Histone deacetylase 6 regulates insulin signaling in pancreatic ß cells.

The reduction of pancreatic ß cell mass is one of the key factors for the onset of type 2 diabetes. Many reports have indicated that insulin signaling is important for type 2 diabetes, but the mechanism by which insulin signaling is altered in pancreatic ß cells remains unclear. This study was designed to examine the role of histone deacetylases (HDACs) in the regulation of insulin signaling in pancreatic ß cells. We found that insulin signaling was downregulated by inhibition of HDAC6. HDAC6 expression was specifically observed in pancreatic ß cells and was decreased in the pancreatic islets of a type 2 diabetes mouse model. When a mouse pancreatic ß cell line (MIN6 cells) was treated with palmitic acid to mimic the effect of a high-fat diet on pancreatic ß cells, HDAC6 was imported into the nucleus. These results suggest that HDAC6 plays an important role in the regulation of insulin signaling in pancreatic ß cells. Therefore, clarifying the regulation of insulin signaling by HDAC6 may be a valuable approach for the treatment of type 2 diabetes.

Histone deacetylase regulates insulin signaling via two pathways in pancreatic ß cells.

Recent studies demonstrated that insulin signaling plays important roles in the regulation of pancreatic ß cell mass, the reduction of which is known to be involved in the development of diabetes. However, the mechanism underlying the alteration of insulin signaling in pancreatic ß cells remains unclear. The involvement of epigenetic control in the onset of diabetes has also been reported. Thus, we analyzed the epigenetic control of insulin receptor substrate 2 (IRS2) expression in the MIN6 mouse insulinoma cell line. We found concomitant IRS2 up-regulation and enhanced insulin signaling in MIN6 cells, which resulted in an increase in cell proliferation. The H3K9 acetylation status of the Irs2 promoter was positively associated with IRS2 expression. Treatment of MIN6 cells with histone deacetylase inhibitors led to increased IRS2 expression, but this occurred in concert with low insulin signaling. We observed increased IRS2 lysine acetylation as a consequence of histone deacetylase inhibition, a modification that was coupled with a decrease in IRS2 tyrosine phosphorylation. These results suggest that insulin signaling in pancreatic ß cells is regulated by histone deacetylases through two novel pathways affecting IRS2: the epigenetic control of IRS2 expression by H3K9 promoter acetylation, and the regulation of IRS2 activity through protein modification. The identification of the histone deacetylase isoform(s) involved in these mechanisms would be a valuable approach for the treatment of type 2 diabetes.

Association between Functional Capacity Decline and Nutritional Status Based on the Nutrition Screening Initiative Checklist: A 2-Year Cohort Study of Japanese Community-Dwelling Elderly.

AIM: To assess whether nutritional status based on the Nutrition Screening Initiative Checklist is useful for predicting functional capacity decline in community-dwelling Japanese elderly. METHODS: This two-year observational cohort study included 536 community-dwelling Japanese (65 years and older at baseline) who were independent in both activities and instrumental activities of daily living. Demographic attributes, chronic illness, lifestyle-related habits, nutritional status, functional capacity, and anthropometric measurements were assessed, with decline in functional capacity used as the outcome measure. RESULTS: Subjects were classified into three groups as follows based on the Nutrition Screening Initiative Checklist: low (59.5%), moderate (23.7%), and high (16.8%) nutritional risk. Significant differences were found between nutritional status and the following four baseline variables: age, hypertension, cerebrovascular diseases, and current smoking. However, no significant differences were evident between nutritional status and sex, body mass index, diabetes, drinking habit, or exercise habit. Logistic regression analysis adjusted for age, sex, body mass index, hypertension, cerebrovascular diseases and smoking habit showed that the high nutritional risk group was significantly associated with a decline in both activities of daily living (odds ratio: 4.96; 95% confidence interval (CI): 1.59-15.50) and instrumental activities of daily living (OR: 2.58; 95% CI: 1.31-5.06) compared with the low nutritional risk group. CONCLUSIONS: Poor nutritional status based on the Nutrition Screening Initiative Checklist was associated with a decline in functional capacity over a 2-year period in community-dwelling Japanese elderly. These results suggest that the Nutrition Screening Initiative Checklist is a suitable tool for predicting functional capacity decline in community-dwelling elderly.

Safety Evaluation of Self-assembling Peptide Gel after Intracranial Administration to Rats Using the Open Field Test.

Self-assembling peptides have been developed as clinical materials, which could scaffold to regenerate nerve cells and hemostatic materials in vivo. However, there has not been enough information for their in vivo application. The safety of self-assembling peptides for the application on the brain was examined using behavioral tests for each rat in this study. Self-assembling peptide gel was administered to the surface of the brain at a volume of 20 µL at 1.5%. After 2 months, the open field test and the prepulse inhibition (PPI) test were performed. There were no significant differences between the peptide gel and the control groups in locomotor distances and in %PPIs in the PPI test. The mean values of the percentage of time the rats stayed in the central area of the open field during the first 5 min and instances of center rearing or face washing in the peptide gel group were significantly higher than those in the control. There were amorphous substance in the subarachnoid region, and infiltrations of mononuclear cells were also observed in the self-assembling peptide gel group. Although the meaning of the effects observed in this study was not fully elucidated, the self-assembling gel produced marginal but significant behavioral and histological effects.

The Diagnosis of Sick House Syndrome: the Contribution of Diagnostic Criteria and Determination of Chemicals in an Indoor Environment.

OBJECTIVE: The study group for sick house syndrome (SHS) in Japan has proposed the classifications, definition and diagnostic criteria for chemical-associated SHS. We compared the physicians' diagnoses to the diagnoses based on the patients' interview sheets including diagnostic criteria only. METHODS: We examined 287 patients with complaints of SHS-like symptoms. We also checked determinations of chemical substances in the patients' homes. RESULTS: A total of 76.0% of the patients were diagnosed as having SHS. Physicians diagnosed 87.6% of those patients as having chemical-associated SHS based on SHS classifications, definition and diagnostic criteria. Based on the patients' interview sheets, 50.3% of the patients who were diagnosed as chemical-associated SHS corresponded to the diagnostic criteria. The 51 of those chemical-associated SHS patients had answered that the chemical substance levels in their homes had been checked, and 20 of those patients answered that at least one of the chemical substance levels was above that set in the guideline by the Japanese Ministry of Health, Labour and Welfare. CONCLUSIONS: Physicians should use all of the classifications, definition and diagnostic criteria. Even if the chemical levels in the home are under the guideline levels, the diagnosis of chemical-associated SHS should not be excluded.

Skin irritation to glass wool or continuous glass filaments as observed by a patch test among human Japanese volunteers.

Glass wool and continuous glass filaments have been used in industry. We examined the irritability of those among Japanese. A patch test was performed on 43 volunteers for the followings: glass wool for non-residential use with and without a urea-modified phenolic resin binder, that for residential use with and without the binder, and continuous glass filaments with diameters of 4, 7, 9, and 13 µm. Materials were applied to an upper arm of each volunteer for 24 h. The skin was observed at 1 and 24 h after the removal. At 1 h after removal, slight erythema was observed on the skin of a woman after the exposure to glass wool for residential use without the binder. Erythema was observed on the skin of another woman at 1 h after a 24-h exposure to glass wool for non-residential use without the binder. There were no reactions at 24 h after the removal. The low reactions in the patch test suggested that the irritability caused by glass wool, irrespective of a resin component, could be induced mechanically, and that the irritability caused by continuous glass filaments with resin could be slight and either mechanical or chemical.

Sarcopenia and falls in community-dwelling elderly subjects in Japan: Defining sarcopenia according to criteria of the European Working Group on Sarcopenia in Older People.

This study assessed the association between sarcopenia (using the definition of the European Working Group on Sarcopenia in Older People) and fall in the past year among community-dwelling Japanese elderly. Subjects were 1110 community-dwelling Japanese aged 65 or older. We used bioelectrical impedance analysis (BIA) to measure muscle mass, grip strength to measure muscle strength, and usual walking speed to measure physical performance in a baseline study. "Sarcopenia" was characterized by low muscle mass and low muscle strength or low physical performance. "Presarcopenia" was characterized only by low muscle mass. Subjects who did not have any of these deficiencies were classified as "normal." We then administered a questionnaire assessing age, sex, household status, chronic illness, lifestyle-related habits, and fall. This study showed the prevalence of fall was 16.9% and 21.3% in men and women, respectively, while that of sarcopenia was 13.4% and 14.9% in men and women, respectively. In men and women, the prevalence of sarcopenia was higher among those who had fallen. A logistic regression analysis using age, body fat, current drinker status, and physical inactivity for men, and age, body fat, smoking, and diabetes for women as covariate variables revealed that sarcopenia was significantly associated with a history of fall. The odds ratio for fall in the sarcopenia group relative to the normal group was 4.42 (95%CI 2.08-9.39) in men and 2.34 (95%CI 1.39-3.94) in women. This study revealed sarcopenia to be associated with falling in elderly Japanese. Sarcopenia prevention interventions may help prevent falls among elderly individuals.

Handgrip strength as a predictor of higher-level competence decline among community-dwelling Japanese elderly in an urban area during a 4-year follow-up.

This 4-year observational study examined whether handgrip strength can predict functional decline in higher-level competence in a cohort of urban community-dwelling Japanese elderly. Subjects were 406 community-dwelling Japanese, 65 years or older at baseline who scored as "independent in higher-level competence" (11 and over) according to the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC). Independent variables were handgrip strength and usual walking speed at baseline survey. Dependent variables were functional status in higher-level competence at 4-year follow-up. Logistic regression analysis, after adjustment for age and body mass index (BMI), revealed that handgrip strength was significantly correlated with decline of higher-level competence in both sexes. Usual walking speed was significantly correlated with decline in higher-level competence only in women. This study revealed that handgrip strength is a predictor for decline in higher-level competence in urban community-dwelling Japanese elderly men and women. Results suggest that handgrip strength may be used to screen for functional capacity decline in community-dwelling elderly.

Association of sarcopenia with functional decline in community-dwelling elderly subjects in Japan.

AIM: The present study aimed to determine the association of sarcopenia, defined by muscle mass, muscle strength and physical performance, with functional disability from a 2-year cohort study of community-dwelling elderly Japanese people. METHOD: Participants were 743 community-dwelling elderly Japanese people aged 65 years or older. We used bioelectrical impedance analysis (BIA) to measure muscle mass, grip strength to measure muscle strength, and usual walking speed to measure physical performance in a baseline study. Functional disability was defined using an activities of daily living (ADL) scale and instrumental activities of daily living (IADL) scale at baseline and during follow-up examinations 2 years later. Logistic regression analysis, adjusted for age and body mass index, was used to examine the association between sarcopenia and the occurrence of functional disability. RESULTS: In the present study, 7.8% of men and 10.2% of women were classified as having sarcopenia. Among sarcopenia patients in the baseline study, 36.8% of men and 18.8% of women became dependent in ADL at 2-year follow up. From the logistic regression analysis adjusted by age and body mass index, sarcopenia was significantly associated with the occurrences of physical disability compared with normal subjects in both men and women. CONCLUSIONS: Sarcopenia, defined by muscle mass, muscle strength and physical performance, was associated with functional decline over a 2-year period in elderly Japanese. Interventions to prevent sarcopenia are very important to prevent functional decline among elderly individuals.

[Factors related to sarcopenia in community-dwelling elderly subjects in Japan].

OBJECTIVES: This study aimed at determining the factors associated with sarcopenia, defined as low muscle mass and strength and low physical performance, in community-dwelling elderly subjects in Japan. METHODS: The subjects included 1,074 elderly, community-dwelling Japanese people aged 65 years or older. We measured appendicular muscle mass (AMM) by bioelectrical impedance analysis, grip strength, and usual walking speed. A low muscle mass was defined by the AMM index (AMI, weight [kg]/height [m(2)] as >2 standard deviations below the mean AMI for normal young subjects. The lowest quartile for grip strength and usual walking speed were classified as low muscle strength and low physical performance, respectively. "Sarcopenia" was characterized by a low muscle mass, combined with either a low muscle strength or low physical performance. Subjects without low muscle mass or strength and low physical performance were classified as "normal." Subjects were classified as being "intermediate" if they were neither "sarcopenic" nor "normal." Items in the questionnaire included residential status, past medical history, admission during the past year, smoking and drinking habits, leisure-time physical activity, health status, depression, masticatory ability, and dietary variety score. RESULTS: Sarcopenia was identified in 13.7% of men and 15.5% of women. Among men, a large proportion of subjects with sarcopenia had poor masticatory ability and a low dietary variety score compared with normal or intermediate subjects. Among women, a large proportion of the subjects with sarcopenia lived alone, had poor exercise habits, considered themselves to be unhealthy, and had poor masticatory ability compared with normal or intermediate subjects. A multiple logistic regression analysis showed that age and dietary variety in men and age and masticatory ability in women were associated with sarcopenia. CONCLUSION: The present study carried out in Japan showed that sarcopenia, assessed by muscle mass, muscle strength, and physical performance, was associated with age, dietary variety score (in men), and masticatory ability (in women).

Association between sarcopenia and higher-level functional capacity in daily living in community-dwelling elderly subjects in Japan.

This study aimed to determine the association between sarcopenia, defined by muscle mass, muscle strength, and physical performance, and higher-level functional capacity in community-dwelling Japanese elderly people. Subjects were 1158 elderly, community-dwelling Japanese people aged 65 or older. We used bioelectrical impedance analysis to measure muscle mass, grip strength to measure muscle strength, and usual walking speed to measure physical performance. Sarcopenia was characterized by low muscle mass, plus low muscle strength or low physical performance. Subjects without low muscle mass, low muscle strength, and low physical performance were classified as "normal." Examination of higher-level functional capacity was performed using the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC). The TMIG-IC is a 13-item questionnaire completed by the subject; it contains five questions on self-maintenance and four questions each on intellectual activity and social role. Sarcopenia was identified in 11.3% and 10.7% of men and women, respectively. The percentage of disability for instrumental activities of daily living (IADL) was 39.0% in men with sarcopenia and 30.6% in women with sarcopenia. After adjustment for age, in men, sarcopenia was significantly associated with IADL disability compared with intermediate and normal subjects. In women, sarcopenia was significantly associated with every subscale of the TMIG-IC disability compared with intermediate and normal subjects. This study revealed that sarcopenia, defined by muscle mass, muscle strength, and physical performance, had a significant association with disability in higher-level functional capacity in elderly Japanese subjects. Interventions to prevent sarcopenia may prevent higher-level functional disability among elderly people.

Association between muscle mass and disability in performing instrumental activities of daily living (IADL) in community-dwelling elderly in Japan.

This study describes the association between low muscle mass and disability in performing IADL in elderly, community-dwelling Japanese subjects. Subjects were 1268 elderly, community-dwelling Japanese aged 65 years or older. Low muscle mass was defined by appendicular muscle mass index (AMI, weight [kg]/height [m(2)]), measured by bioelectrical impedance analysis (BIA). We classified "middle" AMI as a value 1-2 standard deviation (SD) below the young normal mean of AMI and "low" as more than 2 SD below the young normal mean. Examination of IADL was performed using the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) questionnaire. In this study, 17.2% and 26.2% of elderly men and women, respectively, were classified as having low muscle mass. There was a significant association with age and the change from normal to middle to low muscle mass in both men and women. The prevalence of IADL disability also increased significantly as muscle mass decreased. After adjustment for age and BMI, low muscle mass was significantly associated with IADL disability in men and women. Furthermore, middle muscle mass was significantly associated with IADL disability in women. This study revealed that low muscle mass, defined as a value 2 SD below the mean of young adults, had a significant association with IADL disability in elderly Japanese. Interventions to prevent age-related losses in muscle mass may be an effective strategy to prevent IADL disability among the elderly.

[Comparison of diagnostic criteria for the metabolic syndrome among Japanese university faculty].

OBJECTIVES: Diagnostic criteria for the metabolic syndrome (Mets) in Japan have been set by the Medical Committee of the Japanese Association of Medical Sciences (Med), the National Health and Nutrition Examination Survey (Nat), specific health checkups (Ckup), and second medical examination by Worker's Accident Compensation Insurance System (Wor). The purpose of this study was to compare classification of the metabolic syndrome by different organizational criteria and to investigate underlying differences. METHODS: All faculty members of a university in Osaka, Japan, underwent mandatory health checkups in September 2008. The demographic distribution included 769 males (mean age, 49 +/- 12 years) and 415 females (mean age, 43 +/- 10 years). Using the Med, Nat, Ckup and Wor criteria, individuals were assessed for the MetS and pre-metabolic syndrome (pre-Mets), strongly suspected metabolic syndrome (S-Mets) and assumed pre-metabolic syndrome (A-pre-Mets), as well as a positive support level (PSL) and a motivational support level (MSL). All faculty members were categorized into a morbid group (Mets, S-Mets, PSL, and FB) or a pre-morbid group (pre-Mets, A-pre-Mets, and MSL) based on medical data and smoking habits. The incidence of morbid and pre-morbid individuals was compared across the four criteria and analyzed based on gender and age (under 40 and 40 or over). RESULTS: Male incidences for the morbid and pre-morbid classifications were 17% and 20% with Med, 9% and 23% with Nat, 27% and 14% with Ckup, and 1.4% and 0% with Wor. There were significant differences across criteria sets in both the morbid and pre-morbid groups, with significantly greater numbers of males than females, and higher prevalences in those aged 40 or over than in their younger counterparts. Males aged under 40 classified into the pre-morbid group comprised 18% in Med, 16% in Nat, and 13% in Ckup. CONCLUSION: The different disease incidences found between Med and Ckup data in males aged 40 or over might be attributed to varying criteria for blood glucose levels, while Wor data may be influenced by the higher level of blood pressure set as a criterion with this approach. It will be important to continuously validate currently established criteria to identify the actual prevalence of MetS in Japan. Furthermore, incorporation of waist circumference and BMI for females, and a positive approach for young males, may be critical for future developments.

[Objective assessment of walking in housebound elderly who are able to go out alone].

AIM: The aim of this study was to objectively assess the risk parameters associated with walking in housebound elderly. METHODS: The subjects were 622 community-dwelling elderly (210 men and 375 women: age 65-85) with independence in activities of daily living (ADL). We administered questionnaires pertaining to housebound factors and measured walking parameters, twice, in May 2008 and May 2009. Housebound status was defined as leaving the house no more than once a week, and non-housebound status as more than once every 2-3 days. We measured the following walking parameters: usual and maximum walking speed, timed up and go, obstacle-negotiating gait, stair-climbing, and number of daily steps. RESULTS: The overall prevalence of housebound status was 10.0% in men and 8.5% in women. No statistically significant differences were seen in the prevalence of housebound status between genders or age groups. In men, maximum walking speed, timed up and go, and daily steps were slower or less in housebound than in non-housebound subjects. In women, all walking parameters, except usual walking speed, were slower or less in housebound than in non-housebound subjects. Logistic regression analysis showed that obstacle-negotiating gait was a risk factor for men (odds ratio 2.49), and for women, all walking parameters, except walking at usual speed, were risk factors, with the highest odds ratio of 4.77 for obstacle-negotiating gait. A slower obstacle-negotiating gait was a risk factor for housebound status for both men and women. CONCLUSION: Compared with non-housebound subjects, housebound elderly with the ability to go out alone had a similar usual walking speed but a slower obstacle-negotiating gait.

Distribution, elimination, and renal effects of single oral doses of europium in rats.

Single doses of europium (III) chloride hexahydrate were orally administered to several groups of rats. Cumulative urine samples were taken at 0-24 h, and blood samples were drawn after 24-h administration. The europium concentration was determined in these samples by inductively coupled plasma atomic emission spectroscopy. The volume, creatinine, ß-2-microglobulin, and N-acetyl-ß-D-glucosaminidase were measured in the urine samples to evaluate possible europium-induced renal effects. The blood samples showed low europium distribution, with an average of 77.5 µg/L for all groups. Although the urinary concentration and excretion showed dose-dependent increases, the percentage of europium excreted showed a dose-dependent decrease, with an average of 0.31% in all groups. The administration of europium resulted in a significant decrease of creatinine and a significant increase of urinary volume, N-acetyl-ß-D-glucosaminidase, and ß-2-microglobulin. Rare earth elements, including europium, are believed to form colloidal conjugates that deposit in the reticuloendothelial system and glomeruli. This specific reaction may contribute to low europium bioavailability and renal function disturbances. Despite low bioavailability, the high performance of the analytical method for determination of europium makes the blood and urine sampling suitable tools for monitoring of exposure to this element. The results presented in this study will be of great importance in future studies on the health impacts of rare earth elements.

Toxicological aspects of cadmium and occupational health activities to prevent workplace exposure in Japan: A narrative review.

Chemicals are an essential part of modern manufacture processes. Their use must be managed with great attention in occupational settings to avoid serious detrimental effects to the health of employees. For example, cadmium compounds are indispensable for the production of nickel-cadmium rechargeable batteries or as chemical stabilizer in plastics. It is an exceptionally toxic heavy metal and personnel exposed to cadmium in the workplace meet with potential health risks that can lead to the development of kidney, skeletal and respiratory disorders. In consequence, proactive and systematical development of occupational hygiene and health activities are necessary to reduce chemical exposure to cadmium in the workplace. This review describes the known facts of cadmium toxicity, the biological effects of cadmium exposure, possible regulation measures to prevent occupational cadmium exposure in three industrial health management systems and discusses future cooperation programs in these systems, proactive safety activities and occupational safety and health management strategies.

Predictors of Japanese workers' satisfaction with their annual health checkups.

To seek the factors associated with the degree of Japanese workers' satisfaction with their annual health checkups, a survey with an anonymous self-administered questionnaire was conducted. A total of 1,389 questionnaires were analyzed. The average age of the analyzed subjects was 37.4 yr (range, 18-66 yr). Multiple linear regression analysis showed that the degree of such satisfaction was significantly associated with the effectiveness of annual health checkups, the hassle of receiving them, the receptionist's good manners, cleanliness of the examination site, the long waiting time, privacy invasion issues, anxiety concerning the skills of the persons conducting the examinations, and helpful advice from a physician. Various activities including promoting primary preventions, e.g., medical education must be conducted to convey the effectiveness of annual health checkups to examinees and to reduce the hassle of receiving those checkups. Health checkup staffs must keep their health checkup sites clean and try to find ways to reduce the waiting time. Moreover, they must pay particular attention to examinees' privacy. It is imperative that examinees are not anxious concerning the skills of the persons conducting the examinations. Many examinees want helpful advice from a physician regarding their health management.

Relationship between chest X-ray findings and pulmonary function tests in dust workers.

Occupational injuries are decreasing due to the improvement in occupational management in the workplace in recent years. However, pneumoconiosis and its complications remain important occupational diseases. Based on the report 'survey on classification for supervision of pneumoconiosis in Japan' performed in 1994, this study compared age, number of years at the job and pulmonary function tests among work types, and examined the characteristics of cases in which pulmonary function results were worse than expected from the chest X-ray findings. In the comparison among work types, mean age was higher and %VC was lower among workers exposed to silica or asbestos, and FEV1.0% appeared to be lower among silica-exposed workers. Multiple regression analysis showed that silica or asbestos-exposed work environments strongly affected %VC. Some cases showed dissociation between the X-ray findings and pulmonary function tests, which appeared to be caused by certain types of work environments. In this study, all the subjects had findings of pneumoconiosis in their chest X-ray. It is necessary to perform a longitudinal survey on pneumoconiosis-free subjects to clarify the precise association of lung function tests with chest X-ray.

In vitro toxicity of indium arsenide to alveolar macrophages evaluated by magnetometry, cytochemistry and morphological analysis.

The present study was conducted to clarify the toxicity of Indium arsenide (InAs) particles to alveolar macrophages of hamsters by cytomagnetometry, enzyme release assays and morphological examinations. One million alveolar macrophages obtained from hamsters were exposed to 60 microg of ferrosoferric oxide and 2, 4, 10 and 20 microg of InAs particles. Relaxation, which is the rapid decline of strength of the remanent magnetic fields radiating from the alveolar macrophages, was insignificantly delayed and decay constants were not changed due to exposure to such doses of InAs. Because the relaxation is thought to be associated with the cytoskeleton, the exposure to InAs may not have impaired their motor function. An LDH release assay and morphological findings indicate slight damage to macrophages. DNA electrophoresis and the TUNEL method revealed neither necrotic changes nor apoptotic changes. Thus, InAs particles at such doses hardly cause cytostructural changes and cell death.