Cytotoxicity of chemicals used in household products: estimation of eye irritating potency of 25 chemicals tested during 1991-1996

Cytotoxicity potential of chemicals was evaluated by determining the concentrations inducing 50% reduction of neutral red (NR) uptake into Chinese hamster fibroblast V79 cells compared with control culture (IC50). The results of cytotoxicity test for surfactants with the data produced by the in vivo Draize eye and skin irritation test were compared. There was a good correlation between cytotoxicity and eye irritation score obtained from the Draize test. In contrast, no correlation was observed between Draize skin irritation score and cytotoxic potential of chemicals. Therefore, the NR cytotoxicity test was regarded as a possible in vitro model for predicting eye irritation. Based on the IC50 values in the NR cytotoxicity test, the eye irritation classification (weak, moderate and strong) for each chemical used in household products has been established. We evaluated the cytotoxicity of 25 chemicals used for antimicrobial, rubber accelerator, rubber antioxidant, ultraviolet absorber etc. in household products, and estimated the eye irritating potency of these test chemicals according to the criterion.     

In vitro cytotoxicity test for estimating non-ocular irritation dose of ophthalmic solutions

The in vitro cytotoxicity test for estimating the non-ocular irritation dose of ophthalmic solutions was investigated. In the in vitro test, normal human epidermal keratinocytes (NHEK) in a confluent monolayer were incubated for 48 hr in a medium with test compounds. The concentration of a test compound which causes a 50% reduction in NHEK viability was determined as IC50 by MTT colorimetric assay. For comparison, the in vivo rabbit ocular irritation tests were carried out by the standard Draize method. The maximum concentration, which did not show any ocular irritation, was determined as DS0. The results showed the correlation coefficient between the IC50 values and the DS0 values for 19 test compounds to be 0.82. However, the correlation coefficients for 10 compounds, which have IC50 values of less than 300 micrograms/ml, and for 7 alcohols were 0.99. The IC50-DS0 correlation curves obtained could be utilized as the critical concentrations for ocular irritation. These results suggest that our in vitro/in vivo test can estimate non-ocular irritation dose of the ophthalmic preparations in advance of the in vivo tests.     

Intraocular irritation evaluation of benzalkonium chloride in rabbits

The purpose of this study was to define the threshold for intraocular irritation of benzalkonium chloride, a preservative used in some formulations which enter the anterior segment of the eye during ocular surgery. Various concentrations of benzalkonium were injected into anterior chambers of albino rabbit eyes. Conjunctivitis, flare, iritis, and corneal changes occurred in a dose response pattern. The threshold of irritation was 0.03%, with highest nonirritating concentration being 0.01%. In other works in this laboratory, threshold of irritation for topical ocular benzalkonium was 0.05%, but the nature of ocular changes was less substantial than those observed intraocularly. Because the threshold for intraocular irritation is less than that topically, the nature of ocular changes was different for two routes, and there is a paucity of clinical data for intraocular benzalkonium chloride, a safety factor of 10 was utilized in setting the highest safe concentration of 0.001% for intraocular use. The preservative efficacy of 0.001% is questionable; therefore, we cannot endorse benzalkonium chloride as a preservative for formulations which will enter the anterior segment of the eye.     

Mefenamic acid bioequivalence assessment with a new statistical procedure

The bioequivalence of three different formulations of mefenamic acid was tested using the index zeta 2 previously defined by Rescigno. This index is a measure of the distance in Hilbert space of two concentration vs time functions; unlike the approach of Westlake which assumes a multiplicative model for the AUC and Cmax characteristics, this approach does not imply any hypotheses on the structure of the data and no particular model of the absorption or of the elimination processes. The index zeta 2 is simply an indication of how similar two formulations are. Results for this new test were compared with those obtained with two other tests, namely 90 and 95% symmetrical confidence intervals of Westlake and two one-sided t-tests of Shuirmann through the 90% confidence intervals in the ranges 80-125% for AUC and 70-143% for Cmax. Results of the new test are fully comparable with those obtained using the other two tests.     

Decision support issues using a physiology based score

OBJECTIVE: As physiology based assessments of mortality risk become more accurate, their potential utility in clinical decision support and resource rationing decisions increases. Before these prediction models can be used, however, their performance must be statistically evaluated and interpreted in a clinical context. We examine the issues of confidence intervals (as estimates of survival ranges) and confidence levels (as estimates of clinical certainty) by applying Pediatric Risk of Mortality III (PRISM III) in two scenarios: (1) survival prediction for individual patients and (2) resource rationing. DESIGN: A non-concurrent cohort study. SETTING: 32 pediatric intensive care units (PICUs). PATIENTS: 10608 consecutive patients (571 deaths). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: For the individual patient application, we investigated the observed survival rates for patients with low survival predictions and the confidence intervals associated with these predictions. For the resource rationing application, we investigated the maximum error rate of a policy which would limit therapy for patients with scores exceeding a very high threshold. For both applications, we also investigated how the confidence intervals change as the confidence levels change. The observed survival in the PRISM III groups >28, >35, and >42 were 6.3, 5.3, and 0%, with 95% upper confidence interval bounds of 10.5, 13.0, and 13.3%, respectively. Changing the confidence level altered the survival range by more than 300% in the highest risk group, indicating the importance of clinical certainty provisions in prognostic estimates. The maximum error rates for resource allocation decisions were low (e. g., 29 per 100000 at a 95% certainty level), equivalent to many of the risks of daily living. Changes in confidence level had relatively little effect on this result. CONCLUSIONS: Predictions for an individual patient's risk of death with a high PRISM score are statistically not precise by virtue of the small number of patients in these groups and the resulting wide confidence intervals. Clinical certainty (confidence level) issues substantially influence outcome ranges for individual patients, directly affecting the utility of scores for individual patient use. However, sample sizes are sufficient for rationing decisions for many groups with higher certainty levels. Before there can be widespread acceptance of this type of decision support, physicians and families must confront what they believe is adequate certainty.     

基于光谱信息与温度的转炉炼钢终点预测模型

转炉炼钢终点就是在出钢时通过控制使钢水的成分和温度达到一定要求。原子发射光谱法显示的元素特征光谱波长下的光谱信息的变化,能反应成分含量的变化趋势。文章介绍了基于温度和光谱信息的终点预测模型的系统,通过此系统获取转炉炼钢过程中的温度和Mn、Si光谱信息,利用多元回归分析的方法建立终点预测模型,并对模型进行显著性检验和精度分析。研究表明,此模型的终点命中率在80%左右,能比较准确预测转炉炼钢的终点。如果在预测模型中加入更多的元素光谱信息,将能进一步提高终点命中率。     

Non-insulin dependent diabetes--the past, present and future

The aim of this investigation was to establish a new model for phototoxicity which is more advanced than the widely used cultures of yeasts, bacteria or cells of various origin, and at the same time to avoid animal testing. We studied the extraembryonal vasculature of the incubated hen's egg. This model was originally introduced by toxicologists as an alternative to the rabbit's eye irritation test (Draize test). In the photo hen's egg test, substances are applied to the embryo's yolk-sac blood vessel system at a non-toxic concentration and are irradiated with 5 J/cm2 ultraviolet A (UVA) (320-400 nm). Promethazine, haematoporphyrin, ciprofloxacin and 8-methoxypsoralen were tested in this system. Death of the embryo, membrane discoloration and haemorrhage are parameters for phototoxic damage, which were recorded during an observation period of 24 h. These well-known phototoxic substances induced pronounced damage of the yolk-sac membrane and blood vessels which was not found in the controls (test substance alone, UVA alone or untreated) using a 2 x 2 factorial test design. The photo hen's egg test serves as a valid screening model for substances supposed to be photosensitizers owing to a phototoxic mechanism.     

Confidence intervals for the cross-validated multiple correlation in predictive regression models.

Presents improved procedures to approximate confidence intervals for ρ–2 and ρc–2 in both fixed and random predictor models. These approximations require neither point estimates nor variance estimates and are analytically shown to be precise enough for most practical prediction purposes. An application of confidence intervals in regression model development is also given. (16 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

CD4 cell count as a surrogate endpoint in HIV clinical trials: a meta-analysis of studies of the AIDS Clinical Trials Group

OBJECTIVE: To evaluate initial changes in CD4 cell count as a surrogate endpoint for clinical outcome in HIV-infected patients. DESIGN: Meta-analysis of all relevant Phase II and III randomized clinical trials undertaken by the Adult AIDS Clinical Trials Group. METHODS: Individual patient data were obtained from each clinical trial, and the difference between a pair of treatments in their effect on clinical outcome (AIDS or death, or death alone) during 2 years of follow-up was evaluated. The proportion of treatment effect explained (PTE) was the proportion of this difference explained by the change in CD4 cell count 6 months after starting treatment, evaluated using proportional hazards models. A weighted average PTE across treatment comparisons was obtained. The association between the difference between treatments in clinical outcome, expressed as hazard ratio, and the difference in mean change in CD4 cell count was evaluated using regression analysis. RESULTS: There were 15 clinical trials involving 24 treatment comparisons. The weighted average PTE for both progression to AIDS or death was 0.16 [95% confidence interval (Cl), 0.07-0.26] and for death was 0.10 (95% Cl, 0.00-0.20). There were significant associations between treatment differences in effect on AIDS or death, and on death alone, and the difference in mean change in CD4 cell count. A difference in mean change in CD4 cell count of 30 or 40 x 10(6)/l or more in favor of the test treatment indicated with high probability that there was a corresponding difference in progression to AIDS or death. CONCLUSIONS: The small PTE suggest that other mechanisms of drug action not captured by initial change in CD4 cells are important. CD4 cell count is a weak surrogate endpoint, but has some value as an aid for screening treatments for drug development or preliminary regulatory approval.     

Statistical Considerations for Predicting Residual Value of Heavy Equipment

Residual value needs to be considered in owning cost calculations for used heavy construction equipment. Its dependency on factors such as manufacturer and model, equipment age, and condition rating can best be examined by analyzing real market data from equipment auctions. Macroeconomic indicators can also be included to examine any potential influence of the overall economy on auction prices. This paper discusses statistical considerations for performing such a residual value analysis. Considerations include the study type, data properties, identifying outlier observations, regression assumptions, and formulating and selecting an appropriate regression model using the adjusted coefficient of determination. A second-order polynomial of equipment age with additive factors appears promising as the final regression model. Adjusted confidence and prediction intervals are created to correctly display residual value. Cross-validation using randomly split halves of the dataset is performed. Actual data for medium track dozers are used to illustrate the validity of the methodology.     

Metacognitive influences on study time allocation in an associative recognition task: An analysis of adult age differences.

The current study evaluated a metacognitive account of study time allocation, which argues that metacognitive monitoring of recognition test accuracy and latency influences subsequent strategic control and regulation. The authors examined judgments of learning (JOLs), recognition test confidence judgments (CJs), and subjective response time (RT) judgments by younger and older adults in an associative recognition task involving 2 study–test phases, with self-paced study in Phase 2. Multilevel regression analyses assessed the degree to which age and metacognitive variables predicted Phase 2 study time independent of actual test accuracy and RT. Outcomes supported the metacognitive account—JOLs and CJs predicted study time independent of recognition accuracy. For older adults with errant RT judgments, subjective retrieval fluency influenced response confidence as well as (mediated through confidence) subsequent study time allocation. Older adults studied items that had been assigned lower CJs longer, suggesting no age deficit in using memory monitoring to control learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Tests for atopic antigens

It is important to determine what kind of antigen is involved in atopic asthma for appropriate management as well as diagnosis. We can measure total IgE and antigen specific IgE antibodies by means of RIA and EIA in vitro. Antigen specific IgE antibodies can be detected more sensitively by skin tests consisting of intradermal, prick and scratch tests, among which the intradermal test is most sensitive. To study if the antibody thus detected is functional, there are in vivo tests such as the provocation test and eye reaction with the corresponding antigen and in vitro tests such as the histamine release assay and CAST. In Japan we tend to prefer in vitro assays, while the skin test has been recommended more than in vitro assays in the United States.     

A mixture experiment approach for controlling the dissolution rate of a sustained-release tablet

Several sustained-release tablet formulations with acceptable pharmacokinetic properties were found to be unstable because of the effects of lactose. Because the pharmacokinetic properties were acceptable, an attempt was made at developing stable formulations that reproduced the in vitro drug release characteristics of the unstable formulations. Through the use of a statistically designed mixture experiment, alternative formulations were generated and tested for dissolution. The dissolution data collected in the mixture experiment were used to develop a statistical regression model for identifying formulations with dissolution rates equal to those of the unstable formulations. The form of the regression model was based on the Higuchi equation. The data analysis indicated that it is possible to generate dissolution profiles that reproduce those of the original formulations by adjusting the ratios of Methocel K4MCR Premium and Methocel K100MCR Premium and by replacing the detrimental lactose with calcium phosphate dibasic anhydrous.     

Appearance of 1-2 Mbp giant DNA fragments as an early common response leading to cell death induced by various substances that cause oxidative stress

OBJECTIVE: To present an application of logistic regression modelling to estimate ratios of proportions, such as prevalence ratio or relative risk, and the Delta Method to estimate confidence intervals. METHOD: The Delta Method was used because it is appropriate for the estimation of variance of non-linear functions of random variables. The method is based on Taylor's series expansion and provides a good approximation of variance estimates. A computer program, utilizing the matrix module of SAS, was developed to compute the variance estimates. A practical demonstration is presented with data from a cross-sectional study carried out on a sample of 611 women, to test the hypothesis that the lack of housework sharing is associated with high scores of psychological symptoms as measured by a validated questionnaire. RESULTS: Crude and adjusted prevalence ratio estimated by logistic regression were similar to those estimated by tabular analysis. Also, ranges of the confidence intervals of the prevalence ratio according to the Delta Method were nearly equal to those obtained by the Mantel-Haenszel approach. CONCLUSIONS: The results give support to the use of the Delta Method for the estimation of confidence intervals for ratios of proportions. The method should be seen as an alternative for situations in which the need to control a large number of potential confounders limits the use of stratified analysis.     

Guidelines for Two-Parameter Weibull Analysis for Flaw-Containing Materials

Two-parameter Weibull statistics used in the analysis of mechanical data from flaw-containing materials, such as ceramics and castings, are reviewed. Guidelines to estimate Weibull parameters with the linear regression technique are provided. Moreover goodness-of-fit tests for Weibull fits and calculating confidence intervals for the estimated Weibull modulus are discussed. Methods of estimating lower bounds as well as a new hypothesis test for comparing two estimated Weibull moduli are explained. The use of these guidelines is demonstrated by using data from the literature.     

Relative bioavailability of paracetamol in suppositories preparations in comparison to tablets

Relative Bioavailability of Paracetamol as Suppositories Compared to Tablets. The relative bioavailability of paracetamol (CAS 103-90-2) in ben-u-ron 500 mg and ben-u-ron 1000 mg suppositories (test formulations) was compared with that of Benuron tablets 500 mg (reference product) in an open, intraindividual, 3-period-changeover-study in 18 healthy subjects. Plasma concentrations of paracetamol were determined using a specific and sensitive HPLC method with UV detection. For the assessment of bioavailability AUC, Cmax, tmax and HVD were used as pharmacokinetic characteristics. Bioequivalence of the rectal formulations was tested by calculating 90% confidence intervals using the Two-one-sided-t-tests-procedure and log-transformed data of AUC and Cmax. For AUC the confidence intervals were required to be in the 80 and 125% range, for Cmax between 70 and 143% (inclusion rule). Data from 17 subjects could be evaluated. Bioavailability of paracetamol was 89 and 90% for the 500 and 1000 mg suppositories, respectively compared with that of the 500 mg reference tablets. Mean maximum paracetamol plasma concentrations (Cmax) were 3.55 and 6.02 or 7.16 mg/l after administration of the 500 and 1000 mg suppositories or the 500 mg tablets, respectively. These maximum concentrations were achieved 2.0, 2.7 and 0.6 h (tmax) after administration of the respective preparations. The corresponding HVD values were 4.3, 5.2 and 2.0 h, respectively. After dose adjustment of the results for the 1000 mg suppositories relative bioavailabilities of paracetamol from both rectal formulations exceeded 80% of that from the tablets.(ABSTRACT TRUNCATED AT 250 WORDS)     

Data-Driven Approach Using Supervised Learning for Predicting Endpoint Temperature of Molten Steel in the Electric Arc Furnace

This study presents the development of a decision support system that focuses on predicting the endpoint temperature of molten steel to manage the process of an electric arc furnace more systematically. The decision support system leverages a data-driven approach that consists of the following modules: 1) a data preprocessing module that specifically includes raw data filtering, feature engineering, and outlier detection; 2) a feature selection module based on domain knowledge; 3) regression modeling module that employs a supervised learning algorithm to forecast an endpoint temperature; and 4) sensitivity analysis module to identify the correlation between input and output metric. The applicability of the system is demonstrated through a validation study using real-world operational data from Hyundai Steel located in Pohang, South Korea. The validation results show that the endpoint temperatures predicted by the system are evenly scattered to a perfect-fit line within 5% errors of the actual temperatures. The results also indicate that CaO, power, and melting score have the most significant impact on the endpoint temperature, in which temperature decreases as CaO increases and increases as the power and melting score increase.     

Evaluation of skin irritation and sensitization of two diol solutions used as experimental dentin primers in humans and guinea pigs

The purpose of the present study was to evaluate the safety of ethylene glyco (EG) and 1,6-hexanediol (HD) solutions as experimental dentin primers when subjected to the guinea pig maximization test (GPMT), primary irritation test, cumulative skin irritation test and human patch test. No primary and cumulative skin irritation resulting from the use of 62.5% EG or 45% HD solutions was observed. In the case of GPMT, the animals sensitized with 2-hydroxyethyl methacrylate (2-HEMA) responded to 100% HD. 62.5% EG and 45% HD as dentin primers were safer than 2-HEMA such as a methacrylic primer.     

The Mayo Clinic-Canadian Cooperative trial of sulfasalazine in active multiple sclerosis

OBJECTIVE: To determine whether sulfasalazine is better than placebo in slowing disability progression in MS. METHODS: In this randomized, double-blind, placebo-controlled phase III trial, 199 patients with active relapsing-remitting (n = 151) or progressive (n = 48) MS were evaluated at 3-month intervals for a minimum of 3 years (94% completed 3 years of follow-up; mean follow-up, 3.7 years). MRI studies were performed at 6-month intervals on a subset of 89 patients. RESULTS: Sulfasalazine failed to slow or prevent disability progression as measured by the primary outcome (confirmed worsening of the Expanded Disability Status Scale [EDSS] score by at least 1.0 point on two consecutive 3-month visits). Sulfasalazine influenced favorably a number of secondary outcomes during the first 18 months of the trial (e.g., annualized relapse rate, proportion of relapse-free patients; progressive subgroup only: rate of EDSS progression at 1 and 2 years, median time to EDSS progression) but these positive findings were not sustained into the second half of the trial. CONCLUSIONS: Sulfasalazine does not prevent EDSS score progression in the subset of MS patients studied by this protocol. Treatments may improve relapse-related outcomes in MS, at least temporarily, without providing sustained slowing of EDSS progression. Phase III MS trials should be of sufficient length to determine a meaningful impact on disease course.     

Pilot-Scale Evaluation of Chemical Cleaning Protocols for Organic and Biologically Fouled Microfiltration Membranes

The Edward C Little Water Recycling Facility (ECLWRF) is the largest high-purity water recycling facility in the United States. Here, microfiltration (MF) membranes play a critical role in treating the secondary effluent and serving as pretreatment to the downstream reverse osmosis systems. New chemical clean-in-place (CIP) formulations were evaluated through pilot-scale tests for their ability to improve the performance restoration for the Phase III continuous MF (CMF) membranes at the ECLWRF. Membrane autopsies found that the primary fouling mechanisms for the CMF membranes were biological and organic in origin. It was also determined that the current CIP protocol provided an incomplete removal of the biological and organic foulants. The cleaning test results found that the current CIP regime for the Phase III system performed better than the four commercially available cleaning solutions evaluated here. However, improved results were obtained when hydrogen peroxide was added to the current CIP regime consisting of caustic soda and the commercially available Memclean C cleaning solution. The effects of the addition of hydrogen peroxide to the standard cleaning procedure shows some promise; however, further research is needed to understand the cleaning mechanisms and long-term effects of using hydrogen peroxide as a cleaning additive.