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Objective This study examined whether or not the disease control in Japanese patients with systemic lupus erythematosus (SLE) had improved in recent years and its possible association with altered balance between the use of glucocorticoids and immunosuppressants. Methods We enrolled Japanese patients with SLE who visited our medical center during 2013-2017 (Group A, 75 patients) and compared them with patients encountered during 1999-2003 (Group B, 69 patients; not overlapping with Group A). Patient background characteristics, doses of glucocorticoids, and the use of immunosuppressants at the times of SLE onset and disease flares were reviewed from the medical records. Disease flare was defined as new British Isles Lupus Assessment Group 2004 A or B scores in at least one system. Results Lupus nephritis and neuropsychiatric manifestations were less frequently observed in Group A than in Group B (p=0.042 and p=0.045, respectively). Although the initial glucocorticoid dosage was similar between the groups, the inclusion rate of immunosuppressants in the initial SLE treatment was significantly higher in Group A than in Group B (56% vs. 6% in Group B, p0.001). The median number of SLE flares per person-year was significantly lower in Group A than in Group B (0 vs. 0.3, respectively, p0.001), and a propensity score-matched analysis indicated the association of SLE flare with the non-use of immunosuppressants in the initial treatment (p=0.012). The rates of infectious diseases and other complications were similar between the groups. Conclusion The recent aggressive use of immunosuppressants in Japan resulted in a reduction in the rate of SLE flare.

Objective We evaluated the performance of the revised classification criteria for assessing different systemic autoimmune rheumatic diseases and their overlap syndromes. Methods A total of 652 patients with or highly suspected of having systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis (PM)/dermatomyositis (DM) or rheumatoid arthritis (RA) were included in this study. The 1997 revised American College of Rheumatology (ACR) and the 2019 European League Against Rheumatism (EULAR)/ACR criteria for SLE, the 1980 ACR and the 2013 ACR/EULAR criteria for SSc, the criteria by Bohan and Peter and the 2017 EULAR/ACR criteria for PM/DM, and the 1987 revised ACR and 2011 ACR/EULAR criteria for RA were used for disease classification. Results The old and new criteria and a clinical diagnosis were used to respectively classify 103, 106 and 105 SLE patients; 35, 47 and 58 SSc patients; 18, 23 and 33 PM/DM patients; and 297, 389 and 468 RA patients. Sensitivity increased from 82.9% to 92.4% in SLE, from 56.9% to 79.3% in SSc, from 54.5% to 66.7% in PM/DM, and from 62.6% to 80.8% in RA. SLE-SSc was the predominant type of clinical overlap syndrome, while SLE-RA was the most classifiable. Conclusion The revised classification criteria for all the diseases showed an improved sensitivity, and SLE-overlap syndrome was predominant, regardless of the criteria sets.

Background Peak oxygen uptake (peak VO2) is known not only as an index of aerobic fitness but also one of an index of life expectancy. Frailty, sarcopenia, and cachexia are associated with a poor prognosis and high mortality. The purpose of this study was to determine the relationships of peak VO2 with the features of sarcopenia, frailty, and cachexia, to provide insight into which might mediate the poor prognosis. Methods The first group of participants was 175 community‐dwelling older Japanese outpatients (58 men and 117 women; mean age 77.6 ± 6.4 years), in whom we assessed the features of sarcopenia, frailty, and cachexia, and measured peak VO2 during cardiopulmonary exercise. To confirm the relationships, we analysed another group of 162 participants (77.3 ± 5.5 years). Results There were significant correlations between peak VO2 and the features of sarcopenia, frailty, and cachexia, with the exception of high sensitivity C‐reactive protein. Multiple linear regression analysis for the prediction of peak VO2 (mL/min) identified following formula: predicted peak VO2 = −11.6 × age (years) + 25.5 × haemoglobin concentration (g/dL) + 114.2 × skeletal muscle mass index (kg/m2) + 8.9 × hand grip strength (kg) + 226.4 × usual walking speed (m/s) − 65.8 × fatiguability (absence 0, presence 1) − 177.4 × chronic heart failure (absence 0, presence 1) + 437.1 (R2 = 0.627, P

Aims Sarcopenia is a serious problem because of its poor prognosis. Growth differentiation factor 15 (GDF15) is associated with mitochondrial dysfunction, inflammation, insulin resistance and oxidative stress, which may play crucial roles for the development of sarcopenia. We aimed to examine whether serum GDF15 level is associated with muscle mass, strength and lower extremity function in older patients with cardiometabolic disease. Methods Serum GDF15 levels were measured in 257 patients with cardiometabolic diseases (including 133 patients with diabetes) who had visited the frailty clinic, using a latex turbidimetric immunoassay. Appendicular skeletal muscle index, handgrip strength, timed-up-and-go test and gait speed were evaluated. Power, speed, balance and total scores based on the sit-to-stand test were calculated to assess lower extremity function. Results The highest tertile of serum GDF15 was independently associated with low handgrip strength, low gait speed, long timed-up-and-go time and scores of lower extremity function but not an appendicular skeletal muscle index in multiple logistic regression analyses after adjustment for covariates. Patients in the highest tertile of GDF15 were at the risk of having three to nine times lower grip strength, three times lower gait speed, five to six times lower mobility and five to 11 times reduction in lower extremity function as compared with those in the lowest GDF15 tertile dependent on the models. Conclusions Elevated serum GDF15 level was independently associated with low muscle strength and lower extremity function in older patients with cardiometabolic disease. Serum GDF15 could be one of the biomarkers for muscle weakness and low physical performance. Geriatr Gerontol Int 2020; 20: 980-987.

Aim To determine the patterns of concomitant drug use for chronic diseases and examine the risk factors of polypharmacy in older outpatients. Methods Data were extracted from an anonymized health insurance claims database of a public insurance program for older adults in Tokyo, Japan. We analyzed individuals aged ≥75 years who had visited an outpatient clinic, and were regularly prescribed orally administered drugs for chronic diseases for ≥14 days between May and August 2014. The prescription patterns for 16 main drug types were studied using exploratory factor analysis, and the risk factors of polypharmacy, defined as the concomitant prescription of five or more drugs, were identified using multivariate logistic regression models. Results A total of 1 094 199 outpatients were analyzed (mean age 81.8 years, 38.4% men). We identified five prescription patterns that explained almost 40% of all observed variance: edema/heart failure/atrial fibrillation-related drugs, insomnia/anxiety-related drugs, pain-related drugs, lifestyle disease-related drugs and dementia-related drugs. The significant risk factors of polypharmacy included men, octogenarians and nonagenarians, higher number of medical institutions visited, use of physician home visits, and hospitalization during the study period. The main drug types most strongly associated with polypharmacy were analgesics, diuretics and antidiabetics. Conclusions Polypharmacy was found to be prevalent in older outpatients aged ≥75 years in Tokyo. These findings might provide useful evidence that can contribute to the development of practical countermeasures against adverse events associated with polypharmacy in clinical practice. Geriatr Gerontol Int 2020; 20: 304-311.

Aim Selecting optimal energy intake during diet therapy for older patients with diabetes mellitus is difficult because of the large differences in physical function and comorbid diseases. In Japan, although requirements for total energy intake are calculated by multiplying a person's standard bodyweight (BW) by the amount of physical activity, evidence supporting the application of this method among older people is limited. Therefore, we aimed to assess optimal energy intake by evaluating the relationship between energy intake and mortality in older patients. Methods We evaluated data from a 6-year prospective follow up of 756 older patients with diabetes mellitus, and the association between baseline nutrient intake and mortality. Total energy intake and nutrients were evaluated, and energy intake per actual BW was categorized into quartiles (Q). Cox regression analysis was used for statistical analyses. Energy intake per standard BW or age-related target BW was statistically analyzed using the same protocol. Results Analysis of energy intake per actual BW showed that hazard ratios for mortality was significantly higher in Q1 and Q4. Similar associations were found for energy intake per standard or target BW. Subgroup analysis showed that mortality rate was the lowest in Q2 in the young-old population and in Q3 in the old-old population. Conclusions A U-shaped relationship was observed between energy intake per BW and mortality in older patients with diabetes mellitus, which suggests that the optimal energy intake per actual or target BW should encompass a wide range to prevent malnutrition and excessive nutrition in these patients. Geriatr Gerontol Int 2020; 20: 59-65.

Background: Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C) lowering therapy in older individuals, aged ≥75 years, is insufficient. This trial tested whether LDL-C–lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. Methods: This multicenter, prospective, randomized, open-label, blinded end-point evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥75 years, with elevated LDL-C without history of coronary artery disease. Patients, who all received dietary counseling, were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke. Results: Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50–0.86; P =0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37–0.98; P =0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18–0.79; P =0.007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups. Conclusions: LDL-C–lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution. Clinical Registration: URL: https://www.umin.ac.jp . Unique identifier: UMIN000001988.

Background: Postoperative neurologic deficits are associated with severe morbidity in aortic arch replacement. Methods: A group of 198 consecutive patients undergoing isolated total aortic arch replacement with the use of antegrade cerebral perfusion were analyzed for the risk factors for predicting neurologic deficit. With the use of computed tomography, atherothrombotic lesions (defined as extensive intimal thickening exceeding 4 mm) were identified in the proximal aorta (the ascending aorta or aortic arch) in 26.2% of cases and in the distal aorta in 34.9% of cases. Results: Permanent neurologic deficits occurred in 11.1% (including non-disabling stroke confirmed by imaging) and transient neurologic deficits in 8.1% of patients. A univariate analysis identified proximal atherothrombotic aorta (p = 0.0057), distal atherothrombotic aorta (p = 0.032), and retrograde systemic perfusion from the femoral artery in the presence of distal atherothrombotic aorta (p = 0.0022) as risk factors for neurologic deficits. A multivariate logistic regression analysis identified atherothrombotic proximal aorta (odds ratio 2.4, p = 0.033) as the independent risk factor. The presence of carotid stenosis did not affect the rate of neurologic deficit. Intracranial hemorrhagic lesions were found in 23% of permanent neurologic deficit cases. Conclusions: Atherothrombotic lesions found by objectively graded computed tomography were predictors of neurologic deficit. Retrograde perfusion in the presence of a distal atherothrombotic lesion should be avoided whenever possible. Strategies based on the full assessment of the whole aortic morphologic characteristics appear to be mandatory. Anticoagulation therapy should be performed carefully to avoid intracranial hemorrhagic changes., ファイル公開：2020-07-01

This study investigates the associations between sodium intake and diabetes complications in a nationwide cohort of elderly Japanese patients with type 2 diabetes aged 65–85. Data from 912 individuals regarding their dietary intake at baseline is analyzed and assessed by the Food Frequency Questionnaire based on food groups. Primary outcomes are times to diabetic retinopathy, overt nephropathy, cardiovascular disease (CVD), and all-cause mortality during six years. We find that mean sodium intake in quartiles ranges from 2.5 g to 5.9 g/day. After adjustment for confounders, no significant associations are observed between sodium intake quartiles and incidence of diabetes complications and mortality, except for a significant trend for an increased risk of diabetic retinopathy (p = 0.039). Among patients whose vegetable intake was less than the average of 268.7 g, hazard ratios (HRs) for diabetic retinopathy in patients in the second, third, and fourth quartiles of sodium intake compared with the first quartile were 0.87 (95% CI, 0.31–2.41), 2.61 (1.00–6.83), and 3.70 (1.37–10.02), respectively. Findings indicate that high sodium intake under conditions of low vegetable intake is associated with an elevated incidence of diabetic retinopathy in elderly patients with type 2 diabetes.

The aim of this study was to investigate the association between protein intake and mortality risk in patients with type 2 diabetes. We analyzed a pooled data of 2494 diabetic patients from two prospective longitudinal studies. Nutritional intake was assessed using a Food Frequency Questionnaire at baseline. Protein intake per body weight (kg) per day was categorized into quartile groups. Adjusted hazard ratios (HRs) and 95% confidence interval (CI) were calculated using Cox regression analysis. During the six-year follow-up, there were 152 incidents of all-cause mortality. The HR for mortality in the lowest quartile of protein intake per body weight compared with the highest quartile was 2.26 (95% CI: 1.34&ndash, 3.82, p = 0.002) after adjustment for covariates. Subgroup analyses revealed significant associations between low protein intake and mortality in patients aged over 75 years or under 65 years. After further adjustment of the total energy intake, a significant association between protein intake and mortality remained in patients aged &ge, 75 years, whereas the association was attenuated in those aged &lt, 65 years. Our results suggest that adequate protein intake is necessary in older diabetic patients over 75 years, whereas with diabetes, whereas whole optimal total energy intake is required in younger patients with type 2 diabetes.

Objective A shaggy aorta is defined as a very extensive atheromatous disease with diffuse ulcers in combination with fragile and mobile debris, and actual thrombus. Multiple embolisation – resulting in permanent neurological deficits, paraplegia and a large area of mesenteric embolisation – attributed to cholesterol atheromatic mobile plaque caused by shaggy aorta needs to be prevented. Methods Complete exclusion of the shaggy aorta from the distal aortic arch to the end of the descending aorta was presented in two cases: a 71-year-old male and a 51-year-old male. Successful one-stage repair of the extended aortic arch and descending aorta was performed using an isolated selective cerebral perfusion technique via sternotomy and left anterior thoracotomy. Results There were no neurological or embolic events in the present cases. Contrast-enhanced computed tomography showed good reconstruction of the aortic arch and descending aorta. The patients are still being followed up in the outpatient clinic and have shown no atheromatic embolisation for the past 6 years. Conclusions The exclusion technique for an entire shaggy aorta followed by one-stage repair of the aortic arch and descending aorta is a durable and feasible operation for preventing atheromatous embolisation.

Highlights • We examined links between medical claims and health check-up data for older adults. • Patients receiving pharmacotherapies were more likely to participate in health checkups. • Patients with intensive disease control were more likely to be aged ≥ 90 years. • Linking these databases can improve evaluations of diseases control in older adults., The Japanese government encourages older adults to participate in annual health checkups designed to detect lifestyle diseases such as hypertension, diabetes, and dyslipidemia. However, individuals who are already being treated for these diseases are unlikely to benefit from health checkup participation. This retrospective cohort study of older adults evaluated the associations of pharmacological treatments for these diseases with health checkup participation and identified the disease control factors among patients receiving treatments. Using medical claims data and health checkup data between September 2013 and August 2014 from 820,215 older adults aged ≥ 75 years residing in Tokyo, Japan, we examined the associations between pharmacological treatments and health checkup participation using binary logistic regression analysis. Next, patients receiving pharmacological treatments were categorized into intensive, moderate, or limited disease control based on their blood pressure, hemoglobin A1c levels, and lipid levels; multinomial logistic regression analyses were used to identify the disease control factors. The results showed that patients receiving pharmacological treatments were more likely (odds ratio: 1.374; P

GM3, a precursor for synthesis of a- and b-series gangliosides, is elevated in adipocytes of obese model animals and in sera of obese human patients with type 2 diabetes and/or dyslipidemia. GM3 synthase (GM3S)-KO C57BL/6 mice display enhanced insulin sensitivity and reduced development of high-fat diet-induced insulin resistance. However, the pathophysiological roles of GM3 and related gangliosides in the central control of feeding and metabolism remain unclear. We found that a mouse model (KKAy GM3S KO) generated by KO of the GM3S gene in the yellow obese strain, KKAy, displayed significant amelioration of obese phenotype. Whereas KKAy mice were hyperphagic and developed severe obesity, KKAy GM3S KO mice had significantly lower body weight and food intake, and greater glucose and insulin tolerance. The hypothalamic response to intraperitoneal administration of leptin was greatly reduced in KKAy mice, but was retained in KKAy GM3S KO mice. In studies of a cultured mouse hypothalamic neuronal cell line, enhanced leptin-dependent phosphorylation of ERK was observed in GM3S-deficient cells. Furthermore, KKAy GM3S KO mice did show altered coat color, suggesting that GM3S is also involved in melanocortin signaling. Our findings, taken together, indicate that GM3-related gangliosides play key roles in leptin and melanocortin signaling.

Background: Frailty and sarcopenia are age-related morbid states, and a low body mass index (BMI) is a characteristic of frailty and cachexia. However, no common index for assessing these three muscle wasting states is available, making it difficult to understand the relationship among them. Peak oxygen uptake (peak VO 2 ), an index of life expectancy, may be a useful common index. Therefore, this study aimed to investigate the relationship among sarcopenia, frailty, and cachexia using age, BMI, and peak VO 2 . Methods: Participants were 175 Japanese community dwelling older adults (58 men, 117 women; 77.6 years). We assessed biochemical, physiological, and physical factors, and symptoms associated with frailty, and cachexia. Peak VO 2 was assessed with a cardiopulmonary exercise test. Participants were classified into five groups: robust, pre-frail, frail, sarcopenia, and cachexia. We compared the groups by age, BMI, and peakVO 2 with average values and 95% confidence intervals (CIs). Results: 17% (n=30) of participants were classified as robust, 40% (n=70) as pre-frail, 12% (n=21) as sarcopenia, 25% (n=44) as frail, and 6% (n=10) as cachexia. Significant differences were found in age (robust vs. frail, pre-frail vs. frail), BMI (robust vs. cachexia, pre-frail vs. cachexia, frail vs. cachexia), and peak VO 2 (robust vs. frail, robust vs. cachexia, pre-frail vs. cachexia) with average values and 95% CIs. Three dimensions among age, BMI and peak VO 2 revealed two trajectories (from robust to frailty via pre-frailty, and from robust to cachexia via sarcopenia) among muscle wasting diseases. Conclusions: This study revealed two trajectories among muscle wasting diseases.

Aims The association of vascular dysfunction and amyloid beta deposition attracted attentions for its relationship with cognitive decline. Previous studies show the correlation between the declined cardiac function and the cognitive impairment. In the present study, we analysed the association between cognitive functions and cardiac parameters in community-dwelling people with preserved ejection fraction without heart failure. Methods and results Subjects were 108 Japanese community-dwelling middle-aged and older adults with preserved ejection fraction (25 men and 83 women; mean age 74.7 years). Cardiac functional parameters at rest were assessed with B-type natriuretic peptide and echocardiography. The cardiopulmonary exercise test was used to test these parameters during exercise. Cognitive function was assessed with the Japanese version of the Montreal Cognitive Assessment (MoCA-J). Other indices were assessed biochemically, physiologically, and physically. There were significant correlations between MoCA-J score and age (r = -0.388), peak oxygen uptake (VO2 , r = 0.201), peak VO2 /heart rate (HR, r = 0.243), peak VO2 /weight (r = 0.244), peak metabolic equivalents (r = 0.244), usual walking speed (r = -0.200), and the Timed Up and Go test (r = -0.230). Multiple linear regression analysis showed peak VO2 /HR was an independent determinant of MoCA-J score after adjusting for potential confounders (B = 0.424). After 6 months of exercise training with 64 subjects, we found that the per cent change of peak VO2 /HR was related to the per cent change of MoCA-J score (r = 0.296). Conclusions These results suggested that peak VO2 /HR (an index of stroke volume at peak exercise) might be associated with cognitive impairment based on the vascular cascade hypothesis.

An obesity-related prediabetic state is characterised by metabolic abnormalities such as post-glucose load hyperglycaemia and dyslipidaemia and consequently increases the risk for type 2 diabetes and cardiovascular disease. This study aimed to investigate the effects of Lactobacillus casei strain Shirota (LcS) on metabolic abnormalities in obese prediabetic subjects in a randomised, double-blind, placebo-controlled trial. Herein, 100 obese subjects (body mass index ≥25), who had moderate post-load hyperglycaemia (1-hr post-load plasma glucose (PG) levels ≥180 mg/dl during the oral glucose tolerance test), consumed LcS-fermented milk or placebo milk daily for 8 weeks. The post-load PG and fasting blood markers were evaluated. Although post-load PG levels were not significantly different between the groups, 1-hr post-load PG, glycoalbumin, and HbA1c levels decreased at 8 weeks compared with the baseline levels only in the LcS group (p=0.036, p=0.002, and p=0.006, respectively). The reduction in glycoalbumin levels was statistically significantly greater in the LcS group than in the placebo group (p=0.030). Stratified analyses revealed significantly improved 1-hr post-load PG and glycoalbumin levels in the LcS group compared with the placebo group among subjects with severe glucose intolerance (2-hr post-load PG levels higher than the median at baseline; p=0.036 and p=0.034, respectively). In terms of lipidic outcomes, total, low-density lipoprotein, and non-high-density lipoprotein cholesterol levels were significantly lower in the LcS group than in the placebo group (p=0.023, p=0.022, and p=0.008, respectively). These findings suggest that LcS may favourably affect metabolic abnormalities in obese prediabetic subjects, though the effects on glycaemic control may be limited.

Aims This study aimed to investigate the relationship between skeletal muscle mass and cardiac functional parameters in older adults during cardiopulmonary exercise testing (CPET). Methods and results Sixty-three Japanese community-dwelling older adults were enrolled (20 men and 43 women; mean age 80 years, range 65–97 years). Cardiac functional parameters during exercise were assessed using CPET. Skeletal muscle mass index (SMI) was calculated by dividing the appendicular lean mass (measured using dual-energy X-ray absorptiometry) by height in metres squared. Subjects were divided into two groups: men with SMI ≥ 7.0 kg/m2 and women with SMI ≥ 5.4 kg/m2 (non-sarcopenic group); or men with SMI

Background Prostate cancer is the sixth leading cause of cancer-related deaths in Japan. We aimed to elucidate the clinical and histopathological characteristics of patients with prostate cancer in the BioBank Japan (BBJ) project. Methods Four thousand, seven hundred and ninety-three patients diagnosed with prostate cancer in the BBJ project were included. Clinical and histopathological data, including causes of death, were analyzed. Relative survival (RS) rates of prostate cancer were calculated. Results Four thousand, one hundred and seventy-one prostate cancer patients with available histological data had adenocarcinoma. The mean age of the patients was 72.5 years. The proportion of patients who were non-smokers, non-drinkers, had a normal body mass index, did not exercise, had a normal prostate-specific antigen level, and had a family history of prostate cancer were 30.7%, 28.0%, 66.6%, 58.1%, 67.6%, and 6.5%, respectively. The proportion of patients with Stage II, III, and IV disease were 24.4%, 7.3%, and 4.4%, respectively. After limiting to patients with a time from the initial diagnosis of prostate cancer to entry into the study cohort of ≤90 days (n = 869), the 5- and 10-year RS rates were 96.3% and 100.5%, respectively, although we were unable to consider management strategies due to a plenty of data missing. Conclusions We provide an overview of patients with prostate cancer in the BBJ project. Our findings, coupled with those from various high throughput “omics” technologies, will contribute to the implementation of prevention interventions and medical management of prostate cancer patients., Highlights • Prostate cancer represents the second leading cause of cancer incidence worldwide. • We aimed to provide an overview of patients with prostate cancer. • Based on prostate cancer histology, 99.3% had adenocarcinoma. • The 5- and 10-year relative survival rates were 96.3% and 100.5%. • Future studies will help develop preventive programs for prostate cancer.

Background Liver cancer is the fifth cause of cancer-related deaths in Japan. The BioBank Japan (BBJ) project included 200,000 patients with 47 diseases and samples; their clinical information can be used for further studies. Methods Patients diagnosed with liver cancer (n = 1733; 1316 men, 417 women) were included. Histology, patient characteristics, clinical characteristics, and causes of death were collected. Cumulative and relative survival rates for liver cancer were calculated. Results Of the 1354 patients with available liver cancer histology, 91.9% had hepatocellular carcinoma (HCC). Compared with the National Health and Nutrition Examination Survey, greater proportions of the male patients in this cohort were daily alcohol consumers (26%), and a greater proportion of the men was overweight/obesity (22%). Although Japan is the only Asian country with a predominance of hepatitis C virus (HCV)-related HCC, the prevalence of HCV infection (44%) was lower than that in a previous study. The 3-, 5-, and 10-year cumulative survival rates were 57%, 47%, and 25% in men, respectively, and 49%, 41%, and 27% in women, respectively. Conclusions The present results provide an overview of the patients with liver cancer in the BBJ project. We are planning further analyses combined with various high-throughput ‘omics’ technologies., Highlights • Liver cancer is the second leading cause of death worldwide. • We aimed to provide an overview of patients with liver cancer. • Based on liver cancer histology, 91.9% had hepatocellular carcinoma. • The 10-year relative survival rates were 34% in men and 38% in women. • Future studies will help develop preventive programs for liver cancer.

Background Breast cancer is currently the most common type of cancer in Japanese females. Unlike most other types of cancer, breast cancer develops more frequently in middle-aged females than in elderly females. Methods Of all Japanese female breast cancer patients aged ≥20 years whom the BioBank Japan Project originally enrolled between 2003 and 2008, 2034 were registered within 90 days after their diagnosis. We described the lifestyle and clinical characteristics of these patients at study entry. Furthermore, we examined the effect of these characteristics on all-cause mortality. Results In the female patients registered within 90 days after diagnosis, the frequency of stage 0 or unclassified, stage I, II, III and IV were 11.4%, 47.9%, 37.0%, 2.9% and 0.8%, respectively. The proportion of histological types was 12.9% for non-invasive carcinoma (ductal carcinoma and lobular carcinoma), 81.0% for invasive carcinoma (papillotubular carcinoma, solid tubular carcinoma, scirrhous carcinoma and special types), 0.2% for Paget's diseases and 5.8% for others. Those positive for the estrogen and progesterone receptors accounted for 75.8% and 62.1% of all patients, respectively. Among 1860 female participants registered within 90 days, 218 participants died during 144,54 person-years of follow-up. More advanced stage, elevation of serum carcinoembryonic antigen and carbohydrate antigen 15-3 levels and absence of the estrogen receptor at study entry were crudely associated with an increased risk of all-cause mortality after adjustment for age. Conclusions This study showed the association of several clinical characteristics with all-cause mortality in female breast cancer patients., Highlights • About 1% of Japanese female breast cancer patients were diagnosed as stage IV. • Invasive carcinoma was much more common than non-invasive carcinoma. • Papillotubular carcinoma was the most common type of invasive carcinoma. • About 75% were positive for estrogen receptor and 60% for progesterone receptor. • Some characteristics would affect all-cause mortality in breast cancer patients.

Background Colorectal cancer is the third most common cancer worldwide, and in Japan, it is estimated that about 10% of men and 8% of women will be diagnosed with colorectal cancer during their lifetime. Methods We focused on 5864 participants (3699 men and 2165 women) who had colorectal cancer and were registered with BioBank Japan (BBJ) between April 2003 and March 2008. Characteristics of colon and rectal cancer patients were calculated separately. Among the enrolled patients registered in BBJ within 90 days after diagnosis, we also calculated the 5-year cumulative and relative survival rates, and estimated the effect of lifestyle factors on all-cause mortality. Results Our participants included younger men than those in the Patient Survey and the Cancer Registry Japan. In more than 95% of cases the histological type was adenocarcinoma both in colon and rectal cancer. Rectal cancer patients tended to eat more meat and less green leafy vegetables compared with colon cancer patients. The 5-year cumulative survival rate was 73.0% (95% CI; 70.1%–75.7%) and the 5-year relative survival rate was 80.6% (77.4%–83.6%), respectively, for colon cancer. For rectal cancer, the rates were 73.3% (69.1%–77.0%) and 80.9% (76.3%–85.0%), in the same order. Lifestyle factors such as consuming less green leafy vegetables, being underweight, smoking, not consuming alcoholic beverages and being physically inactive were found to be related to poor survival. Conclusions We described lifestyle characteristics of colorectal cancer patients in BBJ and examined the impacts on subsequent all-cause mortality., Highlights • More than 95% were adenocarcinoma both in colon and rectal cancer. • Rectal cancer patients ate more meat and less green vegetables than colon cancer. • Eating green vegetables and drinking alcohol moderately decreased the mortality risk.

Background The number of patients with diabetes is increasing worldwide. Macrovascular disease, chronic kidney disease, chronic respiratory disease, cancer and smoking frequently accompany type 2 diabetes. Few data are available related to mortality of Asians with diabetes associated with these serious comorbidities. The present study aimed to quantify the excess mortality risks of type 2 diabetic patients with comorbidities. Methods We analysed the available records of 30,834 Japanese patients with type 2 diabetes from the BioBank Japan Project between 2003 and 2007. Men and women were followed up for median 8.03 and 8.30 years, respectively. We applied Cox proportional hazard model and Kaplan–Meier estimates for survival curves to evaluate mortality in diabetic patients with or without macrovascular disease, chronic respiratory disease, chronic kidney disease, cancer and smoking. Results Adjusted hazard ratios (HRs) for mortality were 1.39 (95% CI, 1.09–1.78) for male sex, 2.01 (95% CI, 1.78–2.26) per 10-year increment of age. Adjusted HRs of primary interest were 1.77 (95% CI, 1.42–2.22), macrovascular disease; 1.58 (95% CI, 1.08–2.31), chronic respiratory disease; 2.03 (95% CI, 1.67–2.47), chronic kidney disease; 1.16 (95% CI, 0.86–1.56), cancer; and 1.74 (95% CI, 1.30–2.31), current smoking. Conclusions Diabetic patients with a past or current history of chronic kidney, macrovascular or respiratory diseases or smoking habit have exhibited the highest risk of mortality. Data were limited to those of survivors of comorbidities but we propose the need to improve comorbidities and terminate cigarette smoking for better prognosis in patients with diabetes., Highlights • Fatal diseases frequently accompany diabetes. • Data for survival of Asian patients with diabetes with comorbidities are scarce. • Comorbid chronic kidney disease was associated with the most fatalities. • Current smoking was as fatal as 10 years of ageing in diabetic patients. • Values of 1% HbA1c and 10 mmHg blood pressure confer 11% excess mortality risk.

Background Controlling serum cholesterol is critical to prevent cardiovascular disease in patients with dyslipidaemia. Guidelines emphasise the need to select treatment for dyslipidaemia based on specific patient profiles; however, there is little information about the serum cholesterol levels of patients in each profile in Japan. Therefore, we aimed to describe the serum cholesterol levels and prevalence of uncontrolled cases in Japanese patients with dyslipidaemia. Methods We included data for patients with dyslipidaemia between 2003 and 2007 from the BioBank Japan Project (66 hospitals). Then, we reported their serum cholesterol levels by age, body mass index, glycaemic control (glycated haemoglobin A1c), blood pressure, smoking, drinking, comorbidity and medication profiles. Results We included 22,189 male and 21,545 female patients. The mean serum low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG) and non-HDL-C levels in males were 117.4 mg/dL, 51.0 mg/dL, 187.6 mg/dL and 153.6 mg/dL, respectively; the corresponding levels in females were 129.5 mg/dL, 60.5 mg/dL, 144.9 mg/dL and 157.9 mg/dL, respectively. In both males and females, the LDL-C levels were the highest in the following profiles: age 19–44 years, body mass index 18.5–22 kg/m2, glycated haemoglobin A1c, Highlights • Evidence of serum cholesterol control in Japanese dyslipidaemic patients is scarce. • We analysed data for a large-scale population in hospital settings. • Our findings provide serum cholesterol levels by different risk profiles. • Serum lipid levels were the lowest in the youngest patients. • Data should be carefully applied to patients with mild hyperlipidaemia.

Aim Few reports have described the characteristics of hyperglycemic hyperosmolar syndrome (HHS) in the elderly. We investigated the background characteristics and clinical features of 14 elderly patients with HHS. Methods HHS was diagnosed based on a blood glucose level of >600 mg/dL and an effective plasma osmolality [2 (Na) + glu/18] of >320 mOsm/kg. For 14 cases of HHS, we investigated the medical and social backgrounds of the patients, their clinical findings, and the outcomes. Results The mean patient age was 83 years, and the mean body mass index was 17.8 kg/m2. Half had a history of either cerebral infarction or hip fracture. The mean duration of diabetes was 14 years, but 4 diabetes cases were newly diagnosed. There was a high prevalence of acute infection (79%) in HHS patients, especially urinary tract infection and pneumonia, with a seasonal peak in winter. Patients who had been treated with steroids, tube feeding, or both numbered 1, 2, and 1, respectively. Most HHS patients had a history of dementia. More than half of such patients were living alone or only with their spouse, and their activities of daily living showed marked deterioration. The mean blood glucose level, HbA1c, effective serum osmolality, and pH were 881 mg/dL, 10.3%, 353 mOsm/kg, and 7.39, respectively. One patient died during hospitalization, and 9 were discharged to nursing homes or other hospitals. The mean length of hospitalization was 55 days. In most cases, the insulin secretion capacity was preserved, and 9 patients were treatable with oral hypoglycemic agents alone. Conclusions Many cases of HHS in the elderly are associated with infection, a shortage of social support, cognitive impairment, or ADL decline. Although the survival rate in our series was high, the functional prognosis was impaired.

Aim Bullous pemphigoid (BP) is an autoimmune skin disorder characterized by the production of autoantibodies. Several recent reports have described the occurrence of BP in diabetic patients treated with dipeptidyl peptidase-4 (DPP-4) inhibitors. However, the clinical features of BP in diabetic patients, particularly in those treated with DPP-4 inhibitors, have not yet been examined. The aim of this study was to clarify clinical characteristics of BP in elderly type 2 diabetic patients. Methods We found cases of BP in 15 elderly type 2 diabetic patients (11 men, 4 women) and 20 non-diabetic patients (8 men, 12 women) from September, 2012 to September, 2016. These patients had all been treated with corticosteroid therapy. We investigated the participants' basic clinical characteristics and the course of BP treatment. The differences in variables between the two groups were analyzed using Wilcoxon's test and the chi-square test. Results The mean age of type 2 diabetes patients with BP was 81.1±5.5 years. The mean HbA1c was 7.3±1.6%. A total of 87% of diabetic patients had been treated with DPP-4 inhibitors for 11.7 months prior to the BP onset. The diabetic patients had a lower prevalence of neurogenerative disease, severe ADL disabilities, and dementia than the non-diabetic patients. Furthermore, the diabetic patients with BP tended to be younger and more frequently male than those without diabetes. After stopping the DPP-4 inhibitors, the skin lesions were successfully treated with systemic corticosteroid therapy, and glycemic control was achieved using intensive insulin therapy. DPP-4 inhibitors were used in all cases where the aniti-BP180NC16a antibody showed negative conversion. Conclusion BP in patients with type 2 diabetes had different clinical features from that in non-diabetic patients, suggesting an association between BP and the use of DPP-4 inhibitors.

Type 2 diabetes mellitus (DM) is a disease characterized by dysfunction of various organs. Recent studies have shown a close relationship between DM and telomere attrition in leukocytes. In patients with DM or impaired glucose tolerance, excessive oxidative stress induces damage to telomeres and shortens their length. Furthermore, it is suggested that telomere length is a good surrogate marker for mortality and diabetic complications in DM patients. We recently found that telomere length in pancreatic β-cells is also shortened in DM patients, potentially leading to an impaired capacity for proliferation and insulin secretion, and accelerated cell death. In contrast, leukocyte telomere length has also been reported in patients with obesity or insulin resistance, both of which are frequently associated with type 2 DM. In an animal model, it has been shown that telomere attrition in adipose tissue induces insulin resistance. Taken together, the available data suggest that hyperglycemia, oxidative stress, and telomere attrition in pancreatic β-cells and adipocytes create a vicious cycle that underlies the pathophysiology of type 2 DM. Inhibition of telomere attrition in various organs, including pancreatic β-cells, could be a new approach for preventing the progression of DM and its complications.

Background Although frailty and cognitive impairment are critical risk factors for disability and mortality in the general population of older inhabitants, the prevalence and incidence of these factors in individuals treated in the specialty outpatient clinics are unknown. Methods We recently established a frailty clinic for comprehensive assessments of conditions such as frailty, sarcopenia, and cognition, and planned 3-year prospective observational study to identify the risk factors for progression of these aging-related statuses. To date, we recruited 323 patients who revealed symptoms suggestive of frailty mainly from a specialty outpatient clinic of cardiology and diabetes. Frailty status was diagnosed by the modified Cardiovascular Health Study (mCHS) criteria and some other scales. Cognitive function was assessed by Mini-Mental State Examination (MMSE), Japanese version of the Montreal Cognitive Assessment (MoCA-J), and some other modalities. Sarcopenia was defined by the criteria of the Asian Working Group for Sarcopenia (AWGS). In this report, we outlined our frailty clinic and analyzed the background characteristics of the subjects. Results Most patients reported hypertension (78%), diabetes mellitus (57%), or dyslipidemia (63%), and cardiovascular disease and probable heart failure also had a higher prevalence. The prevalence of frailty diagnosed according to the mCHS criteria, cognitive impairment defined by MMSE (≤27) and MoCA-J (≤25), and of AWGS-defined sarcopenia were 24, 41, and 84, and 31%, respectively. The prevalence of frailty and cognitive impairment increased with aging, whereas the increase in sarcopenia prevalence plateaued after the age of 80 years. No significant differences were observed in the prevalence of frailty, cognitive impairment, and sarcopenia between the groups with and without diabetes mellitus, hypertension, or dyslipidemia with a few exceptions, presumably due to the high-risk subjects who had multiple cardiovascular comorbidities. A majority of the frail and sarcopenic patients revealed cognitive impairment, whereas the frequency of suspected dementia among these patients were both approximately 20%. Conclusions We found a high prevalence of frailty, cognitive impairment, and sarcopenia in patients with cardiometabolic disease in our frailty clinic. Comprehensive assessment of the high-risk patients could be useful to identify the risk factors for progression of frailty and cognitive decline.

A genetic risk score (GRS) was developed for predicting fracture risk based on lifetime prevalence of femoral fractures in 924 consecutive autopsies of Japanese males. A total of 922 non-synonymous single nucleotide polymorphisms (SNPs) located in 62 osteoporosis susceptibility genes were genotyped and evaluated for their association with the prevalence of femoral fracture in autopsy cases. GRS values were calculated as the sum of risk allele counts (unweighted GRS) or the sum of weighted scores estimated from logistic regression coefficients (weighted GRS). Five SNPs (α-ʟ-iduronidase rs3755955, C7orf58 rs190543052, homeobox C4 rs75256744, G patch domain-containing gene 1 rs2287679, and Werner syndrome rs2230009) showed a significant association (P

Werner syndrome is a rare autosomal recessive disorder caused by mutations in the human WRN gene and characterized by the early onset of normal aging symptoms. Given that patients with this disease exhibit osteoporosis, the present study aimed to determine whether the WRN gene contributes to the etiology of osteoporosis. A genetic association study of eight non-synonymous polymorphisms in the WRN gene and the incidence of femoral fracture was undertaken in 1,632 consecutive Japanese autopsies in which 140 patients had experienced the fracture during their lifetime. The results were validated in 251 unrelated postmenopausal Japanese women with osteoporosis and 269 non-institutionalized, community-dwelling Japanese adults. A statistically significant association was observed between rs2230009 (c.340G > A)—which results in a Val to Ile substitution—and fracture risk; the incidence of femoral fracture increased dose-dependently with the number of A alleles (p = 0.0120). Femoral neck bone and whole bone densities were lower among postmenopausal women with osteoporosis and community-dwelling adults, respectively, if they were of the AG instead of the GG genotype. The results suggest that Japanese subjects bearing at least one A allele of rs2230009 of the WRN gene are at a significantly higher risk of femoral fracture, possibly due to decreased bone density.

This report describes an atypical case of nonbacterial thrombotic endocarditis in a mitral valve. The patient suffered repeated emboli after achieving remission of Crohn disease in the acute phase. Echocardiography revealed mitral valve leaflet and subvalvular thickening. This initially was considered indicative of infective endocarditis or a cardiac tumor; however, pathologic and laboratory examinations showed nonbacterial thrombotic endocarditis without antiphospholipid syndrome or a malignant tumor. We report a rare case of nonbacterial thrombotic endocarditis complicated with Crohn disease.

Metabolic derangements are a clinically significant complication of major trauma (e.g., burn injury) and include various aspects of metabolism, such as insulin resistance, muscle wasting, mitochondrial dysfunction and hyperlactatemia. Nonetheless, the molecular pathogenesis and the relation between these diverse metabolic alterations are poorly understood. We have previously shown that burn increases farnesyltransferase (FTase) expression and protein farnesylation and that FTase inhibitor (FTI) prevents burn-induced hyperlactatemia, insulin resistance, and increased proteolysis in mouse skeletal muscle. In this study, we found that burn injury activated mTORC1 and hypoxia-inducible factor (HIF)-1α, which paralleled dysfunction, morphological alterations (i.e., enlargement, partial loss of cristae structure) and impairment of respiratory supercomplex assembly of the mitochondria, and ER stress. FTI reversed or ameliorated all of these alterations in burned mice. These findings indicate that these burn-induced changes, which encompass various aspects of metabolism, may be linked to one another and require protein farnesylation. Our results provide evidence of involvement of the mTORC1-HIF-1α pathway in burn-induced metabolic derangements. Our study identifies protein farnesylation as a potential hub of the signaling network affecting multiple aspects of metabolic alterations after burn injury and as a novel potential molecular target to improve the clinical outcome of severely burned patients.

Excessive meat intake has been researched as a major cause of cardiovascular disease (CVD) among healthy adults, but data on this topic in Asian patients with diabetes are sparse. The quantity and variety of available meats vary widely between Asian and Western countries. As part of a nationwide cohort study we investigated the relationship between meat intake and incidence of CVD in Japanese patients with type 2 diabetes aged 40–70 years with HbA1c ≥ 6.5%. Analyzed were 1353 responders to a baseline dietary survey assessed by the Food Frequency Questionnaire based on food groups. Primary outcome was the 8-year risk of a CVD event, including coronary heart disease (CHD) and stroke. Cox regression analyses estimated hazard ratios (HRs) for dietary intake adjusted for age, gender, body mass index, HbA1c, smoking, energy intake, and other confounders. Mean meat intake in quartiles ranged from 9.9 to 97.7 g/day. After adjusting for confounders, HRs of CHD in the 2nd, 3rd, and 4th quartiles for meat intake compared with the 1st quartile were 2.84 (95% confidence interval 1.29–6.24, p = 0.01), 3.02 (1.36–6.70, p

Aims Although evidence has accumulated that white matter hyperintensity (WMH) is associated with the deterioration of cognitive function and impairment of activities of daily living (ADL), the clinical relevance of WMH in elderly patients with diabetes mellitus is not still clear. The aim of this study was to examine whether WMH volume is associated with ADL and cognitive function and whether glucose control and glucose variability can affect WMH volume in these patients. Methods This cross-sectional study investigated the associations of WMH with cognitive function and instrumental ADL (IADL), as well as metabolic and vascular risk factors in a total of 178 elderly patients with diabetes. The study assessed WMH volumes and the functional status of cognition and IADL. WMH volumes were evaluated by obtaining axial T2-weighted and fluid-attenuated inversion recovery sequence images on brain magnetic resonance imaging and assessing the images using Software for Neuro-Image Processing in Experimental Research. Results We found a significant association between WMH volumes and Mini-Mental State Examination (MMSE) scores (p = 0.039) and between WMH and IADL status (p = 0.006). Furthermore, we found significant relations of large WMH volumes with a high glycoalbumin/glycohemoglobin ratio (GA/HbA1c) (p < 0.001). Large WMH volumes were also found to be associated with a low body mass index (p = 0.014) and a low diastolic blood pressure (p = 0.024), but not with HbA1c. Multiple regression analysis showed that high GA/HbA1c, which reflects high glucose variability, was a significant determining factor for large WMH volumes. We also found that GA/HbA1c was negatively associated with both MMSE (p = 0.036) and IADL (p < 0.001). Conclusions GA/HbA1c, which is a marker of glucose variability, was independently associated with WMH volumes, which could lead to the decline of cognition and IADL in elderly patients with diabetes mellitus.

Background We established a patient-oriented biobank, BioBank Japan, with information on approximately 200,000 patients, suffering from any of 47 common diseases. This follow-up survey focused on 32 diseases, potentially associated with poor vital prognosis, and collected patient survival information, including cause of death. We performed a survival analysis for all subjects to get an overview of BioBank Japan follow-up data. Methods A total of 141,612 participants were included. The survival data were last updated in 2014. Kaplan–Meier survival analysis was performed after categorizing subjects according to sex, age group, and disease status. Relative survival rates were estimated using a survival-rate table of the Japanese general population. Results Of 141,612 subjects (56.48% male) with 1,087,434 person-years and a 97.0% follow-up rate, 35,482 patients died during follow-up. Mean age at enrollment was 64.24 years for male subjects and 63.98 years for female subjects. The 5-year and 10-year relative survival rates for all subjects were 0.944 and 0.911, respectively, with a median follow-up duration of 8.40 years. Patients with pancreatic cancer had the least favorable prognosis (10-year relative survival: 0.184) and patients with dyslipidemia had the most favorable prognosis (1.013). The most common cause of death was malignant neoplasms. A number of subjects died from diseases other than their registered disease(s). Conclusions This is the first report to perform follow-up survival analysis across various common diseases. Further studies should use detailed clinical and genomic information to identify predictors of mortality in patients with common diseases, contributing to the implementation of personalized medicine., Highlights • 141,612 participants with any of 32 diseases were included in the follow-up survey. • Subject characteristics at enrollment for the follow-up survey were identified. • The relative survival analysis showed the worst prognosis in pancreatic cancer. • The most common cause of death in all subjects was malignant neoplasms.

Background Evidence of characteristics of Japanese patients with diabetes from a large-scale population is necessary. Few studies have compared glycaemic controls, complications and comorbidities between type 1 and 2 diabetic patients. This paper focuses on illustrating a clinical picture of Japanese diabetic patients and comparing glycaemic control and prognoses between type 1 and 2 diabetes using multi-institutional data. Methods The BioBank Japan Project enrolled adult type 1 and 2 diabetic patients between fiscal years 2003 and 2007. We have presented characteristics, controls of serum glucose, cholesterol and blood pressure, prevalence of complications and comorbidities and survival curves. We have also shown glycaemic controls according to various individual profiles of diabetic patients. Results A total of 558 type 1 diabetic patients and 30,834 type 2 diabetic patients participated in this study. The mean glycated haemoglobin A1c was higher in type 1 diabetes than in type 2 diabetes. In the type 1 diabetic patients, the glycated haemoglobin A1c had no consistent trend according to age and body mass index. The Kaplan–Meier estimates represented a longer survival time from baseline with type 1 diabetes than with type 2 diabetes. Compared with type 1 diabetic patients, type 2 diabetic patients had double the prevalence of macrovascular complications. Conclusions This work has revealed detailed plasma glucose levels of type 1 and 2 diabetic patients according to age, body mass index, blood pressure, serum cholesterol levels and smoking and drinking habits. Our data have also shown that the prognosis is worse for type 2 diabetes than for type 1 diabetes in Japan., Highlights • Detailed glycaemic control data of diabetic patients are necessary. • Few studies have compared the survival times between type 1 and 2 diabetes. • Higher glycated HbA1c was observed in type 1 than in type 2 diabetes. • Data showed higher hazard ratio of mortality in type 1 than in type 2 diabetes. • Fewer macrovascular complications accompany type 1 than type 2 diabetes.

Background To implement personalized medicine, we established a large-scale patient cohort, BioBank Japan, in 2003. BioBank Japan contains DNA, serum, and clinical information derived from approximately 200,000 patients with 47 diseases. Serum and clinical information were collected annually until 2012. Methods We analyzed clinical information of participants at enrollment, including age, sex, body mass index, hypertension, and smoking and drinking status, across 47 diseases, and compared the results with the Japanese database on Patient Survey and National Health and Nutrition Survey. We conducted multivariate logistic regression analysis, adjusting for sex and age, to assess the association between family history and disease development. Results Distribution of age at enrollment reflected the typical age of disease onset. Analysis of the clinical information revealed strong associations between smoking and chronic obstructive pulmonary disease, drinking and esophageal cancer, high body mass index and metabolic disease, and hypertension and cardiovascular disease. Logistic regression analysis showed that individuals with a family history of keloid exhibited a higher odds ratio than those without a family history, highlighting the strong impact of host genetic factor(s) on disease onset. Conclusions Cross-sectional analysis of the clinical information of participants at enrollment revealed characteristics of the present cohort. Analysis of family history revealed the impact of host genetic factors on each disease. BioBank Japan, by publicly distributing DNA, serum, and clinical information, could be a fundamental infrastructure for the implementation of personalized medicine., Highlights • The BioBank Japan Project (BBJ) annually collected clinical information. • Analysis of the clinical information at enrollment characterized the BBJ cohort. • Analysis of family history revealed impacts of host genetic factors on the diseases.

Background Statins are the first-line agents used to treat patients with high serum low-density lipoprotein cholesterol levels, thus reducing the risk of death from arterial sclerotic cardiovascular disease; however, little is known about the effects of non-statin pharmacological interventions on mortality as well as about the potential protective effects of statin use against cancer death. This work aimed to compare all-cause and cancer mortality among patients with hyperlipidaemia who did and did not receive statin treatment. Methods Between 2003 and 2007 fiscal years, we recruited Japanese patients diagnosed with hyperlipidaemia from 66 hospitals. Patients in our cohort were followed up for a maximum of 12 years to observe the causes of death. Kaplan–Meier estimates from the baseline were used to compare the mortality of patients based on the administered medicine. All-cause mortality were compared among patients with/without administration of statins and other agents; any-organ and colorectal cancer mortality were compared between patients with/without administration of statins. Results Our cohort included 41,930 patients with mean ages of 64–66 years and mean body mass indices of 24–25 kg/m2. Patients who received statin monotherapy and were treated with lifestyle modification exhibited nearly identical survival curves, whereas statin use represented a non-significant but potentially protective effect against colorectal cancer-related mortality. The lowest mortality in this cohort was associated with resin monotherapy. Conclusions Mortality rate has been similar for patients treated with statin monotherapy and lifestyle modification. Statin monotherapy could potentially reduce any-organ- and colorectal cancer-related mortality., Highlights • Statin-mediated reduction of low-density lipoprotein levels reduces mortality. • Little is known on the effect of non-statin hyperlipidaemia medicines on mortality. • Statin monotherapy is safe in terms of cancer mortality. • Statin use may reduce colorectal cancer-related mortality. • Resin monotherapy was associated with the lowest mortality.

Background Several studies have evaluated associations between the characteristics of patients with esophageal and gastric cancer and survival, but these associations remain unclear. We described the distribution of demographic and lifestyle factors among patients with esophageal and gastric cancer in Japan, and investigated their potential effects on survival. Methods Between 2003 and 2007, 24- to 95-year-old Japanese patients with esophageal and gastric cancer were enrolled in the BioBank Japan Project. The analysis included 365 patients with esophageal squamous cell carcinoma (ESCC) and 1574 patients with gastric cancer. Hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality were estimated using medical institution-stratified Cox proportional hazards models. Results During follow-up, 213 patients with ESCC (median follow-up, 4.4 years) and 603 patients with gastric cancer (median follow-up, 6.1 years) died. Among patients with ESCC, the mortality risk was higher in ever drinkers versus never drinkers (multivariable HR = 2.37, 95% CI: 1.24, 4.53). Among patients with gastric cancer, the mortality risk was higher in underweight patients versus patients of normal weight (multivariable HR = 1.66, 95% CI: 1.34, 2.05). Compared to patients with gastric cancer with no physical exercise habit, those who exercised ≥3 times/week had a lower mortality risk (multivariate HR = 0.75, 95% CI = 0.61, 0.93). However, lack of stage in many cases was a limitation. Conclusions Among patients with ESCC, alcohol drinkers have a poor prognosis. Patients with gastric cancer who are underweight also have a poor prognosis, whereas patients with physical exercise habits have a good prognosis., Highlights • Among ESCC patients, alcohol drinkers had a poor prognosis. • Underweight gastric cancer patients had a poor prognosis. • Gastric cancer patients who exercised had a good prognosis. • No association between esophageal or gastric cancer and smoking was observed.

Background In Japanese males and females, lung cancer is currently the second and fourth most common type of cancer, and the first and second leading cause of cancer-related deaths, respectively. Methods Of all Japanese male and female lung cancer patients aged ≥20 years whom the BioBank Japan Project originally enrolled between 2003 and 2008, 764 males and 415 females were registered within 90 days after their diagnosis. We described the lifestyle and clinical characteristics of these patients at study entry. Furthermore, we examined the effect of these characteristics on all-cause mortality. Results In the lung cancer patients registered within 90 days, the frequencies of occult or stage 0, stage I, II, III and IV were 0.4%, 55.8%, 10.8%, 22.0% and 11.0% for males and 0.3%, 62.4%, 9.9%, 17.1% and 10.2% for females, respectively. The proportions of histological types in males and females were 56.3% and 82.4% for adenocarcinoma, 26.9% and 8.2% for squamous cell carcinoma, 4.5% and 1.5% for large cell carcinoma, 7.7% and 4.1% for small cell carcinoma and 4.6% and 3.8% for others, respectively. Among 1120 participants who registered within 90 days, 572 participants died during 5811 person-years of follow-up. Low body mass index, ever smoker, more advanced stage, squamous cell or small cell carcinoma and high serum carcinoembryonic antigen level at study entry were crudely associated with an increased risk of all-cause mortality after adjustment for age. Conclusions This study showed the association of several lifestyle and clinical characteristics with all-cause mortality in lung cancer patients., Highlights • Nearly one-tenth of Japanese lung cancer patients were diagnosed as stage IV. • Adenocarcinoma was the most common histological type in both males and females. • Some characteristics would affect all-cause mortality in lung cancer patients.

Many guidelines recommend that patients with type 2 diabetes should reduce their dietary sodium intake. However, the relationship between dietary sodium intake and incidence of diabetic complications in patients with type 2 diabetes has not been explored.Our objective was to investigate the relationship between dietary sodium intake and incidence of diabetes complications.The study was of a nationwide cohort of patients with type 2 diabetes aged 40 to 70 years with hemoglobin A1c (HbA1c) ≥6.5%.After excluding nonresponders to a dietary survey, 1588 patients were analyzed. Baseline dietary intake was assessed by the Food Frequency Questionnaire based on food groups. Primary outcomes were times to cardiovascular disease (CVD), overt nephropathy, diabetic retinopathy, and all-cause mortality.Mean daily dietary sodium intake in quartiles ranged from 2.8 to 5.9 g. After adjustment for confounders, hazard ratios for CVD in patients in the second, third, and fourth quartiles of sodium intake compared with the first quartile were 1.70 (95% confidence interval, 0.98-2.94), 1.47 (0.82-2.62), and 2.07 (1.21-3.90), respectively (trend P.01). In addition, among patients who had HbA1c ≥9.0%, the hazard ratio for CVD in patients in the top vs bottom quartile of sodium intake was dramatically elevated compared with patients with HbA1c9.0% (1.16 [0.56-2.39] and 9.91 [2.66-36.87], interaction P.01). Overt nephropathy, diabetic retinopathy, and all-cause mortality were not significantly associated with sodium intake.Findings suggested that high dietary sodium intake is associated with elevated incidence of CVD in patients with type 2 diabetes and that there is a synergistic effect between HbA1c values and dietary sodium intake for the development of CVD.

Although accelerated β-cell telomere shortening may be associated with diabetes that shows a dramatically increased incidence with aging, β-cell telomere length in diabetes has never been explored.The objective of the present study was to examine telomere length in the β-cells of patients with diabetes.We determined telomere length in β- and α-cells of pancreases obtained at autopsy from 47 patients with type 2 diabetes and 51 controls, all older than 60 years.The normalized telomere to centromere ratio (NTCR), an index of telomere length, was determined for β- (NTCRβ) and α- (NTCRα) cells by quantitative fluorescence in situ hybridization.The NTCRβ was reduced by 27% ± 25% and NTCRα by 15% ± 27% in the patients with diabetes relative to the controls (P.01 for both). Importantly, the degree of shortening was significantly (P.01) greater in β-cells than in α-cells. The histogram of NTCR distribution was significantly skewed to the left in the patients with diabetes relative to the controls for both β- and α-cells, indicating preferential depletion of longer-telomere islet cells. Glycated hemoglobin was negatively correlated with β-cell telomere length, and the telomeres were significantly shorter in patients who had used hypoglycemic agents than in those who had not.The telomeres of β-cells are shortened in patients with type 2 diabetes. There may be a vicious cycle involving β-cell telomere attrition and sustained hyperglycemia.

Aims/Introduction Though there are many differences in dietary habits and in the metabolic basis between Western and Asian people, the actual dietary intake in Asian patients with diabetes has not been investigated in a nationwide setting, unlike in Western countries. We aimed to clarify dietary intake among Japanese individuals with type 2 diabetes, and identify differences in dietary intake between Japanese and Western diabetic patients. Materials and Methods Nutritional and food intakes were surveyed and analyzed in 1,516 patients with type 2 diabetes aged 40–70 years from outpatient clinics in 59 university and general hospitals using the food frequency questionnaire based on food groups (FFQg). Results Mean energy intake for all participants was 1737 ± 412 kcal/day, and mean proportions of total protein, fat, and carbohydrate comprising total energy intake were 15.7, 27.6 and 53.6%, respectively. They consumed a ‘low-fat energy-restricted diet’ compared with Western diabetic patients, and the proportion of fat consumption was within the suggested range that has been traditionally recommended in Western countries. As a protein source, consumption of fish (100 g) and soybean products (71 g) was larger than that of meat (50 g) and eggs (29 g). These results imply that dietary content and food patterns among Japanese patients with type 2 diabetes are quite close to those reported as suitable for prevention of obesity, type 2 diabetes, cardiovascular disease, and total mortality in Europe and America. Conclusions A large difference was shown between dietary intake by Japanese and Western patients. These differences are important to establish ethnic-specific medical nutrition therapy for diabetes.

OBJECTIVE Foods rich in fiber, such as vegetables and fruits, prevent cardiovascular disease (CVD) among healthy adults, but such data in patients with diabetes are sparse. We investigated this association in a cohort with type 2 diabetes aged 40–70 years whose HbA1c values were ≥ 6.5% in Japan Diabetes Society values. RESEARCH DESIGN AND METHODS In this cohort study, 1,414 patients were analyzed after exclusion of patients with history of CVDs and nonresponders to a dietary survey. Primary outcomes were times to stroke and coronary heart disease (CHD). Hazard ratios (HRs) of dietary intake were estimated by Cox regression adjusted for systolic blood pressure, lipids, energy intake, and other confounders. RESULTS Mean daily dietary fiber in quartiles ranged from 8.7 to 21.8 g, and mean energy intake ranged from 1,442.3 to 2,058.9 kcal. Mean daily intake of vegetables and fruits in quartiles ranged from 228.7 to 721.4 g. During the follow-up of a median of 8.1 years, 68 strokes and 96 CHDs were observed. HRs for stroke in the fourth quartile vs. the first quartile were 0.39 (95% CI 0.12–1.29, P = 0.12) for dietary fiber and 0.35 (0.13–0.96, P = 0.04) for vegetables and fruits. There were no significant associations with CHD. The HR per 1-g increase was smaller for soluble dietary fiber (0.48 [95% CI 0.30–0.79], P < 0.01) than for total (0.82 [0.73–0.93], P < 0.01) and insoluble (0.79 [0.68–0.93], P < 0.01) dietary fiber. CONCLUSIONS Increased dietary fiber, particularly soluble fiber, and vegetables and fruits were associated with lower incident stroke but not CHD in patients with type 2 diabetes.

ObjectiveTriglyceride (TG) accumulation in arterial tissue is associated with the development of cardiovascular disease; however, the underlying mechanism remains unclear. Cilostazol (CLZ), a selective inhibitor of phosphodiesterase 3, has antiplatelet and vasodilating effects and may decrease serum TG levels. We examined the effect of CLZ on TG accumulation in the arterial tissue of a rat model of carotid artery ligation.MethodsRats were fed normal chow with 0.1% CLZ (CLZ group) or without CLZ (control group) for 4 weeks after unilateral carotid artery ligation near the carotid bifurcation.ResultsAt the end of this period, the control group showed 3.3-fold higher TG levels in the ligated carotid artery than in the contralateral artery; however, compared with the contralateral artery, the ligated artery in the CLZ group showed significantly lower levels of TG accumulation but similar serum levels of TG, total cholesterol, and high-density lipoprotein cholesterol. Furthermore, matrix-assisted laser desorption/ionization imaging mass spectrometry revealed that the ligated carotid artery in both groups had ubiquitous accumulation of TG in the intima, media, and adventitia, along with decreased heme B signals, which was indicative of ischemia. However, heme B signals were less reduced in the CLZ group than in the control group.ConclusionsOur results indicate that CLZ can inhibit the ubiquitous accumulation of TG in arterial tissues, possibly by ameliorating tissue ischemia. CLZ may be useful in improving arterial tissue hemodynamics and lipid metabolism.Clinical RelevanceTriglyceride (TG) accumulation in arterial tissue is associated with the development of cardiovascular disease; however, the underlying mechanism remains unclear. Cilostazol, an antiplatelet and vasodilating drug, has been widely used for patients with peripheral artery occlusive disease to improve intermittent claudication. This study examined the effect of cilostazol on TG accumulation in the arterial tissue of a rat model of carotid artery ligation. We identified a novel effect of cilostazol on inhibition of accumulating TG in the ligated carotid artery tissue. This effect may be expected in clinical use in humans

OBJECTIVE To develop and validate a risk engine that calculates the risks of macro- and microvascular complications in type 2 diabetes. RESEARCH DESIGN AND METHODS We analyzed pooled data from two clinical trials on 1,748 Japanese type 2 diabetic patients without diabetes complications other than mild diabetic retinopathy with a median follow-up of 7.2 years. End points were coronary heart disease (CHD), stroke, noncardiovascular mortality, overt nephropathy defined by persistent proteinuria, and progression of retinopathy. We fit a multistate Cox regression model to derive an algorithm for prediction. The predictive accuracy of the calculated 5-year risks was cross-validated. RESULTS Sex, age, HbA1c, years after diagnosis, BMI, systolic blood pressure, non-HDL cholesterol, albumin-to-creatinine ratio, atrial fibrillation, current smoker, and leisure-time physical activity were risk factors for macro- and microvascular complications and were incorporated into the risk engine. The observed-to-predicted (O/P) ratios for each event were between 0.93 and 1.08, and Hosmer-Lemeshow tests showed no significant deviations between observed and predicted events. In contrast, the UK Prospective Diabetes Study (UKPDS) risk engine overestimated CHD risk (O/P ratios: 0.30 for CHD and 0.72 for stroke). C statistics in our Japanese patients were high for CHD, noncardiovascular mortality, and overt nephropathy (0.725, 0.696, and 0.767) but moderate for stroke and progression of retinopathy (0.636 and 0.614). By combining macro- and microvascular risks, the classification of low- and high-risk patients was improved by a net reclassification improvement of 5.7% (P = 0.02). CONCLUSIONS The risk engine accurately predicts macro- and microvascular complications and would provide helpful information in risk classification and health economic simulations.

We previously reported 2 osteoporosis-susceptibility genes--formiminotransferase N-terminal sub-domain containing gene (FONG) and thrombospondin, type 1, domain-containing 7A (THSD7A)--in which we identified two common single-nucleotide polymorphisms, rs7605378 (FONG) and rs12673692 (THSD7A). The former was associated with a predisposition to osteoporosis and the latter with bone mineral density. To further elucidate the importance of these polymorphisms in the pathogenesis of osteoporosis, we examined their association with the incidence of vertebral fracture. DNA extracted from the renal cortex of 2427 consecutive Japanese autopsies (1331 men, mean age: 79 years; 1096 women, mean age: 82 years) were examined in this study. The presence or absence of vertebral fracture during each subject's lifetime was determined by a thorough examination of the clinical records, as well as autopsy reports. After adjustments for sex and age at autopsy, logistic regression analysis revealed that homozygotes for the risk alleles of rs7605378 (A-allele) or rs12673629 (A-allele) possess an increased risk of vertebral fracture. The subjects simultaneously homozygous for both the risk alleles of rs7605378 (AA genotype) and rs12673629 (AA genotype) showed significantly higher risk of vertebral fracture (odds ratio 2.401, 95% confidence interval 1.305-4.416, P = 0.0048) than those who had at least one non-risk allele of either rs7605378 (AC/CC genotypes) or rs12673629 (AG/GG genotypes). The results suggest that Japanese subjects homozygous for the risk alleles of rs7605378 and rs12673629 have a higher risk of vertebral fracture.

The purposes of the present study were to clarify age- and season- related androgen patterns, and to compare the reproductive physiology between Japanese captive koala populations and Australian populations. To measure fecal androgens, feces were collected from male koalas (4.2 to 13.8 years of age) kept in Japanese zoos. Fecal androgens were extracted with methanol from the lyophilized samples and determined by enzyme immunoassay using 4-androstene-3,17-dione antibody. Fecal androgen concentration in male koalas increased after sexual maturation and remained relatively high until old age. In the survey with the Japanese zoo studbook of koalas, copulation (conception) month showed a pyramid shape with a peak in March to June (60.7%) in koalas born and reared in Japanese zoos and from July to April with the highest concentration in September to January (69.7%) in Australian institutes. Japanese zoo koala populations have a characteristic physiological cycle adapted to Japan's seasonal changes. The suitable month of year for copulation or conception in Japan is diametrically opposed to that in Australia. Mean fecal androgen concentrations by month in the males born and reared in Japan indicated annual changes with the highest concentration in May and the lowest value in November. Fecal androgen analysis may be a noninvasive alternative tool to monitor circulating testosterone and may be helpful in understanding reproductive activity and physiology in male koalas.