Evaluation of QSAR models for predicting mutagenicity: outcome of the Second Ames/QSAR international challenge project.

Quantitative structure-activity relationship (QSAR) models are powerful in silico tools for predicting the mutagenicity of unstable compounds, impurities and metabolites that are difficult to examine using the Ames test. Ideally, Ames/QSAR models for regulatory use should demonstrate high sensitivity, low false-negative rate and wide coverage of chemical space. To promote superior model development, the Division of Genetics and Mutagenesis, National Institute of Health Sciences, Japan (DGM/NIHS), conducted the Second Ames/QSAR International Challenge Project (2020-2022) as a successor to the First Project (2014-2017), with 21 teams from 11 countries participating. The DGM/NIHS provided a curated training dataset of approximately 12,000 chemicals and a trial dataset of approximately 1,600 chemicals, and each participating team predicted the Ames mutagenicity of each trial chemical using various Ames/QSAR models. The DGM/NIHS then provided the Ames test results for trial chemicals to assist in model improvement. Although overall model performance on the Second Project was not superior to that on the First, models from the eight teams participating in both projects achieved higher sensitivity than models from teams participating in only the Second Project. Thus, these evaluations have facilitated the development of QSAR models.

Longitudinal study of age- and menopause-related metacarpal index changes in Japanese adult females.

To establish a comprehensive mode for cortical bone thinning rate, the metacarpal index (MCI) of the index finger of the nondominant hand was measured using computed X-ray microdensitometry. Statistical analysis was used to study the MCI data in relation to age and menopausal status. A total of 383 healthy Japanese women ranging in age from 30 to 79 yr were investigated in 1996 and 1999. The MCI was generally decreased by 1.11% per year. However, accelerative decreases of 1.78 and 2.05% per year were observed within both the age 50-59 yr group and the early postmenopausal period, respectively. In addition, analysis of age-based longitudinal data showed that the age-related loss of MCI in the age 50-59 yr category was significantly higher than that in the other age categories (p < 0.01), indicating that the changes in MCI were more dependent on menopausal status than on aging. Our study suggests that the cortical bone thinning rate is affected by both aging and menopausal status, but the latter may be a predominant factor.

Prevalence of vertebral fractures in a population-based sample in Japan.

In order to compare the prevalence of vertebral fractures in caucasian American and Japanese women, we examined the occurrence of vertebral fractures in a population of 1092 female residents of Yamanashi prefecture who participated in a screening program for osteoporosis. The relationship between vertebral fractures and bone mineral density (BMD) of the second metacarpal bone was also studied. Our findings regarding the prevalence of vertebral fractures in Yamanashi agreed strongly with the findings of previous reports in Japan. The prevalence of vertebral fractures was equal or lower among women in Japan compared with caucasians in Minnesota aged from 50 to 60 years. A comparison of the fracture and non-fracture groups revealed significant differences in age, height, and metacarpal BMD. However, after correction for age, no significant difference was found between the two groups.

Age and menopause-related changes in phalangeal bone density of Japanese women, measured by a digital image processing method.

The bone density (BD), phalangeal index (PLI), and metacarpal index (MCI) of the proximal phalangeal and metacarpal bones of the index finger of the nondominant hand were measured, using a digital image processing (DIP) method, in a total of 345 normal Japanese women. In this study, two different locations were measured and the BD, PLI, and MCI decreased significantly after the age of 50 years (P < 0.01 vs values for women in their third decade). The BD, PLI, and MCI of the proximal phalangeal and metacarpal bones showed a significant decrease in postmenopausal groups compared with the pre-menopause group (P < 0.01), which indicated that not only trabecular bone but also cortical bone had an accelerative bone loss in the postmenopausal women. The BD in proximal phalangeal and metacarpal bones decreased by 0.69% and 0.74% / per year, respectively, and there were no significant differences between these annual decreases. The BD of proximal phalangeal bone had a good correlation with that of the metacarpal bone (r = 0.77; P < 0.01), which suggested that the measurement of proximal phalangeal BD was as useful as the measurement of metacarpal BD in screening for osteoporosis (coefficient of variation; CV, 0.64%). The data suggest that DIP has a potential application in screening for osteoporosis.

Urinary collagen crosslinks reflect further bone loss of femoral neck in osteoporotic patients undergoing vitamin D therapy.

Bone mineral density (BMD) of the lumbar (L2-LA) spine and femoral neck was measured annually for 2 years (3 times beginning at the beginning of year 1 and after each subsequent year) in 39 female patients with osteoporosis undergoing 0.5 or 1.0 microg daily doses of vitamin D therapy. At the time of the first BMD measurement, biochemical markers including serum alkaline phosphatase (ALP), urinary pyridinoline (Pyr), deoxypyridinoline (Dpyr) and hydroxyproline (Hyp) were also measured. Urinary Pyr and Dpyr correlated with the percent changes of femoral neck BMD measurements taken the year following the sampling (Pyr: r=-0.622, p<0.001, Dpyr: r=-0.385, p<0.05). Only urinary Pyr correlated with the percent changes of femoral neck BMD measurements taken the following 2 years (r=-0.532, p<0.05). Neither serum ALP nor urinary Hyp correlated with the percent changes of spine or femoral neck BMD measurements taken the year or 2 years after the sera and urine sampling. In summary, we believe urinary Pyr and Dpyr can reflect subsequent bone loss of the femoral neck BMD having been measured only once during the course of a year.

Insulin-dependent diabetes mellitus in which glycemic control was improved during pregnancy but deteriorated after delivery with the occurrence of postpartum thyrotoxicosis: a case report.

We report a patient, a twin, with diabetes mellitus whose hyperglycemic state fluctuated during the course of the pregnancy and the subsequent delivery. She was diagnosed as having slowly progressive IDDM because of her clinical course and the findings of serum positive ICA/CF, positive HLA-DR4 and disconcordance of diabetes mellitus with her identical twin. Insulin therapy was not initially needed in the first two years because the endogenous insulin secretion was not completely reduced. After two years of insulin therapy the patient became pregnant. Her glycemic control was remarkably improved without changes in dietary intake and insulin dosage. After delivery glycemic control deteriorated after delivery with the occurrence of postpartum thyroiditis. Urinary excretion of CPR was increased during pregnancy but decreased after delivery. ICA/CF in serum were persistently detected in the whole observation period. It seems that the improved glycemic control during pregnancy was caused by the reduction in the autoimmune reaction and the deterioration in glycemic control during the postpartum period was induced by the acceleration of the autoimmune reaction by the same mechanism of postpartum autoimmune thyroiditis.

Impaired regulation of skin temperature in patients with diabetes mellitus evaluated by the cold exposure test.

This study aimed at evaluating vasomotor response of the hand in patients with diabetes mellitus. A skin temperature of the hand was measured before and after exposure to ice water, and the recovery rates of the skin temperature were determined at 3, 5, and 10 min after the cold exposure. Ninety-two diabetics ranging in age from 25 to 59 years and 43 normal subjects ranging from 23 to 69 years old participated in this study. Since the recovery rate was delayed in normal subjects over the age of 60, comparison was made between the diabetics and the normals under 60 years old. The skin temperature was significantly lower in 26 diabetics with severe peripheral neuropathy (PN) than 40 diabetics without PN. The recovery rate were markedly delayed in the patients with PN, and also delayed in diabetics with severe retinopathy. The recovery rate was not different between the patients with and without ischemic changes in electrocardiogram. The delayed recovery rate was most prominent in the diabetics who had both abnormal heart rate variation (HRV) and orthostatic hypotension, followed by those with abnormal HRV but without orthostatic hypotension. Recovery rates in the diabetics with abnormal HRV alone were within the normal range. Our data suggest that the dysfunction of the regulation of skin temperature in the patients with diabetes mellitus was due to peripheral sympathetic nerve abnormality. The cold exposure test would be useful in the estimation of the sympathetic nerve activity of the diabetics.

[Pathological characteristics of the thyroid gland in patients with triiodothyronine-predominant Graves' disease].

Pathology of the thyroid gland tissue was characterized in patients with Triiodothyronine (T3)-predominant Graves' disease who had normal levels of serum T4 but increased levels of serum T3 during antithyroid drug therapy. In order to compare this group of patients with an usual type of Graves' patients, age, sex, dietary intake of iodide, duration of antithyroid therapy and the dose of thionamide drugs were matched between the two groups of patients. Thyroid tissue was obtained from subtotal thyroidectomy. In examining the histology of the thyroid gland, integration eye piece plate II with regularly arranged 100 lattice points was set on eye lens of a microscope. The number of crossing points which were projected on each 4 histological elements was counted in randomly selected 10 fields of vision in each patient's thyroid. Assuming that the every histological element is arranged in a random manner, errors of each visual field by this method would be less than 12%. In consequence, the significant difference was demonstrated in the weight of subtotally resected thyroid and the ratio of each histological element except interstitial tissue occupied in the total thyroid tissue between T3-predominant Graves' disease and control Graves' disease. The volume composition of the epithelial cells and vacuoles in patients with T3-predominant Graves' disease was significantly greater than that of patients with control Graves' disease (24.7 +/- 10.6 vs 14.4 +/- 6.5%, 5.9 +/- 3.9 vs 2.0 +/- 1.0%, Mean +/- SD, respectively, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Resistance of peripheral tissues and pituitary to thyroid hormone.

We describe a 29-year-old male with thyroid hormone resistance. He was first seen because of a goiter, and was considered to have hyperthyroid Graves' disease. Despite subtotal thyroidectomy followed by radioiodine therapy, serum thyroxine levels were elevated with high serum TSH levels. Baseline thyroid function showed serum thyroxine of 16.6 micrograms/dl, free thyroxine of 4.60 ng/dl, triiodothyronine of 197 ng/dl, and TSH of 34 microU/ml. Triiodothyronine administration by gradually increased doses of 75, 150, 225, 300, and 375 micrograms/d over a 25-day period resulted in gradual reduction of serum TSH and T4 levels, but serum TSH still responded to TRH even during this period. The basal metabolic rate was--14% and showed a minimal rise even with large doses of triiodothyronine. The results led to the diagnosis of generalized thyroid hormone resistance including the pituitary gland. Increased pulse rate, finger tremor and emotional lability in the patient suggest that the severity of peripheral refractoriness to the hormone may vary from tissue to tissue. In addition, a reduced thyroidal responsiveness to TSH as a consequence of inappropriate radioiodine therapy was observed in this patient.