Published papers

Trichloroethylene (TCE), an industrial organic solvent found in the environment, is a known carcinogen in laboratory animals and is believed to be carcinogenic in humans. Its carcinogenicity is subject to species-specific differences in biological activity, causing hepatocellular carcinoma in mouse and renal-cell carcinoma in rat. We have sought to better understand TCE's mode of action (MOA) by studying the alterations in gene expression profiles of liver in mice and rats that were administrated TCE by oral gavage either once or daily for 14 days. Microarray analysis revealed distinct transcriptional profiles and differences in biological pathways not only species-specific, but also pulse-dose effects within each species. For example, inhibition of the TGF-β pathway and activation of MAPK signaling were specific to mice repeatedly exposed to TCE. A better understanding of the MOA in mice and rats will lead to better hypotheses of TCE's affect on humans. © 2009 Springer-Verlag.

Background: The one-leg standing (OLS) test is one of the balance tests used to diagnose musculoskeletal ambulation disability symptom complex (MARS), a condition newly defined by three professional Japanese medical societies in 2006 to help identify the symptoms of motor organ deterioration and establish preventive strategies. Although many studies have used the OLS test, none has shown conclusively that the test can be used as a practical marker of frailty among elderly people, especially in community settings. Based on the type of epidemiological study - i.e., descriptive epidemiology and analytical epidemiology (observational and intervention studies) - we reviewed evidence on three fundamental issues related to the OLS test: (1) testing procedures and reference values; (2) the associations between the OLS time and negative events; (3) improvement of the OLS time by intervention. These issues are key to any discussion of whether the OLS test can be used as a practical marker for predicting frailty in community-dwelling elderly populations. Methods: Articles were collected from MEDLINE databases using the search terms "one- leg standing" and the other names included in the same category. Results: Because various procedures are used to carry out the OLS test, the measured values for the OLS time varied widely from study to study. Some observational studies showed that the OLS time is related to negative events such as falls, declines in activity of daily living, and other morbidity. OLS times could be improved by several interventions. Conclusions: This review suggests that the OLS test can be a tool for predicting frailty in community-dwelling elderly populations. However, our review should be interpreted with caution because we did not confirm the evidence level of each of the studies we selected. Further research on this topic is needed. © 2009 The Japanese Orthopaedic Association.

Background: The number of studies that use objective and quantitative methods to evaluate facial skin aging in elderly people is extremely limited, especially in Japan. Therefore, in this cross-sectional study we attempted to characterize the condition of facial skin (hyperpigmentation, pores, texture, and wrinkling) in Japanese adults aged 65 years or older by using objective and quantitative imaging methods. In addition, we aimed to identify lifestyle factors significantly associated with these visible signs of aging. Methods: The study subjects were 802 community-dwelling Japanese men and women aged at least 65 years and living in the town of Kurabuchi (Takasaki City, Gunma Prefecture, Japan), a mountain community with a population of approximately 4800. The facial skin condition of subjects was assessed quantitatively using a standardized facial imaging system and subsequent computer image analysis. Lifestyle information was collected using a structured questionnaire. The association between skin condition and lifestyle factors was examined using multivariable regression analysis. Results: Among women, the mean values for facial texture, hyperpigmentation, and pores were generally lower than those among age-matched men. There was no significant difference between sexes in the severity of facial wrinkling. Older age was associated with worse skin condition among women only. After adjusting for age, smoking status and topical sun protection were significantly associated with skin condition among both men and women. Conclusions: Our study revealed significant differences between sexes in the severity of hyperpigmentation, texture, and pores, but not wrinkling. Smoking status and topical sun protection were significantly associated with signs of visible skin aging in this study population. © 2009 by the Japan Epidemiological Association.

This study was aimed at clarifying the effect of exposure to N-methyl-2-pyrrolidone (NMP) on workers' health. Fifteen male NMP-exposed workers and 15 referent male workers were recruited for this study. Exposure concentrations were assessed by determining NMP in the breathing zones and urinary NMP. Clinical examinations, motor and sensory nerve conduction velocities in the dominant arm, and neurobehavioral tests were carried out. The subjects were asked to complete self-administered questionnaires for subjective symptoms and psychological assessment. The mean NMP exposure concentrations ranged from 0.14 to 0.26 ppm, and urinary NMP levels at the end of each workday ranged from 0.17 to 0.22 mg/l, throughout the work week. In terms of clinical data, motor and sensory nerve conduction velocities, neurobehavioral tests, and subjective symptom assessments, there were no differences and no dose-dependent changes in either the means or the prevalence of abnormal findings between NMP-exposed and referent workers.

From the perspective of human nutrition, the prevention of age-related macular degeneration (AMD) through diet control is feasible and desirable. We investigated the relationship between serum antioxidants and AMD in the community-dwelling older Japanese eating a typical Japanese diet. In this study, 722 subjects aged 65 years or older (297 males and 425 females) who had gradable fundus photographs were included. The subjects were divided into three groups of early or late AMD or non-maculopathy. Serum antioxidants (alpha-, gammatocopherols, retinol, beta-cryptoxanthin, alpha-, beta-carotenes, lycopene, and lutein and zeaxanthin) were measured with high-performance liquid chromatography. To clarify the combined effect as the group of the antioxidants, we defined the carotene family (alpha-, beta-carotenes and lycopene) and carotenoid family (betacryptoxanthin, alpha-, beta-carotenes, lycopene, lutein and zeaxanthin). Tertiles of each serum antioxidant were obtained and the prevalence of early or late AMD was compared with univariate or multivariate analysis. The overall prevalence of early AMD was 4.4% (95% confidence interval: 3.1-6.2) and late AMD was 1.1% (0.5-2.2). Only alpha-tocopherol and beta-cryptoxanthin were related to late AMD as single antioxidants. On the other hand, the carotene and carotenoid families as a combination of antioxidants were protectively associated with late AMD. No relationship was found between serum antioxidants and early AMD. Our findings support the hypothesis that a combination of serum antioxidants obtained from the traditional Japanese diet is protective for late AMD, but not for early AMD.

Background: Mt. Oyama in Miyakejima Island erupted in June, 2000. All Miyake villagers were forced to evacuate from the island in September, 2000, due to continuous eruptions and emissions of unsafe amounts of volcanic gas, mainly SO2. From February, 2005, Miyake villagers returned to the island despite volcanic gas still being emitted. Objectives: This study examines the 2-yr changes in Miyake residents' respiratory systems from autumn 2004 to November 2006. Methods: The study population was 823 Miyake adult residents who participated in the health check-up in 2006. Respiratory effects were evaluated by a questionnaire for respiratory symptoms and spirometry. SO2 has been continuously monitored at 7 sampling points of the inhabited area. The mean SO2 concentration from February 2005 to November 2006 was 0.031 ppm. The area was categorized into 4 areas by SO2 concentration, namely, areas L, H-1, H-2 and H-3, where average SO2 concentrations were 0.019, 0.026, 0.032, and 0.045 ppm, respectively. Results: The study subjects showed no deterioration in lung function. Prevalence of cough and phlegm among all participants were significantly higher in 2006 than in 2004, and age-, sex- and smoking-adjusted odds ratios of cough and phlegm were 1.75 (95%CI 1.33- 2.30) and 1.44 (1.12-1.87). Prevalence of chronic bronchitis-like symptoms among normosusceptive subjects in 2006 was 4.1% which was significantly higher than that of 2.1% in 2004 (p=0.035). Compared to area L, the frequencies of phlegm and irritation of the nose were significantly increased in areas H-2 and H-3. Conclusion: SO2 exposure-related respiratory symptoms were observed in adult Miyakejima residents after returning to the island.

Epidemiological studies investigating whether mobile phone use is related to cancer risk have been conducted in many countries. The purpose of the work reported here was to introduce the dose metric in the exposure assessment, taking into account the spatial distribution of exposure. Distributions of specific absorption rate (SAR) inside 275 cases of brain tumors (participants in the Japanese epidemiological study) were estimated. Phones had been classified into four categories based on SAR distributions and technical specifications. Results were found to be highly dependent on phone categories. Contralateral tumors were generally categorized as non-exposed tumors (max SAR <2.5% of max SAR in the brain) and, for any phone category, the maximum SAR in 75% of the ipsilateral tumors was less than 15% of the maximum SAR in the brain. Three new exposure indices combining the duration and strength of exposure were created to be used in the Japanese epidemiological study on mobile phone use and the risk of gliomas and meningiomas. © 2008 GET and Springer Verlag France.

Previous studies have shown that transient treatment of animal models of hypertension with an angiotensin receptor blocker (ARB) causes a sustained decrease in blood pressure values that persists even after the drug treatment is discontinued (J Am Soc Nephrol 12: 659-666, 2001; Nephron 91: 710-718, 2002; Hypertens Res 30: 63-75, 2007). These results have been shown to be clinically relevant by the recent TROPHY study (N Engl J Med 354: 1685-1697, 2006). We have recently found that transient treatment with an ARB may also cause regression of established hypertension in hypertensive rats (J Am Soc Nephrol 18: 157A, 2007). The Short Treatment with the Angiotensin Receptor Blocker Candesartan Surveyed by Telemedicine (STAR CAST) study is a prospective, randomized, open, blinded end-point study in patients aged 30-59 with a positive family history of hypertension that will be conducted in several centers in Japan. The aim of the study is to evaluate the antihypertensive drug withdrawal success rate, the median duration of drug withdrawal, and the changes in home and office blood pressure values in patients with mild hypertension after tapering and withdrawal of antihypertensive treatment following treatment for 1 year with the ARB candesartan or the calcium channel blocker (CCB) nifedipine slow-release. A unique feature of this study is the use of a home blood pressure monitoring telemedicine system (i-TECHO) to allow frequent evaluation of the changes in blood pressure in the trial patients. This study will be the first clinical study to examine if regression from stage 1 (mild) hypertension to prehypertension (high-normal blood pressure) is possible using an ARB or CCB.

[Purpose] The purpose of this research was to measure the functional reach (FR) value, as an index of standing balance ability, and to clarify its distribution among community dwelling elderly persons as well as its relationship with fall related factors, such as number of falls in the previous 1 year, history of fracture, and fear of falling. [Subjects] The subjects were 489 persons (226 males, 263 females) over the age of 65 living in K town, Gunma Prefecture, who gave their written consent at the time of their basic health check-up. [Methods] Using a reach measuring apparatus, we performed the FR test, and information regarding fall related factors was gathered by questionnaire. [Results] FR declined in both females and males with advancing age, and at 70 years of age, it had declined significantly in females, as compared to males. Regarding the relationship between FR and the number of falls, a significant decrease in FR was seen among females with 3 or more falls in the past 1 year in a comparison with those with no falls. However, no significant relationship was found between fracture history and fear of falling. [Conclusion] The correlation found between FR values and past number of falls suggests the possibility that FR can be used effectively in local public health programs aiming at fall prevention.

Purpose Obesity contributes to the technical difficulty of rectal surgery and is considered to be a risk factor for postoperative complications. The impact of obesity on the long-term outcomes of rectal cancer surgery remains unclear. Methods A total of 263 consecutive rectal cancer patients who underwent surgery were categorized into two groups according to the body mass index (BMI) based on the Asian BMI classification: non-obese (BMI <25 kg/m2) and obese (BMI ≥25 kg/m2). The postoperative survival and recurrence rates and oncological surgical quality indicators were compared between groups using the univariate and multivariate analyses. The differences in recurrence patterns were assessed by a competing risk regression analysis. Results 64 (24 %) patients were included in the obese group. The number of retrieved lymph nodes was significantly greater in the non-obese group than in the obese group (22.4 vs. 16.0, P < 0.01). The 5-year disease-free survival (DFS) rates were 86.5 and 68.8 % in the obese and non-obese groups, respectively (P = 0.01). The multivariate analysis demonstrated that obesity significantly decreased the postoperative recurrence rate (P = 0.04). Moreover, the BMI was significantly associated with distant metastasis (P = 0.04). Conclusions Obese rectal cancer patients have high DFS rates and a decreased incidence of distant metastases compared to non-obese patients. The BMI may be a key factor for predicting the postoperative prognosis and determination of an appropriate strategy for the treatment of rectal cancer patients. © 2014 Springer Japan.

The aim of this study was to clarify the relationship between long-term changes in body mass index (BMI) during childhood and adolescent blood-pressure levels in a general Japanese population. We used health report data from 900 Japanese children between 1983 and 2007. After adjusting for baseline BMI and other confounding factors multivariate linear regression analyses were performed to examine the relationship between changes in BMI (ΔBMI) over a 6-year period (6-12 years) and blood pressure once children reached ages 14 or 15. Sub-group analyses were also performed to ascertain the relationship between ΔBMI and blood pressure at 9th grade for children who had been in the bottom BMI tertile at 1st grade. Endpoint blood-pressure levels in boys (systolic and diastolic) and girls (systolic) from the group whose BMIs increased the most were significantly higher than those from the group whose BMIs increased the least (P<0.05, analysis of variance). After adjustment for baseline BMI and school-entrance year, the former group showed higher blood pressure at the endpoint than the latter (P<0.05, multiple regression analysis). Further adjustment for baseline blood pressure also showed similar results in a combined-sex analysis (n=592). Higher ΔBMI was associated with higher SBP 9 even in children whose BMI was in the lowest tertile at baseline after adjustment for sex and school-entrance year (P=0.02, multiple regression analysis). Steeper BMI increases during primary school lead to adolescent increases in blood pressure even if baseline BMI is low. Growth during childhood should be carefully managed. © 2014 The Japanese Society of Hypertension All rights reserved.

Background: Client reminders are known to increase cancer screening attendance rates. However, there are significant costs associated with them, and their effect by population size is unknown. Methods. In 2007 and 2008, the Japanese Government surveyed breast and cervical cancer screening in every municipality in Japan. From the results, we selected all 1,464 municipalities that carried out both screening types. We examined whether changes in screening attendance rates between 2007 and 2008 were associated with client reminders, number of public health nurses per 100,000 population, financial strength index, and 2007 attendance rates for different population sizes. We then calculated cost-effectiveness estimates of client reminders by population size and screening type. Results: Client reminders were associated with increased attendance rates in populations <100,000. For populations of 50,000-100,000, there was a 2.76% increase in breast cancer screening (95% CI: 0.41, 5.11), and a 2.25% increase in cervical cancer screening (95% CI: 0.89, 3.61). The incremental cost per additional attendance was higher in populations <50,000 than in populations of 50,000-100,000 (breast, $100 versus $54; cervical, $149 versus $67 respectively). Conclusions: Client reminders for breast and cervical cancer screening increased attendance rates in smaller municipalities in Japan. © 2014 Komoto et al.; licensee BioMed Central Ltd.

We reviewed the difference in data between the inhalation and intratracheal instillation studies of inhaled materials and how to diminish the difference in data between the two studies in order to examine the usefulness of intratracheal instillation study for the estimation of the harmful effects of manufactured nanomaterials. The differences in the data of the intratracheal instillation study from those of the inhalation study, which is the gold standard, are as follows: 1) artificial effect of the bolus, 2) nonuniformity of lung distribution of materials, 3) no threshold of clearance, 4) low deposition level of materials in the brain and neonates, and 5) the effect of dispersant on the lung. We consider that the approaches to diminishing the difference in data between the two studies are as follows: 1) maintain the dispersion of nanomaterials, 2) avoid the overdosing of nanomaterials, and 3) maintain a low concentration of the dispersant in the intratracheal instillation study.

Objective: Dehydroepiandrosterone sulfate (DHEAS) appears to have a protective effect against depression, but evidence from prospective cohort studies is sparse. Therefore, weexamined the associationbetweenserumDHEAS levelsand depressive symptoms in older community-dwelling Japanese. Design: A community-based cohort study. Setting: Kurabuchi Town, Gunma Prefecture, Japan. Participants: A total of 554 residents (248 men and 306 women) age 65 years or older without depressive symptoms at baseline. Measurements: We performed a baseline examination of the subjects between 2005 and 2006 to determine serum DHEAS levels. The subjects were categorized into three groups based on age strata- and sex-specific tertiles of DHEAS. Depressive symptoms were assessed with the Geriatric Depression Scale 15-item version (GDS-15) in face-to-face home visit interviews carried out once in 2007 and once in 2008. The association of DHEAS with depressive symptoms (GDS-15 ≥ 6) was analyzed with the use of logistic regression models. Results: The incidence of depressive symptoms was 12.1% in men and 19.6% in women. In men, the multiadjusted odds ratio of depressive symptoms was 0.24 (95% confidence interval: 0.06-0.94, Wald χ2 = 4.20, degrees of freedom = 1, p = 0.04) for the highest tertile compared with the lowest. The association observed for the highest versus the lowest remained significant even after adjustment for physical performance and cognitive function. In women, DHEAS was not associated with depressive symptoms. Conclusions: In this study, higher serum DHEAS levels were found to be protectively and independently associated with the risk of developing depressive symptoms in men, but not in women. © 2013 American Association for Geriatric Psychiatry.

While hearing aids are recommended for people with age-related hearing loss, many with impaired hearing do not use them. In this study, we investigated how many elderly people in the study area needed hearing aids, and the factors that determined continued wearing of the devices. The study area was Kurabuchi Town, Japan, where 1,437 residents (those aged 65 years or over) were eligible for participation in the study; 1,414 participated, of whom, 103 (7.3%) were already using hearing aids at the start of the study. After the primary screening, hearing aids were lent to 68 participants (4.8%) who did not already have one, 38 of whom (60.3% of the borrowers, representing 2.7% of the total aged population) went on to wear the hearing aid continuously. The Hearing Handicap Inventory for the Elderly (HHIE) score was significantly elevated among these 38 participants. This study indicated that hearing aids are of potential benefit to many local residents. Multivariate logistic regression revealed that HHIE scores were associated with the extent of HA usage. The adjusted odds ratio for a 1-unit increase in HHIE score was 1.08 (95% confidence interval: 1.02-1.14). Programs like this, in which people with impaired hearing are identified at the local level and given appropriate assistance, are useful models for future use in societies with aging populations. © 2013 Mizutari et al.

Recent advances in the treatment of non-small cell lung cancer (NSCLC) with new agents require accurate histological subtyping at diagnosis to avoid the higher risk of an adverse response and to obtain the maximum therapeutic response. However, interobserver variability, tumor heterogeneity and the degree of differentiation may affect the decision concerning a pathological diagnosis of NSCLC. Therefore, the aim of this study was to identify specific microRNAs (miRNAs) as standardized biomarkers with high sensitivity and specificity in order to distinguish between squamous cell carcinoma (SCC) and adenocarcinoma (AC). Quantitative polymerase chain reaction (qPCR)-based miRNA array analysis was performed to identify microRNAs differentially expressed between SCC and AC using 86 resected NSCLC samples in addition to adjacent normal tissues. The results were confirmed by independent qRT-PCR assays with the same test samples and 88 additional validation samples, and from this we evaluated the usefulness of the identified miRNAs as biomarkers to distinguish between SCC and AC. Three miRNAs (hsa-miR-196b, hsa-miR-205 and hsa-miR-375) were identified. Discriminant analysis combining the three miRNAs appeared to distinguish SCC from AC accurately in the test and validation samples, demonstrating a sensitivity and specificity of 76 and 80%, and 85 and 83%, respectively. hsa-miR-196b, hsa-miR-205 and hsa-miR-375 were identified as biomarkers capable of distinguishing between lung SCC and lung AC. These newly identified miRNAs may prove to be highly valuable molecular markers for the classification of NSCLC histological subtypes and may contribute to the pathogenesis of each subtype of NSCLC.