Published papers

Background: Rikkunshito, a standardized Japanese herbal medicine, is thought to accelerate gastric emptying and relieve dyspepsia, although no large-scale, randomized, placebo-controlled trials of rikkunshito have been conducted. This study aimed to determine the efficacy and safety of rikkunshito for treating functional dyspepsia (FD). Methods: FD patients received 2.5 g rikkunshito or placebo three times a day for 8 weeks in this multicenter, randomized, placebo-controlled, parallel-group trial. The primary end point was the proportion of responders at 8 weeks after starting test drug, determined by global patient assessment (GPA). The improvement in four major dyspepsia symptoms severity scale was also evaluated. In addition, plasma ghrelin levels were investigated before and after treatment. Key Results: Two hundred forty-seven patients were randomly assigned. In the eighth week, the rikkunshito group had more GPA responders (33.6%) than the placebo (23.8%), although this did not reach statistical significance (p = 0.09). Epigastric pain was significantly improved (p = 0.04) and postprandial fullness tended to improve (p = 0.06) in the rikkunshito group at week 8. Rikkunshito was relatively more effective among Helicobacter pylori-infected participants (rikkunshito: 40.0% vs placebo: 20.5%, p = 0.07), and seemed less effective among H. pylori-uninfected participants (rikkunshito: 29.3% vs placebo: 25.6%, p = 0.72). Among H. pylori-positive individuals, acyl ghrelin levels were improved just in rikkunshito group. There were no severe adverse events in both groups. Conclusions & Inferences: Administration of rikkunshito for 8 weeks reduced dyspepsia, particularly symptoms of epigastric pain and postprandial fullness. (UMIN Clinical Trials Registry, Number UMIN000003954). © 2014 John Wiley & Sons Ltd.

Aim: To examine the relationship between the type of work and the number of metabolic syndrome diagnostic componentsS (MetS-DC), as well as the risk of MetS, with adjustment for lifestyle habits in Japanese workers. Methods: We examined the baseline data from 4,427 participants (81.4% male) aged 19 to 69 years old. The physical activity of each participant was classified according to the International Physical Activity Questionnaire (IPAQ). We defined the four MetS-DC in this study as follows: 1) high blood pressure (BP): systolic BP ≥ 130 mmHg, or diastolic BP ≥ 85 mmHg, or the use of antihypertensive drugs; 2) dyslipidemia: high-density lipoprotein-cholesterol concentration <40 mg/dl or triglyceride concentration ≥ 150 mg/dl, or on medication for dyslipidemia; 3) dysglycemia: fasting blood sugar level ≥ 110 mg/dl, or if less than eight hours after meals ≥ 140 mg/dl, or on medication for diabetes mellitus; 4) overweight: a body mass index ≥ 25 kg/m2. We defined MetS as overweight plus two or more of the MetS-DC. Results: There were 3,094 subjects in the daytime work group, 73 in the fixed nighttime work group, 1,017 in the shift work group and 243 in the day-to-night work group. The Poisson regression analysis revealed that fixed nighttime (regression coefficient [b] = -0.233, P=0.028) and shift work (b=0.098, P=0.034) independently contributed to the number of MetS-DC, compared to daytime work. The multivariate logistic analysis not including sleep hours in the model showed that shift work was positively related to MetS (odd ratio = 1.47, P<0.01). Conclusion: Shift work were significantly associated with the number of MetS-DC, and was related to risk of MetS compared to daytime work.

Pemphigus is a group of autoimmune blistering diseases that affect the skin and mucous membranes. A reliable and accurate disease severity tool to assess pemphigus severity is crucial for managing pemphigus and for clinical trials. The purpose of this study was to compare the pemphigus disease area index activity score (PDAI), the Japanese pemphigus disease severity score (JPDSS) and the physician's subjective impression, and also to find appropriate severity grading cut-offs for the PDAI. We also evaluated the correlation between PDAI activity score and the JPDSS. Thirty-seven pemphigus patients and 110 assessments were analyzed in this study. The optimal points of pemphigus disease severity score in PDAI were: mild (0-8), moderate (9-24) and severe (≥25). In mild or moderate cases, the JPDSS was well correlated with the PDAI, but in severe cases the JPDSS reached a plateau at a PDAI score of approximately 30. The PDAI evaluates disease severity more accurately than the JPDSS, particularly in severe cases. The PDAI is not only a useful tool to measure the extent of cutaneous lesions, but also an excellent scoring system for evaluating pemphigus disease severity.

Background: Hepatocellular carcinoma (HCC), the fifth most common cancer type and the third highest cause of cancer death worldwide, develops in different types of liver injuries, and is mostly associated with cirrhosis. However, non-alcoholic fatty liver disease often causes HCC with less fibrosis, and the number of patients with this disease is rapidly increasing. The high mortality rate and the pathological complexity of liver diseases and HCC require blood biomarkers that accurately reflect the state of liver damage and presence of HCC. Methods and Findings: Here we demonstrate that a circulating protein, apoptosis inhibitor of macrophage (AIM) may meet this requirement. A large-scale analysis of healthy individuals across a wide age range revealed a mean blood AIM of 4.99±1.8 μg/ml in men and 6.06±2.1 μg/ml in women. AIM levels were significantly augmented in the younger generation (20s-40s), particularly in women. Interestingly, AIM levels were markedly higher in patients with advanced liver damage, regardless of disease type, and correlated significantly with multiple parameters representing liver function. In mice, AIM levels increased in response to carbon tetrachloride, confirming that the high AIM observed in humans is the result of liver damage. In addition, carbon tetrachloride caused comparable states of liver damage in AIM-deficient and wild-type mice, indicating no influence of AIM levels on liver injury progression. Intriguingly, certain combinations of AIM indexes normalized to liver marker score significantly distinguished HCC patients from non-HCC patients and thus could be applicable for HCC diagnosis. Conclusion: AIM potently reveals both liver damage and HCC. Thus, our results may provide the basis for novel diagnostic strategies for this widespread and fatal disease.

Groups of eight male Hartley guinea pigs were exposed to 30, 100 or 300 ppm 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123) by inhalation for 6 hours a day for 4 wk. All the animals were sacrificed 48 h postexposure. Guinea pigs exposed to 300 ppm HCFC-123 had significantly lower body weight and the weight gain than controls, but there was no significant difference and no tendency in absolute and relative organ weight. ICDH, ALT and AST, which were the most sensitive indicators of halothane-induced liver injury, did not differ significantly between exposed groups and controls. In the 100 ppm group, a few vacuolar fatty changes in the portal area (zone I) were identified. In the 300 ppm group, severe fatty degeneration was observed in the portal and intermediate areas, partly centrilobule, and the incidence increased significantly compared to the controls. On the other hand, there was no histopathological change in the control or 30 ppm groups. No increase in any of the liver peroxisomal enzymes (AOX, PT, catalase) was seen in male guinea pigs exposed to HCFC-123. The activity of hepatic ALDH was significantly decreased in the 300 ppm exposed group, suggesting that HCFC-123 or its metabolite inhibited ALDH activity. In conclusion, inhalation exposure to 100 ppm or more of HCFC-123 for 4 wk produced nonfatal liver change in guinea pigs, namely hepatic fatty changes predominantly in the portal area (zone I) without any increase in AST, ALT or ICDH. The no-observed-adverse-effect level (NOAEL) of HCFC-123 for four wk in guinea pigs may be 30 ppm. Peroxisome proliferation, which may result in hepatocellular tumor induction, was not observed in guinea pigs exposed to HCFC-123.

There is no standard for the awareness of standing posture in stabilometry, yet little research addressing the matter has been carried out. In the present study, we evaluated the influence of different instructional sets during, a test on stabilometry. Stabilometry was performed on 349 male subjects. Two different instructions were prepared for the subjects regarding the awareness of their standing posture. These instructions were a) 'Please relax when you stand' (R-standing), and b) 'Please make an effort to minimize your body sway' (E-standing). Subjects were classified into four groups according to the combination of these instructions they received. For the five body sway parameters, a comparison between R-standing and E-standing was performed, controlling for possible confounders such as age, height, body weight, educational history, alcohol consumption, and smoking status. The sway length in E-standing was larger than that in R-standing, even after the adjustment for possible confounders. Our results indicate that the difference in the instructional set caused a significant measurement bias. Thorough-going unification of instructions for the stabilometry should be recommended when stabilometry is performed in an epidemiological investigation.

A cross-sectional observation was performed to assess the relationship between the coagulation-fibrinolysis system and the subclinical indicators of arteriosclerosis in a healthy male population. Subjects were 445 workers (18.9-49.4, Av.36.2yrs) in viscose rayon manufacturing factories in Japan. Coagulation-fibrinolysis parameters determined were D-dimer(DD), thrombin antithrombinlï ï complex (TAT), tissue plasminogen activator fTPA), and plasminogen activator inhibitor 1 (PAH). The following indicators of arteriosclerosis were examined; systolic and diastolic blood pressure (SBP, DBP), stiffness parameter of the carotid artery using ultrasound (, ?), pulse wave velocity of the aorta (PWV), and a number of lacunar infarctions from brain MRI. After age-stratification(-29, 30-39, 40+yrs), the subjects were classified into quartiles by coagulation-fibrinolysis parameters. The mean values of SBP and DBP and and PWV , the prevalence of brain infarctions were compared across these quartiles by means of analysis of variance, chi-square test, respectively. Multivariate analysis was also employed to adjust other risk factors. In conclusion, SBP and DBP and, ?, PWV were elevated by increase of PAH, TAT, respectively, in the 40+ years group even after adjustment for other possible risk factors. DD had no relation to any of the indicators of arteriosclerosis. None of the coagulation-fibrinolysis parameters had any relation to brain infarctions.

A 49-yr-old female cleaning worker first visited a hospital because of acute hepatitis. On admission, laboratory examination revealed severe hepatic damage (AST 2125 IU/L, ALT 2391 IU/L, LDH 1279 IU/L, t-Bil 8.5 mg/d/), but failed to disclose any evidence of viral infection or morphological lesions. She recovered day by day without any specific treatment for hepatitis and was discharged one month later. On the 11th day after restarting her job, she was readmitted due to similar symptoms and signs. Serum biochemistry data again showed severe liver damage (AST 1354, ALT 1604, LDH 1119 t-Bil 2.6). Histopathological diagnosis based on hepatic needle biopsy was chronic active hepatitis with diffuse infiltration of lymphocyte-dominant inflammatory cells, bridging necrosis, intercellular fibrosis in a limited region, and with ballooning, degeneration, and/or necrosis of the hepatic cells. A job-related cause was suspected and 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123), which has been proven to cause acute hepatitis in humans, was detected in a dry-cleaning solvent by gas chromatography-mass spectrometry analysis. A job simulation experiment suggested that the concentration of the patient's exposure to HCFC-123 exceeded 1,000 ppm during the busiest work period, which was sufficiently high to induce severe liver damage.

A cross-sectional observation was performed to assess the relationship between the coagulation-fibrinolysis system and the subclinical indicators of arteriosclerosis in a healthy male population. Subjects were 445 workers (18.9-49.4, Av. 36.2 yrs) in viscose rayon manufacturing factories in Japan. Coagulation-fibrinolysis parameters determined were D-dimer(DD), thrombin antithrombin III complex (TAT), tissue plasminogen activator (TPA), and plasminogen activator inhibitor 1 (PAI1). The following indicators of arteriosclerosis were examined; systolic and diastolic blood pressure (SBP, DBP), stiffness parameter of the carotid artery using ultrasound (beta), pulse wave velocity of the aorta (PWV), and a number of lacunar infarctions from brain MRI. After age-stratification(-29, 30-39, 40+ yrs), the subjects were classified into quartiles by coagulation-fibrinolysis parameters. The mean values of SBP and DBP and beta and PWV, the prevalence of brain infarctions were compared across these quartiles by means of analysis of variance, chi-square test, respectively. Multivariate analysis was also employed to adjust other risk factors. In conclusion, SBP and DBP and beta, PWV were elevated by increase of PAI1, TAT, respectively, in the 40+ years group even after adjustment for other possible risk factors. DD had no relation to any of the indicators of arteriosclerosis. None of the coagulation-fibrinolysis parameters had any relation to brain infarctions.

Under the circumstance that autonomous risk management for chemicals is required in Japan, it is necessary to define fundamental steps for developing chemical management system that are applicable in various types of companies and to understand the effective contribution of chemical or occupational health specialists to the system. For the purposes, we conducted interviews with companies which have an advanced chemical management system in Japan. As the result, each company had a certain policy about detailedness level of collected hazard and exposure information, and also had an efficient risk management system to ensure workers' health in depending on the business type and situations. Moreover, it was commonly observed that the specialists played major roles in developing tools for risk assessment and control, and then business lines led execution of the risk management with their supports. Based on the interviews, we showed a hypothesis of basic steps in introducing autonomous chemical risk management system at the workplaces. It is necessary to verify the hypothesis and to develop a simple system that is applicable to middle or small size companies as the next step.

Objective: To clarify the methodological issues for the High-risk and Population Strategy for Occupational Health Promotion Study (HIPOP-OHP study), which is a 4-year non-randomized control trial, an interim assessment of male participants was performed 3 years after the baseline survey. Methods: We had approximately 2,500 and 4,000 participants in the intervention and control groups, respectively. The population measures and prevalence of risk factors at each year, and between the baseline and 4th examinations were compared between the two groups. The personal trends of returning participants who were in the study at the 1st and 4th examinations were also evaluated. Results: During the 3 years, an increase in serum HDL cholesterol (2.7 mg/dl), and a reduction in the prevalence of hypertriglycemia detected with fasting blood samples (3.6%) and current smokers (5.4%) were observed in the intervention group. The mean HDL cholesterol level was significantly higher in the intervention group than in the control group at the 4th examination, reversed from the baseline survey. The serum non-HDL cholesterol level was significantly increased only in the control group. There was also a significant increase in the prevalence of hypertriglycemia and high plasma glucose detected with fasting blood samples in the control group. The return participation rate after 3 years was 72.2% for the intervention group and 74.9% for the control group. The above-mentioned changes for risk factors were mainly due to returning participants at each examination. Conclusion: These interventional methods may be effective in improving overall cardiovascular risk factors in the population. However, the low return participation rate will dilute the effect of the intervention.

Objective: To examine the effectiveness of newly developed materials for providing health-related information to the worksite population, we compared the amount of attention that employees paid to the materials. Methods: Study subjects were 2,361 employees in six companies partcipating in an intervention program between 2002 and 2003. Three kinds of media were used as tools for providing health information: [1] Point Of Purchase advertising menus (POP menus) were placed on all tables in company restaurants, [2] posters were put on walls and [3] leaflets were distributed at health-related events. One year or more after the introduction of these media, we compared the amount of attention paid to each type of medium. Results: Amongst the three types of media, the POP menu drew the most attention, although results were not consistent in all gender and company groups. Every piece of information provided by the POP menus was "always" or "almost always " read by 41% of the men and 51% of the women surveyed. The corresponding rate for posters was 30% in men and 32% in women. For leaflets, only 16% of men and 22% of women read almost all of the leaflets. More attention was paid to the POP menu when the sample was women, older, and ate at the company restaurant at least three times a week. Conclusion: The POP menu may provide health-related information to a broader range of people than posters and leaflets, therefore, it is an effective material for population strategy.