Biomedical subjects

Isao Yoshimura

Publications and source records attributed to Isao Yoshimura.

At least 19 recordsLinked to original sources

PubMed2007

A method for therapeutic dose selection in a phase II clinical trial using contrast statistics.

This paper proposes a statistical method for determining the therapeutic dose of a test drug in a confirmatory clinical trial based on a phase II clinical trial using 3 or 4 doses of the drug. This method assumes the primary variable has a normal distribution with a common variance, that a test-drug effect is seen when the population means show a response pattern indicating a monotonic increase with dose, and that there is a prior distribution for the population means. Under the proposed method, multiple contrast statistics are determined, such as contrast statistics for linear increase and plateau, and a response pattern is selected based on the maximum contrast statistic. The posterior probability that the selected response pattern is the true one is evaluated, and if this exceeds the cut-off value a therapeutic dose is selected based on the estimated response pattern. To select the appropriate cut-off value, a simulation study was conducted using a loss function for which the loss due to overestimation is greater than the loss due to underestimation. It was found that, as a rule, the appropriate cut-off value to reduce the expected loss for various response patterns is 0.75 for a 3-group trial and 0.70 for a 4-group trial. Using these cut-off values, the proposed method was applied to a previous clinical trial of a leukotriene receptor antagonist in patients with bronchial asthma. The method enabled the selection of what are considered appropriate response patterns and a therapeutic dose. Thus, the proposed method appears reasonable.

Asthma↗

PubMed2006

The confidence interval of allelic odds ratios under the Hardy-Weinberg disequilibrium.

In single nucleotide polymorphism (SNP) data analysis, the allelic odds ratio and its confidence interval (CI) are usually used to evaluate the association between disease and alleles at each SNP. The usual formula for calculating the CI of the allelic odds ratio based on the Hardy-Weinberg equilibrium (HWE) may, however, lead to errors beyond the control assured by the nominal confidence level if HWE is not true. We therefore present a generalized formula for CI that does not assume HWE. CIs calculated by this generalized formula are likely to be wider than those by the usual method if the Hardy-Weinberg disequilibrium (HWD) is toward a relative deficiency of the heterozygotes (fixation index greater than 0), whereas they are likely to be narrower if HWD is toward a relative excess of the heterozygotes (fixation index less than 0). A simulation experiment to examine the influence of the generalization was performed for the case where 2% of SNPs had a fixation index greater than 0. The result revealed that the generalized method slightly decreased the mean number of falsely detected SNPs.

Alleles↗

PubMed2006

Minimization method for balancing continuous prognostic variables between treatment and control groups using Kullback-Leibler divergence.

This paper proposes a method for balancing prognostic variables between treatment and control groups in design of clinical trials. It assumes that some of prognostic variables are continuous and others are categorical and that they are independently distributed. The proposed method uses the Kullback-Leibler divergence (KLD) as the index of difference in distribution between two groups. It sequentially allocates each subject to a group using a biased coin method so as to reduce the estimate of KLD. That is, when first i subjects have been allocated to two groups and the (i+1)th subject is enrolled, the KLD is estimated if the (i+1)th subject was to be allocated to either of the groups, and the subject is then allocated with a certain probability, e.g. 0.80, so as to make the KLD small. Simulation studies based on the hypothetical prognostic variables and on the actual data of hyperlipidemia patients were carried out in order to compare the proposed method with the Pocock-Simon method, which transforms the continuous prognostic variables into categorical variables by dividing the whole scale into several categories. The p values of homogeneity test of means and variances were used to evaluate the achieved balance. The observed p values in the proposed method were better than those in the Pocock-Simon method. In addition to the balance, the precision of parameter estimates assuming analysis of covariance model was examined. The results showed the precision of estimators tended to be more stable in the proposed method than the Pocock-Simon method.

Clinical Trials as Topic↗

PubMed2006

Effective number of subjects and number of raters for inter-rater reliability studies.

A reliability study in which multiple raters evaluate multiple subjects was assumed in order to confirm the inter-rater reliability of rating scales. The two-way ANOVA model defining subjects and raters as random effects was applied, and the combination of the number of subjects and the number of raters that minimizes variance of the intraclass correlation coefficient (ICC) with a fixed total number of ratings (number of subjects x number of raters) was studied. The results revealed that the optimal combination depends on the relative ratio (between-rater variance/error variance), and that large number of raters brings the high precision of estimation of the ICC when the relative ratio was greater. It was concluded that when information concerning the relative ratio is unreliable, the use of identical numbers of raters and subjects minimizes variance when the relative ratio is substantially large and variance is maximized, providing a good study design from the viewpoint of 'maximin'.

Humans↗

PubMed2006

Mouse lymphoma thymidine kinase gene mutation assay: follow-up meeting of the International Workshop on Genotoxicity Testing--Aberdeen, Scotland, 2003--Assay acceptance criteria, positive controls, and data evaluation.

The Mouse Lymphoma Assay (MLA) Workgroup of the International Workshop on Genotoxicity Testing (IWGT), comprised of experts from Japan, Europe, and the United States, met on August 29, 2003, in Aberdeen, Scotland, United Kingdom. This meeting of the MLA Workgroup was devoted to reaching a consensus on the appropriate approach to data evaluation and on acceptance criteria for both the positive and negative/vehicle controls. The Workgroup reached consensus on the acceptance criteria for both the agar and microwell versions of the MLA. Recommendations include acceptable ranges for mutant frequency, cloning efficiency, and suspension growth of the negative/vehicle controls and on criteria to define an acceptable positive control response. The recommendation for the determination of a positive/negative test chemical response includes both the requirement that the response exceeds a defined value [the global evaluation factor (GEF)] and that there also be a positive dose-response (evaluated by an appropriate statistical method).

Animals↗

PubMed2006

Existence of a no effect level for MeIQx hepatocarcinogenicity on a background of thioacetamide-induced liver damage in rats.

As exposure to heterocyclic amines might increase the risk of liver cancer, we investigated the carcinogenic potential of MeIQx under conditions of liver damage caused by TAA. Male, 6-week-old F344 rats (n = 280) were divided into 14 groups; groups 1-7 received TAA (0.03% in drinking water) and groups 8-14 received water for the first 12 weeks. Thereafter, the animals received MeIQx at doses from 0, 0.001, 0.01, 0.1, 1, 10 to 100 p.p.m. (groups 1-7 and 8-14, respectively) in pellet basal diet for 16 weeks. All survivors were killed at week 28 for assessment of numbers and areas of GST-P positive foci, considered to be pre-neoplastic lesions of the liver. Values were increased significantly in all the groups receiving TAA-->MeIQx compared to MeIQx alone (P < 0.01). Numbers of GST-P positive foci were significantly increased in groups 7 and 14 (treated with 100 p.p.m. MeIQx) as compared to 0 p.p.m.-MeIQx (groups 1 and 8) (P < 0.01), along with areas in group 14 compared to group 8 (P < 0.01). However, with the maximum likelihood method, the data for numbers of GST-P positive foci (groups 1-7 and groups 8-14) fitted the hockey stick regression model, representing no differences from groups 1-5 and from groups 8-13, despite a linear dose-dependent increase of MeIQx-DNA adducts from 0.1 to 100 p.p.m. We conclude that there is a no effect level for MeIQx hepatocarcinogenicity, even on a background of TAA-induced liver damage.

5-Methylcytosine↗

PubMed2006

Influence of SNPs in cytokine-related genes on the severity of food allergy and atopic eczema in children.

Although many single nucleotide polymorphism (SNP) studies have reported an association of atopy, allergic diseases and total serum immunoglobulin E (IgE) levels, almost all of these studies sought risk factors for the onset of these allergic diseases. Furthermore, many studies have analyzed a single gene and hardly any have analyzed environmental factors. In these analyses, the results could be masked and the effects of other genes and environmental factors may be decreased. Here, we described the correlation between four genes [interleukin (IL)-4 (C-590T), IL-4 receptor (A1652G), FCER1B (G6842A) and STAT6 (G2964A)] in connection with IgE production; the role of IL-10 (C-627A) as a regulatory cytokine of allergy; and the severity of food allergy (FA) and atopic eczema (AE) in 220 Japanese allergic children. In addition to these SNPs, environmental factors, i.e., patient's attitude, indoor environment, and so on, were also investigated in this study. Our study was retrospective, and the correlation was analyzed by our defined clinical scores divided into three terms: worst symptoms, recent symptoms and general amelioration at the most recent examination during the disease course. Our results indicated that IL-10 AA, the genotype with lower IL-10 production, is associated with higher IgE levels in the serum (p < 0.0001, estimate; 0.912). Marginal liver abnormalities were observed in the subject group with both FA and AE (p < 0.1191, estimate; 0.1490). Our defined clinical scores enabled evaluation of various aspects of disease severity. Based on the scores, while no single SNP selected in this study determined severity, the combination of the SNP with laboratory data and environmental factors appeared to determine severity.

Adolescent↗

PubMed2006

Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial.

OBJECTIVE: We sought to evaluate the long-term efficacy and safety of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy. RESEARCH DESIGN AND METHODS: Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) >or=40 m/s, and HbA(1c) <or=9% were enrolled in this open-label, multicenter study and randomized to 150 mg/day epalrestat or a control group. After excluding the withdrawals, 289 (epalrestat group) and 305 (control group) patients were included in the analyses. The primary end point was change from baseline in median MNCV at 3 years. Secondary end points included assessment of other somatic nerve function parameters (minimum F-wave latency [MFWL] of the median motor nerve and vibration perception threshold [VPT]), cardiovascular autonomic nerve function, and subjective symptoms. RESULTS: Over the 3-year period, epalrestat prevented the deterioration of median MNCV, MFWL, and VPT seen in the control group. The between-group difference in change from baseline in median MNCV was 1.6 m/s (P < 0.001). Although a benefit with epalrestat was observed in cardiovascular autonomic nerve function variables, this did not reach statistical significance compared with the control group. Numbness of limbs, sensory abnormality, and cramping improved significantly with epalrestat versus the control group. The effects of epalrestat on median MNCV were most evident in subjects with better glycemic control and with no or mild microangiopathies. CONCLUSIONS: Long-term treatment with epalrestat is well tolerated and can effectively delay the progression of diabetic neuropathy and ameliorate the associated symptoms of the disease, particularly in subjects with good glycemic control and limited microangiopathy.

Adult↗

PubMed2005

Antioxidants and photoprotection in a lichen as compared with its isolated symbiotic partners.

Extreme desiccation and irradiation increase the formation of reactive oxygen species in organisms. Lichens are highly resistant to potential damage, but it is not known whether biochemical interaction between their fungal and algal partners is involved in conferring stress tolerance. Here, we show that antioxidant and photoprotective mechanisms in the lichen Cladonia vulcani are more effective by orders of magnitude than those of its isolated partners. When alone, both alga and fungus suffer oxidative damage during desiccation, but in the lichen, each appears to induce up-regulation of protective systems in the other. Without the fungal contact, the alga tolerates only very dim light and its photoprotective system is only partially effective; without the alga, the glutathione-based antioxidant system of the fungus is slow and ineffective. In the lichen, this mutually enhanced resistance to oxidative stress and, in particular, its desiccation tolerance are essential for life above ground. This lifestyle, in turn, increases the chance of dispersal of reproductive propagules and ensures their joint evolutionary success.

Antioxidants↗

PubMed2005

Fluorescent compounds from the cultured mycobiont of Amygdalaria panaeola.

New fluorescent compounds, named panaefluorolines D-H, were isolated from the cultured mycobiont of a lichen, Amygdalaria panaeola. The structures were elucidated on the basis of spectroscopic data, especially 2D-NMR. The relative configuration of panaefluoroline D was determined by means of X-ray crystallographic analysis.

Crystallography, X-Ray↗

PubMed2005

An inter-laboratory collaborative study by the Non-Genotoxic Carcinogen Study Group in Japan, on a cell transformation assay for tumour promoters using Bhas 42 cells.

The Bhas promotion assay is a cell culture transformation assay designed as a sensitive and economical method for detecting the tumour-promoting activities of chemicals. In order to validate the transferability and applicability of this assay, an inter-laboratory collaborative study was conducted with the participation of 14 laboratories. After confirmation that these laboratories could obtain positive results with two tumour promoters, 12-O-tetradecanoylphorbol-13-acetate (TPA) and lithocholic acid (LCA), 12 coded chemicals were assayed. Each chemical was tested in four laboratories. For eight chemicals, all four laboratories obtained consistent results, and for two of the other four chemicals, only one of the four laboratories showed inconsistent results. Thus, the rate of consistency was high. During the study, several issues were raised, each of which were analysed step-by-step, leading to revision of the protocol of the original assay. Among these issues were the importance of careful maintenance of mother cultures and the adoption of test concentrations for toxic chemicals. In addition, it is suggested that three different types of chemicals show positive promoting activity in the assay. Those designated as T-type induced extreme growth enhancement, and included TPA, mezerein, PDD and insulin. LCA and okadaic acid belonged to the L-type category, in which transformed foci were induced at concentrations showing growth-inhibition. In contrast, M-type chemicals, progesterone, catechol and sodium saccharin, induced foci at concentrations with little or slight growth inhibition. The fact that different types of chemicals similarly induce transformed foci in the Bhas promotion assay may provide clues for elucidating mechanisms of tumour promotion.

Animal Testing Alternatives↗

PubMed2004

Designing a multistage, SNP-based, genome screen for common diseases.

A genome-wide linkage equilibrium mapping is an emerging strategy to identify risk-modifying genes for common diseases, despite unsettled controversies upon many aspects, including its premises, designs, marker choices and cost benefits. One large-scale attempt in Japan aims to identify disease-associated single nucleotide polymorphisms (SNPs) for five diseases among the Japanese population: Alzheimer's disease, gastric cancer, diabetes, hypertension and asthma. Following an initial screening of c.a. 100,000 SNPs on 940 subjects (five diseases x 188 patients) to select about 2,000 SNPs, we compared which subsequent screening design is more appropriate, and an additional one or two screens to further narrow down any disease-associated SNPs within a fixed total volume of 15,040,000 typings (2,000 SNPs x five diseases x 1,504 subjects, comprising 752 cases and 752 controls). We employed a Monte Carlo simulation to evaluate the probability of identifying truly disease-associated SNPs. The results suggest the single additional stage design (i.e., total two-stage design including the initial screening of 100,000 SNPs) was more practicable for the simple reason that the gain in probability is considered insufficient relative to an associated increase in study complexity in the three-stage design.

Alleles↗

PubMed2004

Statistical comparison of random allocation methods in cancer clinical trials.

The selection of a trial design is an important issue in the planning of clinical trials. One of the most important considerations in trial design is the method of treatment allocation and appropriate analysis plan corresponding to the design. In this article, we conducted computer simulations using the actual data from 2158 rectal cancer patients enrolled in the surgery-alone group from seven randomized controlled trials in Japan to compare the performance of allocation methods, simple randomization, stratified randomization and minimization in relatively small-scale trials (total number of two groups are 50, 100, 150 or 200 patients). The degree of imbalance in prognostic factors between groups was evaluated by changing the allocation probability of minimization from 1.00 to 0.70 by 0.05. The simulation demonstrated that minimization provides the best performance to ensure balance in the number of patients between groups and prognostic factors. Moreover, to achieve the 1 percentile for the p-value of chi-square test around 0.50 with respect to balance in prognostic factors, the allocation probability of minimization was required to be set to 0.95 for 50, 0.80 for 100, 0.75 for 150 and 0.70 for 200 patients. When the sample size was larger, sufficient balance could be achieved even if reducing allocation probability. The simulation using actual data demonstrated that unadjusted tests for the allocation factors resulted in conservative type I errors when dynamic allocation, such as minimization, was used. In contrast, adjusted tests for allocation factors as covariates improved type I errors closer to the nominal significance level and they provided slightly higher power. In conclusion, both the statistical and clinical validity of minimization was demonstrated in our study.

Aged↗

PubMed2003

Mouse lymphoma thymidine kinase gene mutation assay: International Workshop on Genotoxicity Tests Workgroup report--Plymouth, UK 2002.

The Mouse Lymphoma Assay (MLA) Workgroup of the International Workshop on Genotoxicity Tests (IWGT) met on June 28th and 29th, 2002, in Plymouth, England. This meeting of the MLA group was devoted to discussing the criteria for assay acceptance and appropriate approaches to data evaluation. Prior to the meeting, the group conducted an extensive analysis of data from both the microwell and soft agar versions of the assay. For the establishment of criteria for assay acceptance, 10 laboratories (6 using the microwell method and 4 using soft agar) provided data on their background mutant frequencies, plating efficiencies of the negative/vehicle control, cell suspension growth, and positive control mutant frequencies. Using the distribution curves generated from this data, the Workgroup reached consensus on the range of values that should be used to determine whether an individual experiment is acceptable. In order to establish appropriate approaches for data evaluation, the group used a number of statistical methods to evaluate approximately 400 experimental data sets from 10 laboratories entered into a database created for the earlier MLA Workshop held in New Orleans [Environ. Mol. Mutagen. 40 (2002) 292]. While the Workgroup could not, during this meeting, make a final recommendation for the evaluation of data, a general strategy was developed and the Workgroup members agreed to evaluate this new proposed approach using their own laboratory data. This evaluation should lead to a consensus global approach for data evaluation in the near future.

Animals↗

PubMed2003

Evaluation of nonthreshold leukemogenic response to methyl nitrosourea in p53-deficient C3H/He mice.

The classic controversy of whether genotoxic chemicals induce cancers with or without a certain low-dose limit, i.e., the threshold, is revisited because of a number of current publications available addressing the plausibility of "practical" thresholds even for genotoxic carcinogens, the mechanism of which may be hypothesized to be due, in part, to a repair system composed of ordinarily available various defense mechanisms under the steady-state DNA damage. The question of whether an absolute nonthreshold or a relative nonthreshold, i.e., a "practical" threshold specifically in the low-dose level, is present may not be answered even with the use of a prohibitively large number of wild-type mice. Could the excessive incidence of tumorigenesis in p53-deficient mice contribute to our understanding of the threshold vs nonthreshold issue in genotoxic carcinogenesis? This is considered because an exaggeration of tumorigenesis in p53-deficient mice is hypothesized to reduce or eliminate the range of threshold due to the p53-deficiency-mediated reduction of DNA repair and apoptosis. The present study of chemical leukemogenesis in p53-deficient mice by transplantation assay was designed to answer this question. Briefly, 218 C3H/He mice were lethally irradiated and repopulated with bone marrow cells from wild-type, heterozygous p53-deficient, and homozygous p53-deficient C3H/He mice. This was followed by treatment with a single and graded dose of methyl nitrosourea at 6.6, 14.8, 33.3, 50.0, and 75.0 mg/kg body wt, with the vehicle-treated control groups treated with zero dose for each genotype. Whereas mice repopulated with p53-deficient bone marrow cells showed a marked reduction of the threshold for leukemogenicity, mice repopulated with wild-type bone marrow cells did not exhibit leukemia at a dose of 33.3 mg/kg body wt and showed a curve with a high probability for the linear regression model with a positive dose intercept, predicting a threshold by the likelihood ratio test. Thus, the failure of wild-type mice to show an increase in incidence of leukemogenesis at low doses of genotoxic carcinogens may be due not to a statistical rarity, but to various p53-related pharmacophysiological functions, possibly including DNA repair and apoptosis that may account for a threshold.

Alkylating Agents↗

PubMed2003

Effects of particulate matter on daily mortality in 13 Japanese cities.

BACKGROUND: In recent years, numerous reports demonstrating the relationship between an increase in the concentration of fine particulate matter (PM2.5) and daily mortality have been released in the United States and Europe. There have been few studies that clearly characterize the short-term effects of particulate matter on the mortality in Japan. We conducted data analysis to investigate the short-term effects of suspended particulate matter (SPM) on mortality in Japan. METHODS: In this study, we used data sets from the 13 largest cities containing data on the daily mortality of residents aged 65 years or older, concentrations of air pollutants including SPM, temperature, and humidity. Risk ratios for mortality resulting from respiratory diseases, cardiovascular diseases, and all causes other than accidents, from 1990 through 1994, were summarized using a generalized additive model (GAM) and a meta-analysis of random effect model. RESULTS: The risk ratios for an increase of 10 microg/m3 in SPM concentrations adjusted for SO2, NO2, CO, Ox, temperature, and humidity were 1.0077 for all causes of mortality, 1.0109 for respiratory diseases, and 1.0091 for cardiovascular diseases, and the lower limits of the 95% confidence intervals for the risk ratios were greater than one for all cases. With regards to the effects of time lag, risk ratios were higher for the SPM concentrations on the day when the mortality was recorded, and the preceding day. CONCLUSIONS: These results suggest a positive relationship between SPM concentrations and daily mortality in Japan.

Aged↗

PubMed2002

A new statistical method for evaluation of L5178Ytk(+/-) mammalian cell mutation data using microwell method.

A statistical method to evaluate data from the mouse lymphoma L5178Y/tk assay (MLA) using microwell method is proposed. This proposed method is designed for data obtained from a single culture protocol instead of the duplicate culture recommended by United Kingdom Environmental Mutagen Society (UKEMS). The proposed method consists of the following three steps: (1) to apply Dunnett type test for identifying clear negative; (2) to apply a Simpson-Margolin procedure for detecting downturn data; and (3) to apply a trend test to evaluate the dose-dependent increase in mutant frequency (MF). The performance of the proposed method was evaluated through a Monte Carlo study and a case study. False positive rates realized in the Monte Carlo study were comparable with the UKEMS method modified for a single culture protocol with the heterogeneity factors being kept at 1.0. False negative rates were less than those of the modified UKEMS method for dose response patterns with a sharp uprise in higher dose groups, whereas, they were comparable for other patterns. The results of evaluating the data from an International Collaborative Study by the proposed method seem comparable with the UKEMS method. The proposed method enables us to evaluate data from the microwell MLA with a single culture protocol.

Animals↗

PubMed2002

Isofuranonaphthoquinone derivatives from cultures of the lichen Arthonia cinnabarina (DC.) Wallr.

Two isofuranonaphthoquinone derivatives, named arthoniafurones A (1-acetyl-8-hydroxynaphtho[2,3-c]furan-4,9-dione) and B [1-acetyl-4,8-dihydroxynaphtho[2,3-c]furan-9(4H)-one], were isolated from a spore-derived culture of the mycobiont of the lichen Arthonia cinnabarina, that is new to Japan. Bostrycoidin and 8-O-methylbostrycoidin were also identified in the A. cinnabarina culture.

Lichens↗