Healthy Young Japanese Research Articles

β1-Adrenergic Receptor Gene Polymorphisms and the Acute Response to Atenolol in Healthy Young Japanese Subjects

Polymorphisms at codons 49 and 389 of the β1-adrenergic receptor gene have been shown to alter the receptor function in vitro, whereas it remains controversial whether they influence the response to β-blocker in vivo. In the present study, we investigated whether these polymorphisms influence the acute changes of heart rate and blood pressure induced by the β1-adrenergic receptor–selective blocker atenolol in healthy young Japanese. A double-blind study was conducted with 307 subjects randomly allocated 2:1 to atenolol (50 mg) or placebo groups. Heart rate and blood pressure were significantly reduced after administration of atenolol in comparison to the placebo. In 207 subjects allocated to the atenolol group, the numbers of Ser/Ser, Ser/Gly, and Gly/Gly allele carriers for codon 49 were 159, 46, and 2, respectively; and those of Arg/Arg, Arg/Gly, and Gly/Gly for codon 389 were 129, 66, and 12, respectively. No significant association was identified between the changes in heart rate or blood pressure and either of the two polymorphisms. There was also no difference in the changes in heart rate or blood pressure among the diplotypes. The results of the present study do not support clinical use of genotyping for these polymorphisms to predict responses to β-blockers.

Yearlong physical activity and sarcopenia in older adults: the Nakanojo Study

We tested the hypothesis that a low level of regular daily physical activity in elderly individuals would be associated with a clinically significant degree of sarcopenia. Subjects were 78 male and 97 female free-living Japanese, aged 65-84 years. A pedometer/accelerometer measured continuously the number of steps taken and the intensity of activity 24 h/day for 1 year. A whole-body dual X-ray absorptiometry scan assessed skeletal muscle mass in the upper and lower extremities at the end of the year. Sarcopenia was defined as a muscle mass/height(2) value >1 SD below the mean for healthy young Japanese. Linear and exponential regressions showed that after controlling data for age and/or sex, muscle mass was associated with physical activity, more closely for the legs than for the arms, and for duration of moderate activity (>3 METs) than for step count. Muscle mass increased progressively with daily activity, although when data were categorized into quartiles, muscle mass was not significantly greater in men and women who exceeded, respectively, 8,000 and 6,900 steps/day and/or 22 and 19 min/day at >3 METs. All participants meeting such criteria exceeded our sarcopenia threshold. Multivariate-adjusted logistic regressions predicted that individuals who walked <5,300 steps/day and/or spent <15 min/day at >3 METs were, respectively, 2.00-2.66 and/or 2.03-4.55 times more likely to show sarcopenia than those who walked >7,800 steps/day and/or spent >23 min/day at >3 METs. Our hypothesis was proven correct: seniors who walked at least 7,000-8,000 steps/day and/or spent 15-20 min/day at an intensity of >3 METs were likely to have a muscle mass above the sarcopenia threshold.

An Outbreak of Histoplasmosis among Healthy Young Japanese Women after Traveling to Southeast Asia

Histoplasmosis, caused by Histoplasma capsulatum, is an endemic mycosis in many countries of the world except for Japan. Outbreaks of histoplasmosis among Japanese people are very rare and are mainly imported by travelers. We report an outbreak of histoplasmosis among healthy Japanese people who traveled to a resort area in Southeast Asia. Three young Japanese women traveled to Langkawi island, Malaysia and stayed on the island for five days without visiting caves, a known reservoir of H. capsulatum. All three individuals developed flu-like symptoms with multiple nodule shadows on chest X rays or chest CT scans at around ten days after their return to Japan. Serum samples obtained from the three subjects were positive for anti-Histoplasma antibody and specific PCR for H. capsulatum on lung biopsy specimens and the serum from one patient was positive. The clinical course of all three patients improved without the use of anti-fungal agents and no recurrence has been confirmed. Clinical attendants should consider histoplasmosis when they see patients with flu-like symptoms with abnormal chest X-rays after visiting H. capsulatum endemic areas, especially Southeast Asia.

Trp64Arg Polymorphism in Beta3-Adrenergic Receptor Gene Is Associated with Decreased Fat Oxidation Both in Resting and Aerobic Exercise in the Japanese Male

The purpose of our study was to investigate whether the Trp64Arg polymorphism in β3-AR gene and the −3826A/G polymorphism in the UCP1 gene were associated with the reduction in energy expenditure and fat oxidation both in resting and aerobic exercise in Japanese. Eighty-six nonobese young healthy Japanese were recruited. Energy expenditure was measured using indirect calorimetry. The subjects performed an aerobic exercise program at 60% of their maximal heart rate for 30 minutes. The level of fat oxidation at rest and aerobic exercise of the male subjects with Trp/Arg of the β3-AR gene was significantly lower than that of the Trp/Trp genotype. No difference in FO0−30 was observed in the female subjects. There was no association between UCP-1 polymorphism and energy expenditure during aerobic exercise. It was revealed that the Trp64Arg polymorphism in β3-AR gene is associated with reduction of fat oxidation both in resting and aerobic exercise in healthy, young Japanese males.

Energy Expenditure In The Elderly Estimated By Uniaxial And Triaxial Accelerometers And Doubly Labeled Water

PURPOSE: To evaluate TEE estimated by a uniaxial accelerometer (TEE ACCuni) and a triaxial accelerometer (TEEACCtri) in the elderly, and compare the results with those from young adults. METHODS: TEEACCuni and TEEACCtri were measured in healthy young Japanese (n = 32, age 18-23 yr) and elderly men and women (n = 32, age 64-87 yr). In the elderly, TEE was also measured by using the doubly labeled water (DLW) method (TEEDLW). The food quotient (FQ) was calculated from the daily food intake, and the basal metabolic rate (BMR) was measured and predicted. RESULTS: The TEEDLW (7.85 ± 1.54 MJ/d) results were not significantly different from those obtained with TEEACCtri (7.88 ± 1.27 MJ/d) with high correlation coefficients (r = 0.835, p < .001). However, TEEACCuni (6.79 ± 1.08 MJ/d) was significantly lower than TEEDLW with lower correlation coefficients. CONCLUSIONS: While the uniaxial accelerometer method did measure the TEE of young subjects as well as the triaxial accelerometer method, it systematically underestimated the TEE of elderly subjects.

Genetic Variation in the Renin-Angiotensin System and Autonomic Nervous System Function in Young Healthy Japanese Subjects

The renin-angiotensin system (RAS) interacts with the autonomic nervous system (ANS) in the regulation of blood pressure and cardiovascular function. Several genetic polymorphisms in the RAS have been identified and have been implicated as a cause of hypertension and cardiovascular disease. The aim of the present study was to evaluate the relation between genetic polymorphisms of the RAS (M235T of AGT gene, insertion/deletion of ACE gene, A1166C of AT1R gene, and A1675G of AT2R gene) and ANS function. One hundred forty-nine young healthy Japanese males were genotyped for each RAS polymorphism. ANS function was evaluated by power spectral analysis of heart rate variability (HRV) during supine rest and in a standing position. In a supine position, subjects homozygous for the AGT 235T allele had a higher HRV sympathetic index than 235M allele carriers, whereas the orthostatic change in this index was relatively blunted in AGT 235TT carriers. In the analysis of gene-gene interaction, these effects of the AGT 235T homozygotes on HRV sympathetic index were more apparent in the presence of the ACE D allele. Meanwhile, the AT1R 1166C allele was significantly associated with higher HRV low-frequency power and sympathetic index in a standing position. These data suggest that the AGT M235T polymorphism is associated with sympathetic predominance at rest, and AT1R 1166C allele carriers have potentially increased sympathetic response. Cardiac autonomic function can be modulated by genetic variation in the RAS even in young and healthy states.

Pharmacokinetics and Pharmacodynamics of the Oral Direct Thrombin Inhibitor Ximelagatran in Young Healthy Japanese Men

The direct thrombin inhibitor ximelagatran, which is rapidly bioconverted to its active form melagatran after oral administration, is being developed for the prevention and treatment of thromboembolism. This study assessed the effects of food and repeated dosing on the pharmacokinetics and pharmacodynamics of melagatran after oral administration of ximelagatran to young healthy Japanese males. In part one of the two-part study, volunteers (n = 24) were randomised to receive in a crossover fashion a single oral dose of ximelagatran 48mg with or without breakfast on 2 days separated by a 2- to 7-day washout period. In the second part of the study, all volunteers received oral doses of ximelagatran 48mg every 12 hours for 5 days followed by a single dose on the morning of day 6. The area under the plasma concentration-time curve (AUC), peak plasma concentration (C(max)) and urinary excretion of melagatran did not differ as a function of whether ximelagatran was taken with or without food. The relationship between the melagatran plasma concentration and activated partial thromboplastin time (aPTT, which reflects the thrombin inhibitory effect of melagatran) was also independent of concomitant food intake. During repeated dosing, steady-state plasma concentrations of melagatran were achieved after the second dose of ximelagatran on day 1 and remained stable through the rest of the dosing period. The melagatran AUC and C(max) increased slightly (by 18% and 22%, respectively) on day 6 compared with day 1. The interindividual variability in the melagatran AUC and C(max) remained low, as reflected by coefficients of variation of <20% on both day 1 and day 6. The amount of melagatran excreted in urine remained stable over the 6 days of repeated dosing. The pharmacokinetics, pharmacodynamics, safety and tolerability of melagatran after oral administration of ximelagatran were not affected by food or repeated dosing in healthy Japanese volunteers.

Pharmacokinetic differences between Caucasian and Japanese subjects after single and multiple doses of a potential combined oral contraceptive (Org 30659 and EE)

Objectives To compare the pharmacokinetic parameters and safety of the progestagen, Org 30659, (17α)-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one), and ethinyl estradiol (EE) in Caucasian and Japanese women after single and multiple doses. Methods This was an open-label parallel design of a single dose followed by a multiple dose period in healthy young Japanese and Caucasian subjects. Results The area under the curve (AUC) of Org 30659 after single dosing was increased by a factor of 1.75 [90% confidence interval (CI): 1.48–2.08] in Japanese women compared to Caucasian women. At steady state, this difference increased to a factor of 1.90 (90% CI: 1.60–2.25). The AUC of EE after single dosing was similar in Caucasian and Japanese women, but at steady state it was increased by a factor 1.38 (90% CI: 1.15–1.64) in the Japanese group. Weight normalization reduced, but did not remove, all the observed differences. Sex hormone binding globulin played no significant role in the differences between Caucasian and Japanese subjects. Both the single- and multiple-dose treatments with Org 30659/EE were generally well tolerated by all subjects. The Japanese population reported more and different treatment-related adverse events than the Caucasian population. Conclusions The peak concentration and extent of exposure of Org 30659, and to a lesser extent of EE, in Japanese women are higher than in Caucasian women. Furthermore, the peak concentration and extent of exposure at steady state of Org 30659, and to a lesser extent of EE, are higher than would be predicted assuming linear pharmacokinetics over time. No major safety issues were observed.

α2B-Adrenergic Receptor Deletion Polymorphism Associates with Autonomic Nervous System Activity in Young Healthy Japanese

Several polymorphisms of genes involved in autonomic nervous system (ANS) function have been reported to affect metabolic regulation. We have investigated the association of an alpha(2B)-adrenergic receptor (alpha(2B)AR) three-amino acid deletion polymorphism with ANS activity in young healthy subjects by means of electrocardiogram R-R interval power spectral analysis. Three hundred eighty-one young healthy Japanese males (mean +/- SE, 20.6 +/- 0.1 yr) were studied. One hundred sixty-eight (44.1%) were homozygotes of Long allele (Long/Long), 162 (42.5%) were heterozygotes (Long/Short), and 51 (13.4%) were homozygotes of Short allele (Short/Short). The allele frequency of Short allele was 0.35. No significant differences were observed in any of the characteristics investigated: body mass index, plasma glucose, plasma insulin, or family history of diabetes and obesity. In R-R spectral analysis of heart rate variability, carriers of Short/Short had significantly greater low frequency and very low frequency than Long/Long, as well as a higher sympathetic nervous system index. These findings suggest that the alpha(2B)AR deletion polymorphism might result in metabolic disorder by altering ANS function.

Broadband ultrasonic attenuation of children and young adults in Japan.

The purpose of this study was to establish broadband ultrasonic attenuation (BUA: dB/MHz) as bone mineral density (BMD) norms for healthy young Japanese and to evaluate the standard values for an ultrasonic bone analyzer (Cuba Clinical, McCue Ultrasonics Ltd., Winchester, England), which facilitates BMD measurement without exposure to radiation. The subjects were 472 healthy young individuals with no endocrine or skeletal disorders, 197 males (mean age 16 y 5 m) and 275 females (mean age 15 y 7 m) aged from 5 to 29 years. BUA was measured at the left calcaneus. The subjects were divided into five age-stratified different age groups of five years intervals. The mean BUA values (dB/MHz) obtained were 40.6, 60.9, 78.0, 90.4 and 86.0 for males, and 41.9, 61.0, 73.4, 68.4 and 70.8 for females in the 5-9, 10-14, 15-19, 20-24 and 25-29 age groups, respectively. A significant positive correlation was observed between BUA and age in both males and females except in the male 25-29 age group and the female 20-24 and 25-29 age groups. A significantly different BUA between males and females was found in the 20-24 and 25-29 age groups (p < 0.001). The BUA values obtained in this study may serve as BMD norms for children and young adults. It might be thought that measuring BUA from childhood through early adulthood made it possible to determine peak values and peak periods of BMD, providing useful information for assessment of growth and development.

Epidemiological investigation of tinea pedis in groups of healthy students, research workers and females wearing boots

The infection rate, causative dermatophytes, and dermatophyte dissemination of tinea pedis in young healthy Japanese were studied by direct microscopic examination, slant cultures, and foot-press culture method. Questionnaires on subjective symptoms and treatments were also distributed. Among fifty-eight medical students with a mean age of 23.9 years, thirteen (22.4%) showed positive by direct microscopic examination and T. mentagrophytes was more dominant than T. rubrum by slant cultures. In one hundred and sixteen student feet, twelve were infected and disseminating dermatophytes, four were infected but not disseminating, three were not infected but adhering dermatophytes. The infection rate of tinea pedis was thus 24.1%. Among thirty-seven research workers (mean age: 34.8), twenty-one (56.8%) showed positive by direct microscopic examination. All the dermatophytes isolated by slant cultures were T. mentagrophytes. In seventy-four feet, twenty-nine were infected and disseminating, ten were infected but not disseminating, and three were adhering dermatophytes. The infection rate was 64.9%. Among thirty-one females wearing boots (mean age: 21.0), seven (22.6%) were infected and T. mentagrophytes was more dominant. In sixty-two feet, eight were infected and disseminating, one was infected but not disseminating, and five were adhering dermatophytes. The infection rate of tinea pedis was quite high and T.r/T.m rate was low in the three groups. Most of the patients had had no treatment and were disseminating dermatophytes.

Evaluation of Body Composition Using Dual-energy X-ray Absorptiometry, Skinfold Thickness and Bioelectrical Impedance Analysis in Japanese Female College Students.

We compared three methods for evaluating body composition: dual-energy X-ray absorptiometry (DXA), skinfold thickness (Skinfolds), and bioelectrical impedance analysis (BIA). Subjects were 155 healthy young college-aged Japanese females whose mean+/-SD (range) age, body height, body weight and body mass index (BMI) were 20.1+/-0.3 (19.6-21.1) y, 158.9+/-4.7 (145.4-172.6) cm, 52.0+/-6.8 (39.4-84.6) kg and 20.6+/-2.3 (16.5-32.5), respectively. Their mean skinfold thickness at the triceps and subscapular were 16.9+/-4.7 (8.0-31.0) and 16.0+/-5.7 (7.0-40.0) mm, respectively. Mean body fat mass percentages evaluated by DXA, Skinfolds and BIA were 29.6+/-5.1, 22.8+/- 5.3 and 25.8+/-4.7%, respectively. Body fat mass was 15.4+/-4.4, 12.1+/-4.5 and 13.6+/-4.5 kg, respectively. Simple correlation coefficients between the three methods for body fat mass percentages provided the following coefficients: r=0.741 for DXA vs. Skinfolds, r=0.792 for DXA vs. BIA and r=0.781 for Skinfolds vs. BIA. Simple correlation coefficients for body fat mass were as follows: r=0.898 for DXA vs. Skinfolds, r=0.927 for DXA vs. BIA and r=0.910 for Skinfolds vs. BIA (all p<0.001). There were significant differences in the values among the three methods with the Skinfolds providing the lowest body fat mass and percentage, and DXA the highest (p<0.001). They all appear to be strongly correlated for evaluating body composition: however, different cut-off values for defining obese and lean need to be defined for each method.

HLA-A∗24-B∗07-DRB1∗01 Haplotype Implicated with Genetic Disposition of Peak Bone Mass in Healthy Young Japanese Women

HLA exhibits the most extensive polymorphism of any of the known human genes and is known as a genetic marker which allows genetic background of many diseases and physical phenomena. In this study, we, therefore, tried to investigate the regulation of HLA polymorphism and peak bone mass (PBM) in order to elucidate the genetic backgrounds of bone metabolism in young women. Subjects were 67 healthy young Japanese women (average age: 23.6 ± 2.6 years, Body Mass Index (BMI): 19.9 ± 2.0 who were randomly chosen. Allelic polymorphisms in HLA class I (HLA-A and -B) and HLA-class II (DRB1) were investigated by PCR-SSOP and PCR-SSP. Vitamin D Receptor (VDR) and Estrogen Receptor (ER) gene polymorphisms were also analyzed. Lifestyle factors, such as exercise and nutrition, were examined by questionnaire. Bone mineral density was examined using with Lunar DPX-L. Subjects who possessed HLA-B∗07 had a significantly lower PBM than those without B∗07 ( p < 0.05). All subjects were divided into 3 groups according to HLA haplotypes linked with HLA-B∗07, as follows: A∗24(+/−)B∗07(−)DRB1∗01(+/−), A∗24(+)B∗07(+)DRB1∗01(−), and A∗24(+)B∗07(+)DRB1∗01(+). There were no significant differences between these three groups in factors that affect bone metabolism, such as age, age at menarche, BMI, calcium intake, exercise habits, VDR or ER allele frequency. The HLA-A∗24-B∗07-DRB1∗01 haplotype had a significantly lower Z score in the lumbar spine compared with subjects without this haplotype ( p < 0.05). When the Z score was divided by values higher or lower than +1 or −1, all 3 subjects whose Z score was lower than −1.0 were found to have the HLA-A∗24-B∗07-DRB1∗01 haplotype. A significant association between HLA-A ∗24-B∗07-DRB1∗01 and Z score < −1 was found (Yate’s correction χ 2 = 10.82, p = 0.001, RR = 204). In conclusion, the HLA-A∗24-B∗07-DRB1∗01 haplotype can be considered a new genetic marker implicated with low PBM in healthy young Japanese women.

Plasma cortisol concentrations and circadian rhythm in healthy young Japanese and caucasians (author's transl)

We report herein a method of solid-phase radioimmunoassay (RIA) for assessment of plasma cortisol concentration using 125I-labeled ligand [CORTCTK-125]. Plasma cortisol concentrations and its circadian rhythm in healthy young Japanese and American whie women were also evaluated using CORTCTK-125. Nineteen Japanese women, of an average age of 20.3 +/- 0.1 years, and 12 Caucasians of mixed ethnic origin (Minnesota), average 20.0 +/- 0.5 years, were studied using a similar protocol. The distribution of the menstrual stage of the two groups was similar. Blood was drawn from each subject into EDTA containers at 4-hour intervals starting at 0800 on one day and was continued for the ensuing 24 hours. The samples were immediately placed in a refrigerated centrifuge at 4 degrees C, and then stored at -20 degrees C until the assay. The samples from Minnesota were packed in dry ice and brought by air to Japan. Determinations of plasma cortisol concentration in samples from both groups were carried out at Kyushu University. Advantages of the solid-phase RIA method are as follows: (1) 0.05 ml of plasma or serum was sufficient for determination of plasma cortisol concentrations, (2) no other solvents or solutions for the extraction or purification were required, (3) the procedure was simple and readily facilitated, and (4) the concentration of cortisol in heparin-plasma was somewhat higher than that in serum or EDTA-plasma, but there was no statistical difference. Plasma cortisol concentrations in the samples from the Japanese (19.73 +/- 1.44 on the first and 18.94 +/- 1.32 microgram/dl on the second day) and that of the American group (17.48 +/- 2.38 and 19.37 +/- 2.16 microgram/dl, respectively) at 0800 was similar. The average value of 7 determinations at 4-hour intervals was 11.01 +/- 2.00 microgram/dl in the Japanese and 10.29 +/- 1.05 microgram/dl in the American group. A remarkable and similar circadian rhythm was observed in both groups with a peak at 0800 and with nadirs at 2000 in the Japanese (4.80 +/- 0.45 microgram/dl) and 2400 in the American group (5.18 +/- 0.83 microgram/dl). There were statistically significant differences between the values at the peak and the nadir. The related subjects were then classified into Group-F (9 subjects) and Group-T (9); the former included high body mass index [BMI: body weight(kg)/body height(m)2] of more than 24.0, and the latter included a relatively lower BMI of less than 21.5. The circadian rhythm of both groups revealed a similar pattern, whereas plasma cortisol concentration was always higher in Group-F than in Group-T, at all 7 determinations. There were no significant differences except for the value at 0400. Furthermore, the average values of plasma cortisol concentration and circadian rhythm were compared; the group with a larger body surface area (BSA) (Group-L) and the group with a smaller BSA (Group-S). No difference was found in the plasma cortisol concentration of Group-L and -S, and the circadian rhythm was similar in both groups...

Individual Renin-Aldosterone Responses of Clinically Healthy Young Japanese Men to Dietary Sodium and Posture

Responses to the changes in dietary sodium and posture were investigated in 9 young clinically healthy Japanese males who customarily consumed a larger amount of salt than North Americans or Europeans of mixed white ethnic background. Plasma renin activity (PRA), plasma aldosterone concentration (PAC), and urinary aldosterone excretion rate (AER) differed at each end of 3- to 4-day spans on a "control", a high-salt and a low-salt diet and of furosemide administration. PRA and PAC, also determined during the upright position following the supine blood sampling, increased after only 1 hour of standing in each condition (p less than 0.05 or more). PRA and PAC were well correlated in all 4 conditions, regardless of the posture (r = 0.806, p less than 0.001). There were also highly significant correlations between the "supine" PRA or PAC and the preceding 24-hour AER (r = 0.869, p less than 0.001) for PRA; r = 0.855, p less than 0.001 for PAC). Correlation coefficients between PRA and PAC in 9 individual subjects ranged from 0.823 to 0.987. The estimates of constant and slope of the regression line between PRA and PAC varied from subject to subject. The renin-aldosterone axis in response to changes in dietary sodium and posture must be individually assessed.