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Background Fast heart rate and high blood pressure (BP) at rest may raise risk for the development of type-2 diabetes mellitus (DM). We therefore investigated dose–response and interactive effects of resting heart rate and BP on the incidence of DM in a Japanese population. [ABSTRACT FROM PUBLISHER]

To investigate the longitudinal impact of smoking cessation and relapse on the exercise habits of apparently healthy Japanese men, 750 subjects presenting for a checkup at a metropolitan health center were surveyed annually for 7 years. Exercise was dichotomously classified as none or any. Subjects were grouped in two categories: 98 smokers who ceased smoking during the second year of the study, matched with 196 continuing smokers and 196 men who had never smoked; and 52 relapsed smokers (including 2 new smokers) who did not smoke at baseline or at Year 1 but smoked from Year 2 to final follow-up, matched with 104 continuing smokers and 104 never-smokers. Based on self-reported responses to questionnaires, exercise was consistently less prevalent among smokers who did not quit than among never-smokers throughout the study. Habitual exercise in subjects who had quit smoking increased during the follow-up (any exercise: 42.9% at baseline increased to 51% at final follow-up, p for longitudinal trend = .115). Habitual exercise in matched never-smokers did not change during the study and decreased significantly among persistent smokers (p = .025). Habitual exercise in relapsed smokers decreased during the follow-up (any exercise: 50.0% at baseline declined to 32.7% at final follow-up, p = .007), but habitual exercise in matched persistent smokers and never-smokers did not change. We conclude that smoking and sedentary lifestyle coexist continuously, that smoking cessation is associated with increased habitual exercise among healthy men, and that relapse is associated with reduced habitual exercise, suggesting that cigarette smoking weakens exercise habits. [ABSTRACT FROM AUTHOR]

Fabry disease is a hereditary disorder that occurs due to the reduction or absence of alpha-galactosidase A activity, which leads to cardiac involvement including left ventricular hypertrophy (LVH). Enzyme replacement therapy (ERT) provides better patient outcomes by preventing serious complications. However, there have been very few studies on the long-term effects of ERT on the cardiac manifestations in Japanese Fabry patients. We retrospectively analyzed the data from the medical records of 42 Fabry patients (male, n  = 17; female, n  = 25) who were followed at Jikei University Hospital, and in whom the long-term effects of ERT could be evaluated (median follow-up period: male, 11 years; female, 8 years). The slope of the left ventricular mass (LVM) increase was 3.02 ± 3.41 g/m 2 /year in males and 1.69 ± 2.73 g/m 2 /year in females. In a subgroup analysis, the slopes of males with and without LVH did not differ to a statistically significant extent; however, the slope in female patients without LVH was significantly smaller than that of female patients with LVH. We then compared our data to the natural historical data that have previously been reported. In comparison to the previously reported data, we found a significant reduction in the LVM changes (g/height 2.7 /year) of patients who received long-term ERT (male, 4.07 ± 1.03 to 1.25 ± 1.39; female, 2.31 ± 0.81 to 0.78 ± 1.23). Long-term ERT effectively prevents LVH in Fabry patients. This effect was also observed in the patients with LVH prior to the initiation of ERT. [ABSTRACT FROM AUTHOR]

This report describes our onsite medical rounds and fact-finding activities conducted in the acute phase and medical relief work conducted in the subacute phase in Miyagi prefecture following the Great East Japan Earthquake and subsequent tsunami that occurred off northeastern Honshu on March 11, 2011. As part of the All-Japan Hospital Association medical team deployed to the disaster area, a Nippon Medical School team conducted fact-finding and onsite medical rounds and evaluated basic life and medical needs in the affected areas of Shiogama and Tagajo. We performed triage for more than 2,000 casualties, but in our medical rounds of hospitals, clinics, and nursing homes, we found no severely injured person but did find 1 case of hyperglycemia. We conducted medical rounds at evacuation shelters in Kesennuma City during the subacute phase of the disaster, from March 17 through June 1, as part of the Tokyo Medical Association medical teams deployed. Sixty-seven staff members (17 teams), including 46 physicians, 11 nurses, 3 pharmacists, and 1 clinical psychotherapist, joined this mission. Most patients complained of a worsening of symptoms of preexisting conditions, such as hypertension, respiratory problems, and diabetes, rather than of medical problems specifically related to the tsunami. In the acute phase of the disaster, the information infrastructure was decimated and we could not obtain enough information about conditions in the affected areas, such as how many persons were severely injured, how severely lifeline services had been damaged, and what was lacking. To start obtaining this information, we conducted medical rounds. This proved to be a good decision, as we found many injured persons in evacuation shelters without medication, communication devices, or transportation. Also, basic necessities for life, such as water and food, were lacking. We were able to evaluate these basic needs and inform local disaster headquarters of them. In Kesennuma City, we found that some evacuation shelters could not contact others even after 1 week after the earthquake. We realized from our experiences that, unlike our activities following more localized earthquake disasters, the first task following such large-scale disasters is to acquire information on basic life needs, including medication needs, and the number of persons requiring assistance. We must provide medical relief according to the unique characteristics of the disaster-affected areas as well as the specific nature of the disaster, in this case, a tsunami. [ABSTRACT FROM AUTHOR]

On March 11, 2011, after the Great East Japan Earthquake and tsunami, the government declared a nuclear emergency following damage to the Fukushima Daiichi Nuclear Power Plant. A second hydrogen explosion occurred on March 14 at the plant's No. 3 reactor and injured 11 people. At that time the prime minister urged people living 20 to 30 km from the Daiichi plant to stay indoors. Under these circumstances, many residents of Iwaki City, which was largely outside the 30-km zone, left the city, making it difficult to get supplies to the remaining residents. The only transportation route open for supplies and medical resources was roads, and many drivers feared the rumor that the city was contaminated by radioactive materials and, so, refused to go there. Nippon Medical School (NMS) heard that medical resources were running short at Iwaki Kyoritsu Hospital, which requested water, medications, food, fuel (gasoline), medical support, and the evacuation of 300 inpatients. As a first step, NMS decided to evaluate the situation at the hospital and, on March 16, the director of the NMS Advanced Emergency Center visited the hospital and helped provide triage for about 200 patients. Critically ill patients receiving ventilatory support were given priority for evacuation because they would be most at risk of not being able to evacuate should the Japanese government order an immediate evacuation of the city. We tried to evacuate the inpatients via an official framework, such as the Disaster Medical Assistance Team (DMAT), but DMAT could not support this mission because this hospital was not within the 30-km evacuation zone. Moreover, the Iwaki City government could not support the evacuation efforts because they were fearful of the rumor that Iwaki was contaminated by radioactive material. Ultimately, we realized that we had to conduct the mission ourselves and, so, contacted our colleagues in the Tokyo metropolitan area to prepare enough hospital beds. We evacuated 15 patients to 8 hospitals over a 5-day period. As a result, we could reduce the number of patients at Iwaki Kyoritsu Hospital, and, thereby, the collapse of medical services in the city was avoided. In retrospect, someone might say the government--either central or local--should ideally have carried out this mission and created a system by which to do it. At the same time, however, to overcome any future bureaucratic issues, we should also prepare private networks, such as those used by NMS, because they can respond flexibly to unexpected large-scale disasters. [ABSTRACT FROM AUTHOR]

This work describes a set of discovery research studies of an influenza cap-dependent endonuclease (CEN) inhibitor with a carbamoyl pyridone bicycle (CAB) scaffold. Using influenza CEN inhibitory activity, antiviral activity and pharmacokinetic (PK) parameters as indices, structure activity relationships (SAR) studies were performed at the N-1 and N-3 positions on the CAB scaffold, which is a unique template to bind two metals. The hydrophobic substituent at the N-1 position is extremely important for CEN inhibitory activity and antiviral activity, and dihydrodibenzothiepine is the most promising pharmacophore. The compound (S)-13i showed potent virus titer reduction over oseltamivir phosphate in an in vivo mouse model. The CAB compound described herein served as the lead compound of baloxavir marboxil with a tricyclic scaffold, which was approved in Japan and the USA in 2018. [ABSTRACT FROM AUTHOR]

Background: Fabry disease is a hereditary metabolic disorder caused by a decrease in or deficiency of the lysosomal enzyme α-galactosidase A. Enzyme replacement therapy or pharmacological chaperone therapy can improve prognosis, especially in patients in the early phase of cardiac involvement. Longitudinal strain (LS) evaluated using speckle tracking echocardiography can detect early contractile dysfunction. However, there have been no reports of LS in Japanese Fabry disease patients., Methods and Results: We recruited 56 patients with Fabry disease (22 men, 34 women) who were followed up at Jikei University Hospital. Fifty-eight control subjects without overt cardiac diseases were also included in the study. We evaluated LS in each patient, and the values of each of the 17 segments of the left ventricle (LV) were averaged, and global LS (GLS) was also calculated. GLS was significantly worse in Fabry disease patients without LV hypertrophy than in control subjects (-18.5±2.8% vs. -20.4±1.6%; P<0.05). In addition, Fabry disease patients without LV hypertrophy had significantly worse lateral LS (-16.4±5.0% vs. -19.3±1.8%; P<0.05), basal LS (-16.5±3.2% vs. -18.5±1.7%; P<0.05), and mid LS (-18.7±1.7% vs. -20.8±1.6%; P<0.05) than control subjects., Conclusions: These results suggest that early contractile dysfunction in Fabry disease can be observed using GLS, lateral LS, basal LS, and mid LS, even without LV hypertrophy.

Purpose: To assess the impact of interactions between kidney stone formation and conventional risk factors on incident chronic kidney disease (CKD)., Methods: A total of 11,402 subjects (men 30-69 years of age, Japanese) without CKD at baseline were observed over an average period of 4 years. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) to determine the association between incident CKD, kidney stone formation, and conventional risk factors (diabetes mellitus, hypertension, overweight/obesity, dyslipidemia, and hyperuricemia/gout). We also examined the interactions of renal stones and the conventional risk factors for CKD., Results: In total, 2301 men (20.2%) developed incident CKD during the follow-up period. After multivariable adjustment, kidney stones were found to increase the risk of incident CKD (HR 1.16; 95% CI 1.03-1.32). Kidney stone formers with hypertension, dyslipidemia, or hyperuricemia/gout presented a greater risk for incident CKD than those who had either kidney stones or other risk factors. However, no significant interactions between kidney stones and other risk factors were found to increase CKD risk. On the other hand, a negative interactive effect between kidney stones and overweight/obesity was observed, leading to reversed risk of incident CKD in coexistence of both factors., Conclusion: Kidney stones were linked to a higher risk for the development of CKD. However, no positive interactive effects were identified between renal stones and conventional risk factors on the risk of incident CKD.

Objective: The present study was undertaken to establish a useful range for the B-type natriuretic peptide (BNP) level, with the ultimate goal of determining a cut-off BNP level that will make it possible to identify patients with clinically important organic heart disorders among patients encountered in clinical practice., Methods: A total of 11,967 outpatients were evaluated for this study, and, after applying the exclusion criteria, 361 patients were finally recruited for the analysis. Compared to the factors of gender and body mass index, aging was considered to be an indispensable factor in this analysis. The 'median' plasma BNP level was found to increase slowly with age, but remained lower than 30 pg/mL, even in patients aged 60 years or older. In contrast, the overall '95th percentile' of the plasma BNP level in the patients younger than 60 years was 41 pg/mL, which increased to 139.8 pg/mL in the patients aged 60 years or older., Conclusion: These findings suggest that the lower range of the BNP level allowing for identification of patients with clinically important organic heart disorders increases with age; however, it might be appropriate to adopt a level of approximately 40 pg/mL, even in elderly patients, in order to avoid any possible age-related effects of diastolic dysfunction or other factors.

Background: Obesity has recently been shown to have a favorable effect on the prognosis of patients with congestive heart failure (CHF), but only a few such studies are available in Japan. The purpose of the present study was to investigate whether the obesity paradox is still present after adjusting for CHF characteristics., Methods and Results: A total of 219 patients hospitalized with CHF were reviewed, and the impact of body mass index (BMI) on prognosis was examined. Patients were divided into 4 groups according to BMI quartiles. The endpoint was defined as all-cause death or unplanned CHF hospitalization. According to univariate analysis, a higher BMI was associated with better outcomes. High-BMI patients were younger, likely to be male, and had a higher prevalence of hypertension and diabetes. The plasma B-type natriuretic peptide (BNP) levels and blood urea nitrogen (BUN) levels were lower, while the serum hemoglobin and sodium levels were higher in high-BMI patients. The prevalence of atrial fibrillation was lower in high-BMI patients. Predictors for all-cause death or CHF hospitalization based on univariate analysis were age, prior CHF hospitalization, estimated glomerular filtration rate, plasma BNP levels, BUN levels, and serum hemoglobin and sodium levels. According to multivariate analysis, a high BMI was still associated with better outcomes., Conclusions: High BMI was associated with better clinical outcomes in Japanese CHF patients.

This study evaluated the relationship between the severity of coronary artery disease (CAD) and traditional coronary risk factors, metabolic syndrome, and chronic kidney disease (CKD). Three hundred and forty-three patients (35-90 years of age) with initial diagnosis of CAD were separated into two groups: 165 patients with single-vessel coronary artery disease (SVD group) and 178 patients with multivessel coronary artery disease (MVD group). We compared the risk factors for CAD between the two groups. An adjusted multivariate analysis showed that only CKD was associated with MVD (odds ratio, 2.85; 95% confidence interval [CI], 1.76-4.63; P = 0.00002). Next, the relationship between the severity of CAD, CKD, and the incidence of subsequent major adverse cardiac event (MACE) was investigated in 338 patients during the patient follow-up. The risk of MACE was approximately threefold higher in the group with MVD and CKD stage of 3 or greater than in the group with SVD but without CKD stage of 3 or greater (adjusted hazard ratio, 3.40; 95% CI, 1.26-9.17; P = 0.016). A statistical analysis also suggested that having MVD and advanced CKD was a more powerful risk factor for MACE. The comparison of risk factors between patients with SVD and patients with MVD revealed that CKD was the most important risk factor for MVD. In addition, having MVD and advanced CKD together was a crucial risk factor for subsequent MACE. To reduce the progression of CAD and to improve the prognosis of patients with MVD, the renal status should therefore be carefully assessed during treatment for CAD.

Purpose: To investigate interactive effects of cigarette smoking and body mass index (BMI, measured in kilograms per square meter) on the risk for type 2 diabetes mellitus (DM)., Methods: We conducted a follow-up study in 16,829 apparently healthy men 30 to 59 years of age. At baseline, 23.1%, 24.6%, 24.0%, and 28.4% of the men were 'never' smokers, ex-smokers, light smokers (20 cigarettes/d), respectively. BMI was expediently categorized into quartiles (Q1: <21.3; Q2: 21.3-22.9; Q3: 23.0-24.7; and Q4: >24.7 kg/m2). Incident DM was identified by a fasting serum glucose level of 7.00 mmol/L or higher or the criterion 'under treatment for DM.' The risk ratio for incident DM, hazard ratio (HR) and the 95% confidence interval (CI), according to smoking and BMI, were estimated by using Cox proportional hazard models. Age, drinking, exercise, and education were computed as confounders., Results: During mean follow-up of 7.4 years, 869 men developed DM. In Q4 of BMI, heavy smoking raised the risk against 'never smoking' (multivariate-adjusted HR (95%CI): 1.37 [1.05-1.80]), but neither light smoking nor ex-smoking did. In Q1 of BMI, light and heavy smoking reduced the risk (multivariate-adjusted HR (95% CI): 0.45 (0.23-0.88) and 0.74 (0.41-1.33), respectively)., Conclusions: Smoking and BMI interactively influence risk for DM and the interaction is considerably complex. Heavy smoking moderately increases the risk for DM in obese men. But, light smoking reduces the risk in lean men.

Background: Drugs that inhibit the renin-angiotensin-aldosterone system benefit patients at risk for or with existing cardiovascular disease. However, evidence for this effect in Asian populations is scarce. We aimed to investigate whether addition of an angiotensin receptor blocker, valsartan, to conventional cardiovascular treatment was effective in Japanese patients with cardiovascular disease., Methods: We initiated a multicentre, prospective, randomised controlled trial of 3081 Japanese patients, aged 20-79 years, (mean 65 [SD 10] years) who were undergoing conventional treatment for hypertension, coronary heart disease, heart failure, or a combination of these disorders. In addition to conventional treatment, patients were assigned either to valsartan (40-160 mg per day) or to other treatment without angiotensin receptor blockers. Our primary endpoint was a composite of cardiovascular morbidity and mortality. Analysis was by intention to treat. The study was registered at clintrials.gov with the identifier NCT00133328., Findings: After a median follow-up of 3.1 years (range 1-3.9) the primary endpoint was recorded in fewer individuals given valsartan than in controls (92 vs 149; absolute risk 21.3 vs 34.5 per 1000 patient years; hazard ratio 0.61, 95% CI 0.47-0.79, p=0.0002). This difference was mainly attributable to fewer incidences of stroke and transient ischaemic attack (29 vs 48; 0.60, 0.38-0.95, p=0.028), angina pectoris (19 vs 53; 0.35, 0.20-0.58, p<0.0001), and heart failure (19 vs 36; 0.53, 0.31-0.94, p=0.029) in those given valsartan than in the control group. Mortality or tolerability did not differ between groups., Interpretation: The addition of valsartan to conventional treatment prevented more cardiovascular events than supplementary conventional treatment. These benefits cannot be entirely explained by a difference in blood pressure control.

Since occupation, a major socio-economic factor, may be a risk factor for type-2 diabetes mellitus (DM), we compared DM incidence among four groups of white-collar workers in a follow-up study in 13,547 Japanese men. The subjects aged 30-59 years and free from DM at baseline consisted of: (a) 3725 clerical, (b) 5575 technical/professional, (c) 3474 manager/administrative and (d) 774 sales workers. Incident DM was identified by 'fasting serum glucose >or=7.00 mmol/l' or 'under medical treatment for DM'. Hazard ratio (HR) and 95% confidence interval (CI) for incident DM were estimated using clerical workers as the reference group (HR=1.00). Baseline age, body mass index (BMI), drinking, smoking, exercise and education were computed as confounders. During mean follow-up periods of 7.4 years, 176 clerical, 264 technical/professional, 195 manager/administrative and 49 sales workers developed DM (6.0, 6.1, 8.8 and 9.4 per 1000 person-years, respectively). Sales workers aged 40-49 and 50-59 years had increased multivariate-adjusted HRs (95% CIs) of 1.55 (1.02, 2.35) and 2.01 (0.98, 4.10), respectively. Manager/administrative workers aged 50-59 years had an increased crude HR (95% CI) of 1.64 (1.02, 2.63), but the significance disappeared after BMI-adjustment (HR (95% CI: 1.46 (0.91, 2.35)). Technical/professional workers had no significant HR in any model. In conclusion, sales workers in Japan aged >or=40 years may have increased risk for DM (+55 to +100%) independent of BMI, lifestyles and education, and manager/administrative workers aged >or=50 years may have increased risk (about +65%) due to their large BMI.

Background: Policemen/firefighters may have increased risk for mortality from ischemic heart disease and from all causes. We compare incidence of type-2 diabetes mellitus (DM), a well-known predictor for mortality, in policemen/firefighters with that in two other worker-groups., Methods: A follow-up study of 5,130 healthy Japanese men aged 30-49 years at baseline consisted of three worker-groups; 3,111 clerical workers, 1,122 manual/production and transport/communication workers, and 897 policemen/firefighters. Incident DM was identified by "fasting serum glucose >or=7.00 mmol/L" or/and "under medical treatment for DM." Hazard ratio (HR) and 95% confidence interval (95% CI) for incident DM was estimated by Cox's proportional hazard models using clerical workers as a reference group (HR=1.00). Baseline age, body mass index (BMI, kg/m(2)), drinking, smoking, exercise, and education were computed as confounders., Results: During mean follow-up periods of 8.4 years, 155 clerical workers, 51 manual/production and transport/communication workers, and 74 policemen/firefighters had incident DM (5.9, 5.7, and 9.6 per 1,000 person-years, respectively; P=0.001 by chi(2)-test). Policemen/firefighters had significantly increased risk for incident DM against clerical workers (age-adjusted HR (95% CI): 1.65 (1.25, 2.18)), but the significance disappeared after adjustments for BMI (age- and BMI-adjusted HR (95% CI): 1.16 (0.87, 1.54)). Manual/production and transport/communication workers had no increased risk., Conclusions: Policemen/firefighters have increased risk for DM probably due to their large BMI. Body weight control may be more efficient for prevention of DM and DM-related health problems in policemen/firefighters than in other workers., (Am. J. Ind. Med. 49:30-35, 2006. (c) 2005 Wiley-Liss, Inc.)

We examined the chronological change in Type A behavior pattern (TABP) among Japanese male workers for 5 yr. A brief questionnaire to measure TABP was administered to 21,711 male workers who underwent health check-ups at least once during the period from 1995 to 1999 and were born in 1936-1965. The mean TABP scores decreased year by year linearly. Then the repeated measurement analysis of variance was performed with the data of 5,689 subjects who completed the questionnaire successively through the study period. Both year and the age effects were highly significant (p<0.001, respectively), whereas the time trends were comparable by baseline age. In conclusion, TABP among Japanese male workers decreased in all generations during the period from 1995 to 1999.

The Beck Depression Inventory has undergone substantial revision recently as the BDI-II to correspond to DSM-IV criteria. We developed the Japanese version of the BDI-II and examined its psychometric properties. The linguistic equivalence was verified by a back-translation method. The final translation was administered to the visitors at a public health care center, and the responses of 766 adults (age = 24-82 years, women = 40%) were analyzed. Half of the participants completed the Center for Epidemiologic Studies Depression Scale (CES-D) as well. A high level of internal consistency reliability (Cronbach's alpha = 0.87) and item homogeneity was confirmed. Exploratory factor analysis showed a two-factor structure (cognitive and somatic-affective), which was almost identical to the original model demonstrated by Beck et al. (1996, Manual for the Beck Depression Inventor Psychological Corporation, San Antonio, TX, USA). The following confirmatory factor analysis also supported the two-factor structure. Adequate correlation (r = 0.69, P < 0.001) between the total score of the BDI-II and that of the CES-D was observed. A higher score for women compared to men, without significant age differences, was consistent with the results of previous reports. We conclude that the Japanese version of the BDI-II is psychometrically robust and can be used to assess depressive symptoms in Japanese people.