopearl. The baked and fired porcelain powders showed values of about 2.8 ppm at most, those in the form of powder about 25 ppm at most.

The radiation dose to the mucosa of the upper lip was calculated and is discussed.     

Dual-Focus Therapeutic Ultrasound Transducer for Production of Broad Tissue Lesions

In noninvasive high-intensity focused ultrasound (HIFU) treatment, formation of a large tissue lesion per sonication is desirable for reducing the overall treatment time. The goal of this study is to show the feasibility of enlarging tissue lesion size with a dual-focus therapeutic ultrasound transducer (DFTUT) by increasing the depth-of-focus (DOF). The proposed transducer consists of a disc- and an annular-type element of different radii of curvatures to produce two focal zones. To increase focal depth and to maintain uniform beamwidth of the elongated DOF, each element transmits ultrasound of a different center frequency: the inner element at a higher frequency for near field focusing and the outer element at a lower frequency for far field focusing. By activating two elements at the same time with a single transmitter capable of generating a dual-frequency mixed signal, the overall DOF of the proposed transducer may be extended considerably. A prototype transducer composed of a 4.1 MHz inner element and a 2.7 MHz outer element was fabricated to obtain preliminary experimental results. The feasibility the proposed technique was demonstrated through sound field, temperature and thermal dose simulations. The performance of the prototype transducer was verified by hydrophone measurements and tissue ablation experiments on a beef liver specimen. When several factors affecting the length and the uniformity of elongated DOF of the DFTUT are optimized, the proposed therapeutic ultrasound transducer design may increase the size of ablated tissues in the axial direction and, thus, decreasing the treatment time for a large volume of malignant tissues especially deep-seated targets. (E-mail: jongsjeo@usc.edu)     

半军事化管理对航海类高职生心理健康影响的实证研究

目的考察半军事化管理对航海类高职生心理健康的影响。方法采用症状自评量表(SCL-90)、中国大学生适应量表(CCSAS)和总体幸福感量表(GWB)对279名航海类高职生施测。结果①半军事化管理对航海类高职生心理健康水平没有显著影响(t=0.45,P>0.05);②半军事化管理对航海类高职生心理适应性存在显著影响(t=2.36,P<0.05),在校园生活(t=2.27,P<0.05)、自我适应(t=1.93,P<0.05)因子上产生显著影响,在情绪(t=2.55,P<0.01)、择业适应(t=3.65,P<0.001)因子上产生极其显著的影响;③半军事化管理对航海类高职生总体幸福感产生极其显著影响(t=4.01,P<0.001),在对健康的担心(t=-20.13,P<0.001)、精力(t=3.04,P<0.01)、忧郁或愉快的心境(t=-24.61,P<0.001)、松弛和紧张(t=2.83,P<0.01)各因子上均产生极其显著影响。结论半军事化管理对航海类高职生的心理适应性和总体幸福感产生显著影响。     

Eclipse最小剂量参数对鼻咽癌调强计划影响的研究

目的:探讨Eclipse鼻咽癌调强计划中最小剂量参数(Minimize dose)对靶区和危及器官受照剂量的影响，为临床计划优化提供参考。方法:运用Varian Eclipse 10.0计划系统回顾性对10例鼻咽癌患者重新设计调强计划，采用相同的约束条件，最小剂量参数分别选取5、8、10、15、20。比较靶区适形度指数和均匀性指数、危及器官照射剂量或受照体积、机器跳数和子野数，并做统计学分析。结果:最小剂量参数由5增大到20，靶区CI减小，HI增大，OARs受照剂量增加。统计学比较显示当最小剂量为8时PCTV1 HI的P值首次小于0.05（P=0.031），差异有统计学意义。当最小剂量大于等于10时全部靶区的CI和HI的P＜0.05，差异有统计学意义。脑干和脊髓从最小剂量参数为10开始P<0.05（P=0.025,P=0.008），统计学比较差异显著。右侧腮腺和下颌骨在最小剂量参数大于等于15时P<0.05（P=0.041，P=0.005），差异有统计学意义。随最小剂量参数的增大，总机器跳数由2 186.3±175.7减少到2 085±149.5，无统计学差异。子野数由1 603.3±278.0减少到1 567.4±270.0，最小剂量参数大于等于10时差异有统计学意义。结论:考虑最小剂量参数对靶区、危及器官、机器跳数和子野数的影响，Eclipse鼻咽癌调强计划中最小剂量参数选择5到8之间是合适的。     

Review of the Toxicology of Three Alkyl Diamines

Three alkyl diamines, which are by-products formed and separated during the production of hexamethylene diamine, have been tested, mostly for their acute toxicity. This paper reviews methodologies used and the results obtained from these three chemicals. All three tested [2-methyl-1,5-pentanediamine (2-MP), 1,3-diaminopentane (DAMP), and 1,2-cyclohexanediamine (DCH)] were 95% pure and were supplied by the DuPont Company. The acute toxicity of all three chemicals is relatively low with acute oral lethal levels in the rat ranging from 1000 to 2300 mg/kg. Single 4-h inhalation exposures show similarly low toxicity with lethality produced in the rat at concentrations ranging from 2.9 to 4.3 mg/L. These diamines are severe skin irritants in both the rabbit and the guinea pig and are also severe eye irritants (studied only in 2-MP). Dermal sensitization was seen in the guinea pig with DAMP and DCH but not with 2-MP. The irritant dose of these materials was shown in repeated exposure inhalation studies when 2-MP and DCH produced irritation in the upper respiratory tract (point of contact) with some lower lung involvement but no significant systemic effects. 2-MP when fed to rats produced a slight body weight effect at dose equivalents of 800 mg/kg with no other parameters affected. All three materials were inactive in Salmonella, and 2-MP did not produce chromosomal aberrations in cultured human lymphocytes. The main effects of this series of diamines appear related to their irritant properties, and attention needs to be paid to their delayed hypersensitivity potential.     

Antigen dose‐dependent suppression of murine IgE responses is mediated by CD4−CD8− double‐negative T cells

Background The IgE response against protein antigens is profoundly influenced by the dose used for sensitization. Objective The aim of the study was to identify immune cells that are involved in antigen dose‐dependent regulation of IgE formation. Methods Wild‐type mice as well as T helper (Th)1‐deficient IL‐12p40^?/? and IFN‐γ^?/? mice were immunized by repeated intraperitoneal injection of either low doses (K01 mice) or high doses (K100 mice) of keyhole limpet haemocyanin adsorbed to aluminium hydroxide. Splenocytes of immunized mice were restimulated in vitro and antigen‐dependent T cell proliferation and cytokine production were measured. The frequency of regulatory T cell subsets among splenocytes from K01 and K100 mice was compared using fluorocytometry and RT‐PCR analysis. Splenocytes or T cell subpopulations were transferred into naïve mice and the effect of lymphocyte transfer on IgE production after priming of recipients with low antigen doses was determined. Results Specific IgE production was considerably impaired in K100 mice. Antigenic restimulation revealed hypoproliferation of K100 splenocytes and reduced production of Th2 cytokines IL‐4, IL‐5 and IL‐13, but no induction of IFN‐γ production. Moreover, lymphocytes from K01 and K100 mice did not show significant differences in the expression of molecules associated with the phenotype or activity of conventional regulatory T cells. Transfer of splenocytes or purified T cells from K100 mice substantially suppressed the induction of IgE production in the recipients in an antigen‐ and isotype‐specific manner. Neither CD4⁺ nor CD8⁺ T cells from K100 mice were able to inhibit IgE formation; instead, we identified CD4^?CD8^? double‐negative T cells (dnT cells) as the principal T cell population, which potently suppressed IgE production. Conclusion Our data demonstrate that CD4^?CD8^? dnT cells play a major role in the regulation of IgE responses induced by high antigen doses.     

Anchor Points in Transitions to a New School Environment

This exposition provides a theoretical framework for designing and implementing prevention programs for students in school-related transitions (e.g., entering kindergarten, transition to high school). For this purpose, an anchor point is defined in an ecological and developmental perspective as an element of the person-in-environment system that facilitates transaction between the person and the environment. Depending upon the context, anchor points can lead to adaptive transaction or maladaptive transaction. Features and examples of anchor points are discussed and proposed are procedures to plant positive anchor points which lead to adaptive transaction and children's development in a new person-in-environment system. Finally, its strengths in prevention programs for school-related transitions are addressed.