Comprehensive Evaluation of (+)-Usnic Acid-induced Cardiotoxicity in Rats by Sequential Cross-omics Analysis.

Two-week administration of (+)-usnic acid (UA) induces mitochondrial swelling of cardiomyocytes, and toxicogenomic analysis of the heart revealed upregulation of oxidative stress, amino acid limitation, and endoplasmic reticulum stress-related genes in rats. To analyze the pathogenesis, UA was orally administrated to rats for 1, 4, 7, and 14 days, and sequential histopathological, genomic, and metabolomic analyses were performed on the heart, liver, and plasma. As a result, mitochondrial swelling of cardiomyocytes was observed on day 15 preceded by genomic upregulation on days 5 and 8. Of the focused gene groups, amino acid limitation-related genes represented by Mthfd2 showed numerically higher values or upregulation from day 5, which was sustained through the experimental period. On the contrary, oxidative stress-related genes were upregulated temporally on day 5. In metabolomic analysis, amino acids such as taurocholate and their metabolites fluctuated in concert with the upregulation of amino acid limitation-related genes in the heart, liver, and plasma. Moreover, accumulations of bile acids were manifested in all the tested tissues, while no histopathological change was seen in the liver. Increased bile acids might have an indirect effect on the myocardium; however, more detailed analysis is required. In conclusion, amino acid limitation was suggested as the pivotal toxic trigger of UA-induced cardiotoxicity.

Alcohol dehydrogenase 2 variant is associated with cerebral infarction and lacunae.

The authors examined the association of the alcohol dehydrogenase 2 (ADH2) genotype with vascular events in community-dwelling Japanese (1,102 men/1,093 women). The allele ADH2*2 encodes an isozyme with a higher level of activity than ADH2*1. Here, the authors show that the ADH2*1 carriage is associated with high prevalence of cerebral infarction and lacunae in men. Multiple regression analyses confirmed that the risk of lacunae and cerebral infarction was increased by the ADH2*1 allele.

Association of polymorphisms in the estrogen receptor alpha gene with body fat distribution.

OBJECTIVE: To examine whether polymorphisms of the estrogen receptor (ER) alpha gene are associated with body fat distribution. DESIGN: Cross-sectional, epidemiological study of two single-nucleotide polymorphisms, a T --> C (PvuII) and an A --> G (XbaI), in the first intron of the ERalpha gene. SUBJECTS: A total of 2238 community-dwelling middle-aged and elderly Japanese population (age: 40-79 y). MEASUREMENTS: The ERalpha genotypes (by automated fluorescent allele-specific DNA primer assay system), anthropometric variables, fat mass (FM) and percentage FM (%FM) (by dual-energy X-ray absorptiometry). RESULTS: FM and waist were inversely associated with age (r=-0.630 and -0.504, respectively) in women with the GG genotype. On the other hand, waist circumference of the AA genotype was positively correlated with age (r=0.231). Thus, for middle-aged women (40-59 y) with the AG or GG genotype body mass index (BMI), %FM, FM, waist, hip and waist-to-hip ratio (WHR) were larger than those with the AA genotype. In particular, FM and waist were greater by 20% and 9%, respectively, for the GG genotype, compared to the AA genotype. Alternatively, FM and waist were smaller by 18% and 6%, respectively, in older women with the GG genotype, compared to the AA genotype. No effect was found among the A --> G polymorphisms for men. For both genders, no difference was found in any variables among the TT, TC and CC genotypes with the exception of BMI of older men (60-79 y). CONCLUSION: No association was found between the ERalpha gene polymorphisms and body fat distribution in men. For women, the A --> G polymorphism, in particular the GG genotype, may contribute to the development of upper-body obesity in middle-aged individuals, but may serve to decrease the whole-body and abdominal fat tissue of older individuals.

[Present condition of health information control and attitudes of occupational health professionals in collecting and utilizing health information in workplaces].

Since the Labor Safety and Health Law of Japan provides that the employer is responsible for taking custody of personal information obtained in periodic health examinations, we are anxious about infringement of privacy. This study was conducted to investigate the present condition of health information control in each workplace and attitudes of occupational health professionals in collecting and utilizing personal health information by means of self-administered mail questionnaires. The numbers of respondents were a total of 549 (physicians: 237, public health nurses: 175, nurses 122, others & unknown: 15). The major results were as follows. 1. Percentage of workplaces in which only health professionals can know personal health data from periodic health examinations was 24% altogether, but it was 39% in large workplaces where full-time occupational physicians were working. 2. More than half of the respondents were of the opinion that the results of routine health activities could be presented in academic conferences unconditionally or under comprehensive approval of the representative of each workplace. 3. About a half of the respondents believed that it was necessary to consider the intention of each examinee in utilizing blood specimen collected at health examinations for research purposes, even though personal identification had been erased. 4. There were many differences among types of occupation or age groups in the attitude to changing the procedure for health examination. And it was the majority opinion that personal health data provided to the employer should be the minimum in order to protect individual benefits. 5. The proportion of physicians who felt it necessity to ask about the occupational history at the employment health examination was significantly higher than that of public health nurses. 6. When a disease was discovered, there were great differences among types of disease in the attitude to give the name or condition of the disease to the employer without the consent of the patient or his family. In view of these results, we feel that occupational health professionals are in a dilemma in introducing modern ideas which lay stress on privacy into the Japanese occupational health care system which is still operating on the basis of traditional paternalism.

Hip fracture prevention trial using hip protectors in Japanese nursing homes.

A method to protect the hips during falls could effectively reduce the incidence of hip fractures. We report the results of the first hip protector trial in Japan, performed between July 1996, and September 1999. One hundred and sixty-four elderly female residents of nursing homes, with Activities of Daily Living above the wheelchair level, agreed to participate in this study. Among them, 88 were randomly selected to wear a hip protector and 76 controls did not. All falls and resulting injuries were recorded daily. In anthropometric measurements and ultrasonic bone evaluation, no significant differences were found between the two groups, except in height. During an average of 377 days, the wearers and the non-wearers fell a total of 131 and 90 times, respectively. Among the wearers, there were two non-hip fractures and one hip fracture, so the annual hip fracture rate was calculated at 1.2%, against 8 hip fractures among the non-wearers, or 9.7% per year. The hip fracture rate was significantly lower among the wearers than non-wearers, while the annual number of falls per subject and the distribution of fallers remained the same. According to Cox's proportional hazard regression analysis, the effect of the hip protector on hip fracture prevention was independent of anthropometric data, ultrasonic bone assessment values or number of falls. Moreover, even after limiting the subjects to fallers only, the annual hip fracture rate in non-wearers was higher than in wearers (19.8% vs 2.0%) and the annual hip fracture rate per fall in wearers was lower than that in non-wearers (0.8% vs 8.2%). It was thus concluded that the hip protector is a beneficial device for the prevention of hip fractures.

Estimation of anterior nucleus of lens by Scheimpflug image before and after pupil dilatation.

PURPOSE: To compare the accuracy of lens transparency evaluations by Scheimpflug image in the anterior nucleus of the lens before and after pupil dilatation. METHODS: Scheimpflug lens images were recorded in 70 eyes of 38 subjects (age: 28-75 years) before and after pupil dilatation, and light scattering intensity measurements before and after dilatation were compared. RESULTS: There was a significant positive correlation between the light scattering intensity before and after dilatation at the anterior cortex, anterior nucleus, and central clear zone of the lens (r > 0.9, P <.0001). CONCLUSIONS: It is possible to estimate the transparency in the anterior nucleus of the lens from the Scheimpflug image without pupil dilatation. If nuclear type cataracts are regarded as a structural marker of aging in epidemiological studies, measuring the light scattering intensity in the anterior nucleus of the lens without dilatation seems to be a safe, useful, and quantitative method.

[Behavioral competence among community dwelling older people with disability in basic activities of daily living].

This study observed the status of independence in behavioral competence among older people who have any disability in basic activities of daily living (BADL) living in a rural community in Japan. Study participants (N = 76) who were regarded as bedridden were surveyed by means of a questionnaire in July to August 1996. The independence variables were age, sex, BADL status, hearing impairment, visual impairment, history of stroke, and cognitive impairment. The dependent variable was each item of the Tokyo Metropolitan Institute of Gerontology (TMIG) Index of Competence, which is a multidimensional 13-item index of behavioral competence. Percentages of subjects who were independent in each item of the TMIG Index of Competence varied from 1% to 36%. Multiple logistic regression analyses revealed that BADL status was independently associated with independence in using a telephone, being interested in news stories or programs dealing with health, being called on for advice, and initiating conversations with young people, after adjustment for age, sex, hearing impairment, visual impairment, history of stroke, and cognitive impairment. These findings suggest that programs for preventing decline in behavioral competence of older people with BADL disability might be important as well as physical therapy for them.

A new comprehensive study on aging--the National Institute for Longevity Sciences, Longitudinal Study of Aging (NILS-LSA).

A new comprehensive longitudinal study of aging, the National Institute for Longevity Sciences, Longitudinal Study of Aging (NILS-LSA) started in November 1997. The participants of this study will be 2,400 residents aged 40 to 79 years who were age- and gender-stratified random samples selected from the NILS area. All participants provided written informed consent after a detailed explanation of the study. They will be examined at the NILS-LSA Examination Center every two years. Their first wave examinations will be finished by the end of March 2000. The examined variables number over 1,000, including clinical evaluations, medical examinations, anthropometry, body composition, physical functions, physical activities, psychological assessments, nutritional analysis and molecular epidemiology. By the end of September 1999, 1,643 men and women had completed their first wave examinations.

Ultrasonic evaluation of common carotid intima-media thickness (IMT)--influence of local plaque on the relationship between IMT and age.

Ultrasonic evaluation of the intima-media thickness in the common carotid artery (IMT-CCA) has been widely used as a marker of atherosclerosis. However, the definition of IMT-CCA is not uniform and it includes two quite different pathological changes; a general intima-media thickening and a local atherosclerotic change (plaque formation). The aim of this paper was to evaluate the IMT-CCA and local atherosclerosis separately, and to clarify how the IMT-CCA itself changes with age and how local plaques influence the relationship between the IMT-CCA and age. The subjects were 979 men and women aged 40 to 79 years who participated in the first wave examination of the National Institute for Longevity Sciences--Longitudinal Study of Aging (NILS-LSA). The IMT-CCA measured at the thinnest point was significantly higher in men (0.61 +/- 0.15 mm) than in women (0.58 +/- 0.14 mm, p < 0.01) and it increased with age (trend p < 0.0001) in both genders. The IMT-CCA was higher with the presence of plaque in the bulbs (PLQ-BLB) than without PLQ-BLB (p < 0.0001). Although this was a cross-sectional study, the IMT-CCA increased 0.06 mm/10 years with PLQ-BLB and 0.04 mm/10 years without PLQ-BLB. The IMT-CCA could be partially explained by age, gender and PLQ-BLB (r2 = 0.317). In this middle-aged and elderly population, an increase in the IMT-CCA showed a moderate relationship with local atherosclerosis and age.

Eye examinations at the National Institute for Longevity Sciences--Longitudinal Study of Aging: NILS-LSA.

The National Institute for Longevity Sciences--Longitudinal Study of Aging (the NILS-LSA) started in 1997, and involves many kinds of examination. The objective of this paper is to outline the eye examinations in the NILS-LSA. The eye examinations consist of checks on refractometry, visual acuity, intraocular pressure, contrast sensitivity, kinetic visual acuity, visual fields, fundus photography, and lens estimation. The subjects were 1,077 men and women aged 40-79 years who participated in the first year examination of the NILS-LSA. All subjective measurements (distant visual acuity, kinetic visual acuity, contrast sensitivity, and mean sensitivity of visual field) declined significantly from the 50s. Age-related structural changes in the lens or hypertensive and arteriosclerotic changes in retinal vessels began at least in the 40s. It is suspected that aging affects the subjective visual functions from the 50s. However, changes in the structure of eye may begin before the 40s. The data from the eye examinations of the NILS-LSA are useful to assess the aging effects on vision and to investigate the relationship between visual function and physical or psychosocial health problems among the elderly.

The effects of age on hearing and middle ear function.

Audiometric test results from 933 community dwelling males and females were presented to obtain the norm for each generation after middle age. Three aspects were adopted in this analysis; the cross-sectional aging transition of pure tone thresholds, the comparison in the self-perceived hearing difficulty among generations and the evaluation of middle ear function using multifrequency tympanometry. Subjects were divided into four age groups; 40s, 50s, 60s and 70s. There were statistically significant differences in pure tone thresholds between almost any two age groups at each frequency in both genders, especially at higher frequencies. The pure tone thresholds were also discussed in regard to gender difference and laterality. A contradiction between self-perceived hearing difficulty and auditory accuracy was observed in the elderly generation. Analysis of tympanometric measurements was performed on static admittance at 226 Hz, tympanometric peak pressure at 226 Hz and resonance frequency of the middle ear. These variables did not show any systematic aging change. However, it was considered they represented the reference values of each generation.

Age and gender differences in skin sensory threshold assessed by current perception in community-dwelling Japanese.

The purpose of this study was to investigate age and gender differences in current perception thresholds (CPT) in Japanese citizens. CPT values at frequencies of 2000, 250 and 5 Hz reflect different types of peripheral sensory nerve functions. Since there have been only a limited number of reports which investigated CPT values in community-dwelling people, little is known about variations with age and gender. The present study therefore concentrated on a large population of 1632 individuals (men; 818 mean age +/- standard deviation 59.4 +/- 10.9, women; 814, 59.4 +/- 11.1) in a Japanese community. Significant gender differences in CPT values at 250 and 5 Hz were observed. Multiple comparisons among 4 age groups (40s, 50s, 60s and 70s) showed age-related differences in CPT values at 2000 and 250 Hz in both genders. However, age and gender interactions with reference to CPT values appeared to be different between these latter two frequencies. At 5 Hz, only men showed age-related variations. These results indicated gender differences in fiber-specific aging changes.

Bone mineral density obtained by peripheral quantitative computed tomography (pQCT) in middle-aged and elderly Japanese.

To clarify age-related changes in bone mineral density (BMD) by peripheral quantitative computed tomography (pQCT), 1,124 Japanese middle-aged and elderly community-dwelling people were examined. The BMD of the trabecular bone was assessed at the distal part of the radius (D50), and the BMD of the cortical bone was assessed at the diaphysis of the radius (P100). P100 during age 40 to 49 was significantly higher in females (1359.6 +/- 10.7 mg/cm3, mean +/- SE) than in males (1253.5 +/- 9.5 mg/cm3), while there was no difference in D50, 245.3 +/- 5.1 mg/cm3 in females and 293.0 +/- 5.5 mg/cm3 in males. Females and males aged 50 to 59 lost 8.09 +/- 2.08 (mean +/- SE) mg/cm3 and 3.80 +/- 1.77 mg/cm3 of D50 every year, respectively. As for P100, females lost 25.1 +/- 4.48 mg/cm3, and males lost 6.37 +/- 3.89 mg/cm3 every year. Because of these gender differences, both D50 and P100 were significantly higher in males than in females aged 50 and over. Assuming that the average BMD between ages 40 and 44 was the maximum bone mineral density (BMD max), the percentage change from the BMD max with age was examined. Females aged 60 to 69 whose BMD were under 70% of the BMD max made up 73.9% in D50 and 23.2% in P100. Only 21.1% of males aged 60 to 69 showed less than 70% of the BMD max in D50 and only 3.8% in P100. The percentage decrease in BMD by age was larger in D50 than in P100 in both males and females. The individual difference in BMD was larger in D50 than in P100. These results suggest that pQCT may be useful to independently assess aging effects on cortical and trabecular bone density.

The factors related to age awareness among middle-aged and elderly Japanese.

The purpose of this article was to expand past research by examining relationships between age awareness and related factors in Japanese middle-aged and elderly people. The subjects were 1,129 participants (575 men and 554 women, aged 40 to 79 years) of the National Institute for Longevity Sciences--Longitudinal Study of Aging (NILS-LSA). They were examined with a questionnaire and interview. As a result, chronological age, self-rated health, and visual and hearing ability tend to be the related factors for awareness of aging. Comparing the demographic and physiological factors, however, major life events, difficulties and daily life experiences showed a stronger influence on age awareness. These results provide an interesting basis for the future understanding of adult development and the meaning of aging.

Distribution of geriatric disease-related genotypes in the National Institute for Longevity Sciences, Longitudinal Study of Aging (NILS-LSA).

Phenotypes of various genes related to geriatric diseases and the aging process were assessed in the National Institute for Longevity Sciences, Longitudinal Study of Aging (NILS-LSA). The subjects were 1,297 participants in the NILS-LSA. They were community-living males and females aged 40 to 79 years who were randomly selected from the area of the NILS. Genotypic and allelic frequencies of genes in the subjects were analyzed. Age and gender differences in the distribution of genotypes were also tested. The genotypic frequencies were as follows: (1) Angiotensin I-converting enzyme (ACE) genotype was I/I 46.2%, I/D 38.3% and D/D 15.5%. (2) alpha 1-adrenoreceptor genotype was C/C 84.4%, C/T 12.7%, and T/T 3.0%. (3) Apolipoprotein E genotype was epsilon 2/epsilon 2 0%, epsilon 2/epsilon 3 7.9%, epsilon 3/epsilon 3 70.0%, epsilon 3/epsilon 4 20.8%, epsilon 2/epsilon 4 0%, and epsilon 4/epsilon 4 1.4%. (4) Cholecystokinin type-A receptor (CCKAR) nucleotide-81 (nt-81) genotype was A/A 59.1%, A/G 35.1%, and G/G 5.9%. The CCKAR nucleotide-128 genotype (nt-128) was G/G 74.3%, G/T 23.6%, and T/T 2.2%. The combination of nucleotide (nt-81, nt-128) was (A/A, G/G) 59.1%, (A/G, G/G) 14.1%, (G/G, G/G) 1.1%, (A/G, G/T) 21.0%, (G/G, G/T) 2.6%, and (G/G, T/T) 2.1%. There were no subjects with (A/A, G/T), (A/A, T/T) or (A/G, T/T) genotypic combinations. (5) beta 3-adrenoreceptor genotype was T/T 66.8%, T/A 28.5%, and A/A 4.7%. (6) Dihydrolipoamide succinyltransferase (DLST) nucleotide 19117 genotype was A/A 25.1%, A/G 49.7%, and G/G 25.1%. The DLST nucleotide 19183 genotype was C/C 55.8%, C/T 38.2%, and T/T 5.9%. The combination of nucleotide (nt19117, nt19183) was (A/A, C/C) 6.7%, (A/G, C/C) 24.1%, (G/G, C/C) 25.1%, (A/G, C/T) 25.6%, (A/A, T/T) 5.9%, and (A/A, C/T) 12.6%. There were no subjects with (A/G, T/T), (G/G, T/T) or (G/G, T/C) genotypic combinations. (7) Transforming growth factor-beta 1 genotype T/T 35.2%, T/C 44.6%, and C/C 20.2%. (8) The platelet-activating factor acetylhydrolase genotype was M/M 71.7%, M/m 27.2%, and m/m 1.2%. The mitochondria DNA 5178 genotype A was 42.1% and C was 57.9%. There were no significant gender or age differences in tested genotypic and allelic distribution except for the DLST and apolipoprotein E. Differences in the genotypic frequencies of distribution using the Hardy-Weinberg equilibrium were significant in the ACE and alpha 1-adrenoreceptor genotypes.

Effects of social support and self-esteem on depressive symptoms in Japanese middle-aged and elderly people.

We examined the relationship among social support, self-esteem, and depression. The subjects were 1,116 Japanese community-dwelling adults aged between 40-79, who were the first wave participants of the National Institute for Longevity Sciences--Longitudinal Study of Aging (NILS-LSA). Exploratory and confirmatory factor analyses were performed on the Rosenberg's self-esteem scale that supported the superiority of the bi-dimensional structure of the scale marked by self-confidence and self-deprecation subscales. The subsequent causal analyses, using structural equation modeling, demonstrated that social support reduced depressed affect through an increase in self-confidence and a decrease in self-deprecation. By contrast, social support did not show a direct effect on depressed affect. The findings suggest the importance of esteem-improving elements of social support in reducing depressive symptoms.

Nutritional assessments of 3-day dietary records in National Institute for Longevity Sciences--Longitudinal Study of Aging (NILS-LSA).

Food and nutrient intake of NILS-LSA participants 40 to 79 years of age were assessed through 3-day weighed dietary records by gender and age. The results were as follows. The intake of fats and oils, meats and beverages tended to decrease, but fruits increased with age in both males and females. Regarding nutrient intake, energy, protein, fat, and cholesterol showed a decrease as individuals aged. The nutrient intake in the 70 to 79 yr group was significantly lower than other age groups of both genders. The total dietary fiber and vitamin C intake increased. Salt intake exceeded 10 g/day in every group. The percentage of energy from fat to total energy was higher than 25% in most age groups. The proportion of fatty acids was almost appropriate in all groups.

Age-related changes in gait velocity and leg extension power in middle-aged and elderly people.

To prevent a decline in gait with age, it is necessary to investigate age-related changes in gait performance and detect related factors. The purpose of this study was to assess the association between gait ability and leg extension power among middle-aged and elderly people. Height, weight, maximum gait velocity (MGV) and leg extension power (LEP) were measured in 752 males and females who participated in the National Institute for Longevity Sciences, Longitudinal Study of Aging (NILS-LSA). Age-related changes in MGV and LEP and the association between MGV and LEP were assessed. There were significant decline trends in height, weight, MGV and LEP with advancing age (p < 0.001). MGV showed a significantly positive correlation with LEP (in males: r = 0.48 p < 0.001, in females: r = 0.47; p < 0.001). Subjects aged 60 yrs and over showed a significantly higher correlation than those under 60 yrs in males, but not in females, after adjustment for height and weight. Although the relationships between MGV and LEP were different by age and gender, LEP may be one of the important factors in maintaining gait ability.