Performance in population models for count data,part II: A new SAEM algorithm

Analysis of count data from clinical trials using mixed effect analysis has recently become widely used. However, algorithms available for the parameter estimation, including LAPLACE and Gaussian quadrature (GQ), are associated with certain limitations, including bias in parameter estimates and the long analysis runtime. The stochastic approximation expectation maximization (SAEM) algorithm has proven to be a very efficient and powerful tool in the analysis of continuous data. The aim of this study was to implement and investigate the performance of a new SAEM algorithm for application to count data. A new SAEM algorithm was implemented in MATLAB for estimation of both, parameters and the Fisher information matrix. Stochastic Monte Carlo simulations followed by re-estimation were performed according to scenarios used in previous studies (part I) to investigate properties of alternative algorithms (Plan et al., 2008, Abstr 1372 []). A single scenario was used to explore six probability distribution models. For parameter estimation, the relative bias was less than 0.92% and 4.13% for fixed and random effects, for all models studied including ones accounting for over- or under-dispersion. Empirical and estimated relative standard errors were similar, with distance between them being <1.7% for all explored scenarios. The longest CPU time was 95 s for parameter estimation and 56 s for SE estimation. The SAEM algorithm was extended for analysis of count data. It provides accurate estimates of both, parameters and standard errors. The estimation is significantly faster compared to LAPLACE and GQ. The algorithm is implemented in Monolix 3.1, (beta-version available in July 2009).     

柯萨奇病毒诱发实验性多发性肌炎的初步研究

分别用不同量的柯萨奇病毒Ｂ１、２、３感染和兔肌匀浆加完全弗氏佐剂免疫正常豚鼠；拟建立多发性肌炎模型。结果发现：０．１ｍｌ毒力为１０－５ＴＣＩＤ５０柯萨奇病毒Ｂ１感染豚鼠组，３周后出现多发性肌炎症状。肌酶谱异常与其它组有明显差异，病理检查证实为多发性肌炎改变。单纯兔肌匀浆免疫对照组未发病。提示柯萨奇病毒Ｂ１感染及感染的病毒量与多发性肌炎的发病相关     

The influence of support conditions in the loading fixture on failure mechanisms in the push-out test: a finite element study

The usefulness of the push-out test as an indicator of interface strength was evaluated using finite element models of intact and partially failed cylindrical push-out specimens loaded against a rigid annular support. The irregular stress distributions that were found in intact specimens depended more on interface conditions at the loading fixture than on a 35% increase in interface area. The maximum stress at the interface was a tensile stress. Critical energy release rates for interface failure were calculated for flawed specimens in which flaw size was either 10 or 100 microns, and for boundary conditions at the loading fixture that were either fixed or slipping in the radial direction. The critical energy release rates depended heavily on the support boundary conditions. Thus, the results of parametric push-out tests can be reasonably compared only for specimens that are very similar in geometry and that are loaded in very carefully controlled fixtures.     

Lower level of serum potassium and higher level of C-reactive protein as an independent risk factor for giant aneurysms in Kawasaki disease

Giant aneurysms are the most serious issue of patients with Kawasaki disease (KD). To clarify risk factors for these giant aneurysms, we conducted a matched case-control study. Among the patients reported in nationwide surveys, 117 patients with giant aneurysms had an unequivocal new diagnosis and presented at the treatment center within 9 d of illness. We obtained clinical information on admission of about 69 patients (case) from the treatment centers. One control was selected for each case, an age- and sex-matched patient without coronary involvement, reported from the same treatment center at about the same time as the case, and we obtained the same clinical information about controls. Fourteen variables were analysed with a conditional logistic regression model: body temperature, hematocrit, hemoglobin, numbers of leukocyte and platelets, concentrations of serum albumin, globulin, total cholesterol, sodium, potassium and chloride, erythrocyte sedimentation rate, C-reactive protein and alanine aminotransferase activity. After adjustment for age, duration of illness before admission and use of intravenous gamma globulin therapy, C-reactive protein [odds ratio (OR) = 1.142, 95% confidence interval (CI) 1.054-1.237], alanine aminotransferase activity (OR = 1.008, 95% CI 1.002-1.014), serum sodium concentration (OR = 0.877, 95% CI 0.770-0.999) and serum potassium concentration (OR = 0.319, 95% CI 0.124-0.822) were significantly related to the risk for giant aneurysms. Further analyses with these four explanatory variables revealed that C-reactive protein (OR = 1.159, 95% CI 1.022-1.315) and serum potassium concentration (OR = 0.222, 95% CI 0.052-0.948) met the significant level. Thus, the values for serum C-reactive protein and potassium are independent risk factors for the development of the giant aneurysms of Kawasaki disease.     

金地鼠颊囊癌模型PCNA,BrdU及光镜观察结果的相关分析

癌变的早期诊断对提高疗效具有特殊意义，为了寻求简捷，高效，超前，可靠的诊断方法，实验以ＤＭＢＡ（二甲基苯并蒽）诱导的金地鼠颊囊致癌模型为对象，以ＰＣＮＡ（增殖细胞核抗原）ＢｒｄＶ（溴脱氧尿嘧啶）等免疫组化技术为手段；以光镜观察诊断为对照，对三种观察结果进行相关分析，发现三者间有高度显著的相关性，证实了免疫组化方法在癌变诊断中有一定的参考价值，实验还发现ＰＣＮＡ和ＢｒｄＵ检测结果比较每天敏感，简捷，     

Estimation of instantaneous flow from the indicator-dilution curve after bolus injection of indicator

The indicator-dilution technique is commonly used to determine mean flow estimates. The estimation of instantaneous flow from the shape of an indicator-dilution curve is the objective of this study. Based on a mixing chamber approach to the flow system, a mathematical relationship is derived to reconstruct momentary flow from an indicator-dilution curve. This relationship is verified in a model setup both with only constant flow and with a sinusoidal flow variation superimposed. This method proved to give good flow estimates for limited values of flow parameters. Also, some preliminary experiments were performed in a pulsating flow system simulating heart action. The results were promising although the method proved to be very sensitive to baseline offset.     

Persistent otitis media with effusion: A new experimental model

Objectives/Hypothesis: Numerous mechanical animal models for the creation of otitis media with effusion (OME) have been described since the 1920s. However, there are many problems associated with these models, including high infection rates, unreliability, and high resolution rates. The aim of the current study was to create a suitable mechanical animal model that would produce a sterile and long-lasting effusion. Study Design: A new technique using an external surgical approach on specific pathogen–free rats is described. Method: The eustachian tubes of 56 rats were obstructed in the mid portion along the skull base with gutta percha. Results: All animals developed an effusion within 1 week of the procedure. The resolution rate was 8%, with 80% maintaining sterile effusions for up to 1 year. Conclusions: This new procedure for an OME model has proved consistently reliable in creating a persistent and long-lasting effusion. It has a low infection rate and should benefit future studies on the prolonged effects of OME on the tympanic membrane and middle ear.     

Olopatadine hydrochloride suppresses the rebound phenomenon after discontinuation of treatment with a topical steroid in mice with chronic contact hypersensitivity

BACKGROUND: Olopatadine hydrochloride (olopatadine; Allelock) is one of the second-generation antihistamines that are treated for allergic disorders such as rhinitis, urticaria and eczema dermatitis. Olopatadine has recently been shown to have inhibitory effects on the chronic contact hypersensitivity induced by repeated application of oxazolone in mice. Although topical steroids have widely been prescribed for atopic dermatitis, a relapse often occurs within several days after discontinuation of their prolonged use. OBJECTIVES: We investigated the possible efficacy of olopatadine against the relapse after discontinuation of prolonged use of topical prednisolone in the Balb/c mice with oxazolone-induced chronic contact hypersensitivity. METHODS: Mice with the chronic contact hypersensitivity induced by repeated application of oxazolone were treated with olopatadine as a sequential therapeutic agent. The effects of olopatadine were quantified by measurements of ear-swelling, and levels of cytokines and histamine in the lesioned ear. Results Topical prednisolone (0.05 mg/ear/day) significantly inhibited the increases in ear swelling and production of IL-1beta, IL-4, IL-18, granulocyte-macrophage colony-stimulating factor (GM-CSF) and histamine. However, after discontinuation of the treatment with topical prednisolone, the inflammation relapsed and the IL-4 level exceeded the control one. The sequential treatment with olopatadine (10 mg/kg/day) after discontinuation of the treatment with topical prednisolone alone, or topical prednisolone with olopatadine, significantly inhibited the increases in ear swelling and levels of IL-1beta, IL-4, IL-18, GM-CSF, nerve growth factor and histamine. CONCLUSIONS: These results indicate that olopatadine is an antihistamine agent having inhibitory activities against the rebound phenomenon following the discontinuation of topical steroid therapy. Olopatadine is thus expected to be a sequential therapeutic agent after discontinuation of the chronic treatment with a topical steroid.     

The Dubbelman eye model analysed by ray tracing through aspheric surfaces

Dubbelman and co-workers have determined intraocular spacings and surface shapes in living eyes by means of corrected Scheimpflug images in a large number of subjects of different age at several levels of accommodation. They give relationships for key anterior segment parameters as a function of age and level of accommodation. These are used in this paper to build a schematic eye incorporating aspheric surfaces. This eye model is analysed by means of ray tracing with a technique developed for use with a common spreadsheet computer program. The Dubbelman eye model appears to be well corrected for spherical aberration. Compared with measurements on real eyes it agrees well in general, but spherical aberration is negative, while in real eyes it tends to be positive.