研究者詳細 - 杉山　大典

論文 - 杉山　大典

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The association between sleep parameters and sarcopenia in Japanese community-dwelling older adults

Shibuki T., Iida M., Harada S., Kato S., Kuwabara K., Hirata A., Sata M., Matsumoto M., Osawa Y., Okamura T., Sugiyama D., Takebayashi T.

Archives of Gerontology and Geriatrics （Archives of Gerontology and Geriatrics） 109 2023年06月

ISSN 01674943

Purpose: This study aimed to examine the association between sleep duration and quality and sarcopenia, assessed by factors such as low muscle mass (LMM), low muscle strength (LMS), and low physical performance (LPP) among older community-dwellers in Japan. Methods: In this cross-sectional study, a total of 2,069 (men, 902; women, 1,167) participants aged 65 to 80 years were included. Sarcopenia and each low physical function were defined using the definitions of the Asian Working Groups of Sarcopenia 2019. Sleep duration was stratified into three categories: short sleep (<6 h), normal sleep (6-8 h), and long sleep (>8 h). Sleep quality was classified into two groups based on 8-item Athens Insomnia Scale score: insomnia (≥6), and non-insomnia (<6). We analyzed the association between sleep parameters and sarcopenia, including low physical functions, by logistic regression analysis. Results: Compared to normal sleepers, long sleepers had a positive association with sarcopenia (odds ratio [OR] 2.11, 95% confidence interval [CI] 1.25-3.58). In particular, long sleep was strongly associated with LMS (OR 1.77, 95%CI 1.07-2.94) and LPP (OR 1.90, 95%CI 1.25-2.88). On the other hand, poor sleep quality was not associated with sarcopenia in long sleepers, but in normal sleepers. Conclusions: Long sleep was associated with sarcopenia, including LMS and LPP. However, in long sleepers, insomnia was not associated with sarcopenia or any of its components.

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Tsuji M., Fukahori H., Sugiyama D., Doorenbos A., Nasu K., Mashida Y., Ogawara H.

PLoS ONE （PLoS ONE） 18 （ 5 May ） 2023年05月

Globally, residents of long-term care facilities (LTCFs) often experience adverse events (AEs) and corresponding lawsuits that result in suffering among the residents, their families, and the facilities. Hence, we conducted a study to clarify the factors related to the facilities’ liabilities for damages for the AEs that occur at LTCFs in Japan. We analyzed 1,495 AE reports from LTCFs in one Japanese city. A binomial logistic regression analysis was conducted to identify factors associated with liability for damages. The independent variables were classified as: residents, organizations, and social factors. In total, 14% of AEs resulted in the facility being liable for damages. The predictors of liability for damages were as follows: for the resident factors, the increased need for care had an adjusted odds ratio (AOR) of 2.00 and care levels of 2–3; and AOR of 2.48 and care levels of 4–5. The types of injuries, such as bruises, wounds, and fractures, had AORs of 3.16, 2.62, and 2.50, respectively. Regarding the organization factors, the AE time, such as noon or evening, had an AOR of 1.85. If the AE occurred indoors, the AOR was 2.78, and if it occurred during staff care, the AOR was 2.11. For any follow-ups requiring consultation with a doctor, the AOR was 4.70, and for hospitalization, the AOR was 1.76. Regarding the type of LTCF providing medical care in addition to residential care, the AOR was 4.39. Regarding the social factors, the reports filed before 2017 had an AOR of 0.58. The results of the organization factors suggest that liability tends to arise in situations where the residents and their family expect high quality care. Therefore, it is imperative to strengthen organizational factors in such situations to avoid AEs and the resulting liability for damages.

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Fatty liver index predicts the development of hypertension in a Japanese general population with and without dysglycemia

Wu D., Hirata A., Hirata T., Imai Y., Kuwabara K., Funamoto M., Sugiyama D., Okamura T.

Hypertension Research （Hypertension Research） 46 （ 4 ） 879 - 886 2023年04月

ISSN 09169636

Fatty liver has been suggested to be associated with the development of hypertension. However, whether this association is related to glycemia has not been elucidated. Therefore, we investigated whether the fatty liver index (FLI) predicts the development of hypertension among individuals with and without dysglycemia in a general Japanese population. A total of 3114 participants (1036 males and 2078 females) without hypertension who underwent a Specific Health Checkup in the fiscal year 2013 were followed up until 2018. The participants were divided into six groups based on FLI tertiles (low, moderate, or high) and whether they had dysglycemia. We estimated the hazard ratios (HRs) of each group by sex using the Cox proportional hazard model. Models were adjusted for age, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, smoking, and alcohol consumption and further adjusted for systolic blood pressure (SBP). During the mean follow-up period of 2.8 years, 160 of the 3114 participants developed hypertension. Using the low FLI group with normoglycemia as a reference, the HR for incident hypertension was increased in the high FLI group with and without dysglycemia in both sexes after adjusting for confounders, except SBP (HR [95% confidence interval]: male: 1.52 (1.06–2.17) in normoglycemia and 2.05 (1.43–2.92) in dysglycemia, and female: 1.86 (1.43–2.42) in normoglycemia and 2.98 (2.19–4.07) in dysglycemia). Furthermore, in females, this association was observed after adjusting for SBP. We concluded that FLI was independently associated with an increased risk of incident hypertension in individuals with and without dysglycemia. [Figure not available: see fulltext.].

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Impact of hypertension and diabetes on the onset of chronic kidney disease in a general Japanese population

Kaneyama A., Hirata A., Hirata T., Imai Y., Kuwabara K., Funamoto M., Sugiyama D., Okamura T.

Hypertension Research （Hypertension Research） 46 （ 2 ） 311 - 320 2023年02月

ISSN 09169636

Hypertension (HT) and diabetes mellitus (DM) are both major risk factors for chronic kidney disease (CKD); however, few studies have examined the impacts of the combination of HT and DM on CKD development in general populations. We aimed to explore whether HT or DM contributes more to CKD development in a Japanese community. A total of 5823 individuals without a history of CKD who underwent specific health checkups in fiscal year 2013 were monitored until the end of March 2018. Participants were categorized as having neither HT nor DM (none group), either HT or DM, and both (HT + DM). We calculated the hazard ratios (HRs) for developing CKD in each category using Cox proportional hazards models after adjusting for age, dyslipidemia, smoking, and alcohol drinking and with the none group as the reference. We also estimated the population attributable fraction (PAF) for CKD development in populations with either HT or DM or both. During a mean follow-up of 3.0 years, 759 individuals developed CKD, with HRs of 1.56 with a 95% confidence interval (CI) [1.33, 1.83], 1.22 with a 95% CI [0.86, 1.75], and 2.83 with a 95% CI [2.22, 3.63] for the HT only, DM only and HT + DM categories, respectively. Sex-specific analysis showed similar findings. The PAFs for CKD (14.1% and 17.2% for men and women, respectively) were the highest among participants with HT only. We concluded that in this Japanese community, HT contributed more than DM to CKD development; hence, managing hypertension is important to prevent CKD as well as diabetes.

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Association between visceral fat accumulation and decline in the estimated glomerular filtration rate based on cystatin C in the Japanese urban population: the KOBE study

Tanabe A., Hirata A., Kuwabara K., Kubo S., Higashiyama A., Hirata T., Sugiyama D., Nishida Y., Kubota Y., Kadota A., Nishikawa T., Miyamatsu N., Miyamoto Y., Okamura T.

Endocrine journal （Endocrine journal） 70 （ 1 ） 97 - 106 2023年01月

Although metabolic syndrome, including visceral fat accumulation, causes kidney and cardiovascular diseases, the impact of visceral fat accumulation on mild decreased renal function remains unclear. This study examines the association between visceral fat area (VFA) measured by bioimpedance methods and the estimated glomerular filtration rate based on serum cystatin C (eGFRcys) in the Japanese urban population. This community-based cross-sectional study enrolled 952 individuals (287 men, 665 women) who participated in the second follow-up survey of the Kobe Orthopedic and Biomedical Epidemiological (KOBE) study. We compared the multivariate-adjusted means of eGFRcys among VFA quartile groups by gender using the analysis of covariance. Models were adjusted for age, high blood pressure, hypercholesterolemia, glucose intolerance, smoking, and alcohol use, and further adjusted for body mass index (BMI). The highest VFA quartile group had lower eGFRcys than the lowest VFA quartile group after adjusted for cardiometabolic risk factors, except for BMI (93.1 [95% confidence interval (CI), 90.1-96.2] vs. 82.1 [95% CI, 79.1-85.0] in men and 95.8 [95% CI, 94.1-97.5] vs. 89.4 [95% CI, 87.8-90.9] in women). Moreover, further adjustment for BMI revealed a similar result in men (93.5 [95% CI, 89.8-97.2] vs. 81.6 [95% CI, 77.9-85.3]), while no significant association was found in women. This study suggests a significant association between increased VFA levels and lower eGFRcys levels independent of cardiometabolic risk factors, such as glucose intolerance and hypercholesterolemia in men and women, as well as independent of BMI in men.

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Determinants of double product: a cross-sectional study of urban residents in Japan

Nakagoshi N., Kubo S., Nishida Y., Kuwabara K., Hirata A., Sata M., Higashiyama A., Kubota Y., Hirata T., Tatsumi Y., Kawamura K., Miyazaki J., Miyamatsu N., Sugiyama D., Miyamoto Y., Okamura T.

Environmental Health and Preventive Medicine （Environmental Health and Preventive Medicine） 28 （ 1 ） 2023年

ISSN 1342078X

Background: The current study aimed to investigate the determinants of high double product (DP) by evaluating the association between resting DP, which is calculated as systolic blood pressure (SBP) multiplied by heart rate (HR), and blood test results and lifestyle factors. Methods: This research included 973 participants in the baseline survey of the KOBE study, which included a cohort of urban residents. The possible DP determinants were identified by examining the association between lifestyle factors and laboratory findings and DP by analyzing covariance adjusted for sex and age. Logistic regression analysis was performed with high DP (SBP © HR ² 9145 mmHg beats/min or quintile according to sex) as outcome and DP determinants as independent variables. Results: Age, hematocrit, and gamma-glutamyl transferase (log) level were positively associated with a high DP in both men and women. In addition, a high DP was positively associated with Homeostatic Model Assessment for Insulin Resistance score in women alone. Meanwhile, the amount of exercise was negatively associated with a high DP in men alone. Conclusions: High DP values at rest were associated with insulin resistance, gamma-glutamyl transferase, and the amount of exercise in participants without underlying disease.

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Impact of Resting Heart Rate on Cardiovascular Mortality According to Serum Albumin Levels in a 24-year Follow-up Study on a General Japanese Population: NIPPON DATA80

Liu Y., Hirata A., Okamura T., Sugiyama D., Hirata T., Kadota A., Kondo K., Ohkubo T., Miura K., Okayama A., Ueshima H.

Journal of Epidemiology （Journal of Epidemiology） 33 （ 5 ） 227 - 235 2023年

ISSN 09175040

Background: Elevated resting heart rate (RHR) is associated with an increased risk of cardiovascular disease (CVD) and all-cause mortality. However, the findings of cohort studies differed. Thus, the impact of RHR on CVD mortality might be different according to the background of the population. Therefore, we examined the relationship of RHR and CVD mortality according to serum albumin (ALB) levels in a Japanese general population. Methods: In total, 8,363 individuals without a history of CVD were followed for 24.0 years. The participants were divided into four groups according to the quartiles of RHR (Q1–Q4), and they were further classified into the high and low ALB groups based on a median value of 44 g/L. We estimated the multivariable-adjusted hazard ratios (HRs) of CVD mortality in each RHR group based on ALB levels, and the interaction between RHR and ALB groups on CVD mortality was evaluated. Results: We found no significant association between RHR and CVD mortality. However, the Q4 of RHR was significantly associated with an increased risk for CVD mortality (HR 1.27; 95% confidence interval [CI], 1.02–1.57) in participants with a low ALB level. Meanwhile, the Q4 of RHR was significantly correlated with a decreased risk for CVD morality in those with a high ALB level (HR 0.61; 95% CI, 0.47–0.79) after adjusting for covariates. A significant interaction between RHR and ALB for CVD mortality was shown (P < 0.001). Conclusion: The impact of RHR on CVD mortality differed according to ALB levels in a general Japanese population.

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Japanese version of the Patient-rated elbow evaluation score correlates with physician-rated Japanese orthopaedic association-Japan elbow society elbow function score

Sato K., Ishigaki D., Iwabu S., Okazaki M., Koh S., Soejima O., Funakoshi T., Moriya K., Suzuki T., Ozasa Y., Sugiyama D.

Journal of Orthopaedic Science （Journal of Orthopaedic Science） 2023年

ISSN 09492658

Background: The association between Patient-Rated Elbow Evaluation: Japanese version (PREE-J) and Japanese Orthopaedic Association-Japan Elbow Society Elbow Function score (JOA-JES score) is unclear. This study evaluated the association between PREE-J and JOA-JES scores. Methods: The patients with elbow disorders were divided into two groups: Group A (conservative treatment, n = 97) and Group B (surgical treatment, n = 156). The patients were also divided into four disease subgroups according to the JOA-JES classification (rheumatoid arthritis, trauma, sports, and epicondylitis groups), and the association between PREE-J and JOA-JES scores in each disease category was examined. In group B, associations between PREE-J and JOA-JES scores were examined pre-and postoperatively. Results: In group A, there were significant associations between PREE-J and JOA-JES scores. In group B, a strong association between preoperative PREE-J and JOA-JES scores was observed in all disease categories. There was also a significant association between postoperative PREE-J and JOA-JES scores. Additionally, group B showed significant postoperative improvements in PREE-J and JOA-JES scores. Conclusions: The PREE-J score correlates well with the JOA-JES score and reflects treatment response before and after treatment.

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Effect of Chronic Kidney Disease or Anemia or Both on Cardiovascular Mortality in a 25-Year Follow-Up Study of Japanese General Population (From NIPPON DATA90)

Kubo K., Okamura T., Sugiyama D., Hisamatsu T., Hirata A., Kadota A., Kondo K., Hirata T., Higashiyama A., Hayakawa T., Miyamoto Y., Okayama A., Miura K., Ueshima H.

American Journal of Cardiology （American Journal of Cardiology） 184 1 - 6 2022年12月

ISSN 00029149

The relation between chronic kidney disease (CKD) and cardiovascular disease (CVD) in the general population is well elucidated. In patients with CKD, anemia is associated with adverse outcomes. However, the effects of CKD and anemia on CVD in the general population remains poorly explored, especially in Asian populations. This study aimed to investigate the effect of CKD and/or anemia on CVD mortality in a long-term cohort study involving Japanese community dwellers. We assessed 7,339 participants (aged ≥30 years) with no CVD history. These participants were divided into 4 categories according to their CKD (estimated glomerular filtration rate <60 or urine protein >1+ by dipstick qualitative test) and/or anemia (hemoglobin: <13 g/100 ml [men], <12 g/100 ml [women]) statuses. For each category, we calculated the hazard ratios (HRs) of CVD mortality by using the Cox proportional hazards model after adjusting for age, body mass index, hypertension, diabetes, dyslipidemia, smoking, and alcohol drinking. Within 25 years of follow-up, 637 participants died because of CVD. The HRs of CVD in patients with CKD only, anemia only, and both were 1.27, 1.59, and 2.60 (95% confidence intervals [CI] 1.06 to 1.53, 1.34 to 1.90, and 1.80 to 3.76) in men and 1.42, 1.08, and 2.00 (95% CI 1.19 to 1.69, 0.99 to 1.18, and 1.54 to 2.60) in women, respectively. In conclusion, CKD with anemia is associated with an increased risk for CVD mortality in a general population in Japan.

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Real-Time Survey of Vaccine Safety of the mRNA-1273 SARS-CoV-2 Vaccine in Workplace Vaccination at Keio University

Okumura K., Hara A., Inada I., Sugiyama D., Hoshino T., Yakoh T., Yokoyama H., Urushihara H.

Vaccines （Vaccines） 10 （ 9 ） 2022年09月

The mRNA-1273 Moderna COVID-19 vaccine was introduced to combat the COVID-19 global pandemic in 2020. Although the safety of the vaccine has been investigated worldwide, real-world safety data is scarce in Japan. An online, real-time survey of adverse events following immunization (AEFIs) with mRNA-1273 was conducted in the setting of a workplace vaccination program at the School of Pharmacy, Keio University from 26 June 2021, to 11 June 2022. Participants were requested to take four surveys during a seven-day follow-up period after each of the first, second, and third booster doses. The maximum number of responses, from 301 respondents, was obtained on day 0 (vaccination date) for the first dose. 98% of respondents reported local and systemic AEFIs for the second dose on day 1. No noticeable difference in local reactions was seen among the three doses. Females reported more AEFIs than males, and the young group (18–29 years) reported a higher rate than the middle age group (≥30 years) after the first dose. Age and gender differences in rates decreased at the second and third doses. This survey confirmed that the safety profile of mRNA-1273 in a real-world setting was similar to that derived from the clinical trials, and that the agent was well-tolerated.

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An Accelerated Failure Time Cure Model with Shifted Gamma Frailty and Its Application to Epidemiological Research

Aida H., Hayashi K., Takeuchi A., Sugiyama D., Okamura T.

Healthcare (Switzerland) （Healthcare (Switzerland)） 10 （ 8 ） 2022年08月

Survival analysis is a set of methods for statistical inference concerning the time until the occurrence of an event. One of the main objectives of survival analysis is to evaluate the effects of different covariates on event time. Although the proportional hazards model is widely used in survival analysis, it assumes that the ratio of the hazard functions is constant over time. This assumption is likely to be violated in practice, leading to erroneous inferences and inappropriate conclusions. The accelerated failure time model is an alternative to the proportional hazards model that does not require such a strong assumption. Moreover, it is sometimes plausible to consider the existence of cured patients or long-term survivors. The survival regression models in such contexts are referred to as cure models. In this study, we consider the accelerated failure time cure model with frailty for uncured patients. Frailty is a latent random variable representing patients’ characteristics that cannot be described by observed covariates. This enables us to flexibly account for individual heterogeneities. Our proposed model assumes a shifted gamma distribution for frailty to represent uncured patients’ heterogeneities. We construct an estimation algorithm for the proposed model, and evaluate its performance via numerical simulations. Furthermore, as an application of the proposed model, we use a real dataset, Specific Health Checkups, concerning the onset of hypertension. Results from a model comparison suggest that the proposed model is superior to existing alternatives.

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Influence of the COVID-19 pandemic on regular clinic visits and medication prescriptions among people with diabetes: Retrospective cohort analysis of health care claims

Maeda T., Nishi T., Harada M., Tanno K., Nishiya N., Asayama K., Okuda N., Sugiyama D., Yatsuya H., Okayama A., Arima H.

Medicine (United States) （Medicine (United States)） 101 （ 29 ） 2022年07月

ISSN 00257974

The aim of this study was to investigate the effect of the COVID-19 pandemic on regular clinic visits among people with diabetes and to elucidate the factors related to visit patterns among these patients during the pandemic. This was a longitudinal study using anonymized insurance claims data from the Joint Health Insurance Society in Tokyo from October 2017 to September 2020. First, we identified patients with diabetes who were fully enrolled in the health plan from fiscal year 2017 until September 2020 and who were regularly receiving glucose-lowering medications (every 1-3 months) from October 2017 to September 2018. We divided follow-up into the pre-pandemic period (October 2018 to March 2020) and the pandemic period (April 2020 to September 2020). A multilevel logistic regression model was used to determine the risks of delayed clinic visits/medication prescriptions (i.e., >3 months after a previous visit/prescription) during the pandemic period. We identified 1118 study participants. The number of delayed clinic visits/medication prescriptions during the pre-pandemic and pandemic periods was 188/3354 (5.6%) and 125/1118 (11.2%), respectively. There was a significant increase in delayed clinic visits during the pandemic (adjusted odds ratio 3.68 (95% confidence interval 2.24 to 6.04, P <.001), even after controlling for confounding factors. We also found a significant interaction between sex and delayed visits; women had significantly fewer clinic visits during the COVID-19 pandemic than men. We clarified the relationship of the COVID-19 pandemic with delays in regular clinic visits and medication prescriptions among people with diabetes. The response to the COVID-19 pandemic differed between men and women.

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Disparities in co-payments for influenza vaccine among the elderly, during the COVID-19 pandemic in Japan

Ando T., Maruyama T., Tamai A., Murakami T., Kido Y., Ishida T., Taya H., Haruta J., Sugiyama D., Fujishima S.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy） 28 （ 7 ） 896 - 901 2022年07月

ISSN 1341321X

Introduction: Seasonal influenza vaccination for the elderly is highly recommended during the COVID-19 pandemic. In Japan, the amount of subsidy for influenza differs among municipalities. Thus, we investigated the amount of and variation in subsidy for influenza vaccination for the elderly in 2020. Methods: This was an ecological study of 1,922 municipalities in Japan. The amount of subsidy for influenza vaccines for the elderly in each municipality was surveyed through websites or via telephone. Geographic and financial data for municipalities and prefectures were obtained from the open data. The amount of co-payment for the influenza vaccine and the geographical and financial status of each municipality were compared, according to the aging rate. Univariate logistic regression analysis was performed to explore factors related to the free influenza vaccine. Results: Municipalities with higher aging rates tended to have higher median co-payments for vaccines in 2020. (0 yen vs 1000 yen, p < 0.001) In addition, they tended to have worse financial conditions and lower per capita incomes. A similar trend was observed in the analysis by prefecture, i.e., a higher influenza mortality rate in prefectures with a higher aging rate. Despite having lower incomes, municipalities and prefectures with higher aging populations had higher mortality rates from influenza and higher co-payments for influenza vaccination. Conclusions: In Japan, there is a disparity among elderly people; areas with an aging population have higher co-payments for influenza vaccines despite lower incomes, suggesting that the government needs to implement corrective measures to reduce this disparity.

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Accumulated unhealthy behaviours and insomnia in Japanese dwellers with and without cardiovascular risk factors: A cross-sectional study

Kato S., Harada S., Iida M., Kuwabara K., Sugiyama D., Takeuchi A., Sata M., Matsumoto M., Kurihara A., Hirata A., Okamura T., Takebayashi T.

BMJ Open （BMJ Open） 12 （ 4 ） 2022年04月

Objectives To date, the association between accumulated unhealthy behaviours and insomnia in individuals stratified according to the presence or absence of major cardiovascular risk factors is unclear. This study aimed to examine the effect of accumulated unhealthy behaviours on insomnia in Japanese dwellers. Design Cross-sectional study. Setting Baseline data between April 2012 and March 2015. Participants Our study used cross-sectional data among Japanese aged 35-74 years in a rural community (N=9565), the attendees of annual municipal or work site health check-up programmes. Main outcome measures Insomnia was assessed by Athens Insomnia Scale, which was set at 6 points and greater; other scales were given. Participants were categorised into three groups by their number of unhealthy behaviours (no exercise habit, smoking, alcohol drinking, skipping breakfast and obesity): 0-1, 2-3, 4 or more. The association between accumulated unhealthy behaviours and insomnia was estimated by logistic regression analysis. Further analysis was done after stratification of cardiovascular risk factors assessed by anthropometrics and clinical biochemistry measurements. Results The overall prevalence of insomnia was 13.3% for men and 19.3% for women. Men with unhealthy behaviour factors were more likely to have insomnia after adjusting for potential confounders, compared with the least unhealthy group (trend p=0.013). Women with four or more unhealthy behaviour factors were more likely to have insomnia, compared with the lowest groups (OR 1.175, 95% CI 1.077 to 1.282). Insomnia has an association with the unhealthy behaviours among men without cardiovascular risk factors (lowest groups: OR 1.133, 95% CI 1.037 to 1.238, trend p=0.026). Women without hypertension were more likely to have suspected insomnia, compared with the lowest group (OR 1.215, 95% CI 1.101 to 1.341). Conclusion The results showed accumulated unhealthy behaviours were associated with increased risk of insomnia in Japanese dwellers. For healthy population without cardiovascular risk factors, unhealthy behaviours should be considered as background conditions for insomnia.

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Changes in Smoking Habits and Behaviors Following the Introduction and Spread of Heated Tobacco Products in Japan and Its Effect on FEV<inf>1</inf> Decline: A Longitudinal Cohort Study

Harada S., Sata M., Matsumoto M., Iida M., Takeuchi A., Kato S., Hirata A., Kuwabara K., Shibuki T., Ishibashi Y., Sugiyama D., Okamura T., Takebayashi T.

Journal of Epidemiology （Journal of Epidemiology） 32 （ 4 ） 180 - 187 2022年04月

ISSN 09175040

Background: Heated tobacco product (HTP) use in Japan has rapidly increased. Despite this rapid spread, little is known about the health effects of HTP use. We conducted a longitudinal cohort study to investigate the change in smoking habits following the spread of HTP use and its effect on forced expiratory volume in 1 second (FEV1) decline. Methods: Participants consisted of a resident population (n = 2,612; mean age, 67.7 years) with FEV1 measurement in 2012–2014 and 2018–2019, and a worksite population (n = 722; mean age 49.3 years) without FEV1 data. Participants were categorized as combustible cigarette-only smokers, HTP-only users, dual users, past smokers, and never smokers. The association between smoking group and the change in smoking consumption over a mean 5.6 years was examined. Differences in annual FEV1 change between smoking groups were examined in the resident population. Results: Prevalence of HTP-only and dual users in 2018–2019 was 0.8% and 0.6% in the resident population, and 5.0% and 1.9% in the worksite population, respectively. The overall number of tobacco products smoked=used increased in dual users compared to baseline, but not in others. Annual FEV1 decline in dual users tended to be greater than that in cigarette-only smokers (16; 95% confidence interval, −34 to 2 mL=year after full adjustment). Participants switching to HTP-only use 1.7 years before had a similar FEV1 decline as cigarette-only smokers. Conclusions: HTP use, including dual use, is prevalent even in a rural region of Japan. Dual users appear to smoke=use tobacco products more and have a greater FEV1 decline. Tobacco policy should consider dual use as high-risk.

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The association of high Vancomycin trough concentration with acute kidney injury during combination therapy of Piperacillin/Tazobactam and Vancomycin

Saito S., Sugimoto T., Takenaka K., Goto H., Kumahara A., Watanabe R., Sugiyama D., Yasutomo Y., Takatsuki K.

Practical Laboratory Medicine （Practical Laboratory Medicine） 29 2022年03月

Background: Co-administration of Piperacillin/Tazobactam (PIPC/TAZ) and Vancomycin (VCM) as an antibiotic therapy for severe infectious diseases increases the risk of nephrotoxicity. We retrospectively investigated the utility of monitoring VCM trough concentration in early stage of developing acute kidney injury (AKI) on this combination therapy. Methods: We enrolled all infectious disease patients who were managed with concurrent PIPC/TAZ and VCM. The record of dosage and the administration interval of each antibiotic and its clinical parameters, as well as the VCM trough concentrations, blood culture for bacteria, and serum creatinine values, were collected. VCM trough concentration was measured during the initial 48–72 h of VCM administration. Nephrotoxicity was evaluated as the degree of AKI. Results: A total of 47 patients fulfilling the criteria were registered, and AKI developed in 10 patients. There was no statistical difference between the AKI and non-AKI groups with regard to age, height, weight, basal creatinine level, body surface area, body mass index, PIPC/TAZ dose, VCM dose, gender, artificial management, and death within around 30 days. The VCM trough level was increased significantly in the AKI group (mean [standard deviation {SD}]: 25.9 [7.8] μg/mL) compared to that in the non-AKI group (mean [SD]: 15.7 [6.9] μg/mL) (p = 0.003). During the clinical course, renal function returned to normal levels in three out of four AKI stage 2 patients, whereas only partial recovery was achieved in all AKI stage 3 patients. Conclusions: A high VCM trough concentration may have an influence on the occurrence of AKI during combination therapy of PIPC/TAZ and VCM. Careful monitoring of VCM trough concentration will be required to prevent AKI progression.

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Metabolic profiling of charged metabolites in association with menopausal status in Japanese community-dwelling midlife women: Tsuruoka Metabolomic Cohort Study

Watanabe K., Iida M., Harada S., Kato S., Kuwabara K., Kurihara A., Takeuchi A., Sugiyama D., Okamura T., Suzuki A., Amano K., Hirayama A., Sugimoto M., Soga T., Tomita M., Kobayashi Y., Banno K., Aoki D., Takebayashi T.

Maturitas （Maturitas） 155 54 - 62 2022年01月

ISSN 03785122

Background: Emerging evidence has shown that charged metabolites, such as amino acids, may play an important role in the pathogenesis of various metabolic disorders, many of which women in the postmenopausal period are at high risk of developing. This study examined the metabolic profile of middle-aged Japanese women to investigate alterations in charged metabolites induced by menopausal transition. Methods: The participants were 1193 female residents aged 40–60 at the baseline survey of the Tsuruoka Metabolomics Cohort Study. We investigated the cross-sectional association of menopausal status with 94 metabolomic biomarkers assayed in fasting plasma samples via capillary electrophoresis time-of-flight mass spectrometry using linear regression analysis. Results: Among the participants, 529 were premenopausal, 132 were in menopausal transition (MT), and 532 were postmenopausal. Significant differences were found in age, blood pressure, glucose and lipid levels, and smoking and drinking habits among the three groups. The concentrations of 5 metabolites in the MT group and 15 metabolites in the postmenopausal group were significantly higher than those in the premenopausal group after adjusting for confounding factors. When classified into pathways, these metabolites were related to the tricarboxylic cycle, urea cycle, and homocysteine metabolism, some of which are linked to arteriosclerosis. Conclusion: Multiple charged metabolites were associated with women's menopausal status, showing a gradual increase as women shifted from pre-, to peri-, to postmenopause. These findings might reflect the early changes behind the increased risk of dyslipidemia, diabetes, cardiovascular disease, and osteoporosis in later life.

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Physique at Birth and Cardiovascular Disease Risk Factors in Japanese Urban Residents: the KOBE Study

Umemoto K., Kubo S., Nishida Y., Higashiyama A., Kawamura K., Kubota Y., Hirata T., Hirata A., Sata M., Kuwabara K., Miyazaki J., Kadota A., Iida M., Sugiyama D., Miyamatsu N., Miyamoto Y., Okamura T.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis） 29 （ 2 ） 188 - 199 2022年

ISSN 13403478

Aim: This study investigated the relationship between birth physique and cardiovascular risk factors in Japanese urban residents aged 40 years and more. Methods: A self-administered questionnaire on birth physique was performed among 624 individuals (165 men and 459 women) who participated in the KOBE study. We examined whether self-reported birth physique and available recorded birth weights matched for 72 participants. Then the association between birth physique and risk factors for all participants was examined by gender. Body size at birth in the questionnaire (large, medium, small) was set as an exposure and laboratory values from the baseline survey (2010-2011) were used as outcomes. Results: Mean (standard deviation) recorded birth weight of 72 participants was 3665 (318), 3051 (300), and 2653 (199) g, in the large, medium, and small group, respectively. In the analysis for all participants, odds ratio for having both hypertension and impaired glucose tolerance were significantly higher in the small versus large birth weight group, which was 7.42 (95% CI 1.75–31.50) for men and 4.44 (95% CI 1.14–17.30) for women after adjusting for age, body mass index, smoking/alcohol/exercise habits, and menstrual status in women. Similar results were observed in participants with recorded birth weight. Conclusions: The present study indicates that individuals with small physique at birth might be at higher risk for hypertension and impaired glucose tolerance in middle age compared to those with large birth weight.

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Relationship Between Non-fasting Triglycerides and Cardiovascular Disease Mortality in a 20-year Follow-up Study of a Japanese General Population: NIPPON DATA90

Hirata A., Okamura T., Hirata T., Sugiyama D., Ohkubo T., Okuda N., Kita Y., Hayakawa T., Kadota A., Kondo K., Miura K., Okayama A., Ueshima H.

Journal of Epidemiology （Journal of Epidemiology） 32 （ 7 ） 303 - 313 2022年

ISSN 09175040

Background: Non-fasting triglycerides (TG) are considered a better predictor of cardiovascular disease (CVD) than fasting TG. However, the effect of non-fasting TG on fatal CVD events remains unclear. In the present study, we aimed to explore the relationship between non-fasting TG and CVD mortality in a Japanese general population. Methods: A total of 6,831 participants without a history of CVD, in which those who had a blood sampling over 8 hours or more after a meal were excluded, were followed for 18.0 years. We divided participants into seven groups according to non-fasting TG levels: ≤59 mg=dL, 60–89 mg=dL, 90–119 mg=dL, 120–149 mg=dL, 150–179 mg=dL, 180–209 mg=dL, and ≥210 mg=dL, and estimated the multivariable-adjusted hazard ratios (HRs) of each TG group for CVD mortality after adjusting for potential confounders, including high density lipoprotein cholesterol. Additionally, we performed analysis stratified by age <65 and ≥65 years. Results: During the follow-up period, 433 deaths due to CVD were detected. Compared with a non-fasting TG of 150–179 mg=dL, non-fasting TG ≥210 mg=dL was significantly associated with increased risk for CVD mortality (HR 1.56: 95% CI, 1.01–2.41). Additionally, lower levels of non-fasting TG were also significantly associated with increased risk for fatal CVD. In participants aged ≥65 years, lower levels of non-fasting TG had a stronger impact on increased risk for CVD mortality, while higher levels of non-fasting TG had a stronger impact in those aged <65 years. Conclusion: In a general Japanese population, we observed a U-shaped association between non-fasting TG and fatal CVD events.

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Bone Marrow Infiltration Is a Distinctive Risk Factor for Rituximab Infusion-Related Reactions in CD20-Positive B-Cell Non-Hodgkin Lymphoma

Ohata S., Takenaka K., Sugiyama D., Sugimoto T.

Advances in Hematology （Advances in Hematology） 2022 2022年

ISSN 16879104

Background. Bone marrow infiltration of lymphoma cells is a candidate risk factor for infusion-related reactions (IRRs) in patients with CD20-positive B-cell non-Hodgkin lymphoma (B-NHL). However, despite with the lack of sufficient data, the effect of bone marrow infiltration of B-NHL cells on the incidence rate of grade 2 or higher IRRs with the administration of rituximab has been retrospectively studied in this paper. Methods. Patients with CD20-positive B-NHL who received the rituximab induction therapy for the first time were enrolled in this study. To evaluate the bone marrow infiltration of B-NHL cells, May-Giemsa stain of bone marrow films and flow cytometry examination of bone marrow aspiration samples were performed. IRR grade was determined using the IRR criteria in the Common Terminology Criteria for Adverse Events version 4.0. Results. A total of 127 patients were eligible for this study. Grade 2 or higher IRRs were observed in 43 (34%) patients. In univariate analysis, use of glucocorticoid before rituximab infusion was a strong risk-avoiding factor for grade 2 or higher IRRs. Advanced stage of disease (Ann Arbor: stages III and IV) or bone marrow infiltration of B-NHL cells revealed the risk factors, regardless of glucocorticoid premedication. Using multivariate analysis, bone marrow infiltration was found to be an independent risk factor for patients without prior glucocorticoid use. Conclusion. Bone marrow infiltration of B-NHL cells is a risk factor for grade 2 or higher IRRs at the first rituximab induction therapy without glucocorticoid premedication.

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Reliability of urinary charged metabolite concentrations in a large-scale cohort study using capillary electrophoresis-mass spectrometry

Ishibashi Y., Harada S., Takeuchi A., Iida M., Kurihara A., Kato S., Kuwabara K., Hirata A., Shibuki T., Okamura T., Sugiyama D., Sato A., Amano K., Hirayama A., Sugimoto M., Soga T., Tomita M., Takebayashi T.

Scientific Reports （Scientific Reports） 11 （ 1 ） 2021年12月

Currently, large-scale cohort studies for metabolome analysis have been launched globally. However, only a few studies have evaluated the reliability of urinary metabolome analysis. This study aimed to establish the reliability of urinary metabolomic profiling in cohort studies. In the Tsuruoka Metabolomics Cohort Study, 123 charged metabolites were identified and routinely quantified using capillary electrophoresis-mass spectrometry (CE-MS). We evaluated approximately 750 quality control (QC) samples and 6,720 participants’ spot urine samples. We calculated inter- and intra-batch coefficients of variation in the QC and participant samples and technical intraclass correlation coefficients (ICC). A correlation of metabolite concentrations between spot and 24-h urine samples obtained from 32 sub-cohort participants was also evaluated. The coefficient of variation (CV) was less than 20% for 87 metabolites (70.7%) and 20–30% for 19 metabolites (15.4%) in the QC samples. There was less than 20% inter-batch CV for 106 metabolites (86.2%). Most urinary metabolites would have reliability for measurement. The 96 metabolites (78.0%) was above 0.75 for the estimated ICC, and those might be useful for epidemiological analysis. Among individuals, the Pearson correlation coefficient of 24-h and spot urine was more than 70% for 59 of the 99 metabolites. These results show that the profiling of charged metabolites using CE-MS in morning spot human urine is suitable for epidemiological metabolomics studies.

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Experimental study on the efficacy of a hybrid artificial nerve: The hot dog method

Tamura R., Hashikawa K., Sakakibara S., Osaki T., Kitano D., Maruguchi H., Nomura T., Sugiyama D., Terashi H.

International Journal of Artificial Organs （International Journal of Artificial Organs） 44 （ 10 ） 711 - 717 2021年10月

ISSN 03913988

Introduction: We hypothesized that hybrid artificial nerves might overcome the limitations of a nerve conduit by isolating nerve fascicles from autologous nerves. Nerve sacrifice during harvest, a drawback of conventional autologous nerve transplantation, may be reduced by the hot dog method. The hot dog method (based on the morphology of hybrid artificial nerves) adds nerve conduits to autologous nerve fascicles. Methods: Forty-eight rats with a 10-mm sciatic nerve defect were divided into six groups (n = 8 per group) according to the neural reconstruction method: autologous nerve transplantation, the hot dog method, nerve conduit, nerve fascicle transplantation, sham control, and nerve fascicle isolation were classified as Groups I, II, III, IV, V, and VI, respectively. The sciatic nerve function was assessed in these groups, a histological evaluation was performed, and statistical analyses were conducted based on these data. Results: Group III (nerve conduit) and Group IV (nerve fascicle transplantation) showed the lowest functional and axonal regenerative effects, followed by Group II (hot dog method) and Group I (autologous nerve transplantation). Group VI (nerve fascicle isolation) tended to achieve better recovery in motor function and axonal regeneration than Group I (autologous nerve transplantation). Conclusions: The hot dog method is simple, safe, and easy to execute. This method can serve as a new neural reconstruction method that uses artificial nerves.

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Prevalence of anti-dense fine speckled 70 antibodies in healthy individuals and patients with antinuclear antibody-associated autoimmune rheumatic diseases in Japan

Hayashi N., Uto K., Imanishi A., Sugiyama D., Morinobu A., Saegusa J.

Medicine （Medicine） 100 （ 9 ） 2021年03月

ISSN 00257974

ABSTRACT: Previous studies from various countries have reported anti-dense fine speckled pattern (DFS)70 antibody prevalence but few studies have been from Asia. We investigated the prevalence of anti-DFS70 autoantibodies in a Japanese cohort of healthy individuals (HI) and patients with antinuclear antibody-associated autoimmune rheumatic diseases (AARD).Enzyme-linked immunosorbent assay and indirect immunofluorescence were performed using samples from 250 HI and 276 AARD patients.The overall anti-DFS70 antibody prevalence in HI was 16.4%, with 12.8% for males and 20.0% for females (sex difference; P = .12). In AARD patients, the anti-DFS70 antibody prevalence in systemic lupus erythematosus, mixed connective tissue disease, systemic sclerosis, dermatomyositis and polymyositis (DM/PM), Sjögren syndrome, and rheumatoid arthritis (RA) was 22.1%, 14.3%, 14.3%, 3.0%, 21.3%, and 18.1%, respectively (no significant difference between AARD patients except DM/PM and HI). The prevalence of isolated anti-DFS70 antibody in HI and all AARD patients excluding RA was 14.8% (37/250) and 4.4% (9/204), respectively (P < .01 vs HI). Among anti-DFS70 antibody-positive cases, 63.4% (26/41) were DFS pattern by IIF and 23.5% (8/34) were HI and AARD patients excluding RA, respectively.The anti-DFS70 antibody prevalence in HI and AARD patients in Japan was similar. Furthermore, the anti-DFS70 antibody prevalence in HI and AARD in Japan is higher than in HI and AARD in regions other than Asia. This makes AARD differential diagnosis by antinuclear antibody screening difficult.

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The effect of soy isoflavones on arterial stiffness: a systematic review and meta-analysis of randomized controlled trials

Man B., Cui C., Zhang X., Sugiyama D., Barinas-Mitchell E., Sekikawa A.

European Journal of Nutrition （European Journal of Nutrition） 60 （ 2 ） 603 - 614 2021年03月

ISSN 14366207

Purpose: Some but not all randomized controlled trials (RCTs) of soy isoflavones showed their beneficial effect on arterial stiffness, a predictor of cardiovascular events, dementia, and all-cause mortality, independent of traditional risk factors. To test the hypothesis that supplementation of soy isoflavones reduces arterial stiffness, we performed a systematic review and meta-analysis of RCTs of soy isoflavones on arterial stiffness. Methods: The protocol of this systematic review was registered with PROSPERO (CRD42019126128) and written in accordance with PRISMA. The PubMed, Embase, and clinicaltrials.gov databases were searched using the following criteria: human subjects, soy isoflavones as intervention, and arterial stiffness as primary outcome. A random-effects meta-analysis was used to pool estimates across studies. Standardized mean difference (SMD) was used to synthesize quantitative results. Results: Among 998 articles retrieved, 8 articles met our criteria. Duration of intervention was relatively short (maximum of 12 weeks). Outcome measurements extracted were pulse wave velocity (PWV), systemic arterial compliance (SAC), augmentation index (AI), and cardio-ankle vascular index (CAVI). Soy isoflavones reduced arterial stiffness compared to placebo (standardized mean difference − 0.33, 95% confidence interval − 0.47, − 0.19). Subgroup analyses showed no difference between treatment effects for intervention duration (< 6 weeks vs. ≥ 6 weeks) or gender (women only vs. men only vs. combined). Sensitivity analysis showed no difference in the effect of soy isoflavones between PWV, CAVI, SAC, and AI. Conclusion: Supplementation of soy isoflavones reduced arterial stiffness. Longer duration trials with larger number of participants are warranted.

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Charged metabolite biomarkers of food intake assessed via plasma metabolomics in a population-based observational study in Japan

Shibutami E., Ishii R., Harada S., Kurihara A., Kuwabara K., Kato S., Iida M., Akiyama M., Sugiyama D., Hirayama A., Sato A., Amano K., Sugimoto M., Soga T., Tomita M., Takebayashi T.

PLoS ONE （PLoS ONE） 16 （ 2 February ） 2021年02月

Food intake biomarkers can be critical tools that can be used to objectively assess dietary exposure for both epidemiological and clinical nutrition studies. While an accurate estimation of food intake is essential to unravel associations between the intake and specific health conditions, random and systematic errors affect self-reported assessments. This study aimed to clarify how habitual food intake influences the circulating plasma metabolome in a free-living Japanese regional population and to identify potential food intake biomarkers. To achieve this aim, we conducted a cross-sectional analysis as part of a large cohort study. From a baseline survey of the Tsuruoka Metabolome Cohort Study, 7, 012 eligible male and female participants aged 40-69 years were chosen for this study. All data on patients' health status and dietary intake were assessed via a food frequency questionnaire, and plasma samples were obtained during an annual physical examination. Ninety-four charged plasma metabolites were measured using capillary electrophoresis mass spectrometry, by a non-targeted approach. Statistical analysis was performed using partial-least-square regression. A total of 21 plasma metabolites were likely to be associated with long-term food intake of nine food groups. In particular, the influential compounds in each food group were hydroxyproline for meat, trimethylamine- N-oxide for fish, choline for eggs, galactarate for dairy, cystine and betaine for soy products, threonate and galactarate for carotenoid-rich vegetables, proline betaine for fruits, quinate and trigonelline for coffee, and pipecolate for alcohol, and these were considered as prominent food intake markers in Japanese eating habits. A set of circulating plasma metabolites was identified as potential food intake biomarkers in the Japanese community-dwelling population. These results will open the way for the application of new reliable dietary assessment tools not by self-reported measurements but through objective quantification of biofluids.

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Validity assessment of self-reported medication use for hypertension, diabetes, and dyslipidemia in a pharmacoepidemiologic study by comparison with health insurance claims

Matsumoto M., Harada S., Iida M., Kato S., Sata M., Hirata A., Kuwabara K., Takeuchi A., Sugiyama D., Okamura T., Takebayashi T.

Journal of Epidemiology （Journal of Epidemiology） 31 （ 9 ） 495 - 502 2021年

ISSN 09175040

Background: Although self-reported questionnaires are widely employed in epidemiologic studies, their validity has not been sufficiently assessed. The aim of this study was to evaluate the validity of a self-reported questionnaire on medication use by comparison with health insurance claims and to identify individual determinants of discordance in the Tsuruoka Metabolomics Cohort Study. Methods: Participants were 2,472 community-dwellers aged 37 to 78 years from the Tsuruoka Metabolomics Cohort Study. Information on lifestyle and medications was collected through a questionnaire. Sensitivity and specificity were determined using health insurance claims from November 2014 to March 2016, which were used as a standard. Potential determinants of discordance were assessed using multivariable logistic regression. Results: The self-reported questionnaire on medication use showed high validity. Sensitivity and specificity were 0.95 (95% CI, 0.93–0.96) and 0.97 (95% CI, 0.96–0.98) for antihypertensive medications, 0.94 (95% CI, 0.91–0.97) and 0.98 (95% CI, 0.98–0.99) for diabetes medications, and 0.84 (95% CI, 0.82–0.87) and 0.98 (95% CI, 0.97–0.99) for dyslipidemia medications, respectively. Males without high education and those who currently smoke cigarettes were found to be associated with discordant reporting which affected sensitivity, especially those with medication use for dyslipidemia. Conclusions: In this population-based cohort study, we found that the self-reported questionnaire on medication use was a valid measure to capture regular medication users. Sensitivity for dyslipidemia medications was lower than those for the other medications. Type of medication, sex, education years, and smoking status influenced discordance, which affected sensitivity in self-reporting.

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Association of the estimated coronary artery incidence risk according to the japan atherosclerosis society guidelines 2017 with cardio-ankle vascular index

Sata M., Okamura T., Harada S., Sugiyama D., Kuwabara K., Hirata A., Takeuchi A., Iida M., Kato S., Matsumoto M., Kurihara A., Takebayashi T.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis） 28 （ 12 ） 1266 - 1274 2021年

ISSN 13403478

Aims: The categories in the comprehensive lipid and risk management guidelines were proposed by the Japan Atherosclerosis Society (JAS Guidelines 2017), which adopted the estimated 10 year absolute risk of coronary artery disease (CAD) incidence in the Suita score. We examined whether those categories were concordant with the degree of arterial stiffness. Methods: In 2014, the cardio-ankle vascular index (CAVI), an arterial stiffness parameter, was measured in 1,972 Japanese participants aged 35–74 years in Tsuruoka City, Yamagata Prefecture, Japan. We examined the mean CAVI and the proportion and odds ratios (ORs) of CAVI ≥ 9.0 on the basis of the following three management classifications using the analysis of variance and logistic regression: “Category I (Low risk),” “Category II (Middle risk),” and “Category III (High risk).” Results: The mean CAVI and proportion of CAVI ≥ 9.0 were 8.6 and 34.8% among males and 8.1 and 18.3% among females, respectively. The mean CAVI and proportion of CAVI ≥ 9.0 were associated with an estimated 10 year absolute risk for CAD among males and females, excluding High risk for females. These results were similar to the management classification by the guideline: the multivariable-adjusted ORs (95% confidence intervals) of CAVI ≥ 9.0 among Category II and Category III compared with those among Category I were 2.96 (1.61–5.43) and 7.33 (4.03–13.3) for males and 3.99 (2.55–6.24) and 3.34 (2.16–5.16) for females, respectively. Conclusions: The risk stratification, which was proposed in the JAS Guidelines 2017, is concordant with the arterial stiffness parameter.

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A combination of blood pressure and total cholesterol increases the lifetime risk of coronary heart disease mortality: EPOCH–JAPAN

Satoh M., Ohkubo T., Asayama K., Murakami Y., Sugiyama D., Waki T., Tanaka-Mizuno S., Yamada M., Saitoh S., Sakata K., Irie F., Sairenchi T., Ishikawa S., Kiyama M., Okayama A., Miura K., Imai Y., Ueshima H., Okamura T.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis） 28 （ 1 ） 6 - 24 2021年

ISSN 13403478

Aim: Lifetime risk (LTR) indicates the absolute risk of disease during the remainder of an individual’s lifetime. We aimed to assess the LTRs for coronary heart disease (CHD) mortality associated with blood pressure (BP) and total cholesterol levels in an Asian population using a meta-analysis of individual participant data because no previous studies have assessed this risk. Methods: We analyzed data from 105,432 Japanese participants in 13 cohorts. Apart from grade 1 and 2–3 hypertension groups, we defined “normal BP” as systolic/diastolic BP ＜130/＜80 mmHg and “high BP” as 130–139/80–89 mmHg. The sex-specific LTR was estimated while considering the competing risk of death. Results: During the mean follow-up period of 15 years (1,553,735 person-years), 889 CHD deaths were recorded. The 10-year risk of CHD mortality at index age 35 years was ≤ 0.11%, but the corresponding LTR was ≥ 1.84%. The LTR of CHD at index age 35 years steeply increased with an increase in BP of participants with high total cholesterol levels [≥ 5.7 mmol/L (220 mg/dL)]. This risk was 7.73%/5.77% (95% confidence interval: 3.53%–10.28%/3.83%–7.25%) in men/women with grade 2–3 hypertension and high total cholesterol levels. In normal and high BP groups, the absolute differences in LTRs between the low and high total cholesterol groups were ≤ 0.25% in men and ≤ 0.40% in women. Conclusions: High total cholesterol levels contributed to an elevated LTR of CHD mortality in hypertensive individuals. These findings could help guide high-risk young individuals toward initiating lifestyle changes or treatments.

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Electrocardiographic left atrial abnormality and b-type natriuretic peptide in a general Japanese population: NIPPON DATA2010

Shoji S., Kohsaka S., Sawano M., Okamura T., Hirata A., Sugiyama D., Ohkubo T., Nakamura Y., Watanabe M., Kadota A., Ueshima H., Okayama A., Miura K.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis） 28 （ 1 ） 34 - 43 2021年

ISSN 13403478

Aims: P-wave terminal force in lead V1 (PTFV1) is an electrocardiogram marker of increased left atrial pressure and may be a noninvasive and early detectable marker for future cardiovascular events in the general population compared to serum B-type natriuretic peptide (BNP) concentration. The clinical significance of PTFV1 in the contemporary general population is an area of unmet need. We aimed to demonstrate the correlation between PTFV1 and BNP concentrations in a contemporary representative Japanese population. Methods: Among 2,898 adult men and women from 300 randomly selected districts throughout Japan (NIPPON DATA2010), we analyzed 2,556 participants without cardiovascular disease (stroke, myocardial infarction, and atrial fibrillation). Elevated BNP was defined as a value of ≥ 20 pg/mL based on the definition from the Japanese Circulation Society guidelines. Results: In total, 125 (4.9%) participants had PTFV1. Participants with PTFV1 were older with a higher prevalence of hypertension, major electrocardiographic findings, and elevated BNP concentrations (13.5 [6.9, 22.8] versus 7.8 [4.4, 14.5] pg/mL; P＜0.001). After adjustment for confounders, PTFV1 was correlated with elevated BNP (odds ratio, 1.66; 95% confidence interval, 1.05–2.62; P= 0.030). This correlation was consistent among various subgroups and was particularly evident in those aged ＜65 years or those without a history of hypertension. Conclusions: In the contemporary general population cohort, PTFV1 was independently related to high BNP concentration. PTFV1 may be an alternative marker to BNP in identifying individuals at a higher risk of future cardiovascular events in the East Asian population.

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Estimated 24 h urinary sodium-to-potassium ratio is related to renal function decline: A 6-year cohort study of japanese urban residents

Hattori H., Hirata A., Kubo S., Nishida Y., Nozawa M., Kawamura K., Hirata T., Kubota Y., Sata M., Kuwabara K., Higashiyama A., Kadota A., Sugiyama D., Miyamatsu N., Miyamoto Y., Okamura T.

International Journal of Environmental Research and Public Health （International Journal of Environmental Research and Public Health） 17 （ 16 ） 1 - 12 2020年08月

ISSN 16617827

The effect of the sodium-to-potassium ratio (Na/K) on renal function within the clinically normal range of renal function are limited. We investigated the effects of an estimated 24 h urinary Na/K (e24hUNa/K) on a 6-year renal function decline among 927 urban Japanese community dwellers with no history of cardiovascular diseases and medication for hypertension, diabetes, or dyslipidemia. We partitioned the subjects into quartiles according to the e24hUNa/K. The estimated glomerular filtration rate (eGFR) was calculated using the chronic kidney disease epidemiology collaboration (CKD/EPI) formula and renal function decline was defined as an absolute value at or above the third quartile of the eGFR decline rate. A multivariable logistic regression model was used for estimation. Compared with the first quartile of the e24hUNa/K, multivariable-adjusted odds ratios (ORs) for eGFR decline in the second, third, and fourth quartiles were 0.96 (95% confidence interval: 0.61–1.51), 1.06 (0.67–1.66), and 1.65 (1.06–2.57), respectively. These results were similar when the simple spot urine Na/K ratio was used in place of the e24hUNa/K. Apparently healthy urban residents with an almost within normal range mean baseline eGFR and high e24hUNa/K ratios had an increased risk for a future decline in renal function. Reducing the Na/K ratio may be important in the prevention of chronic kidney disease in its early stage.

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US detection of medial meniscus extrusion can predict the risk of developing radiographic knee osteoarthritis: a 5-year cohort study

Chiba D., Sasaki E., Ota S., Maeda S., Sugiyama D., Nakaji S., Ishibashi Y.

European Radiology （European Radiology） 30 （ 7 ） 3996 - 4004 2020年07月

ISSN 09387994

Objectives: To clarify the relationship between the baseline value of medial meniscus extrusion (MME) and the radiographic change of knee osteoarthritis (KOA) through a 5-year follow-up. Methods: Overall, 472 participants and 944 knees were eligible. MME (mm) was measured at the baseline, and KOA was radiographically evaluated at both baseline and 5-year follow-up by Kellgren-Lawrence grade (KLG). Radiographic KOA (ROA) was defined as the knee showing KLG ≥ 2. Incident ROA (iROA) was defined if the baseline KLG of 0–1 increased to KLG ≥ 2 in 5 years. Progressive ROA (pROA) was defined if the baseline KLG of 2–3 worsened to a higher grade in 5 years. Receiver operating characteristic (ROC) curve and generalized estimating equations were used for analysis. Results: Of 574 non-ROA knees at the baseline, 43 knees (7.5%) developed iROA; of 370 ROA knees, 47 knees (12.7%) developed pROA. Based on the ROC curves, 4 mm was the optimal cutoff to detect the risk of iROA (area under curve [AUC] 0.639 [right knee]; AUC 0.641 [left knee]) and that of pROA (AUC 0.750 [right knee]; AUC 0.863 [left knee]). Multiple regression analysis showed that the 4-mm cutoff of MME was significantly associated with both the prevalence of iROA (regression coefficient [B] 1.909; p ≤ 0.001; adjusted odds ratio [aOR] 6.746) and that of pROA (B 1.791; p ≤ 0.001; aOR 5.993). Conclusions: On ultrasonography, the participants with more extruded medial meniscus showed a higher prevalence of both iROA and pROA. Ultrasonography could identify patients who had a risk of developing KOA. Key Points: • Through a 5-year follow-up, the current cohort study was conducted to clarify the relationship between the baseline value of medial meniscus extrusion (MME) and the radiographic change of knee osteoarthritis (KOA). • More extruded medial meniscus evaluated by ultrasonography was associated with the development of radiographic KOA. • Ultrasonography could identify the patients who had a risk of developing KOA, and the 4-mm cutoff of MME was optimal to detect this risk.

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Hypercholesterolemia and lifetime risk of coronary heart disease in the general japanese population: Results from the suita cohort study

Sugiyama D., Turin T.C., Yeasmin F., Rumana N., Watanabe M., Higashiyama A., Takegami M., Kokubo Y., Okamura T., Miyamoto Y.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis） 27 （ 1 ） 60 - 70 2020年

ISSN 13403478

Lifetime risk (LTR) is a measure of disease burden, which presents the probability of occurrence of a specific disease in the remaining lifetime of a group of people for a given index age. This measure is useful for presenting the risk dynamics of a disease at the population level, which constitutes important public health information toward prevention. To date, there have been no studies investigating the LTR for coronary heart diseases (CHDs) in relation to hypercholesterolemia in Asian populations. Therefore, we estimated the LTR of CHDs according to serum low-density lipoprotein cholesterol (LDL-C). Methods: The participants included in this study were 2,559 men and 2,848 women, enrolled in the Suita Cohort Study of urban residents followed up from 1989 to 2007 for a total of 69,823 person-years. We estimated the sex-and index-age-specific LTR for the first CHD event among participants with or without hypercholesterolemia (LDL-C ≥ 160 mg/dL), accounting for the competing risk for mortality. Results: For men with hypercholesterolemia, the LTR was 47.2% (95% confidence interval [CI]: 29.3–65.1%) and 44.5% (95% CI: 21.4–68.5%) for those aged 45 and 75, respectively. The LTRs of women with hypercholesterolemia were also higher than of those without hypercholesterolemia. However, their LTRs were lower for all index ages compared to men. These results did not differ for hypercholesterolemia defined by non-high-density lipoprotein cholesterol. Conclusions: The presence of hypercholesterolemia increases the LTR for CHDs in the Japanese population, especially in men. This estimate can be used in preventive knowledge translation efforts at the population level.

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Association between dyslipidemia and plasma levels of branched-chain amino acids in the Japanese population without diabetes mellitus

Fukushima K., Harada S., Takeuchi A., Kurihara A., Iida M., Fukai K., Kuwabara K., Kato S., Matsumoto M., Hirata A., Akiyama M., Tomita M., Hirayama A., Sato A., Suzuki C., Sugimoto M., Soga T., Sugiyama D., Okamura T., Takebayashi T.

Journal of Clinical Lipidology （Journal of Clinical Lipidology） 13 （ 6 ） 932 - 939.e2 2019年11月

ISSN 19332874

Background: Branched-chain amino acids (BCAAs) play a key role in energy homeostasis. Objective: We aimed to investigate the association between plasma BCAA levels and dyslipidemia in the Japanese population without diabetes mellitus. Methods: This cross-sectional study included 4952 participants without diabetes mellitus, enrolled in the Tsuruoka Metabolomic Cohort Study. Plasma BCAA levels were measured by capillary electrophoresis–mass spectrometry. Correlations between lipid and BCAA profiles were evaluated by sex-stratified multiple linear regression analyses, after adjusting for confounders. Logistic regression was used to identify associations between BCAAs and metabolic dyslipidemia (MD) defined as triglyceride levels ≥150 mg/dL, high-density lipoprotein cholesterol levels ≤40 mg/dL for men and ≤50 mg/dL for women, or low-density lipoprotein cholesterol (LDL-C) levels ≥140 mg/dL. Results: In both sexes, the levels of individual BCAAs and the total BCAA levels correlated positively with triglyceride levels and negatively with high-density lipoprotein cholesterol levels. Valine, leucine, and total BCAA levels were weakly and positively correlated with LDL-C levels. Increased BCAA levels showed positive associations with MD. However, associations between BCAAs and elevated LDL-C levels were unclear. Furthermore, the associations between BCAA levels and MD regardless of fasting blood sugar (FBS) levels (high or low). Although valine, leucine, and total BCAA levels were weakly associated with elevated LDL-C levels in the high-FBS group, no such association was observed in the low-FBS group. Conclusions: BCAAs might be associated with MD independently of the FBS level and might play an important role in lipid metabolism and dyslipidemia.

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Effect of high-dose marine omega-3 fatty acids on atherosclerosis: A systematic review and meta-analysis of randomized clinical trials

Sekikawa A., Cui C., Sugiyama D., Fabio A., Harris W.S., Zhang X.

Nutrients （Nutrients） 11 （ 11 ） 2019年11月

A recent randomized controlled trial (RCT), the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), reported that high-dose marine omega-3 fatty acids (OM3) significantly reduce cardiovascular disease (CVD) outcomes, yet the mechanisms responsible for this benefit remain unknown. To test the hypothesis that high-dose OM3 is anti-atherosclerotic, we performed a systematic review and meta-analysis of RCT of high-dose OM3 on atherosclerosis. The protocol of this systematic review was registered with PROSPERO (CRD42019125566). PubMed, Embase, Cochran Central Register for Controlled Trials, and Clinicaltrials.gov databases were searched using the following criteria: adult participants, high-dose OM3 (defined as ≥3.0 g/day, or in Japan 1.8 g/day and purity ≥90%) as the intervention, changes in atherosclerosis as the outcome, and RCTs with an intervention duration of ≥6 months. A random-effects meta-analysis was used to pool estimates across studies. Among the 598 articles retrieved, six articles met our criteria. Four RCTs evaluated atherosclerosis in the coronary and two in the carotid arteries. High-dose OM3 significantly slowed the progression of atherosclerosis (standardized mean difference −1.97, 95% confidence interval −3.01, −0.94, p < 0.001). The results indicate that anti-atherosclerotic effect of high-dose OM3 is one potential mechanism in reducing CVD outcomes demonstrated in the REDUCE-IT trial.

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Being conscious of water intake positively associated with sufficient non-alcohol drink intake regardless of seasons and reasons in healthy Japanese; the KOBE study: A cross sectional study

Nishikawa T., Miyamatsu N., Higashiyama A., Kubota Y., Nishida Y., Hirata T., Sugiyama D., Kuwabara K., Kubo S., Miyamoto Y., Okamura T.

International Journal of Environmental Research and Public Health （International Journal of Environmental Research and Public Health） 16 （ 21 ） 2019年11月

ISSN 16617827

The present study sought to clarify if being conscious of water intake (CWI) is associated with sufficient non-alcohol drink (NAD) intake. We used data of healthy participants without diabetes, aged 40–74 years, in the Kobe Orthopedic and Biomedical Epidemiologic (KOBE) study. The association between being CWI and NAD intake was evaluated by multivariate linear regression analyses after adjusting for age, sex, surveyed months (seasons), alcohol drinking, health-awareness life habits, socioeconomic factors, serum osmolarity, estimated daily salt intake, and reasons for NAD intake. Among 988 (698 women and 290 men) participants eligible for the present analyses, 644 participants (65.2%) were CWI and 344 participants (34.8%) were not CWI (non-CWI). The most popular reason for being CWI was to avoid heat stroke in summer and to prevent ischemic cerebral stroke in winter. The CWI group took more NAD, especially decaffeinated beverages, than the non-CWI group (1846.7 ± 675.1 mL/day vs. 1478.0 ± 636.3 ml/day, p < 0.001). There was a significant association between being CWI and NAD intake in multivariate linear regression analyses ever after adjusting for the relevant variables (β = 318.1, p < 0.001). These findings demonstrated CWI, regardless of the reasons and the seasons, was associated with high NAD intake in Japanese healthy population.

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Daily habit of water intake in patients with cerebral infarction before its onset; Comparison with a healthy population: A cross-sectional study

Nishikawa T., Miyamatsu N., Higashiyama A., Hojo M., Nishida Y., Fukuda S., Hirata T., Ichiura K., Kubota Y., Kubo S., Ueba T., Kadota A., Sugiyama D., Okamura T.

Cerebrovascular Diseases （Cerebrovascular Diseases） 47 （ 3-4 ） 143 - 150 2019年07月

ISSN 10159770

Background: While water intake is frequently recommended to prevent cerebral infarction (CI), only few studies have been published on this topic. Objectives: This study retrospectively estimated the daily non-alcohol drink (NAD) intake in CI patients before CI onset and compared it with NAD in healthy subjects. Methods: We performed a cross-sectional study on CI patients in 3 hospitals and healthy subjects in the Kobe Orthopedic and Biomedical Epidemiologic (KOBE) study. Data from 1,287 subjects (274 CI patients and 1,013 healthy subjects) were used for the analyses. By dividing the CI patients into "increased", "unchanged", and "decreased" groups according to their current NAD intake, we compared the NAD intake between these 3 groups and healthy subjects by analyses of covariance and the post hoc test, adjusting for sex, age, surveyed month, body mass index, alcohol drinking history, and smoking history. Under the assumption that the NAD intake in the "unchanged" group was equal to the NAD intake before CI onset, the OR of less NAD intake for CI adjusting for the relevant variables in the "unchanged" group and the healthy subjects was calculated; the cut-off point was chosen using Youden's index. Results: The mean age (mean ± SD) of the participants was 62.8 ± 9.3 years. One hundred and fifty-one patients (36 women) were included in the "increased" group; 105 (30 women), in the "unchanged" group; 18 (2 women), in the "decreased" group; and 1,013 (706 women), in the "healthy" group. The mean NAD intake was 1,702.5 ± 670.2 mL in the "increased" group, 1,494.2 ± 611.2 mL in the "unchanged" group, 1,268.0 ± 596.1 mL in the "decreased" group, and 1,720.6 ± 686.0 mL in the "healthy" group. After adjusting for the relevant variables, a significant difference in NAD intake between the groups was observed (F = 6.1, p < 0.001), and a post hoc test demonstrated significant differences (p < 0.05) in NAD intake between the "healthy" and "unchanged" groups, and between the "increased" and "unchanged" groups. The OR of less NAD intake (<1,570 mL/day, chosen using Youden's index) for CI was 2.48 (95% CI 1.52-4.07). Conclusion: This study showed that daily NAD intake before CI onset in CI patients was less than that in healthy persons, indicating that sufficient intake of NAD may be protective for CI.

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Higher serum uric acid level is inversely associated with renal function assessed by cystatin C in a Japanese general population without chronic kidney disease: The KOBE study

Kubo S., Nishida Y., Kubota Y., Higashiyama A., Sugiyama D., Hirata T., Miyamatsu N., Tanabe A., Hirata A., Tatsumi Y., Kadota A., Kuwabara K., Nishikawa T., Miyamoto Y., Okamura T.

BMC Nephrology （BMC Nephrology） 20 （ 1 ） 2019年04月

© 2019 The Author(s). Background: Although several epidemiological studies have suggested that high serum uric acid (SUA) levels are related to a decline in kidney function, only a few studies have investigated using cystatin C to calculate estimated glomerular filtration rate (eGFR). We aimed to clarify the relationship between SUA levels and kidney function assessed by cystatin C in a Japanese general community population without chronic kidney disease (CKD). Methods: We conducted a community-based cross-sectional study that included 1086 healthy participants, aged 40-74 years, without CKD and not undergoing treatment of hyperuricemia, who had participated in the baseline survey of the Kobe Orthopedic and Biomedical Epidemiological (KOBE) study. The preconditions for participation in this study were no past histories of cardiovascular disease or cancer, and not undergoing treatment for diabetes, hypertension, or dyslipidemia. We classified the participants into quartiles stratified by sex according to their SUA level and then examined the relationship with eGFR. The odds ratios for having a low eGFR, defined as the lowest quartile of eGFR (i.e., ≤78.4 mL/min/1. 73m 2 ) was estimated according to SUA quartiles (men, Q1 ≤ 5.0, Q2 5.1-5.9, Q3 6.0-6.6, and Q4 ≥ 6.7; women, Q1 ≤ 3.8, Q2 3.9-4.3, Q3 4.4-4.9, and Q4 ≥ 5.0 mg/dL) after adjustment for age, body mass index, systolic blood pressure, HbA1c, high and low density lipoprotein cholesterol, and smoking and drinking habits. The adjusted mean of each quartile was also calculated. Results: Multivariable-adjusted means of eGFR showed a graded decrease in higher SUA quartiles (men, Q1 90.5, Q2 88.0, Q3 83.5, and Q4 82.0; women, Q1 95.7, Q2 91.3, Q3 89.2, and Q4 86.7). In addition, the multivariable-adjusted odds ratios for having a lower eGFR (95% confidence interval) for each SUA quartile compared with Q1 was Q2 2.29 (0.98, 5.35), Q3 4.94 (2.04, 11.97), and Q4 8.01 (3.20, 20.04) for men, and was Q2 2.20 (1.12, 4.32), Q3 2.68 (1.39, 5.20), and Q4 4.96 (2.62, 9.41) for women. Conclusions: There was a graded inverse relationship between mild elevations in SUA levels and eGFR assessed by cystatin C in an apparently healthy Japanese population without CKD. This association was similar in both men and women.

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Impact of hypertension on hospitalizations for cardiovascular diseases in a worksite population: An epidemiologic study using claims data for workers

Fukushima A., Khabtheni W., Guelfucci F., Onishi Y., Sugiyama D., Okamura T., Toumi M.

American Journal of Hypertension （American Journal of Hypertension） 32 （ 3 ） 298 - 307 2019年02月

ISSN 08957061

BACKGROUND Few of studies investigated the effect of antihypertensives among working population. We aimed to describe the impact of hypertension with and without antihypertensives on hospitalizations because of cardiovascular diseases (CVDs) in the Japanese working population. METHODS This retrospective study included adults aged 40-64 years whose systolic and diastolic blood pressure (BP) readings taken between 2008 and 2015 were available in the Japanese claims database. Individuals were categorized as treated (T) or untreated (UT) depending on their hypertension treatment history. Time to first CVD-related hospitalization was compared among individuals with different BP levels using Cox models that included baseline characteristics with either baseline BP level or a time-dependent variable reflecting BP changes over time. RESULTS Of 740,784 UT individuals (male: 61.9%, mean age: 47.9 years), 2,121 individuals were hospitalized due to a CVD over a 957.3-day average follow-up. Among 72,828 T individuals (male: 74.3%, mean age: 53.7 years), the corresponding figure was 470 individuals over an 813.4-day average follow-up. The risk of hospitalization increased with baseline hypertension severity among UT (hazard ratios [HRs] = 1.93, 2.82, and 6.32 for grade 1, grade 2, and grade 3, respectively; P < 0.0001, reference: Optimal) but not among T individuals. UT individuals with hypertension at any given time had a significantly higher probability of hospitalization compared to nonhypertensive individuals (HR = 1.74, P < 0.0001). CONCLUSIONS This study adds quantitative evidence on the impact of hypertension on the risk of CVD-related hospitalization in the Japanese working population. It suggests that antihypertensive treatment had beneficial effects in this relatively young, working population aged 40-64 years.

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Outcomes of transcatheter mitral valve replacement for degenerated bioprostheses, failed annuloplasty rings, and mitral annular calcification

Yoon S., Whisenant B., Bleiziffer S., Delgado V., Dhoble A., Schofer N., Eschenbach L., Bansal E., Murdoch D., Ancona M., Schmidt T., Yzeiraj E., Vincent F., Niikura H., Kim W., Asami M., Unbehaun A., Hirji S., Fujita B., Silaschi M., Tang G., Kuwata S., Wong S., Frangieh A., Barker C., Davies J., Lauten A., Deuschl F., Nombela-Franco L., Rampat R., Nicz P., Masson J., Wijeysundera H., Sievert H., Blackman D., Gutierrez-Ibanes E., Sugiyama D., Chakravarty T., Hildick-Smith D., De Brito F., Jensen C., Jung C., Smalling R., Arnold M., Redwood S., Kasel A., Maisano F., Treede H., Ensminger S., Kar S., Kaneko T., Pilgrim T., Sorajja P., Van Belle E., Prendergast B., Bapat V., Modine T., Schofer J., Frerker C., Kempfert J., Attizzani G., Latib A., Schaefer U., Webb J., Bax J., Makkar R.

European Heart Journal （European Heart Journal） 40 （ 5 ） 441 - 451 2019年

ISSN 0195668X

© 2018 The Author(s). All rights reserved. Aims: We sought to evaluate the outcomes of transcatheter mitral valve replacement (TMVR) for patients with degenerated bioprostheses [valve-in-valve (ViV)], failed annuloplasty rings [valve-in-ring (ViR)], and severe mitral annular calcification [valve-in-mitral annular calcification (ViMAC)]. Methods and results: From the TMVR multicentre registry, procedural and clinical outcomes of ViV, ViR, and ViMAC were compared according to Mitral Valve Academic Research Consortium (MVARC) criteria. A total of 521 patients with mean Society of Thoracic Surgeons score of 9.0± 7.0% underwent TMVR (322 patients with ViV, 141 with ViR, and 58 with ViMAC). Trans-septal access and the Sapien valves were used in 39.5% and 90.0%, respectively. Overall technical success was excellent at 87.1%. However, left ventricular outflow tract obstruction occurred more frequently after ViMAC compared with ViR and ViV (39.7% vs. 5.0% vs. 2.2%; P < 0.001), whereas second valve implantation was more frequent in ViR compared with ViMAC and ViV (12.1% vs. 5.2% vs. 2.5%; P< 0.001). Accordingly, technical success rate was higher after ViV compared with ViR and ViMAC (94.4% vs. 80.9% vs. 62.1%; P< 0.001). Compared with ViMAC and ViV groups, ViR group had more frequent post-procedural mitral regurgitation ≥moderate (18.4% vs. 13.8% vs. 5.6%; P< 0.001) and subsequent paravalvular leak closure (7.8% vs. 0.0% vs. 2.2%; P = 0.006). All-cause mortality was higher after ViMAC compared with ViR and ViV at 30 days (34.5% vs. 9.9% vs. 6.2%; log-rank P<0.001) and 1 year (62.8% vs. 30.6% vs. 14.0%; log-rank P< 0.001). On multivariable analysis, patients with failed annuloplasty rings and severe MAC were at increased risk of mortality after TMVR [ViR vs. ViV, hazard ratio (HR) 1.99, 95% confidence interval (CI) 1.27-3.12; P= 0.003; ViMAC vs. ViV, HR 5.29, 95% CI 3.29-8.51; P < 0.001]. Conclusion: The TMVR provided excellent outcomes for patients with degenerated bioprostheses despite high surgical risk. However, ViR and ViMAC were associated with higher rates of adverse events and mid-term mortality compared with ViV.

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Influence of workplace environment, working conditions and health status of taxi drivers on vehicle collisions or near-miss events

Baba M., Miyama G., Sugiyama D., Hitosugi M.

Industrial Health （Industrial Health） 57 （ 4 ） 530 - 536 2019年

ISSN 00198366

© 2019 National Institute of Occupational Safety and Health. Sudden illness while driving has been identified as a major cause of vehicle collisions, particularly among taxi drivers. However, no previous studies have examined the factors contributing to the occurrence of health-related vehicle collisions. The current study aimed to identify the risk factors causing health-related vehicle collisions among taxi drivers, and to inform preventative interventions. A cross-sectional survey involving a written anonymous questionnaire was conducted for company-employed taxi drivers in Chiba Prefecture, Japan. A total of 1,739 drivers returned questionnaires. Drivers were classified into those who had experienced collisions or near-miss incidents caused by health problems (Event group), and those who had not (Non-event group). According to a multivariable logistic regression analysis, being unable to take vacation time (odds ratio [OR] 4.59, 95% confidence interval [CI] 2.2–9.58), having chronic diseases (OR 1.52, 95% CI 1.02–2.27), taking insufficient vacation time (OR 1.81, 95% CI 1.19–2.79), and difficulty reporting poor health conditions (OR 2.29, 95% CI 1.36–3.87) were significant factors for the likelihood of an event. Support for drivers to maintain well-balanced control of illnesses and improvement of working environments could prevent health-related events while driving.

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Association between body mass index and all-cause death in japanese population: Pooled individual participant data analysis of 13 cohort studies

Hozawa A., Hirata T., Yatsuya H., Murakami Y., Kuriyama S., Tsuji I., Sugiyama D., Satoh A., Tanaka-Mizuno S., Miura K., Ueshima H., Okamura T.

Journal of Epidemiology （Journal of Epidemiology） 29 （ 12 ） 457 - 463 2019年

ISSN 09175040

Background: We sought to investigate the optimal values of BMI for the lowest risk of all-cause death and whether the optimal BMI differs according to smoking status in large-scale pooled analysis of 13 Japanese cohorts. Methods: Data from 179,987 participants of 13 well-qualified cohort studies conducted throughout Japan were used for our analysis. A cohort-stratified Cox proportional hazard model was used. P values for interactions were calculated based on the cross product of BMI and age, sex, or smoking status. Results: In the entire study population, all-cause mortality risk was lowest when the BMI was 22.0–24.9 kg=m . This was also the case for selected healthy participants (never smoked, baseline total cholesterol level ≥4.1 mmol=L; the first 5 years of follow-up data were excluded). No effect modification of age, sex, or smoking status was observed. Regardless of their BMI, never smokers always had a lower all-cause mortality risk than did current smokers even with an ideal BMI in terms of mortality risk. Conclusion: A BMI of 22–24.9 kg=m correlated with the lowest risk of mortality, regardless of whether all participants or selected healthy participants were analyzed. The fact that smoking was more strongly associated with mortality than obesity emphasizes the urgency for effective anti-smoking programs. 2 2

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Vegetable protein intake was inversely associated with cardiovascular mortality in a 15-year follow-up study of the general Japanese population

Kurihara A., Okamura T., Sugiyama D., Higashiyama A., Watanabe M., Okuda N., Kadota A., Miyagawa N., Fujiyoshi A., Yoshita K., Ohkubo T., Okayama A., Miura K., Ueshima H.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis） 26 （ 2 ） 198 - 206 2019年

ISSN 13403478

Aim: To examine the relationship between the intake of dietary vegetable protein and CVD mortality in a 15-year follow-up study of a representative sample of the Japanese population. Methods: A total of 7,744 participants aged 30 years or older (3,224 males and 4,520 females) who were free of CVD at baseline were included in this analysis. Vegetable protein intake (% energy) was assessed using a threeday semi-weighed dietary record at baseline. Multivariable-adjusted hazard ratios (HRs) were calculated using Cox’s proportional hazards model after adjusting for confounding factors. Results: The total person-years studied were 107,988 with a mean follow-up period of 13.9 years. There were 1,213 deaths during the follow-up period, among which 354 (29.2%) were due to CVD. Vegetable protein intake was associated inversely with CVD and cerebral hemorrhage mortality, with the HRs for a 1% energy increment in vegetable protein intake being 0.86 (95% CI, 0.75-0.99) and 0.58 (95% CI, 0.35-0.95), respectively. In the subgroup analysis of participants with or without hypertension, the inverse association between vegetable protein intake and CVD mortality was more evident in the nonhypertensive group, with the HRs for CVD and stroke being 0.68 (95% CI, 0.50- 0.94) and 0.50 (95% CI, 0.30-0.84), respectively. Conclusions: Vegetable protein intake may prevent future CVD, particularly in nonhypertensive subjects in the Japanese population. However, further studies are necessary to examine the biological mechanisms of this effect.

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Lifetime Risk of Stroke and Coronary Heart Disease Deaths According to Blood Pressure Level: EPOCH-JAPAN (Evidence for Cardiovascular Prevention from Observational Cohorts in Japan)

Satoh M., Ohkubo T., Asayama K., Murakami Y., Sugiyama D., Yamada M., Saitoh S., Sakata K., Irie F., Sairenchi T., Ishikawa S., Kiyama M., Ohnishi H., Miura K., Imai Y., Ueshima H., Okamura T., Iso H., Kitamura A., Ninomiya T., Kiyohara Y., Nakagawa H., Nakayama T., Okayama A., Tamakoshi A., Tsuji I., Miyamoto Y., Yatsuya H.

Hypertension （Hypertension） 73 （ 1 ） 52 - 59 2019年

ISSN 0194911X

Lifetime risk (LTR) provides an absolute risk assessment during the remainder of one's life. Few studies have focused on the LTRs of stroke and coronary heart disease (CHD), categorized by fine blood pressure in Asian populations. We aimed to assess it using a large database of a meta-analysis with the individual participant data. The present meta-analysis included 107 737 Japanese (42.4% men; mean age, 55.1 years) from 13 cohorts. During the mean follow-up of 15.2±5.3 years (1 559 136 person-years), 1922 died from stroke and 913 from CHD. We estimated risks after adjusting for competing risk of death other than the outcome of interest. The 10-year risk of stroke and CHD deaths at index age of 35 years was ≤1.9% and ≤0.3%, respectively. The LTRs of stroke death at the index age of 35 years (men/women) were 6.1%/4.8% for optimal, 5.7%/6.3% for normal, and 6.6%/6.0% for high-normal blood pressure groups, and 9.1%/7.9% for grade 1, 14.5%/10.3% for grade 2, and 14.6%/14.3% for grade 3 hypertension groups. The LTRs of CHD death similarly elevated with an increase in blood pressure but were lower (≤7.2%) than those of stroke death. In conclusion, blood pressure was clearly associated with an elevated LTR of stroke or CHD death, although the LTR of CHD death was one-half of that of stroke death in an Asian population. These results would help young people with hypertension to adopt a healthy lifestyle or start antihypertensive therapy early.

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Association between impairment of salty taste recognition and masked hypertension based on home blood pressure in Japanese residents: the KOBE study

Kubota Y., Higashiyama A., Sugiyama D., Nishida Y., Kubo S., Hirata T., Kadota A., Miyamatsu N., Wakabayashi I., Miyamoto Y., Okamura T.

Hypertension Research （Hypertension Research） 41 （ 9 ） 756 - 762 2018年09月

ISSN 09169636

© 2018, The Japanese Society of Hypertension. Excessive salt intake is an established risk factor for hypertension. We conducted a cross-sectional study to examine the association between salty taste recognition and estimated salt intake and masked hypertension in a healthy Japanese normotensive population. The participants were 892 apparently healthy community residents (246 men and 646 women) aged between 40 and 74 years with blood pressure below 140/90 mm Hg. Salty taste recognition was assessed using a salt-impregnated taste strip. Daily salt intake was calculated as estimated 24 h urinary sodium excretion using spot urine tests. Each participant performed home blood pressure measurements for a minimum of 5 days per week. The participants were classified into three groups according to their salty taste recognition threshold evaluated by the salt concentrations of the taste strips (0.6%, 0.8%, and ≥ 1.0%). In women, the multivariate odds ratio (95% confidence interval) for masked hypertension (≥ 135/85 mm Hg) was 2.98 (1.16–7.64) in the ≥ 1.0% group compared with that in the 0.6% group. In men, the proportion of masked hypertension in the ≥ 1.0% group did not differ from that in the 0.6% group, and no correlation was identified between estimated daily salt intake and the salty taste recognition threshold. In conclusion, impairment of salty taste recognition was associated with masked hypertension in women even with normal blood pressure in the clinical setting.

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Fatty liver index predicts incident diabetes in a Japanese general population with and without impaired fasting glucose

Hirata A., Sugiyama D., Kuwabara K., Hirata T., Tsutatani H., Funamoto M., Watanabe K., Miyamatsu N., Okamura T.

Hepatology Research （Hepatology Research） 48 （ 9 ） 708 - 716 2018年08月

ISSN 13866346

© 2018 The Japan Society of Hepatology Aim: Fatty liver is associated with the development of diabetes. However, to our knowledge, no study has examined the relationship between the fatty liver index (FLI), calculated scores of hepatic steatosis, and the development of diabetes among individuals without impaired fasting glucose (IFG). We aimed to examine whether FLI predicts the development of diabetes in individuals with and without IFG in a Japanese general population. Methods: We selected 1498 men and 2941 women who participated in Specific Health Checkups in Japan. We divided all participants into six groups according to tertiles of FLI (low, moderate, and high) and the presence or absence of IFG, by sex. We calculated hazard ratios for incident diabetes for each group using a Cox proportional hazard model, adjusting for potential confounders. Results: During a mean follow-up period of 3.0 years, 176 cases of diabetes in men and 320 cases in women were identified. Compared with the low FLI group without IFG, the high FLI group without IFG was significantly associated with incident diabetes in both men (hazard ratio, 1.90; 95% confidence interval, 1.08–3.36) and women (hazard ratio, 1.72; 95% confidence interval, 1.18–2.51). All IFG groups were significantly associated with incident diabetes regardless of FLI levels. Conclusions: Our results showed that FLI is associated with the development of diabetes regardless of sex and the presence or absence of IFG, and that it may be a useful predictor of future risk of incident diabetes even in individuals without IFG.

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Overweight or underweight and the risk of decline in activities of daily living in a 22-year cohort study of a Japanese sample

Okamoto S., Okamura T., Sugiyama D., Hayakawa T., Nakamura Y., Miyagawa N., Kurita S., Takashima N., Ohkubo T., Kadota A., Fujiyoshi A., Miura K., Okayama A., Ueshima H.

Geriatrics and Gerontology International （Geriatrics and Gerontology International） 18 （ 5 ） 799 - 805 2018年05月

ISSN 14441586

© 2018 Japan Geriatrics Society Aim: The present study aimed to clarify the association between body mass index (BMI) and the activities of daily living (ADL). Although BMI is likely to be concerned regarding the relationship with specific diseases or mortality, few studies have focused on the relationship of BMI and ADL. Methods: A total of 3353 Japanese participants of a 22-year cohort study from 1990 to 2012 aged 45–74 years at baseline were divided into four groups according to their BMI levels: ≤18.5, 18.5–21.9 (reference), 22.0–24.9 and ≥25.0 kg/m 2 . Outcomes were becoming dependent in ADL (including death after ADL decline) and death without observation of ADL decline as a competing risk. Sex-specific multinomial logistic regression analysis was carried out in 2017 to estimate the odds ratios (OR) after adjusting for age, smoking, alcohol drinking, hypertension, hypercholesterolemia, diabetes and serum albumin. Results: After multivariable adjustment, though the relationship between BMI and risk of ADL decline was U-shaped among women, only those with BMI ≥25.0 showed a higher risk for ADL decline (OR 1.39, 95% CI 1.01–1.92) compared with the reference. The OR for death without observation of ADL decline was significantly lower for men with BMI ≥25.0 (OR 0.70, 95% CI 0.50–0.98). Conclusions: This study suggests being overweight is a good predictor of future decline in ADL for women, whereas men with BMI 22.0–24.9 had lower risks of ADL decline. Appropriate management of weight in older women could prevent disabilities. Geriatr Gerontol Int 2018; 18: 799–805.

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Association of extremely high levels of high-density lipoprotein cholesterol with cardiovascular mortality in a pooled analysis of 9 cohort studies including 43,407 individuals: The EPOCH–JAPAN study

Hirata A., Sugiyama D., Watanabe M., Tamakoshi A., Iso H., Kotani K., Kiyama M., Yamada M., Ishikawa S., Murakami Y., Miura K., Ueshima H., Okamura T., Okamura T., Imai Y., Ohkubo T., Irie F., Iso H., Kitamura A., Ninomiya T., Kiyohara Y., Miura K., Murakami Y., Nakagawa H., Nakayama T., Okayama A., Sairenchi T., Saitoh S., Sakata K., Tamakoshi A., Tsuji I., Yamada M., Miyamoto Y., Ishikawa S., Yatsuya H.

Journal of Clinical Lipidology （Journal of Clinical Lipidology） 12 （ 3 ） 674 - 684.e5 2018年05月

ISSN 19332874

© 2018 National Lipid Association Background: The effect of very high or extremely high levels of high-density lipoprotein cholesterol (HDL-C) on cardiovascular disease (CVD) is not well described. Although a few recent studies have reported the adverse effects of extremely high levels of HDL-C on CVD events, these did not show a statistically significant association between extremely high levels of HDL-C and cause-specific CVD mortality. In addition, Asian populations have not been studied. Objective: We examine the impact of extremely high levels of HDL-C on cause-specific CVD mortality using pooled data of Japanese cohort studies. Methods: We performed a large-scale pooled analysis of 9 Japanese cohorts including 43,407 participants aged 40–89 years, dividing the participants into 5 groups by HDL-C levels, including extremely high levels of HDL-C ≥2.33 mmol/L (≥90 mg/dL). We estimated the adjusted hazard ratio of each HDL-C category for all-cause death and cause-specific deaths compared with HDL-C 1.04–1.55 mmol/L (40–59 mg/dL) using a cohort-stratified Cox proportional hazards model. Results: During a 12.1-year follow-up, 4995 all-cause deaths and 1280 deaths due to overall CVD were identified. Extremely high levels of HDL-C were significantly associated with increased risk of atherosclerotic CVD mortality (hazard ratio = 2.37, 95% confidence interval: 1.37–4.09 for total) and increased risk for coronary heart disease and ischemic stroke. In addition, the risk for extremely high HDL-C was more evident among current drinkers. Conclusion: We showed extremely high levels of HDL-C had an adverse effect on atherosclerotic CVD mortality in a pooled analysis of Japanese cohorts.

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Reliability of plasma polar metabolite concentrations in a large-scale cohort study using capillary electrophoresis-mass spectrometry

Harada S., Hirayama A., Chan Q., Kurihara A., Fukai K., Iida M., Kato S., Sugiyama D., Kuwabara K., Takeuchi A., Akiyama M., Okamura T., Ebbels T., Elliott P., Tomita M., Sato A., Suzuki C., Sugimoto M., Soga T., Takebayashi T.

PLoS ONE （PLoS ONE） 13 （ 1 ） 2018年01月

© 2018 Harada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Cohort studies with metabolomics data are becoming more widespread, however, large-scale studies involving 10,000s of participants are still limited, especially in Asian populations. Therefore, we started the Tsuruoka Metabolomics Cohort Study enrolling 11,002 community-dwelling adults in Japan, and using capillary electrophoresis-mass spectrometry (CE-MS) and liquid chromatography–mass spectrometry. The CE-MS method is highly amenable to absolute quantification of polar metabolites, however, its reliability for large-scale measurement is unclear. The aim of this study is to examine reproducibility and validity of large-scale CE-MS measurements. In addition, the study presents absolute concentrations of polar metabolites in human plasma, which can be used in future as reference ranges in a Japanese population. Methods Metabolomic profiling of 8,413 fasting plasma samples were completed using CE-MS, and 94 polar metabolites were structurally identified and quantified. Quality control (QC) samples were injected every ten samples and assessed throughout the analysis. Inter- and intra-batch coefficients of variation of QC and participant samples, and technical intraclass correlation coefficients were estimated. Passing-Bablok regression of plasma concentrations by CE-MS on serum concentrations by standard clinical chemistry assays was conducted for creatinine and uric acid. Results and conclusions In QC samples, coefficient of variation was less than 20% for 64 metabolites, and less than 30% for 80 metabolites out of the 94 metabolites. Inter-batch coefficient of variation was less than 20% for 81 metabolites. Estimated technical intraclass correlation coefficient was above 0.75 for 67 metabolites. The slope of Passing-Bablok regression was estimated as 0.97 (95% confidence interval: 0.95, 0.98) for creatinine and 0.95 (0.92, 0.96) for uric acid. Compared to published data from other large cohort measurement platforms, reproducibility of metabolites common to the platforms was similar to or better than in the other studies. These results show that our CE-MS platform is suitable for conducting large-scale epidemiological studies.

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Very high frequency of fragility fractures associated with high-dose glucocorticoids in postmenopausal women

Kageyama Goichi, Okano Takaichi, Yamamoto Yuzuru, Nishimura Keisuke, Sugiyama Daisuke, Saegusa Jun, Tsuji Goh, Kumagai Shunichi, Morinobu Akio

Bone Reports 6 3 - 8 2017年06月

Purpose To evaluate the incidence of fragility fractures associated with high-dose glucocorticoid therapy in patients with systemic rheumatic disease. Methods: A retrospective study of patients who were treated with high-dose prednisolone (> 0.8 mg/kg) for systemic rheumatic disease at Kobe University Hospital from April 1988 to March 2012. The primary outcome was a major osteoporotic fracture (defined as a clinical vertebral, hip, forearm, or proximal humerus fracture) after high-dose glucocorticoid therapy. For postmenopausal women and men over 40 of age, the patient's fracture risk at the beginning of high-dose glucocorticoid therapy was assessed by the World Health Organization's Fracture Risk Assessment Tool (FRAX®). Results Of 229 patients (median age: 49 years), 57 suffered a fragility fracture during the observation period (median observation period: 1558 days). Of 84 premenopausal patients, 5 suffered a fracture. In contrast, of 86 postmenopausal female, 36 suffered a fracture. Fragility fractures were far more frequent than predicted by the FRAX® score. Patients with FRAX® scores over 8.3% had a particularly high risk of fracture. Conclusions Fragility fractures associated with high-dose glucocorticoid therapy are common among postmenopausal women. Extreme care should be taken especially for postmenopausal women when high-dose glucocorticoid therapy is required.

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Continuous Regional Arterial Infusion of Protease Inhibitors Has No Efficacy in the Treatment of Severe Acute Pancreatitis

Horibe Masayasu, Sasaki Mitsuhito, Sanui Masamitsu, Sugiyama Daisuke, Iwasaki Eisuke, Yamagishi Yoshiyuki, Sawano Hirotaka, Goto Takashi, Ikeura Tsukasa, Hamada Tsuyoshi, Oda Takuya, Yasuda Hideto, Shinomiya Wataru, Miyazaki Dai, Hirose Kaoru, Kitamura Katsuya, Chiba Nobutaka, Ozaki Tetsu, Yamashita Takahiro, Koinuma Toshitaka, Oshima Taku, Yamamoto Tomonori, Hirota Morihisa, Moriya Takashi, Shirai Kunihiro, Mayumi Toshihiko, Kanai Takanori

Pancreas 46 （ 4 ） 510 - 517 2017年04月

ISSN 0885-3177

Objective The aim of this study is to assess the effectiveness of continuous regional arterial infusion (CRAI) of protease inhibitors in patients with severe acute pancreatitis (SAP) including acute necrotizing pancreatitis. Methods This retrospective study was conducted among 44 institutions in Japan from 2009 to 2013. Patients 18 years or older diagnosed with SAP according to the criteria of the Japanese Ministry of Health, Labour and Welfare study group (2008) were consecutively enrolled. We evaluated the association between CRAI of protease inhibitors and mortality, incidence of infection, and the need for surgical intervention using multivariable logistic regression analysis. Results Of 1159 patients admitted, 1097 patients with all required data were included for analysis. Three hundred and seventy-four (34.1%) patients underwent CRAI of protease inhibitors and 723 (65.9%) did not. In multivariable analysis, CRAI of protease inhibitors was not associated with a reduction in mortality, infection rate, or need for surgical intervention (odds ratio [OR] 0.79, 95% confidence interval [CI] 0.47-1.32, P = 0.36; OR 0.97, 95% CI 0.61-1.54, P = 0.89; OR 0.76, 95% CI 0.50-1.15, P = 0.19; respectively). Conclusions Continuous regional arterial infusion of protease inhibitors was not efficacious in the treatment of patients with SAP.

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Impacts of chronic kidney disease and diabetes on cardiovascular mortality in a general Japanese population

Hirata Aya, Okamura Tomonori, Sugiyama Daisuke, Kuwabara Kazuyo, Kadota Aya, Fujiyoshi Akira, Miura Katsuyuki, Okuda Nagako, Ohkubo Takayoshi, Okayama Akira, Ueshima Hirotsugu

European Journal of Preventive Cardiology 24 （ 5 ） 505 - 513 2017年03月

ISSN 2047-4873

Background Studies have shown significant associations of chronic kidney disease (CKD) and diabetes mellitus (DM) with cardiovascular disease (CVD) mortality. The impact on the general population is an important public health issue. However, the population attributable fraction (PAF) of CVD because of CKD and/or DM in a general population is uncertain. Methods We followed 7229 participants (age: ≥30 years) with no history of CVD in a Japanese community. We divided participants into four categories according to CKD and/or DM and calculated hazard ratios (HRs) of CVD mortality for each category using a Cox proportional hazards model adjusted for age, dyslipidemia, smoking and alcohol consumption. In addition, PAFs of CVD were estimated among populations with CKD and/or DM. Results During 20-year follow-up, 488 participants died. HRs for CVD were 1.63 [95% confidence interval (CI): 1.16-2.30] with DM only, 1.42 (95% CI: 1.08-1.86) with CKD only and 2.37 (95% CI: 1.40-4.01) with CKD + DM. In men, the corresponding HRs for CVD were 1.88 (95% CI: 1.19-2.97), 1.71 (95% CI: 1.15-2.56) and 3.26 (95% CI: 1.69-6.30), respectively; the corresponding PAFs of CVD were 4.1%, 5.1% and 2.9%, respectively. PAFs for CVD among women were lower than those in men, 1.6% for DM only, 2.0% for CKD only and 0.7% for CKD + DM. Conclusions PAFs of CVD mortality due to CKD and/or DM were not so high in past 20 years; however, they might increase in the future because of recent increase in prevalence of these in Japanese population.

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Plasmapheresis therapy has no triglyceride-lowering effect in patients with hypertriglyceridemic pancreatitis

Miyamoto Kyohei, Horibe Masayasu, Sanui Masamitsu, Sasaki Mitsuhito, Sugiyama Daisuke, Kato Seiya, Yamashita Takahiro, Goto Takashi, Iwasaki Eisuke, Shirai Kunihiro, Oe Kyoji, Sawano Hirotaka, Oda Takuya, Yasuda Hideto, Ogura Yuki, Hirose Kaoru, Kitamura Katsuya, Chiba Nobutaka, Ozaki Tetsu, Oshima Taku, Yamamoto Tomonori, Nagata Keiji, Mine Tetsuya, Saito Koji, Sekino Motohiro, Furuya Tomoki, Matsuda Naoyuki, Hayakawa Mineji, Kanai Takanori, Mayumi Toshihiko

Intensive Care Medicine 1 - 3 2017年02月

ISSN 0342-4642

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Risk of New Native-Vessel Occlusion After Coronary Artery Bypass Grafting

Yoon Sung Han, Kim Young Hak, Yang Dong Hyun, Roh Jae Hyung, Lee Eun Young, Lee Pil Hyung, Sugiyama Daisuke, Chang Mineok, Ahn Jung Min, Choi Won Jin, Kang Joon Won, Lim Tae Hwan, Kim Joon Bum, Jung Sung Ho, Chung Cheol Hyun, Choo Suk Jung, Lee Jae Won, Kang Soo Jin, Park Duk Woo, Lee Seung Whan, Lee Cheol Whan, Park Seong Wook, Park Seung Jung

American Journal of Cardiology 119 （ 1 ） 7 - 13 2017年01月

ISSN 0002-9149

Coronary computed tomography angiography is widely used to evaluate the graft patency, but information on the progression of native-vessel disease remains limited. We sought to evaluate the impact of bypass grafting on native-vessel progression after coronary artery bypass grafting. We evaluated new native-vessel occlusion defined as occlusion length ≥15 mm as a surrogate marker of native-vessel progression. We evaluated 911 patients with 2,271 nonoccluded vessels who underwent coronary artery bypass grafting and received follow-up coronary computed tomography angiography. Over a mean follow-up period of 4.7 years, the new occlusion rates were 9.2% for left anterior descending artery (LAD), and 13.9% for non-LAD, respectively. For non-LAD, new occlusion rate of vessels with bypass grafts was higher compared to those without bypass graft regardless of baseline native-vessel stenosis (intermediate stenosis: 8.6% vs 1.7%, p <0.001; severe stenosis: 20.5% vs 9.9%, p = 0.003). Furthermore, new occlusion rate of vessels with venous graft was the highest, followed by vessels with arterial graft and vessels without bypass graft, regardless of baseline stenosis (intermediate stenosis: 11.1% vs 5.2% vs 1.7%, p <0.001; severe stenosis: 23.7% vs 15.9% vs 9.9%, p <0.001). By multivariate analysis, bypass grafting was associated with new native-vessel occlusion for non-LAD (odds ratio 3.04, 95% confidence interval 1.79 to 5.14; p <0.001). Bypass graft was associated with new native-vessel disease progression regardless of baseline stenosis. In conclusion, the decision to bypass or leave a native vessel with intermediate stenosis should cautiously be considered.

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A pooled analysis of the association of isolated low levels of high-density lipoprotein cholesterol with cardiovascular mortality in Japan

Hirata Takumi, Sugiyama Daisuke, Nagasawa Shin ya, Murakami Yoshitaka, Saitoh Shigeyuki, Okayama Akira, Iso Hiroyasu, Irie Fujiko, Sairenchi Toshimi, Miyamoto Yoshihiro, Yamada Michiko, Ishikawa Shizukiyo, Miura Katsuyuki, Ueshima Hirotsugu, Okamura Tomonori, Ueshima Hirotsugu, Okamura Tomonori, Imai Yutaka, Ohkubo Takayoshi, Irie Fujiko, Iso Hiroyasu, Kitamura Akihiko, Kiyohara Yutaka, Miura Katsuyuki, Murakami Yoshitaka, Nakagawa Hideaki, Nakayama Takeo, Okayama Akira, Sairenchi Toshimi, Saitoh Shigeyuki, Sakata Kiyomi, Tamakoshi Akiko, Tsuji Ichiro, Yamada Michiko, Kiyama Masahiko, Miyamoto Yoshihiro, Ishikawa Shizukiyo, Yatsuya Hiroshi, Okamura Tomonori

European Journal of Epidemiology 1 - 11 2016年10月

ISSN 0393-2990

Low levels of serum high-density lipoprotein cholesterol (HDL-C) have been shown to be associated with increased risk of coronary heart disease (CHD). However, because this is usually observed in the context of other lipid abnormalities, it is not known whether isolated low serum HDL-C levels are an independent risk factor for CHD. We performed a large pooled analysis in Japan using data from nine cohorts with 41,206 participants aged 40–89 years who were free of cardiovascular disease at baseline. We divided participants into three groups: isolated low HDL-C, non-isolated low HDL-C, and normal HDL-C. Cohort-stratified Cox proportional hazards models were used to estimate multivariate-adjusted hazard ratios (HRs) for death due to CHD, ischemic stroke, and intracranial cerebral hemorrhage; during a 12.9-year follow-up, we observed 355, 286, and 138 deaths, respectively, in these groups. Non-isolated low HDL-C was significantly associated with increased risk of CHD compared with normal HDL-C (HR 1.37, 95 % confidence interval (CI) 1.04–1.80); however, isolated low HDL-C was not. Although isolated low HDL-C was significantly associated with decreased risk of CHD (HR 0.51, 95 % CI 0.29–0.89) in women, it was significantly associated with increased risk of intracranial cerebral hemorrhage in all participants (HR 1.62, 95 % CI 1.04–2.53) and in men (HR 2.00, 95 % CI 1.04–3.83). In conclusion, isolated low HDL-C levels are not associated with increased risk of CHD in Japan. CHD risk may, therefore, be more strongly affected by serum total cholesterol levels in this population.

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Predictors for Paravalvular Regurgitation After TAVR With the Self-Expanding Prosthesis

Yoon Sung Han, Ahn Jung Min, Ohno Yohei, Barbanti Marco, Chan Jason, Lin Mao Shin, Kim Young Hak, Yang Dong Hyun, Sugiyama Daisuke, Chan Kam Tim, Immé Sebastiano, Tamburino Claudia I., Sgroi Carmelo, Park Duk Woo, Kang Soo Jin, Lee Seung Whan, Lee Cheol Whan, Park Seong Wook, Lee Michael, Kao Hsien Li, Tamburino Corrado, Park Seung Jung

JACC: Cardiovascular Imaging 9 （ 10 ） 1233 - 1234 2016年10月

ISSN 1936-878X

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Metabolic profiling of total physical activity and sedentary behavior in community dwelling men

Fukai Kota, Harada Sei, Iida Miho, Kurihara Ayako, Takeuchi Ayano, Kuwabara Kazuyo, Sugiyama Daisuke, Okamura Tomonori, Akiyama Miki, Nishiwaki Yuji, Oguma Yuko, Suzuki Asako, Suzuki Chizuru, Hirayama Akiyoshi, Sugimoto Masahiro, Soga Tomoyoshi, Tomita Masaru, Takebayashi Toru

PLoS One 11 （ 10 ） 2016年10月

ISSN 1932-6203

Objective: Physical activity is known to be preventive against various non-communicable diseases. We investigated the relationship between daily physical activity level and plasma metabolites using a targeted metabolomics approach in a population-based study. Methods: A total of 1,193 participants (male, aged 35 to 74 years) with fasting blood samples were selected from the baseline survey of a cohort study. Information on daily total physical activity, classified into four levels by quartile of metabolic equivalent scores, and sedentary behavior, defined as hours of sitting per day, was collected through a self-administered questionnaire. Plasma metabolite concentrations were quantified by capillary electrophoresis mass spectrometry method. We performed linear regression analysis models with multivariable adjustment and corrected p-values for multiple testing in the original population (n = 808). The robustness of the results was confirmed by replication analysis in a separate population (n = 385) created by random allocation. Results: Higher levels of total physical activity were associated with various metabolite concentrations, including lower concentrations of amino acids and their derivatives, and higher concentrations of pipecolate (FDR p <0.05 in original population). The findings persisted after adjustment for age, body mass index, smoking, alcohol intake, and energy intake. Isoleucine, leucine, valine, 4-methyl-2-oxoisopentanoate, 2-oxoisopentanoate, alanine, and proline concentrations were lower with a shorter sitting time. Conclusions: Physical activity is related to various plasma metabolites, including known biomarkers for future insulin resistance or type 2 diabetes. These metabolites might potentially play a key role in the protective effects of higher physical activity and/or less sedentary behavior on non-communicable diseases.

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Casual serum triglyceride as a predictor of premature type 2 diabetes mellitus

Nishikawa Tomofumi, Okamura T., Shima A., Kawatsu Y., Sugiyama D., Kadota A., Morimoto A., Tatsumi Y., Godai K., Miyamatsu N.

Diabetology International 7 （ 3 ） 252 - 258 2016年09月

ISSN 2190-1678

Background: The utility of casual serum triglyceride (TG) as a predictor of type 2 diabetes mellitus (DM) is unclear, especially during the most productive years. Methods: Participants were 3271 workers (913 men and 2358 women, age 20–57) without DM at baseline. They underwent consecutive annual medical check-ups for 8 years. The association between newly diagnosed DM and casual serum TG level was determined by classifying the participants into 4 groups according to casual serum TG level at baseline: below 50 mg/dL (group A), 50–100 mg/dL (group B), 100–150 mg/dL (group C), and ≥150 mg/dL (group D). The effects of casual serum TG level in combination with sex, obesity, or serum glucose level on newly diagnosed DM were also evaluated. Results: A total of 222 newly diagnosed type 2 DM cases with a mean age of 50 years old were observed during the follow-up period, i.e., 10/406 in group A, 66/1534 in group B, 58/712 in group C, and 88/619 in group D. Compared with group A, the odds ratio (ORs) for newly diagnosed DM (after adjusting for DM-associated factors) was found to increase with casual serum TG level: 1.38 (group B), 1.79 (group C), and 2.36 (group D). Moreover, the OR for newly diagnosed DM was higher in participants with high casual serum TG levels who were also male (OR 2.46), obese (OR 4.18), or had a high serum glucose level (OR 6.96) than in the reference group. Conclusions: Serum TG level ≥150 mg/dL when fasting or nonfasting is a significant predictor of type 2 diabetes in middle-aged Japanese workers.

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Validation of the european SCORE risk chart in the healthy middle-aged Japanese

Sawano Mitsuaki, Kohsaka Shun, Okamura Tomonori, Inohara Taku, Sugiyama Daisuke, Watanabe Makoto, Nakamura Yasuyuki, Higashiyama Aya, Kadota Aya, Okud Nagako, Murakami Yoshitaka, Ohkubo Takayoshi, Fujiyoshi Akira, Miura Katsuyuki, Okayama Akira, Ueshima Hirotsugu

Atherosclerosis 252 116 - 121 2016年09月

ISSN 0021-9150

Background and aims The European Society of Cardiology developed prediction models (SCORE) for low- and high-risk populations in the European countries. However, whether or not these models are valid in different ethnicities is unknown. We aimed to evaluate the performance of the low-risk SCORE model in the general Japanese population. Methods Healthy middle-aged Japanese participating in the NIPPON DATA80 cohort had been observed. The predicted 10-year cardiovascular death risk was calculated using the low-risk SCORE model for the overall population as well as for each gender individually. The model performance of the low-risk SCORE model was evaluated with the Harrel's c-statistics for discrimination and the Grønnesby and Borgan goodness-of-fit test for calibration. Results A total of 4842 participants aged 40–64 years old and 47,606 person-years were evaluated in our study. 203 (4.19%) died within the ten-years of follow-up and 44 (0.91%) CV deaths were observed. The low-risk SCORE model in the overall population had reasonable discrimination (c statistics 0.72, 95% CI 0.71–0.73) but poor calibration (R², 0.67, Chi-square value 6.15, p = 0.01). Discrimination was reasonable in both men (c statistics 0.71, 95% CI 0.69–0.73) and women (c statistics 0.71, 95% CI 0.70–0.73). However, calibration was poor in men (R², 0.22, Chi-square value 0.749, p = 0.38) compared to women (R², 0.96, Chi-square value 1.39, p = 0.24). Conclusions Although the low-risk SCORE model performs reasonably well in women, the SCORE models generally overestimated the risk of cardiovascular death risk in the Japanese general population.

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Efficacy of urinary midkine as a biomarker in patients with acute kidney injury

Hayashi Hiroki, Sato Waichi, Kosugi Tomoki, Nishimura Kunihiro, Sugiyama Daisuke, Asano Naoko, Ikematsu Shinya, Komori Kimihiro, Nishiwaki Kimitoshi, Kadomatsu Kenji, Matsuo Seiichi, Maruyama Shoichi, Yuzawa Yukio

Clinical and Experimental Nephrology 1 - 11 2016年08月

ISSN 1342-1751

Background: The mortality and morbidity associated with acute kidney injury (AKI) remains high, despite advances in interventions. A multifunctional heparin-binding growth factor, midkine (MK), is involved in the pathogenesis of ischemic kidney injury. However, the clinical relevance of MK has not yet been elucidated. The present study investigated whether urinary MK can serve as a novel biomarker of AKI. Methods: We initially compared the predictive value of MK with other urinary biomarkers, including N-acetyl-β-d-glucosaminidase (NAG), interleukin (IL)-18, and neutrophil gelatinase-associated lipocalin (NGAL), for the detection and differential diagnosis of established AKI (549 patients). Subsequently, the reliability of MK for the early detection of AKI was prospectively evaluated in 40 patients undergoing elective abdominal aortic aneurysm surgery. Urine samples were obtained at baseline, the period of aortic cross-clamping and declamping, the end of the surgery, and on post-operative day 1. Results: The areas under the receiver operating characteristic curves for the diagnosis of AKI in various kidney diseases were 0.88, 0.70, 0.72, and 0.84 for MK, NAG, IL-18, and NGAL, respectively. When the optimal cutoff value of urinary MK was set at 11.5 pg/mL, the sensitivity and specificity were 0.87 and 0.85, respectively. In the second study, urinary MK peaked at the period of aortic declamping, about 1 h after cross-clamping in patients with AKI. Interestingly, the rise of MK in AKI patients was very precipitous compared with other biomarker candidates. Conclusion: Urinary MK was prominent in its ability to detect AKI and may allow the start of preemptive medication.

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Predictive Risk Factors of Cervical Spine Instabilities in Rheumatoid Arthritis

Terashima Yoshiki, Yurube Takashi, Hirata Hiroaki, Sugiyama Daisuke, Sumi Masatoshi

Spine 2016年08月

ISSN 0362-2436

STUDY DESIGN.: A prospective multicenter >10-year cohort study of outpatients with rheumatoid arthritis (RA). OBJECTIVE.: To identify predictive risk factors of cervical spine instabilities which may induce compression myelopathy in RA patients. SUMMARY OF BACKGROUND DATA.: Many reports described the natural course of cervical spine involvement in RA. However, only a few studies conducted comprehensive evaluation of its prognostic factors. METHODS.: Cervical spine instability was radiographically defined as atlantoaxial subluxation (AAS) with the atlantodental interval (ADI) >3?mm, vertical subluxation (VS) with the Ranawat value 10 years. The Cox proportional hazards regression analysis was performed to determine predictors for the development of “severe” instabilities. To exclude biases from the low follow-up rate, similar assessments were performed in 223 patients followed for >5 years from baseline. RESULTS.: The incidence of cervical spine instabilities and “severe” instabilities significantly increased during >10 years in both 143 and 223 cohorts (all P10-year analysis of two different settings.Level of Evidence: 3

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Prognostic significance of endogenous erythropoietin in long-term outcome of patients with acute decompensated heart failure

Nagai Toshiyuki, Nishimura Kunihiro, Honma Takehiro, Higashiyama Aya, Sugano Yasuo, Nakai Michikazu, Honda Satoshi, Iwakami Naotsugu, Okada Atsushi, Kawakami Shoji, Kanaya Tomoaki, Asaumi Yasuhide, Aiba Takeshi, Nishida Yoko, Kubota Yoshimi, Sugiyama Daisuke, Okamura Tomonori, Noguchi Teruo, Kusano Kengo, Ogawa Hisao, Yasuda Satoshi, Anzai Toshihisa

European Journal of Heart Failure 18 （ 7 ） 803 - 813 2016年07月

ISSN 1388-9842

Aims: Although previous reports suggest that an elevated endogenous erythropoietin (EPO) level is associated with worse clinical outcomes in chronic heart failure (HF) patients, the prognostic implication of EPO in patients with acute decompensated HF (ADHF) and underlying mechanisms of the high EPO level in severe HF patients who have a poor prognosis remain unclear. Methods and results: We examined 539 consecutive ADHF patients with EPO measurement on admission from our registry. During a median follow-up period of 329 days, a higher EPO level on admission was independently associated with worse clinical outcomes [hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.06–1.48, P = 0.008], and haemoglobin level was the strongest determinant of EPO level (P <0.001), whereas estimated glomerular filtration rate (eGFR) was not significant in multivariate regression analysis. In the anaemic subgroup of 318 patients, a higher EPO level than expected on the basis of their haemoglobin level was related to increased adverse events (HR 1.63, 95% CI 1.05–2.49, P = 0.028). Moreover, estimated plasma volume excess rate was positively associated with EPO level (P = 0.003), and anaemic patients with a higher than expected EPO level tended to have a higher estimated plasma volume excess rate and plasma lactate level, and lower systemic oxygen saturation level with the preservation of the reticulocyte production index than those with a lower than expected EPO level. Conclusion: A high EPO level predicts long-term worse clinical outcomes in ADHF patients, independent of anaemia and impaired renal function. Anaemia and hypoxia due to severe congestion may synergistically contribute to a high EPO level in high-risk HF patients.

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Independent prognostic value of single and multiple non-specific 12-lead electrocardiographic findings for long-term cardiovascular outcomes

Sawano Mitsuaki, Kohsaka Shun, Okamura Tomonori, Inohara Taku, Sugiyama Daisuke, Shiraishi Yasuyuki, Watanabe Makoto, Nakamura Yasuyuki, Higashiyama Aya, Kadota Aya, Okuda Nagako, Murakami Yoshitaka, Ohkubo Takayoshi, Fujiyoshi Akira, Miura Katsuyuki, Okayama Akira, Ueshima Hirotsugu

PLoS One 11 （ 6 ） 2016年06月

ISSN 1932-6203

Aims The long-term prognostic effect of non-specific 12-lead electrocardiogram findings is unknown. We aimed to evaluate the cumulative prognostic impact of axial, structural, and repolarization categorical abnormalities on cardiovascular death, independent from traditional risk scoring systems such as the Framingham risk score and the NIPPON DATA80 risk chart. Methods and Results A total of 16,816 healthy men and women from two prospective, longitudinal cohort studies were evaluated. 3,794 (22.6%) individuals died during a median follow-up of 15 years (range, 2.0-24 years). Hazard ratios for cardiovascular death, all-cause death, coronary death and stroke death were calculated for the cumulative and independent axial, structural, and repolarization categorical abnormalities adjusted for the Framingham risk score and the NIPPON DATA80 risk chart. Individuals with two or more abnormal categories had a higher risk of cardiovascular death after adjustment for Framingham risk score (men: HR 4.27, 95%CI 3.35-5.45; women: HR 4.83, 95%CI 3.76-6.22) and NIPPON DATA80 risk chart (men: HR 2.39, 95%CI 1.87-3.07; women: HR 2.04, 95%CI 1.58-2.64). Conclusion Cumulative findings of axial, structural, and repolarization abnormalities are significant predictors of long-term cardiovascular death in asymptomatic, healthy individuals independent of traditional risk stratification systems.

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Effects of daily glucose fluctuations on the healing response to everolimus-eluting stent implantation as assessed using continuous glucose monitoring and optical coherence tomography

Kuroda Masaru, Shinke Toshiro, Otake Hiromasa, Sugiyama Daisuke, Takaya Tomofumi, Takahashi Hachidai, Terashita Daisuke, Uzu Kenzo, Tahara Natsuko, Kashiwagi Daiji, Kuroda Koji, Shinkura Yuto, Nagasawa Yoshinori, Sakaguchi Kazuhiko, Hirota Yushi, Ogawa Wataru, Hirata Ken ichi

Cardiovascular Diabetology 15 （ 1 ） 2016年05月

Background: Several studies have revealed that glucose fluctuations provoke oxidative stress that leads to endothelial cell dysfunction, progression of coronary atherosclerosis, and plaque vulnerability. However, little is known regarding their effect on neointimal growth after stenting in patients with coronary artery disease (CAD). We aimed to investigate the effects of glucose fluctuations on neointimal growth after everolimus-eluting stent (EES) implantation. Methods: This study examined 50 patients who underwent a 9-month follow-up using optical coherence tomography (OCT) after EES implantation. Glucose fluctuation was expressed as the mean amplitude of glycemic excursion (MAGE), and was determined via continuous glucose monitoring before stenting. At the OCT follow-up, we evaluated the percentage of uncovered struts and three-dimensional uniformity of neointimal distribution by calculating the mean neointimal thickness (NIT) within 360 equally-spaced radial sectors for every 1-mm cross-sectional OCT analysis, and assessed the incidence of major adverse cardiovascular events (MACE). Results: We evaluated 60 lesions in 50 patients. Linear mixed effect models were used to explore the influence of different variables on variability in NIT and the percentage of uncovered struts and to adjust for covariates. Univariate analysis showed that MAGE was most strongly correlated with the previously mentioned OCT measurements (coefficient β±standard error=0.267±0.073 and 0.016±0.003, t=3.668 and 6.092, both P<0.001, respectively). In multivariate analysis, MAGE had the strongest effect on variability in NIT (coefficient β±standard error=0.239±0.093, P=0.014) and the percentage of uncovered struts (coefficient β±standard error=0.019±0.004, P<0.001). Five lesions in four patients required target lesion revascularization (10.0%) at a mean duration of 9months after EES implantation. Compared to non-MACE cases, cases of MACE exhibited a significantly higher MAGE (99vs.68; P=0.004), maximum NIT (580vs. 330μm; P=0.002), and variability in NIT (100vs.65; P=0.007), although there was no significant difference in these groups' HbA1c levels. Conclusions: Glucose fluctuation may affect vessel healing after EES implantation in patients with CAD who are receiving lipid-lowering therapy. Therefore, glucose fluctuations may be an important target for secondary prevention after coronary stenting, which is independent of dyslipidemia control.

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Profiling of plasma metabolites in postmenopausal women with metabolic syndrome

Iida Miho, Harada Sei, Kurihara Ayako, Fukai Kota, Kuwabara Kazuyo, Sugiyama Daisuke, Takeuchi Ayano, Okamura Tomonori, Akiyama Miki, Nishiwaki Yuji, Suzuki Asako, Hirayama Akiyoshi, Sugimoto Masahiro, Soga Tomoyoshi, Tomita Masaru, Banno Kouji, Aoki Daisuke, Takebayashi Toru

Menopause 2016年04月

ISSN 1072-3714

OBJECTIVE:: The aim of the study was to investigate the associations of amino acids and other polar metabolites with metabolic syndrome (MetS) in postmenopausal women in a lean Asian population. METHODS:: The participants were 1,422 female residents enrolled in a cohort study from April to August 2012. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III modified for Japanese women. Associations were examined between MetS and 78 metabolites assayed in fasting plasma samples using capillary electrophoresis-mass spectrometry. Replication analysis was performed to confirm the robustness of the results in a separate population created by random allocation. RESULTS:: Analysis was performed for 877 naturally postmenopausal women, including 594 in the original population and 283 in the replication population. The average age, body mass index, and levels of high- and low-density lipoprotein cholesterol of the entire population were 64.6 years, 23.0?kg/m, 72.1?mg/dL, and 126.1?mg/dL, respectively. There was no significant difference in low-density lipoprotein cholesterol levels between women with and without MetS. Thirteen metabolites were significantly related to MetS: multiple plasma amino acids were elevated in women with MetS, including branched-chain amino acids, alanine, glutamate, and proline; and alpha-aminoadipate, which is generated by lysine degradation, was also significantly increased. CONCLUSIONS:: Our large-scale metabolomic profiling indicates that Japanese postmenopausal women with MetS have abnormal polar metabolites, suggesting altered catabolic pathways. These results may help to understand metabolic disturbance, including in persons with normal body mass index and relatively high levels of high-density lipoprotein cholesterol, and may have clinical utility based on further studies.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0

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Relationship between non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol in the general population

Kuwabara Kazuyo, Harada Sei, Sugiyama Daisuke, Kurihara Ayako, Kubota Yoshimi, Higashiyama Aya, Hirata Takumi, Nishida Yoko, Kawasaki Midori, Takebayashi Toru, Okamura Tomonori

Journal of Atherosclerosis and Thrombosis 23 （ 4 ） 477 - 490 2016年04月

ISSN 1340-3478

Aim: The Japan Atherosclerosis Society (JAS) Guidelines for Diagnosis and Prevention of Atherosclerotic Cardiovascular Diseases for Japanese 2012 version have set a non-high-density lipoprotein cholesterol (non-HDL-C)-management target of low-density lipoprotein cholesterol (LDL-C) + 30 mg/ dL. However, the actual difference between non-HDL-C and LDL-C is not clear. Therefore, we evaluated its joint distribution and assessed the validity of this criterion in the general Japanese population. Methods: We used baseline cross-sectional data of 4,110 participants from two studies; the KOBE Study (n=1,108) and the Tsuruoka Metabolomic Cohort Study (n= 3,002). To evaluate whether the difference between LDL-C and non-HDL-C in the general population match that of the current guidelines, we classified LDL-C levels into four groups according to the JAS Guideline and evaluated its agreement with the corresponding non-HDL-C group. Analysis was also done using six groups (the previous four groups plus the upper and lower cut-off values). Results: The mean difference (mg/dL) between the non-HDL-C and LDL-C (for the KOBE Study and Tsuruoka Metabolomic Cohort Study, respectively) was 19.6 and 24.1 (p <0.001) for men and 15.9 and 18.3 (p <0.001) for women. In both the cohort studies, the difference was lower than 30 mg/dL. It was especially small among individuals with normal triglyceride levels. Conclusions: In the general Japanese population, the difference between non-HDL-C and LDL-C was lower than the expected difference of 30 mg/dL. Changes to the criteria for non-HDL-C target levels may be considered in the future.

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Diagnostic accuracy of neuropsychological tests for classification of dementia

Yagi Takuya, Ito Daisuke, Sugiyama Daisuke, Iwasawa Satoko, Tabuchi Hajime, Konishi Mika, Araki Machiko, Saitoh Naho, Nihei Yoshihiro, Mimura Masaru, Suzuki Norihiro

Neurology Asia 21 （ 1 ） 47 - 54 2016年03月

ISSN 1823-6138

Although numerous studies have shown that each neuropsychological test is effective for diagnosing mild cognitive impairment (MCI) or Alzheimer’s disease (AD), studies comparing diagnostic accuracies of various neuropsychological tests are relatively rare and practical cutoff values are not available. The present study aimed to investigate the validity of neuropsychological tests and develop cutoff values for each in differentiating healthy control (HC), MCI and AD groups. A total of 84 HC, 187 with MCI and 195 with AD were evaluated by the selected seven neuropsychological tests using receiver operating characteristic (ROC) curve analysis. Logical Memory (LM) delayed recall (cutoff, 7) and Rey Auditory Verbal Learning Test (RAVLT) delayed recall (cutoff, 6) were effective for differentiating HC from MCI. To distinguish MCI and AD, Rey Osterrieth Complex Figure Test (ROCFT) 3 mindelayed recall (cutoff, 6) and LM immediate recall (cutoff, 4) were excellent. Delayed recall of verbal materials, as indexed by LM and RAVLT was sensitive for discriminating MCI from HC. Handling visual memory traces, as indexed by ROCFT and immediate verbal information by LM were sensitive for differentiating MCI and AD.

Effect of daily glucose fluctuation on coronary plaque vulnerability in patients pre-treated with lipid-lowering therapy

Kuroda M., Shinke T., Sakaguchi K., Otake H., Takaya T., Hirota Y., Sugiyama D., Nakagawa M., Hariki H., Inoue T., Osue T., Taniguchi Y., Iwasaki M., Nishio R., Kinutani H., Konishi A., Hiranuma N., Takahashi H., Terashita D., Hirata K.

Diabetes Technology and Therapeutics 18 S13 - S14 2016年02月

ISSN 1520-9156

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Underweight young women without later weight gain are at high risk for osteopenia after midlife

Tatsumi Yukako, Higashiyama Aya, Kubota Yoshimi, Sugiyama Daisuke, Nishida Yoko, Hirata Takumi, Kadota Aya, Nishimura Kunihiro, Imano Hironori, Miyamatsu Naomi, Miyamoto Yoshihiro, Okamura Tomonori

Journal of Epidemiology 26 （ 11 ） 572 - 578 2016年

ISSN 0917-5040

Background: Although underweight young women are targets for interventions to prevent low bone mineral density (BMD), the relationship between change in body mass index (BMI) from youth to older age and BMD has not been widely investigated in community dwellers. Methods: In 749 healthy Japanese women aged 40-74 years, BMD was measured by quantitative ultrasound and anthropometric measurements, and BMI was calculated from body weight and height. The BMI of participants at age 20 years was estimated by self-reported body weight and their present height. They were classified into four groups according to the presence of underweight (BMI <18.5 kg/m²) at 20 and/or at present. Logistic regression models were used to estimate multivariate-adjusted odds ratios (ORs) of the presence of underweight at 20 and/or at present for osteopenia (BMD T score <-1 standard deviations) compared with participants with BMI ≥18.5 kg/m² both at 20 and at present. Results: The participants who were underweight both at 20 and at present had a higher OR for osteopenia compared with those with BMI ≥18.5 kg/m² at 20 and at present (OR 3.94; 95% confidence interval [CI], 1.97-7.89). Those underweight only at present also had significantly increased OR of developing osteopenia (OR 2.95; 95% CI, 1.67-5.24). The OR of those underweight only at 20 was 0.87 (95% CI, 0.51-1.48). Conclusions: Current underweight was associated with increased risk for osteopenia among Japanese women, especially in those who were underweight both at 20 and at present. To prevent low BMD in the future, maintaining appropriate body weight might be effective for young underweight women.

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Serum uric acid and mortality form cardiovascular disease

Zhang Wen, Iso Hiroyasu, Murakami Yoshitaka, Miura Katsuyuki, Nagai Masato, Sugiyama Daisuke, Ueshima Hirotsugu, Okamura Tomonori, Ueshima Hirotsugu, Imai Yutaka, Ohkubo Takayoshi, Irie Fujiko, Kitamura Akihiko, Kiyohara Yutaka, Nakagawa Hideaki, Nakayama Takeo, Okayama Akira, Sairenchi Toshimi, Saitoh Shigeyuki, Sakata Kiyomi, Tamakoshi Akiko, Tsuji Ichiro, Yamada Michiko, Kiyama Masahiko, Miyamoto Yoshihiro, Ishikawa Shizukiyo, Yatsuya Hiroshi

Journal of Atherosclerosis and Thrombosis 23 （ 6 ） 692 - 703 2016年

ISSN 1340-3478

Aim: To investigate the relationship between serum uric acid levels and cardiovascular disease in Asians. Methods: We examined the above relationship using the data of Evidence for Cardiovascular Prevention from Observational Cohorts in Japan (EPOCH-JAPAN Study). The data of 36,313 subjects (15,628 men and 20,685 women aged 35 –89 years without histories of stroke, coronary heart disease, or cancer at baseline) were used for the analyses. Sex-specific hazard ratios (HRs) of mortality from cardiovascular disease were estimated according to the quintiles of serum uric acid using Cox hazard models stratified by cohorts. Results: During 441,771 person-years of follow-up, we documented 1,288 cardiovascular deaths. A J-or U-shaped relationship between serum uric acid level and cardiovascular disease mortality was observed. Compared with the lowest quintile of serum uric acid levels, the highest quintile was associated with an increased cardiovascular disease mortality in men [HR: 1.28; 95% confidence interval (CI): 1.01– 1.63] and women (HR: 1.51; 95% CI: 1.14–1.99). However, there was no significant association with mortality from stroke, coronary heart disease or heart failure in both men and women. Conclusion: This large pooled analysis in Japan suggested a J-or U-shaped relationship between serum uric acid levels and cardiovascular mortality. The highest quintile of serum uric acid levels was associated with increased cardiovascular disease mortality in both Japanese men and women.

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The relationship between very high levels of serum high-density lipoprotein cholesterol and cause-specific mortality in a 20-year follow-up study of japanese general population

Hirata Aya, Okamura Tomonori, Sugiyama Daisuke, Kuwabara Kazuyo, Kadota Aya, Fujiyoshi Akira, Miura Katsuyuki, Okuda Nagako, Ohkubo Takayoshi, Okayama Akira, Ueshima Hirotsugu, Saitoh Shigeyuki, Sakata Kiyomi, Hozawa Atsushi, Hayakawa Takehito, Nakamura Yoshikazu, Nishi Nobuo, Kasagi Fumiyoshi, Murakami Yoshitaka, Izumi Toru, Matsumura Yasuhiro, Ojima Toshiyuki, Tamakoshi Koji, Nakagawa Hideaki, Kita Yoshikuni, Miyamatsu Naomi, Yoshita Katsushi, Miyamoto Yoshihiro, Kodama Kazunori, Kiyohara Yutaka

Journal of Atherosclerosis and Thrombosis 23 （ 7 ） 800 - 809 2016年

ISSN 1340-3478

Aims: There is no community-based cohort study to examine the effect of very high level of highdensity lipoprotein cholesterol (HDL-C) on coronary heart disease (CHD) and other cause-specific mortality. Therefore, we investigated the relationship between HDL-C including very high level and cause-specific mortality in a 20-year cohort study of the representative sample of Japanese. Methods: We followed 7,019 individuals from the Japanese general population (2,946 men and 4,073 women). We defined HDL-C levels as follow: low (HDL-C

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Metabolomic profiling reveals novel biomarkers of alcohol intake and alcohol-induced liver injury in community-dwelling men

Harada Sei, Takebayashi Toru, Kurihara Ayako, Akiyama Miki, Suzuki Asako, Hatakeyama Yoko, Sugiyama Daisuke, Kuwabara Kazuyo, Takeuchi Ayano, Okamura Tomonori, Nishiwaki Yuji, Tanaka Taichiro, Hirayama Akiyoshi, Sugimoto Masahiro, Soga Tomoyoshi, Tomita Masaru

Environmental Health and Preventive Medicine 2015年10月

ISSN 1342-078X

Objective: Metabolomics is a promising approach to the identification of biomarkers in plasma. Here, we performed a population-based, cross-sectional study to identify potential biomarkers of alcohol intake and alcohol-induced liver injury by metabolomic profiling using capillary electrophoresis-mass spectrometry (CE-MS). Methods: Fasting plasma samples were collected from 896 Japanese men who participated in the baseline survey of the Tsuruoka Metabolomics Cohort Study, and 115 polar metabolites were identified and absolutely quantified by CE-MS. Information on daily ethanol intake was collected through a standardized, self-administered questionnaire. The associations between ethanol intake and plasma concentration of metabolites were examined. Relationships between metabolite concentrations or their ratios and serum liver enzyme levels in the highest ethanol intake group (>46.0 g/day) were then examined by linear regression analysis. Replication analysis was conducted in 193 samples collected from independent population of this cohort. Results: Nineteen metabolites were identified to have an association with daily alcohol consumption both in the original and replication population. Three of these metabolites (threonine, glutamine, and guanidinosuccinate) were found to associate well with elevated levels of serum liver enzymes in the highest ethanol intake group, but not in the non-drinker group. We also found that the glutamate/glutamine ratio had a much stronger relation to serum γ-glutamyltransferase, aspartate transaminase, and alanine transaminase than glutamate or glutamine alone (standardized beta = 0.678, 0.558, 0.498, respectively). Conclusions: We found 19 metabolites associated with alcohol intake, and three biomarker candidates (threonine, guanidinosuccinate and glutamine) of alcohol-induced liver injury. Glutamate/glutamine ratio might also be good biomarker.

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Serum polyunsaturated fatty acid composition and serum high-sensitivity C-reactive protein levels in healthy Japanese residents

Kubota Yoshimi, Higashiyama A., Imano H., Sugiyama D., Kawamura K., Kadota A., Nishimura K., Miyamatsu N., Miyamoto Y., Okamura T.

Journal of Nutrition, Health and Aging 19 （ 7 ） 719 - 728 2015年08月

ISSN 1279-7707

Background/Objectives: Serum polyunsaturated fatty acid (PUFA) composition reflects dietary intake and is related to risks for cardiovascular diseases. We hypothesized that serum n-3 PUFA composition, especially including long-chain n-3 PUFA such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is associated with inflammatory status, which is related to increased risk for cardiovascular diseases. Subjects/Methods: We investigated the relationship between serum PUFA composition and high-sensitivity C-reactive protein (hs-CRP) levels in a cross-sectional study among 1,102 healthy men and women aged 40–74 years who reside in Kobe City. Multiple linear regression models that predict hs-CRP level were prepared to confirm the contribution of serum total n-3 PUFA, long-chain n-3 PUFA, EPA and DHA compositions after adjusting for other PUFAs and atherosclerotic risk factors. Results: The serum n-3 PUFA, particularly long-chain n-3 PUFA, compositions were inversely associated with the hs-CRP levels. The standardized regression coefficient was −0.089 (p < 0.01) for total n-3 PUFA, −0.091 (p < 0.01) for long-chain n-3 PUFA, −0.071 (p = 0.03) for EPA, and −0.068 (p = 0.04) for DHA. The n-6 PUFA compositions were also inversely associated with the hs-CRP levels (−0.169 [p < 0.01] for total n-6 PUFA and −0.159 [p < 0.01] for linoleic acid). Conclusions: The serum n-3 PUFA compositions were inversely related with the hs-CRP levels, similar associations were also observed in n-6 PUFA compositions. Our results suggest that dietary PUFA intake was inversely associated with attenuated inflammation in healthy Japanese population.

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Effect of daily glucose fluctuation on coronary plaque vulnerability in patients pre-treated with lipid-lowering therapy

Kuroda Masaru, Shinke Toshiro, Sakaguchi Kazuhiko, Otake Hiromasa, Takaya Tomofumi, Hirota Yushi, Sugiyama Daisuke, Nakagawa Masayuki, Hariki Hirotoshi, Inoue Takumi, Osue Tsuyoshi, Taniguchi Yu, Iwasaki Masamichi, Nishio Ryo, Kinutani Hiroto, Konishi Akihide, Hiranuma Noritoshi, Takahashi Hachidai, Terashita Daisuke, Hirata Ken Ichi

JACC: Cardiovascular Interventions 8 （ 6 ） 800 - 811 2015年05月

ISSN 1936-8798

Objectives This study sought to investigate the effect of daily glucose fluctuation on coronary plaque properties in patients with coronary artery disease (CAD) pre-treated with lipid-lowering therapy. Background There is growing evidence that glucose fluctuation, as a residual risk apart from dyslipidemia, is an important factor contributing to the development of CAD. Methods This prospective study enrolled 70 consecutive CAD patients who were referred for percutaneous coronary intervention and whose low-density lipoprotein cholesterol level was

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Effects of stroke education of junior high school students on stroke knowledge of their parents

Matsuzono Kosuke, Yokota Chiaki, Takekawa Hidehiro, Okamura Tomonori, Miyamatsu Naomi, Nakayama Hirofumi, Nishimura Kunihiro, Ohyama Satoshi, Ishigami Akiko, Okumura Kosuke, Toyoda Kazunori, Miyamoto Yoshihiro, Minematsu Kazuo, Sugiyama Daisuke, Nagao Masanori, Morimoto Akiko, Kadota Aya, Takizawa Nobue, Ieiri Kayo, Watanabe Teruki

Stroke 46 （ 2 ） 572 - 574 2015年02月

ISSN 0039-2499

BACKGROUND AND PURPOSE - : Educating the youth about stroke is a promising approach for spreading stroke knowledge. The aim of this study was to verify communication of stroke knowledge to parents by educating junior high school students about stroke. METHODS - : We enrolled 1127 junior high school students (age, 13-15 years) and their parents in the Tochigi prefecture, Japan. All students received a stroke lesson, watched an animated cartoon, and read the related Manga comic as educational aids. The students took back home the Manga and discussed what they learned with their parents. Questionnaires on stroke knowledge were given to all at baseline and immediately after the lesson. RESULTS - : A total of 1125 students and 915 parents answered the questionnaires. In the students, the frequency of correct answers increased significantly for all questions on stroke symptoms except for headache, and for all questions on risk factors after the lesson. In the parents, the correct answer rates increased for stroke symptoms except for headache and numbness in one side of the body, and for all questions on risk factors except for hypertension. Ninety-one percent of students and 92.7% of parents correctly understood the Face, Arm, Speech, and Time (FAST) mnemonic after the lesson. CONCLUSIONS - : Improvement of stroke knowledge immediately after the stroke lesson was observed in parents as well as their children, which indicated that our teaching materials using the Manga was effective in delivering the stroke knowledge to parents through their children.

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HOMA-IR values are associated with glycemic control in Japanese subjects without diabetes or obesity

Hirata Takumi, Higashiyama Aya, Kubota Yoshimi, Nishimura Kunihiro, Sugiyama Daisuke, Kadota Aya, Nishida Yoko, Imano Hironori, Nishikawa Tomofumi, Miyamatsu Naomi, Miyamoto Yoshihiro, Okamura Tomonori

Journal of Epidemiology 25 （ 6 ） 407 - 414 2015年

ISSN 0917-5040

Background: Several studies have reported that insulin resistance was a major risk factor for the onset of type 2 diabetes mellitus in individuals without diabetes or obesity. We aimed to clarify the association between insulin resistance and glycemic control in Japanese subjects without diabetes or obesity. Methods: We conducted a community-based cross-sectional study including 1083 healthy subjects (323 men and 760 women) in an urban area. We performed multivariate regression analyses to estimate the association between the homeostasis model assessment of insulin resistance (HOMA-IR) values and markers of glycemic control, including glycated haemoglobin (HbA1c), 1,5-anhydroglucitol (1,5-AG), and fasting plasma glucose (FPG) levels, after adjustment for potential confounders. Results: Compared with the lowest tertile of HOMA-IR values, the highest tertile was significantly associated with HbA1c and FPG levels after adjustment for potential confounders, both in men (HbA1c: β = 1.83, P = 0.001; FPG: β = 0.49, P < 0.001) and women (HbA1c: β = 0.82, P = 0.008; FPG: β = 0.39, P < 0.001). The highest tertile of HOMA-IR values was inversely associated with 1,5-AG levels compared with the lowest tertile (β = -18.42, P = 0.009) only in men. Conclusions: HOMA-IR values were associated with markers of glycemic control in Japanese subjects without diabetes or obesity. Insulin resistance may influence glycemic control even in a lean, non-diabetic Asian population.

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Cryoablation Provides Superior Local Control of Primary Hepatocellular Carcinomas of >2 cm Compared with Radiofrequency Ablation and Microwave Coagulation Therapy

Ei Shigenori, Hibi Taizo, Tanabe Minoru, Itano Osamu, Shinoda Masahiro, Kitago Minoru, Abe Yuta, Yagi Hiroshi, Okabayashi Koji, Sugiyama Daisuke, Wakabayashi Go, Kitagawa Yuko

Annals of Surgical Oncology 22 （ 4 ） 1294 - 1300 2015年

ISSN 1068-9265

Background: Although cryoablation (Cryo) has been advocated as an effective locoregional therapy for hepatocellular carcinoma (HCC), few studies have compared the outcomes with those of radiofrequency ablation (RFA) and microwave coagulation therapy (MCT). Methods: Consecutive patients with primary HCCs of <5 cm received Cryo or RFA/MCT between 1998 and 2011 and were monitored for local recurrence (defined as a recurrent tumor at or in direct contact with the ablated area) and overall complication rates. Results: The median tumor size was 2.5 cm in the Cryo group (n = 55) and 1.9 cm in the RFA/MCT group (n = 64; P < 0.001), but other patient characteristics were similar. Multivariate Cox regression analysis revealed Cryo as the only independent factor for improved 2-year local recurrence-free survival, with a hazard ratio (HR) of 0.3 (95 % confidence interval, 0.1–0.9; P = 0.02). Tumor diameter was a negative indicator of local recurrence-free survival (HR, 2.0; 95 % confidence interval, 1.1–3.5; P = 0.02). Subgroup analysis of patients with tumors of >2 cm demonstrated significantly better local recurrence rates in the Cryo group compared with the RFA/MCT group (21 vs. 56 % at 2 years; P = 0.006). Overall complication rates and incidences of Clavien–Dindo classification grade ≥III were identical (both P = 1.00). No in-hospital mortality occurred. Conclusions: Appropriate use of Cryo, as shown in this series, is safe and provides significantly improved local control for the treatment of primary HCCs of >2 cm compared with RFA/MCT.

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The relationship between lectin-like oxidized low-density lipoprotein receptor-1 ligands containing apolipoprotein B and the cardio-ankle vascular index in healthy community inhabitants

Sugiyama Daisuke, Higashiyama Aya, Wakabayashi Ichiro, Kubota Yoshimi, Adachi Yoshiko, Hayashibe Akiko, Kawamura Kuniko, Kuwabara Kazuyo, Nishimura Kunihiro, Kadota Aya, Nishida Yoko, Hirata Takumi, Imano Hironori, Miyamatsu Naomi, Miyamoto Yoshihiro, Sawamura Tatsuya, Okamura Tomonori

Journal of Atherosclerosis and Thrombosis 22 （ 5 ） 499 - 508 2015年

ISSN 1340-3478

Aims: Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 ligands containing apolipoprotein B (LAB) and lectin-like oxidized LDL receptor-1 (LOX-1) are known as LOX-1-related modified LDL indicators. These indicators play an important role in the early phase atherosclerosis, but the relationship between these indicators and subclinical atherosclerosis, as represented by the cardioankle vascular index (CAVI), has not been assessed. We herein investigated the association of LOX-1- related modified LDL indicators and the CAVI in healthy, Japanese urban community inhabitants who were considered to be at low risk for cardiovascular disease (CVD). Methods: The participants were 515 healthy Japanese (310 men and 205 women) without a history of CVD, cancer or the use of medication for hypertension, diabetes or dyslipidaemia. To estimate the association between LOX-1-related modified LDL indicators (LAB, soluble form of LOX-1 (sLOX- 1)) and the CAVI, we performed multivariable linear regression analyses with possible confounders such as the serum LDL cholesterol level. Results: The plasma LAB showed a positive association with the CAVI in men (standardized coefficient: 0.11, p= 0.04). This relationship was not observed in women. On the other hand, no clear association was observed between the CAVI and the plasma sLOX-1 level in either sex. Conclusions: The plasma LAB levels may represent a useful marker for detecting potential atherosclerosis in healthy individuals considered to be at low risk for atherosclerosis and CVD. Further studies are needed to confirm the present findings.

Risk of Hypercholesterolemia for Cardiovascular Disease and the Population Attributable Fraction in a 24-year Japanese Cohort Study

Sugiyama Daisuke, Okamura Tomonori, Watanabe Makoto, Higashiyama Aya, Okuda Nagako, Nakamura Yasuyuki, Hozawa Atsushi, Kita Yoshikuni, Kadota Aya, Murakami Yoshitaka, Miyamatsu Naomi, Ohkubo Takayoshi, Hayakawa Takehito, Miyamoto Yoshihiro, Miura Katsuyuki, Okayama Akira, Ueshima Hirotsugu

Journal of Atherosclerosis and Thrombosis 22 （ 1 ） 95 - 107 2015年

ISSN 1340-3478

Aims: The population-attributable fraction (PAF) is an indicator of the disease burden. In Western countries, the PAF of hypercholesterolemia in cardiovascular disease (CVD) is the highest among that for traditional risk factors; however, data for Asian populations are limited. Methods: A 24-year cohort study was conducted among 9,209 randomly selected participants who were not taking statins. We estimated the hazard ratio (HR) after adjusting for covariates and PAF associated with the serum total cholesterol (TC) levels in relation to CVD mortality. Results: The TC level was found to be positively associated with an increased risk of CVD, coronary heart disease (CHD) and cardiac death (CHD plus heart failure), with an HR of 1.08 (95% confidence interval [CI]: 1.00-1.16), 1.33 (95% CI: 1.14-1.55) and 1.21 (95% CI: 1.08-1.35) for a 1-SD increment in the serum TC level, respectively. Similar positive associations between the TC level and both CHD and cardiac death were observed after classifying the patients by age and sex. Furthermore, the highest serum TC level (≥6.72 mmol/L) was positively associated with CVD death, with an HR of 1.76 (95% CI: 1.25-2.47), as well as both CHD death and cardiac death. In contrast, no significant relationships were observed between the serum TC level and stroke. Meanwhile, the PAF for CVD, CHD, and cardiac deaths due to hypercholesterolemia (serum TC level ≥5.69 mmol/L, defined by the Japan Atherosclerosis Society) was 1.7%, 10.6% and 5.6%, respectively. Conclusions: The estimated PAF of CVD death due to hypercholesterolemia is moderately high, but lower than that for other risk factors, such as hypertension.

Blood circulation in the fingers is aggravated after creating a vascular access for dialysis

Sato Makoto, Tahara Shinya, Sugiyama Daisuke, Terashi Hiroto

Journal of Plastic Surgery and Hand Surgery 48 （ 5 ） 327 - 329 2014年10月

ISSN 2000-656X

Internal vascular shunts for haemodialysis can cause different complications. One of the most serious complications is steal syndrome, which can result in disturbed peripheral circulation causing finger necrosis and lead to amputation. Thus, prevention of these complications is important. Measurement of skin perfusion pressure (SPP) has been used in various clinical settings, including wound-healing management, and its usefulness has been increasingly unveiled. The present study was undertaken to evaluate changes in haemodynamics after internal shunt creation by measuring SPP of the thumb and the little finger before and after surgery in five patients undergoing shunt surgery using the radial artery and the cephalic vein. The study revealed average changes of-22.8 mmHg in thumb SPP. The change in the thumb was statistically significant (p <0.05). If the effect of surgery and the threshold for wound healing are taken into account, the present results indicate the necessity to pay extra attention to fingers with extremely low preoperative SPP values. For the prevention of serious disturbances of peripheral circulation (e.g. steal syndrome), routine preoperative SPP measurement seems effective for screening of high-risk patients.

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Obesity was associated with a decreased postoperative recurrence of rectal cancer in a Japanese population

Seishima Ryo, Okabayashi Koji, Hasegawa Hirotoshi, Sugiyama Daisuke, Ishii Yoshiyuki, Tsuruta Masashi, Takebayashi Toru, Kitagawa Yuko

Surgery Today 2014年05月

ISSN 0941-1291

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

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Erratum

Nagata Tomoki, Sugiyama Daisuke, Kise Takako, Tsuji Satomi, Ohira Hideo, Sato Itsuko, Yamamoto Mari, Kohsaka Hitomi, Kawano Seiji, Yamashita Shizuya, Ishikawa Yuichi, Fujioka Yoshio

Lipids in Health and Disease 13 （ 1 ） 2014年04月

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Accelerated development of cervical spine instabilities in rheumatoid arthritis

Yurube Takashi, Sumi Masatoshi, Nishida Kotaro, Miyamoto Hiroshi, Kohyama Kozo, Matsubara Tsukasa, Miura Yasushi, Hirata Hiroaki, Sugiyama Daisuke, Doita Minoru

PLoS ONE 9 （ 2 ） 2014年02月

Objective: To clarify the incidence and predictive risk factors of cervical spine instabilities which may induce compression myelopathy in patients with rheumatoid arthritis (RA). Methods: Three types of cervical spine instability were radiographically categorized into "moderate" and "severe" based on atlantoaxial subluxation (AAS: atlantodental interval >3 mm versus ≥10 mm), vertical subluxation (VS: Ranawat value, 13 mm versus ≤10 mm), and subaxial subluxation (SAS: irreducible translation ≥2 mm versus ≥4 mm or at multiple). 228 "definite" or "classical" RA patients (140 without instability and 88 with "moderate" instability) were prospectively followed for >5 years. The endpoint incidence of "severe" instabilities and predictors for "severe" instability were determined. Results: Patients with baseline "moderate" instability, including all sub-groups (AAS⁺ [VS^- SAS^-], VS⁺ [SAS^- AAS ^±], and SAS⁺ [AAS^± VS ^±]), developed "severe" instabilities more frequently (33.3% with AAS⁺, 75.0% with VS⁺, and 42.9% with SAS⁺) than those initially without instability (12.9%; p<0.003, p<0.003, and p = 0.061, respectively). The incidence of cervical canal stenosis and/or basilar invagination was also higher in patients with initial instability (17.5% with AAS⁺, 37.5% with VS⁺, and 14.3% with SAS⁺) than in those without instability (7.1%; p = 0.028, p<0.003, and p = 0.427, respectively). Multivariable logistic regression analysis identified corticosteroid administration, Steinbrocker stage III or IV at baseline, mutilating changes at baseline, and the development of mutilans during the follow-up period correlated with the progression to "severe" instability (p<0.05). Conclusions: This prospective cohort study demonstrates accelerated development of cervical spine involvement in RA patients with pre-existing instability - especially VS. Advanced peripheral erosiveness and concomitant corticosteroid treatment are indicators for poor prognosis of the cervical spine in RA. © 2014 Yurube et al.

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Alterations in HbAlc resulting from the donation of autologous blood for elective surgery in patients with diabetes mellitus

Sugimoto Takeshi, Hashimoto Makoto, Hayakawa Ikuyo, Tokuno Osamu, Ogino Tomoko, Okuno Mariko, Hayashi Nobuhide, Kawano Seiji, Sugiyama Daisuke, Minami Hironobu

Blood Transfusion 12 （ SUPPL.1 ） 2014年

ISSN 1723-2007

Background. The aim of this study was to confirm the change in haemoglobin A1c consequent to pre-operative donation of autologous blood for elective surgery in patients with diabetes mellitus. Material and methods. For enrolment in this prospective study, patients had to be scheduled for multiple autologous blood donations at different times and have a haemoglobin A1c level more than 5.8% at the first donation. The values of four factors, haemoglobin, haemoglobin A1c, glycated albumin, and glycated albumin/haemoglobin A1c ratio were determined. Changes in the values of these four factors between before and after the blood donations were calculated. Results. In all 24 patients studied, haemoglobin and haemoglobin A1c decreased as a result of the autologous blood donations. The group with a reduced glycated albumin/haemoglobin A1c ratio had short intervals between blood donations. Correlations were observed between donation interval and change in haemoglobin A1c (r=0.63, P=0.003), and between donation interval and change in the glycated albumin/haemoglobin A1c ratio (r=0.489, P=0.045). Discussion. Haemoglobin A1c levels are likely to be underestimated after autologous blood donation by patients with diabetes mellitus, so glycated albumin may be a better indicator of these patients' glycaemic control.

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Worksite wellness for the primary and secondary prevention of cardiovascular disease in Japan

Okamura Tomonori, Sugiyama Daisuke, Tanaka Taichiro, Dohi Seitaro

Progress in Cardiovascular Diseases 56 （ 5 ） 515 - 521 2014年

ISSN 0033-0620

In the Japanese workplace, employers are required to provide annual health checkups for workers in accordance with the "Industrial Safety and Health Law," which also mandates that an occupational physician be assigned to companies employing at least 50 workers. The annual medical examination includes testing for the early detection of cardiovascular risk factors such as hypertension, dyslipidemia, diabetes, and the metabolic syndrome. This approach has successfully contributed to the extremely low incidence of coronary artery disease among Japanese workers. However, problems such as poor health and the low rate of participation in health checkups among small-scale companies still persist. Furthermore, although most wellness delivery systems in Japan employ strategies targeting high-risk individuals, instituting a strategy addressing the broader population irrespective of screening may be effective in reducing disease risk in the overall population. As a future direction, we should therefore develop practical methods for implementing a population strategy.

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What is the most adapted indication of prophylactic pancreatic duct stent within the high-risk group of post-endoscopic retrograde cholangiopancreatography pancreatitis? Using the propensity score analysis

Takenaka Mamoru, Fujita Tsuyoshi, Sugiyama Daisuke, Masuda Atsuhiro, Shiomi Hideyuki, Sugimoto Maki, Sanuki Tsuyoshi, Hayakumo Takanobu, Azuma Takeshi, Kutsumi Hiromu

Journal of Hepato-Biliary-Pancreatic Sciences 21 （ 4 ） 275 - 280 2014年

ISSN 1868-6974

Background Conducting randomized controlled trial (RCT) for each of the risk factors associated with prophylactic pancreatic duct stent (PPDS) for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is difficult owing to the volume of cases and ethical considerations. In this study, we tried to reveal the degree of preventive effects of PPDS for each individual risk factor within the high-risk group of PEP using the propensity score analysis. Methods The clinical data of 1131 ERCP practices performed at Kobe University Hospital from April 2006 to February 2009 were collected prospectively. We investigated their clinical characteristics including the risk factors of PEP, the use of PPDS and complications of ERCP. We conducted the stratification analysis using the propensity score matching analysis. Results In 210 propensity score-matched ERCPs, PPDS proved to be effective in preventing PEP in patients with a history of pancreatitis (odds ratio 0.11, 95% CI 0.01-0.76, P = 0.01) and cases of difficult cannulation (requiring more than 30 min) (odds ratio 0.13, 95% CI 0.01-1.14, P = 0.08). Conclusions Patients with a history of pancreatitis and cases of difficult cannulation are strongly recommended for PPDS placement. The propensity score analysis can be adapted to the ERCP-related analysis with many procedure-related factors with using retrospective data, and may be adapted to investigate the matters that are unsuitable for RCT by volume and ethical issue.

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What is the effect of laparoscopic colectomy on pattern of colon cancer recurrence? A propensity score and competing risk analysis compared with open colectomy

Hasegawa Hirotoshi, Okabayashi Koji, Watanabe Masahiko, Ashrafian Hutan, Harling Leanne, Ishii Yoshiyuki, Sugiyama Daisuke, Seishima Ryo, Darzi Ara, Athanasiou Thanos, Kitagawa Yuko

Annals of Surgical Oncology 21 （ 8 ） 2627 - 2635 2014年

ISSN 1068-9265

Background. Variability in colon cancer recurrence after laparoscopic colectomy (LAC) remains poorly understood. The aim of our study was to quantify the influence of LAC on colon cancer recurrence patterns. Methods. We included 986 patients undergoing curative colectomy at our institution between 1992 and 2008. Kaplan-Meier, multivariable Cox regression, propensity score adjustment, and competing risks modeling were used to evaluate the influence of laparoscopic surgery on the site of colon cancer recurrence, including the following: liver metastasis, lung metastasis, local recurrence, peritoneal dissemination, other, and multiple sites. We estimated the risk factors for each recurrence site. Results. Laparoscopic surgery was used in 419 (42.5 %) of 986 patients, with an overall median follow-up time of 5.0 years (interquartile range 3.5). The overall 5-year disease-free survival rate was 86.1 % (open surgery 81.8 % vs. laparoscopic surgery 92.0 %; p < 0.001). However, after covariates and propensity score adjustment, laparoscopic surgery was not a significant risk factor for each type of recurrence: liver hazard ratio (HR) 0.93 (95 % CI 0.45-1.89), p = 0.84; lung HR 0.67 (95 % CI 0.26-1.70), p = 0.39; local HR 0.56 (95 % CI 0.12-2.63), p = 0.46; peritoneal HR 2.49 (95 % CI 0.75-8.27), p = 0.14; others HR 0.47 (95 % CI 0.04-5.13), p = 0.53; multiple HR 0.88 (95 % CI 0.25-3.14), p = 0.84. The risk factors for each type of recurrence were variable and characterized by specific clinicopathological features. Conclusion. Our study reveals that LAC and open colectomy demonstrate comparable overall colon cancer recurrence rates and recurrence sites. Specific clinicopathological characteristics may have a stronger influence on colon cancer recurrence site compared with the surgical technique.

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Long-term deleterious effects of aortohepatic conduits in primary liver transplantation

Hibi Taizo, Nishida Seigo, Levi David M., Sugiyama Daisuke, Fukazawa Kyota, Tekin Akin, Fan Ji, Selvaggi Gennaro, Ruiz Phillip, Tzakis Andreas G.

Liver Transplantation 19 （ 8 ） 916 - 925 2013年08月

ISSN 1527-6465

Aortohepatic conduits provide a vital alternative for graft arterialization during liver transplantation. Conflicting results exist with respect to the rates of comorbidities, and long-term survival data on primary grafts are lacking. To identify the complications associated with aortohepatic conduits in primary liver transplantation and their impact on survival, we conducted a single-center, retrospective cohort analysis of all consecutive adult (n = 1379) and pediatric primary liver transplants (n = 188) from 1998 to 2009. The outcomes of aortohepatic conduits were compared to those of standard arterial revascularization. Adults with a conduit (n = 267) demonstrated, in comparison with adults with standard arterialization (n = 1112), an increased incidence of late (>1 month after transplantation) hepatic artery thrombosis (HAT; 4.1% versus 0.7%, P < 0.001) and ischemic cholangiopathy (7.5% versus 2.7%, P < 0.001) and a lower 5-year graft survival rate (61% versus 70%, P = 0.01). The adjusted hazard ratio (HR) for graft loss in the conduit group was 1.38 [95% confidence interval (CI) = 1.03-1.85, P = 0.03]. Notably, the use of conduits (HR = 4.91, 95% CI = 1.92-12.58) and a warm ischemia time > 60 minutes (HR = 11.12, 95% CI = 3.06-40.45) were independent risk factors for late HAT. Among children, the complication profiles were similar for the conduit group (n = 81) and the standard group (n = 107). In the pediatric cohort, although the 5-year graft survival rate for the conduit group (69%) was significantly impaired in comparison with the rate for the standard group (81%, P = 0.03), the use of aortohepatic conduits did not emerge as an independent predictor of diminished graft survival via a multivariate analysis. In conclusion, in adult primary liver transplantation, the placement of an aortohepatic conduit should be strictly limited because of the greater complication rates (notably late HAT) and impaired graft survival; for children, its judicious use may be acceptable. © 2013 American Association for the Study of Liver Diseases.

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Cancer incidence in systemic sclerosis

Onishi Akira, Sugiyama Daisuke, Kumagai Shunichi, Morinobu Akio

Arthritis and Rheumatism 65 （ 7 ） 1913 - 1921 2013年07月

ISSN 0004-3591

Objective To examine cancer incidence in patients with systemic sclerosis (SSc) through a meta-analysis of population-based cohort studies. Methods Five different databases (Medline, Scopus, CINAHL [Cumulative Index to Nursing and Allied Health Literature], Web of Science, and Cochrane Collaboration) were searched for articles published between January 1966 and May 2012; review articles and the reference lists from the articles that resulted from the search were also evaluated. Population-based cohort studies with data relevant to the determination of cancer risk in patients with SSc were included. All articles that met strict inclusion criteria were analyzed for data on population size, time of followup, and observed-to-expected cancer ratios, also known as standardized incidence ratios (SIRs). Results Six articles met criteria and were included in the meta-analysis. The pooled SIR for the incidence of cancer overall was 1.41 (95% confidence interval [95% CI] 1.18-1.68), and significant heterogeneity was observed as a consequence of variability in the participants, outcome, study design, and risk of bias among the studies. Men had a significantly higher pooled SIR (1.85 [95% CI 1.49-2.31]) than women (SIR 1.33 [95% CI 1.18-1.49]) (P < 0.01), and stratification for sex eliminated heterogeneity, which indicates that variability among the studies greatly contributed to differences between the sexes. There were no differences between limited cutaneous SSc and diffuse cutaneous SSc (P = 0.77). Significant increases were observed in the risk of cancer of the lung, liver, hematologic system, and bladder, as well as of non-Hodgkin's lymphoma and leukemia. Conclusion SSc is associated with an increased risk of cancer, particularly lung, liver, hematologic, and bladder cancers, although absolute risk is relatively low. Men with SSc have a higher risk of developing cancer than women. Copyright © 2013 by the American College of Rheumatology.

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Mycophenolate mofetil versus intravenous cyclophosphamide for induction treatment of proliferative lupus nephritis in a Japanese population

Onishi Akira, Sugiyama Daisuke, Tsuji Go, Nakazawa Takashi, Kogata Yoshinori, Tsuda Kosaku, Naka Ikuko, Nishimura Keisuke, Misaki Kenta, Kurimoto Chiyo, Hayashi Hiroki, Kageyama Goichi, Saegusa Jun, Sugimoto Takeshi, Kawano Seiji, Kumagai Shunichi, Morinobu Akio

Modern Rheumatology 23 （ 1 ） 89 - 96 2013年01月

ISSN 1439-7595

Objectives: Recent studies have shown that mycophenolate mofetil (MMF) is similar to intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis (LN), but that treatment response may vary according to location and race/ethnicity. Moreover, no studies have been conducted to compare the efficacy of MMF with that of IVC for a Japanese population. We therefore conducted a retrospective study to clarify the efficacy and safety of MMF compared with that of IVC for induction therapy for active LN, classes III and IV, in a Japanese population of 21 patients, 11 of whom received MMF and 10 IVC. Methods: The primary endpoint was expressed as the percentage of responders, who in turn were defined as the patients who met complete or partial response criteria according to the European consensus statement. The secondary endpoints comprised the renal activity component and serological activity. Results: The primary endpoint was achieved in nine (81.8 %) patients receiving MMF and in four (40.0 %) receiving IVC, with no significant difference between the two groups (p = 0.081), while there was also no significant difference between them in terms of secondary endpoints. However, the MMF group suffered significantly fewer hematologic toxic effects than the IVC group. Conclusions: MMF may be used as an alternative to IVC for inducing renal remission of LN in Japanese patients. © 2012 Japan College of Rheumatology.

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Comparison of nine second-and third-generation anti-cyclic citrullinated peptide antibody assays for the diagnosis of rheumatoid arthritis

Hayashi Nobuhide, Kumagai Shunichi, Onuma Kenichiro, Uto Kenichi, Sugiyama Daisuke, Saegusa Jun, Kawano Seiji

Japanese Journal of Clinical Immunology 36 （ 2 ） 104 - 114 2013年

ISSN 0911-4300

The aim of this study was to compare the diagnostic and analytical performances of nine anti-cyclic citrullinated peptide (CCP) antibody assays. Anti-CCP antibody titers were measured in sera from 89 patients with rheumatoid arthritis (RA), 121 with rheumatic diseases other than RA (non-RA), 47 with osteoarthritis (OA), 142 with chronic inflammatory diseases (CID) and 168 healthy subjects. Reproducibility, sensitivity, specificity, correlation and concordance rate of the nine assays were compared. Coeficients of variations of within-run and between-run reproducibility at two different concentrations for each assay ranged from 0.7 to 8.5% and from 0.6 to 8.3%, respectively. With our proposed optimal cut-oFF value for the third-generation assay, concordance rates were 96.8~99.6%. The range of sensitivity was 75.3~78.7% and the ranges of specificity for non-RA, OA, CID, and healthy subjects were 93.4~97.5%, 97.9%, 96.5~98.6% and 98.8~100%, respectively. However, several discrepant samples were detected and their titer levels were about 3 times higher than the normal upper limit in the 2010 RA classification criteria. Good positive correlations were observed for parts of the second-generation assay. Our study showed that each of the nine assays has good reproducibility and high diagnostic accuracy, and is thus equally useful for the diagnosis of RA.

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Incidence and aggravation of cervical spine instabilities in rheumatoid arthritis

Yurube Takashi, Sumi Masatoshi, Nishida Kotaro, Miyamoto Hiroshi, Kohyama Kozo, Matsubara Tsukasa, Miura Yasushi, Sugiyama Daisuke, Doita Minoru

Spine 37 （ 26 ） 2136 - 2144 2012年12月

ISSN 0362-2436

STUDY DESIGN. A prospective minimum 5-year follow-up study of the cervical spine in patients with rheumatoid arthritis (RA) initially without cervical involvement. OBJECTIVE. To clarify the incidence and aggravation of cervical spine instabilities and their predictive risk factors in patients with RA. SUMMARY OF BACKGROUND DATA. Many reports have shown the progression of cervical spine involvement in RA. However, few articles have described comprehensive evaluation of its prognostic factors. METHODS. A total of 140 patients with "definite" or "classical" RA initially without cervical involvement were prospectively followed for more than 5 years. Radiographical cervical findings were classified into 3 instabilities: atlantoaxial subluxation (AAS: atlantodental interval >3 mm), vertical subluxation (VS: Ranawat value <13 mm), and subaxial subluxation (SAS: irreducible translation ≥2 mm). "Severe" extents were defined as AAS with atlantodental interval 10 mm or more, VS with Ranawat value 10 mm or less, and SAS with translation 4 mm or more or at multiple levels. Incidence of these developments and predictors for "severe" instabilities were investigated. RESULTS. During 6.0 ± 0.5 years, 43.6% of 140 patients developed cervical instabilities: AAS in 32.1%, VS in 11.4%, and SAS in 16.4% with some combinations. "Severe" instabilities were exhibited in 12.9% of patients: AAS in 3.6%, VS in 6.4%, and SAS in 5.0%. Furthermore, 4.3% presented canal stenosis, with 13 mm or less space available for the spinal cord (SAC) due to "severe" AAS or "severe" VS in 2.9% and 12 mm or less SAC due to "severe" SAS in 2.1%. Multivariable logistic regression analysis identified corticosteroid administration, mutilating changes at baseline, and the development of nonmutilating into mutilating changes during the follow-up period correlated with "severe" instabilities (P < 0.05). CONCLUSION. A minimum 5-year follow-up reveals the occurrence of cervical instabilities in 43.6%, "severe" aggravation in 12.9%, and decreased SAC in 4.3% of patients with RA. Characteristics of severe disease activity - established mutilating changes, progressive development into mutilating changes, and potentially concomitant corticosteroid treatment - are indicators for poor prognosis of the cervical spine in RA. © 2012, Lippincott Williams & Wilkins.

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Comparison of reinnervation for preservation of denervated muscle volume with motor and sensory nerve

Omori Makoto, Sakakibara Shunsuke, Hashikawa Kazunobu, Terashi Hiroto, Tahara Shinya, Sugiyama Daisuke

Journal of Plastic, Reconstructive and Aesthetic Surgery 65 （ 7 ） 943 - 949 2012年07月

ISSN 1748-6815

Prevention of the atrophy of denervated muscles is essential for a good outcome in facial contouring and oral reconstruction. In this study, we compared the effectiveness of end-to-end and end-to-side neurorrhaphy of the motor nerve, and end-to-end neurorrhaphy of the sensory nerve, all of which are frequently used in such reconstruction for the prevention of muscle atrophy. Wistar rats were divided into four groups: group 1, motor nerve division of semi-membranosus without repair; group 2, motor nerve division and end-to-end coaptation to the saphenous nerve; group 3, motor nerve division and end-to-side coaptation to the sciatic nerve; and group 4, motor nerve division and end-to-end repair. Measurement of semi-membranosus volume, histological evaluation and staining of neuromuscular junctions that were carried out 3 months postoperatively revealed that muscle volume preservation was larger in groups 3 and 4 than in the other two groups (p < 0.05), but slightly superior in group 4 (p < 0.05). There was no statistical difference between groups 2 and 1; histologically, muscle architecture was better preserved in group 2 than in group 1; reactivation of the neuromuscular junctions was observed in all except group 1. End-to-side repair of motor nerves is one of the better options for the preservation of muscle volume when end-to-end nerve repair is not indicated. Sensory protection may also provide some advantages in the preservation of muscle volume. © 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

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Predicting scores for left ventricular dysfunction in Duchenne muscular dystrophy

Yamamoto Tetsushi, Kawano Seiji, Sugiyama Daisuke, Onishi Tetsuari, Hayashi Nobuhide, Takeshima Yasuhiro, Kawai Hiroya, Hirata Ken Ichi, Matsuo Masafumi, Kumagai Shunichi

Pediatrics International 54 （ 3 ） 388 - 392 2012年06月

ISSN 1328-8067

Background: The aim of this study was to predict left ventricular (LV) dysfunction and the timing to perform echocardiography in patients with Duchenne muscular dystrophy (DMD). We developed a scoring system using clinical parameters and examined its efficacy. It is indispensable to utilize echocardiogram for evaluating myocardial damage of DMD patients, but there is no established guideline for determining the clinical conditions which require echocardiographic examination. Methods: We retrospectively analyzed 86 patients with DMD who were treated in Kobe University Hospital from 2007 to 2009. The multiple logistic regression analysis on routine clinical data was performed to identify parameters that can find abnormal LV contraction, and to develop a weighted scoring system. Echocardiogram was performed as the gold standard for detecting LV dysfunction. Results: Four parameters were associated with abnormal LV contraction: (i) brain natriuretic peptide (BNP); (ii) creatine kinase; (iii) scoliosis; and (iv) body surface area. When BNP was used as the only predictor to evaluate LV systolic dysfunction, sensitivity and specificity were 36.4% and 92.1%, respectively. In contrast, abnormal LV contraction was detected in high accuracy (sensitivity: 95.5%; specificity: 68.3%) when we used a two-step scoring system in which BNP was combined with the other three factors, raising the sensitivity compared to using BNP levels as the single parameter (P= 0.008). Conclusion: Our scoring system detects the early heart dysfunction of DMD patients, especially when BNP level is not elevated. This system is useful to determine the timing for echocardiographic examination and consulting cardiologists. © 2012 Japan Pediatric Society.

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SS-A/Ro52 promotes apoptosis by regulating Bcl-2 production

Jauharoh Siti Nur Aisyah, Saegusa Jun, Sugimoto Takeshi, Ardianto Bambang, Kasagi Shimpei, Sugiyama Daisuke, Kurimoto Chiyo, Tokuno Osamu, Nakamachi Yuji, Kumagai Shunichi, Kawano Seiji

Biochemical and Biophysical Research Communications 417 （ 1 ） 582 - 587 2012年01月

ISSN 0006-291X

SS-A/Ro52 (Ro52), an autoantigen in systemic autoimmune diseases such as systemic lupus erythematosus and Sjögren's syndrome, has E3 ligase activity to ubiquitinate proteins that protect against viral infection. To investigate Ro52's role during stress, we transiently knocked it down in HeLa cells by siRo52 transfection. We found that Ro52 ^low HeLa cells were significantly more resistant to apoptosis than wild-type HeLa cells when stimulated by H ₂O ₂- or diamide-induced oxidative stress, IFN-α, IFN-γ and anti-Fas antibody, etoposide, or γ-irradiation. Furthermore, Ro52-mediated apoptosis was not influenced by p53 protein level in HeLa cells. Depleting Ro52 in HeLa cells caused Bcl-2, but not other Bcl-2 family molecules, to be upregulated. Taken together, our data showed that Ro52 is a universal proapoptotic molecule, and that its proapoptotic effect does not depend on p53, but is exerted through negative regulation of the anti-apoptotic protein Bcl-2. These findings shed light on a new physiological role for Ro52 that is important to intracellular immunity. © 2011 Elsevier Inc.

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Diagnostic accuracy of serum 1,3-β-D-glucan for Pneumocystis jiroveci pneumonia, invasive candidiasis, and invasive aspergillosis

Onishi Akira, Sugiyama Daisuke, Kogata Yoshinori, Saegusa Jun, Sugimoto Takeshi, Kawano Seiji, Morinobu Akio, Nishimura Kunihiro, Kumagaia Shunichi

Journal of Clinical Microbiology 50 （ 1 ） 7 - 15 2012年01月

ISSN 0095-1137

Serum 1,3-β-D-glucan (BG) assay may be helpful as a marker for the diagnosis of Pneumocystis jiroveci pneumonia (PJP) and invasive fungal infection (IFI). We conducted a systematic review to assess the diagnostic accuracy of this assay. We searched MEDLINE, Web of Science, Cochrane Collaboration databases, Ichushi-Web, reference lists of retrieved studies, and review articles. Our search included studies of serum BG assay that used (i) positive cytological or direct microscopic examination of sputum or bronchoalveolar lavage fluid for PJP and (ii) European Organization for Research and Treatment of Cancer or similar criteria for IFI as a reference standard and provided data to calculate sensitivity and specificity. Only major fungal infections such as invasive candidiasis and invasive aspergillosis were included in the IFI group. Twelve studies for PJP and 31 studies for IFI were included from January 1966 to November 2010. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic curve (AUC-SROC) for PJP were 96% (95% confidence interval [95% CI], 92% to 98%), 84% (95% CI, 83% to 86%), 102.3 (95% CI, 59.2 to 176.6) and 0.96 (95% CI, 0.94 to 0.99), respectively. No heterogeneity was found. For IFI, the values were 80% (95% CI, 77% to 82%), 82% (95% CI, 81% to 83%), 25.7 (95% CI, 15.0 to 44.1), and 0.88 (95% CI, 0.82 to 0.93). Heterogeneity was significant. The diagnostic accuracy of the BG assay is high for PJP and moderate for IFI. Because the sensitivity for PJP is particularly high, the BG assay can be used as a screening tool for PJP. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

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Importance of vital signs to the early diagnosis and severity of sepsis

Kenzaka Tsuneaki, Okayama Masanobu, Kuroki Shigehiro, Fukui Miho, Yahata Shinsuke, Hayashi Hiroki, Kitao Akihito, Sugiyama Daisuke, Kajii Eiji, Hashimoto Masayoshi

Internal Medicine 51 （ 8 ） 871 - 876 2012年

ISSN 0918-2918

Objective While much attention is given to the fifth vital sign, the utility of the 4 classic vital signs (blood pressure, respiratory rate, body temperature, and heart rate) has been neglected. The aim of this study was to assess a possible association between vital signs and the Sequential Organ Failure Assessment (SOFA) score in patients with sepsis. Methods We performed a prospective, observational study of 206 patients with sepsis. Blood pressure, respiratory rate, body temperature, and heart rate were measured on arrival at the hospital. The SOFA score was also determined on the day of admission. Results Bivariate correlation analysis showed that all of the vital signs were correlated with the SOFA score. Multiple regression analysis indicated that decreased values of systolic blood pressure (multivariate regression coefficient [Coef] = -0.030, 95% confidence interval [CI] = -0.046 to -0.013) and diastolic blood pressure (Coef = -0.045, 95% CI = -0.070 to -0.019), increased respiratory rate (Coef = 0.176, 95% CI = 0.112 to 0.240), and increased shock index (Coef = 4.232, 95% CI = 2.401 to 6.062) significantly influenced the SOFA score. Conclusion Increased respiratory rate and shock index were significantly correlated with disease severity in patients with sepsis. Evaluation of these signs may therefore improve early identification of severely ill patients at triage, allowing more aggressive and timely interventions to improve the prognosis of these patients. © 2012 The Japanese Society of Internal Medicine.

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Fasting remnant lipoproteins can predict postprandial hyperlipidemia

Nagata Tomoki, Sugiyama Daisuke, Kise Takako, Tsuji Satomi, Ohira Hideo, Sato Itsuko, Yamamoto Mari, Kohsaka Hitomi, Kawano Seiji, Yamashita Shizuya, Ishikawa Yuichi, Fujioka Yoshio

Lipids in Health and Disease 11 2012年

Background: Hypertriglyceridemia and postprandial hyperlipidemia is thought to play an important role in atherosclerosis, but to select patients at high-risk for cardiovascular diseases is difficult with triglycerides (TG) alone in these patients. Methods. To predict postprandial hyperlipidemia without inconvenient test meal loading, we examined lipid concentrations before and after test meal loading and fasting adiponectin, and investigated which of these other than TG were significant during the fasting period in 45 healthy individuals (men: women, 26:19). Results: TG, remnant-like particle-cholesterol and -triglyceride (RemL-C, RLP-C, and RLP-TG), and TG/apolipoprotein(apo)B were significantly elevated after loading and fasting values significantly and positively correlated with incremental area under the curve (iAUC) (r=0.80, r=0.79, r=0.63, r=0.58, r=0.54; p<0.0001). Fasting adiponectin positively correlated with fasting high-density lipoprotein-cholesterol (r=0.43, p<0.005) and apoA-I (r=0.34, p<0.05), and negatively correlated with iAUC of TG, RemL-C, RLP-C, RLP-TG, and TG/apoB (r=-0.37, r=-0.41, r=-0.37, r=-0.36, r=-0.37; p<0.05). We constructed the model of multivariable linear regression analysis without fasting TG. In the sex-, BMI-, age-, and waist circumference-adjusted analysis of postprandial TG elevation 2 h after test meal loading in all participants, RemL-C, RLP-C, RLP-TG, and TG/apoB were significant factors, but adiponectin was not. Conclusion: Fasting triglyceride-rich lipoprotein-related values, especially RemL-C, RLP-C, RLP-TG, and TG/apoB are useful predictors of postprandial hyperlipidemia in young healthy individuals. Although fasting adiponectin concentration correlated with the iAUCs for TG, RemL-C, RLP-C, RLP-TG, and TG/apoB, it was not a significant predictor of postprandial hyperlipidemia in multivariable linear regression analysis. © 2012 Nagata et al.; licensee BioMed Central Ltd.

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Novel theory for surgical reconstruction of segmental mandibular defect

Hashikawa Kazunobu, Sugiyama Daisuke, Yokoo Satoshi, Tahara Shinya

Japanese Journal of Head and Neck Cancer 38 （ 1 ） 84 - 89 2012年

ISSN 1349-5747

We propose the "CAT concept", a new theory for surgical reconstruction after oncological segmental mandibulectomy. The essence of the theory is to reconstruct three reference points on the mandible - "C" (condylar head) "A" (mandibular angle) and "T" - necessary and sufficient for its surgical reconstruction. An anthropometric analysis of the mandible of ten preserved human cadavers showed that the mandibular contour can be made merely 3 to 7 mm smaller than the original when the CAT concept is adopted, suggesting that the concept sufficiently satisfies the condition for surgical reconstruction of the mandible. A review of our 45 clinical cases of mandibular reconstruction after oncological ablation demonstrated a positive trend between the number of reconstructed or non-resected reference points of the CAT concept and the esthetic outcome of each patient (Fisher's exact test, p<0.01), suggesting that the concept satisfies the necessary condition. Given these results, we concluded that the CAT concept is a highly practical theory for the surgical reconstruction of segmental mandibular defects.

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Does high-sensitivity c-reactive protein or low-density lipoprotein cholesterol show a stronger relationship with the cardio-ankle vascular index in healthy community dwellers?

Higashiyama Aya, Wakabayashi Ichiro, Kubota Yoshimi, Adachi Yoshiko, Hayashibe Akiko, Nishimura Kunihiro, Sugiyama Daisuke, Kadota Aya, Imano Hironori, Miyamatsu Naomi, Miyamoto Yoshihiro, Okamura Tomonori

Journal of Atherosclerosis and Thrombosis 19 （ 11 ） 1027 - 1034 2012年

ISSN 1340-3478

Aim: High-sensitivity C-reactive protein (hs-CRP) identifies individuals at risk for cardiovascular disease (CVD) without an increased level of low-density lipoprotein cholesterol (LDL-C). The present study was performed to compare hs-CRP and LDL-C in association with the cardio-ankle vascular index (CAVI) in Japanese community dwellers considered to be at low risk for atherosclerosis from their level of traditional CVD risk factors. Methods: A community-based study involving 386 healthy Japanese (261 men and 125 women) without a history of CVD and medications for hypertension, diabetes, and dyslipidemia was performed. Multiple adjustments were performed with linear regression models to estimate the association between CAVI and hs-CRP or LDL-C levels. The participants were divided into four groups on the basis of whether they were above or below the median hs-CRP and LDL-C values, and CAVI was compared among the four groups by analysis of covariance after adjusting for confounders. Results: In multiple linear regression models, hs-CRP showed a significant positive association with CAVI; however, no clear association was observed between CAVI and LDL-C. These results were similar in the analyses among the participants with LDL-C <140 mg/dL or hs-CRP <1.0 mg/L. CAVI was higher in the groups with high hs-CRP than in those with low hs-CRP, irrespective of LDL-C; however, CAVI was highest in the group with high LDL-C and high hs-CRP. Conclusions: The present study suggests that hs-CRP could be a better risk factor assessor for atherosclerosis than LDL-C in individuals considered to be at low risk for atherosclerosis assessed by their traditional CVD risk factors.

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Utility of right ventricular free wall speckle-tracking strain for evaluation of right ventricular performance in patients with pulmonary hypertension

Fukuda Yuko, Tanaka Hidekazu, Sugiyama Daisuke, Ryo Keiko, Onishi Tetsuari, Fukuya Hiroyuki, Nogami Munenobu, Ohno Yoshiharu, Emoto Noriaki, Kawai Hiroya, Hirata Ken Ichi

Journal of the American Society of Echocardiography 24 （ 10 ） 1101 - 1108 2011年10月

ISSN 0894-7317

Background: The objectives of this study were to test the utility of right ventricular (RV) speckle-tracking strain as an assessment tool for RV function in patients with pulmonary hypertension (PH) compared with conventional echocardiographic parameters and to investigate the relationship of the findings obtained with RV speckle-tracking strain with the hemodynamic parameters of RV performance. Methods: Forty-five prospective consecutive patients with PH were studied. RV free wall longitudinal speckle-tracking strain (RV-free) and RV septal wall longitudinal speckle-tracking strain (RV-septal) were calculated by averaging each of three regional peak systolic strains along the entire right ventricle. The conventional echocardiographic parameters - RV fractional area change, RV myocardial performance index, tricuspid annular plane systolic excursion, and tricuspid annular peak systolic velocity - were also studied. For comparison, 22 age-matched volunteers with normal ejection fractions were studied. Results: RV-free in patients with PH was significantly lower than that in normal controls, but RV-septal in the two groups was similar. Importantly, multivariate analysis revealed that RV-free was an independent echocardiographic predictor of hemodynamic RV performance items, including mean pulmonary artery pressure (β = -0.844, P =.001) and pulmonary vascular resistance (β = -0.045, P <.001). RV-free was also correlated with RV ejection fraction and RV end-systolic volume measured by cardiac magnetic resonance imaging and with 6-min walking distance (r = 0.60, r = 0.56, and r = 0.49, respectively, P <.05). Furthermore, the improvement in RV-free 5 ± 3 months after adding medical treatment was significantly correlated with that in 6-min walking distance (r = 0.68, P <.0001). Conclusions: RV-free has the potential to allow for noninvasive follow-up of patients with PH. Copyright 2011 by the American Society of Echocardiography.

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Reverse remodelling induces progressive ventricular resynchronization after cardiac resynchronization therapy 'from vicious to virtuous cycle'

Matsumoto Kensuke, Tanaka Hidekazu, Okajima Katsunori, Hayashi Takatoshi, Kajiya Teishi, Sugiyama Daisuke, Kawai Hiroya, Hirata Ken Ichi

European Journal of Echocardiography 12 （ 10 ） 782 - 789 2011年10月

ISSN 1525-2167

Aims: Cardiac resynchronization therapy (CRT) can stop the vicious cycle resulting from dyssynchrony and generates left ventricular (LV) reverse remodelling. Our objective was to assess the time course and the relationship between improvement in LV dyssynchrony and reverse remodelling after CRT. Methods and results: Sixty-four consecutive patients were evaluated before, immediately after, and 3- and 6 months after CRT. We measured LV volumes, ejection fraction (EF), and sphericity index, and dyssynchrony was assessed using speckletracking radial strain. Response was defined as a >15% decrease in end-systolic volume (ESV) 6 months after CRT, and event-free survival was followed for 24 months. Responders and non-responders had similar baseline LV volumes and EF. During the first and the following 3 months after CRT, LV volumes gradually decreased (enddiastolic volume: 195±73 to 164+60* to 129±51 mL†, ESV: 141±70 to 110±47* to 82±40 mL†), and sphericity index and EF progressively increased (sphericity index: 1.52±0.20 to 1.75±0.31* to 1.94±0.34†, EF: 28±7 to 34±7* to 38±8%†, *†P < 0.001) in responders. No such changes were observed in non-responders. Furthermore, dyssynchrony diminished progressively during the first and the following 3 months after CRT and patients with progressive resynchronization experienced fewer major cardiovascular events than those without (P < 0.001). Conclusion: CRT can stop the vicious cycle of remodelling and dyssynchrony, and actually, turn it into the virtuous cycle of reverse remodelling and further resynchronization. All rights reserved. © The Author 2011.

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Plasma platelet-derived microparticles in patients with connective tissue diseases

Oyabu Chinami, Morinobu Akio, Sugiyama Daisuke, Saegusa Jun, Tanaka Shino, Morinobu Sahoko, Tsuji Goh, Kasagi Shimpei, Kawano Seiji, Kumagai Shunichi

Journal of Rheumatology 38 （ 4 ） 680 - 684 2011年04月

ISSN 0315-162X

Objective. To clarify the role of platelet-derived microparticles (PDMP), which are small vesicles with thrombotic and immunological properties, in systemic lupus erythematosus (SLE), systemic sclerosis (SSc), dermatomyositis/polymyositis (PM/DM), and mixed connective tissue disease (MCTD). Methods. Plasma levels of PDMP were measured by ELISA, and compared among patients with one of the 4 diseases. Association of PDMP levels with clinical characteristics and medication of the patients was also examined. Results. PDMP levels were higher in patients with MCTD and SSc than in controls. Multiple linear regression analysis revealed that patients with Raynaud's phenomenon (RP) showed higher PDMP levels than those without. PDMP levels in individual patients did not fluctuate significantly over several months. Conclusion. PDMP level is associated with MCTD, SSc, and RP, and could be a novel marker for RP. The Journal of Rheumatology Copyright © 2011. All rights reserved.

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Association of calcineurin A gamma subunit (PPP3CC) and early growth response 3 (EGR3) gene polymorphisms with susceptibility to schizophrenia in a Japanese population

Kyogoku Chieko, Yanagi Masaya, Nishimura Kunihiro, Sugiyama Daisuke, Morinobu Akio, Fukutake Masaaki, Maeda Kiyoshi, Shirakawa Osamu, Kuno Takayoshi, Kumagai Shunichi

Psychiatry Research 185 （ 1-2 ） 16 - 19 2011年01月

ISSN 0165-1781

To examine the association of PPP3CC (rs10108011 and rs2461491) and EGR3 (rs3750192) single-nucleotide polymorphisms (SNPs) with Japanese schizophrenia, we performed a case-control association study using 337 patients and 369 healthy controls. As a result, by our moderated cohort-size study, PPP3CC and EGR3 are not genetic risk factors for schizophrenia, whereas meta-analysis showed weak association of rs10108011 with schizophrenia in the Japanese population (odds ratio (OR) = 1.12, P= 0.01). © 2009 Elsevier Ireland Ltd.

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Dobutamine-induced improvement in inferior myocardial contractile function predicts reduction in functional mitral regurgitation

Tatsumi Kazuhiro, Kawai Hiroya, Sugiyama Daisuke, Norisada Kazuko, Kataoka Toshiya, Onishi Tetsuari, Tanaka Hidekazu, Hirata Ken Ichi

Circulation: Cardiovascular Imaging 3 （ 6 ） 638 - 646 2010年11月

ISSN 1941-9651

Background - Left ventricular (LV) remodeling can increase tethering force to mitral valve and functional mitral regurgitation (FMR). Because the relationship between FMR and regional myocardial function has not been quantitatively evaluated, we conducted a quantitative investigation of this association. Methods and Results-The effective regurgitant orifice (ERO) of FMR in 51 patients with depressed LV ejection fraction (32±9%) secondary to ischemic or nonischemic cardiomyopathy was compared with mitral deformation (valve and annulus), global LV remodeling (volume indices, function, and sphericity), and regional myocardial contractile function, as assessed by longitudinal peak systolic strain rate (Ssr) in LV anterior, anteroseptal, inferoseptal, inferior, inferolateral, and anterolateral segments at rest. Low-dose dobutamine (10 μg/kg per minute)-induced changes in ERO were compared with changes in the variables. Multivariable analysis identified the predictors of ERO at rest as mitral valvular tenting (β=0.062; P<0.001), Ssr in the inferior segment (inferior Ssr) (β=-0.178; P<';.001), and LV sphericity (β=0.414; P=0.001) and the predictors of valvular tenting at rest as inferior Ssr (β=1.680; P<;0.001), LV end-systolic volume index (β=0.022; P=0.001), and LV sphericity (β=3.886; P=0.012). Furthermore, dobutamineinduced reduction in ERO was predicted by reduction in valvular tenting (β=-0.087; P<;0.001) and increase in inferior Ssr (β=-0.082; P<;0.001), and dobutamine-induced reduction in valvular tenting was predicted by increase in inferior Ssr (β=-0.860; P<;0.001).Conclusions-Inferior regional myocardial dysfunction was quantitatively associated with mitral valvular tenting and FMR. Moreover, improvement with dobutamine of inferior myocardial contractile function attenuated valvular tenting and FMR. Inferior myocardial contractile function can affect the configuration of the mitral apparatus and predict FMR severity. © 2010 American Heart Association, Inc.

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Congenital cholesteatoma

Inokuchi Go, Okuno Taeko, Hata Yuko, Baba Miyuki, Daisuke Sugiyama

Annals of Otology, Rhinology and Laryngology 119 （ 7 ） 490 - 494 2010年07月

ISSN 0003-4894

Objectives: We described the characteristics of congenital cholesteatoma in Japanese patients and assessed whether the staging system is useful for predicting the rate of residual disease, the need for reexploration, and surgical outcomes. Methods: We performed a retrospective chart analysis of 23 consecutive patients with congenital cholesteatoma. Results: The proportion of cases with anterior-superior quadrant involvement was significantly lower in the Asian group than in Western patients. The total residual rate was 26%, and there was a positive association between stage and residual rate, ranging from 0% in stage ? and ?? to 44% in stage IV. Canal wall-up tympanomastoidectomy was the most frequent procedure (57%), and 61% had reexploration. Conclusions: Congenital cholesteatoma in Asia is less likely to involve the anterior-superior quadrant than in Western patients. The 4-stage system was useful for predicting residual rates, even in patients in whom anterior-superior quadrant involvement was less common. Postoperative hearing was significantly related to the stages. A routine second-look procedure may be unnecessary in the early stages, whereas reexploration would be better performed in advanced stages. Endoscopy might reduce residual disease and the need for reexploration in the near future. © 2010 Annals Publishing Company. All rights reserved.

Preoperative systolic strain rate predicts postoperative left ventricular dysfunction in patients with chronic aortic regurgitation

Onishi Tetsuari, Kawai Hiroya, Tatsumi Kazuhiro, Kataoka Toshiya, Sugiyama Daisuke, Tanaka Hidekazu, Okita Yutaka, Hirata Ken Ichi

Circulation: Cardiovascular Imaging 3 （ 2 ） 134 - 141 2010年03月

ISSN 1941-9651

Background-The best predictor for postoperative left ventricular (LV) systolic dysfunction in patients with chronic aortic regurgitation is still a matter of debate. The aim of this study was to assess the clinical significance of preoperative systolic radial strain rate (Ssr) derived from tissue Doppler echocardiography as a predictor of postoperative LV systolic dysfunction in patients with chronic aortic regurgitation. Methods and Results-In 52 patients (mean age, 58 years; 13 women) with isolated chronic aortic regurgitation, we performed standard and tissue Doppler echocardiography before and after operation, obtained echocardiographic parameters such as LV dimensions and LV ejection fraction, and measured Ssr in 4 walls of the LV. Linear regression analysis determined correlations between preoperative parameters and postoperative LV ejection fraction. Receiver-operating characteristic curve analysis assessed the optimal cutoff values of parameters that predicted postoperative LV systolic dysfunction (ejection fraction <50%). The operation caused significant decreases in LV dimensions and volumes and significant increases in Ssr (1.94±0.64 to 2.39±0.83 per second; P<0.001) and ejection fraction (53.0±8.7 to 59.0±8.8%; P<0.001). Multiple regression analysis demonstrated that averaged Ssr was the only independent predictor of postoperative LV systolic dysfunction among the covariates examined (P<0.001). Using receiver-operating characteristic curve analysis, averaged Ssr yielded the greatest area under the curve among preoperative parameters (0.80) and was indicated to be a good predictor of postoperative LV dysfunction, with 90.9% sensitivity and 73.2% specificity (cutoff value, 1.82 per second). Conclusions-Measurement of preoperative averaged Ssr is useful in predicting postoperative LV systolic dysfunction and optimizing surgical timing in patients with isolated chronic aortic regurgitation.

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Haemodynamic changes in the fingers after free radial forearm flap transfer

Yanagisawa Akira, Hashikawa Kazunobu, Sugiyama Daisuke, Makiguchi Takaya, Yanagi Hideyuki, Kumagai Shunichi, Yokoo Satoshi, Terashi Hiroto, Tahara Shinya

Journal of Plastic, Reconstructive and Aesthetic Surgery 63 （ 3 ） 539 - 543 2010年03月

ISSN 1748-6815

Harvesting the radial forearm flap may cause circulatory problems in the donor arm. To investigate the influence on donor hands after radial forearm flap harvesting, we assessed the process of circulatory changes prospectively by measuring skin perfusion pressure (SPP) that is clinically useful in detecting vascular lesions. The records of 17 patients (14 men and 3 women aged 59.7 ± 11.8 years) who had undergone free radial forearm flap transfer for head and neck reconstruction, between December 2005 and April 2007, were analysed. SPP in the thumb (finger I), the middle finger (III) and the little finger (V) was measured in the 17 patients preoperatively and 1 month and 3, 6, 9 and 12 months postoperatively. All statistical tests were two sided, with a significance level defined as p < 0.05. Preoperatively, baseline SPP was more dominant in finger I than in finger V. Postoperatively, SPP changed significantly in both fingers, while it showed no change in finger III and tended to be higher in finger I than in the other two. Harvesting the free radial forearm flap reduces skin perfusion in the fingers of the donor arm and, we assume, leads to a re-distribution of blood flow to the fingers, with the residual ulnar artery still supplying more blood flow to finger I than to finger V. This suggests the presence of an autoregulating mechanism whereby blood perfusion to the fingers is controlled by the physiological demands of individual fingers. © 2010 British Association of Plastic, Reconstructive and Aesthetic Surgeons.

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Impact of smoking as a risk factor for developing rheumatoid arthritis

Sugiyama D., Nishimura K., Tamaki K., Tsuji G., Nakazawa T., Morinobu A., Kumagai S.

Annals of the Rheumatic Diseases 69 （ 1 ） 70 - 81 2010年01月

ISSN 0003-4967

Objectives: To assess whether smoking is a risk factor for developing rheumatoid arthritis (RA). Design: Meta-analysis. Method: Data sources were observational studies that examined the association between smoking history and the risk of developing RA identified through Medline and EMBASE (from 1966 to December 2006), relevant books and a reference search. Two authors independently extracted the following: authors' names, publication year, sample size, participant characteristics, odds ratios (OR) or relative risks, adjustment factors, study design and area where the study was conducted. Data syntheses were based upon random effects model. Summarised syntheses effects were expressed by OR. Results: Sixteen studies were selected from among 433 articles. For men, summary OR for ever, current and past smokers were 1.89 (95% CI 1.56 to 2.28), 1.87 (1.49 to 2.34) and 1.76 (1.33 to 2.31), respectively. For rheumatoid factor-positive (RF+) RA, summary OR for ever, current and past smokers were 3.02 (2.35 to 3.88), 3.91 (2.78 to 5.50) and 2.46 (1.74 to 3.47), respectively. Summary OR for 20 or more pack-years of smoking was 2.31 (1.55 to 3.41). For women, summary OR for ever, current and past smokers were 1.27 (1.12 to 1.44), 1.31 (1.12 to 1.54) and 1.22 (1.06 to 1.40), respectively. For RF+ RA, summary OR for ever, current and past smokers were 1.34 (0.99 to 1.80), 1.29 (0.94 to 1.77) and 1.21 (0.83 to 1.77). Summary OR for 20 or more pack-years of smoking was 1.75 (1.52 to 2.02). Conclusion: Smoking is a risk factor for RA, especially RF+ RA men and heavy smokers.

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Serum matrix metalloproteinase-3 as predictor of joint destruction in rheumatoid arthritis, treated with non-biological disease modifying anti-rheumatic drugs

Mamehara Akira, Sugimoto Takeshi, Sugiyama Daisuke, Morinobu SAHOKO, Tsuji Goh, Kawano Seiji, Morinobu Akio, Kumagai Shunichi

Kobe Journal of Medical Sciences 56 （ 3 ） 2010年

ISSN 0023-2513

Background: Rheumatoid factor (RF), anti-citrullinated peptide antibody (ACPA), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) have been studied extensively as prognostic markers of rheumatoid arthritis (RA). However, despite the fact that matrix metalloproteinase-3 (MMP-3) is linked to RA activity, few studies have evaluated MMP-3 as prognostic marker. Objective: To evaluate the performance of MMP-3 as predictor of joint destruction in RA treated with non-biological disease modifying anti-rheumatic drugs. Methods: In a retrospective study of 58 early to moderate stage RA patients who consulted the Department of Clinical Pathology and Immunology, Kobe University Hospital between May 2002 and April 2009, we evaluated the performance of MMP-3 and other biomarkers as predictors of joint destruction, by comparing them between radiographically progressive and non-progressive group. Results: Serum levels of RF at entry and ACPA, but not MMP-3 at entry, were significantly higher for the progressive group. Ratios of patients with MMP-3 levels higher than healthy control were not significantly different for the two groups. However, cutoff values determined through receiver operating characteristic analysis showed that the ratio of patients with elevated RF was significantly higher in the progressive group (p=0.001), while MMP-3 (p=0.092), ACPA (p=0.052), CRP (p=0.056), and ESR (p=0.069) tended to be more elevated in the progressive group. Multiple logistic regression analysis using the cutoff value identified MMP-3 positive and RF positive, but not ACPA, CRP or ESR, as significant factors for radiographic progression (OR 16.79 [95% CI: 1.34-414.19]). Conclusion: MMP-3 can be a useful marker for prediction of joint destruction.

Validity and utility of cat classification system for oncological mandibular defects A multi-institutional study

Hashikawa Kazunobu, Tahara Shinya, Sugiyama Daisuke, Yokoo Satoshi, Hyodo Ikuo, Motomura Hisashi, Kubo Tateki, Kurita Tomoyuki, Yoshimoto Seiichi, Takushima Akihiko, Yamashita Tetsuro, Sakuraba Minoru, Yagihara Kazuhiro, Nakagawa Masahiro, Yano Tomoyuki, Ishida Katsuhiro, Sakurai Hiroyuki, Terao Yasunobu, Tanaka Katsumi, Kimata Yoshihiro

Toukeibu Gan 36 （ 3 ） 309 - 315 2010年

ISSN 1349-5747

Background: We have previously proposed the CAT classification system, a simple and clear-cut system for classifying segmental mandibular defects after oncological surgery: “C” refers to the loss of the condylar head of the mandible, “A” the mandibular angle and “T” the mental tubercle. Here, we report a statistical and mathematical taxonomical study on the validity and utility of the classification system. Methods: Data were collected from 17 medical institutions in Japan on 259 patients who had undergone surgical ablation and simultaneous microsurgical oromandibular reconstruction (osteocutaneous free flap or soft tissue free flap with reconstruction-plate) attributed to head and neck cancer. The mandibular defects were classified according to the CAT system and the two commonly used systems HCL and Urken, and the validity and utility of the CAT system were tested as follows: 1) the tendency among the numbers of the three reference points of the CAT system (C, A and T) and the esthetic outcome of each patient were analyzed by Jonckheere's trend test, 2) each of the classified patterns of the three systems was analyzed by cluster analysis based on the esthetic results using Ward's method. Results: 1) There was a statistically significant trend among the numbers of the three reference points in the CAT system and the esthetic outcome, 2) each of the grouped clusters in the CAT system was clinically explicable and demonstrated a significant difference in the esthetic outcome; the two other systems did not yield such information. Conclusion: The CAT classification system is valid and useful for oncological segmental mandibular defects.

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Plasma tetrahydrobiopterin/dihydrobiopterin ratio - A possible marker of endothelial dysfunction

Takeda Masafumi, Yamashita Tomoya, Shinohara Masakazu, Sasaki Naoto, Takaya Tomofumi, Nakajima Kenji, Inoue Nobutaka, Masano Tomoya, Tawa Hideto, Satomi-Kobayashi Seimi, Toh Ryuji, Sugiyama Daisuke, Nishimura Kunihiro, Yokoyama Mitsuhiro, Hirata Ken Ichi, Kawashima Seinosuke

Circulation Journal 73 （ 5 ） 955 - 962 2009年05月

ISSN 1346-9843

Background: Although endothelium-dependent vasodilatation has been used as a marker of endothelial dysfunction (ED), there have been no reliable plasma markers for ED. Oxidative stress, which is a major determinant of ED, oxidizes tetrahydrobiopterin (BH4), an essential cofactor of endothelial type nitric oxide synthase (eNOS), and resulted in the relative deficiency of BH4. Methods and Results: In 163 patients with cardiovascular disorders, the plasma levels of BH4 and 7, 8-dihydrobiopterin (BH2) by high performance liquid chromatography were measured and compared with the flow-mediated (FMD) vasodilatory response of the brachial artery, which was measured by ultrasonography. The effects of atorvastatin on plasma pteridine levels and FMD were examined in patients with multiple coronary risk factors. There was a positive relationship between FMD and plasma BH4 levels and a negative relationship between FMD and plasma BH2 levels. Subsequently, a strong positive relationship between FMD and the BH4/BH2 ratio (r=0.585, P<0.0001) was found. Although we did not find any significant relationship between pteridine levels and individual traditional risk factors, the BH4/BH2 ratio in patients with more than 2 risk factors showed significant reductions compared with that in those without risk factors. Statin treatment improved FMD in association with an increase in the plasma BH4/BH2 ratio. Conclusions: Plasma pteridine levels were associated with endothelial dysfunction in cardiovascular disorders.

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Delivery may affect arterial elasticity in women

Hashimoto Masayoshi, Miyamoto Yoshitomo, Iwai Chikao, Matsuda Yasuaki, Hiraoka Eiji, Kanazawa Kenji, Nishimura Kunihiro, Sugiyama Daisuke, Ito Kazuo, Yamori Yukio, Akita Hozuka

Circulation Journal 73 （ 4 ） 750 - 754 2009年04月

ISSN 1346-9843

Background: Estrogen is considered to be cardioprotective, but estrogen replacement therapy for postmenopausal women has not shown results for either primary or secondary cardiovascular event prevention. During normal pregnancy, women have significantly higher levels of estrogen and it may be endogenous estrogen that helps prevent atherosclerosis. Methods and Results: The present cross-sectional study examined the association between pregnancy followed by delivery and clinical atherosclerosis using the brachial-ankle pulse wave velocity (PWV). A total of 2,560 women undergoing annual health screening at the Institute of Hyogo Prefecture Health Promotion Association in Japan were recruited. Pregnancy history (the age of menarche/menopause and the number of gravida/para), conventional coronary risk factors, and brachial-ankle PWV were recorded. Multivariate linear regression by stepwise selection analysis demonstrated that women who had 1 or more deliveries had a significantly lower PWV, independent of age and other conventional coronary risk factors. Conclusions: Pregnancy followed by delivery may decrease arterial stiffness and prevent the progress of atherosclerosis in women. The contribution of such a pregnancy followed by delivery-related decrease in arterial stiffness to the reduction of cardiovascular disease in women should be further evaluated.

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Comparison of remnant lipoprotein-cholesterol measurements

Hihara Mari, Sato Itsuko, Hayashi Fujio, Sugiyama Daisuke, Kawano Seiji, Fujioka Yoshio, Ishikawa Yuichi, Kumagai Shunichi

Rinsho byori. The Japanese journal of clinical pathology 57 （ 1 ） 24 - 30 2009年01月

ISSN 0047-1860

Elevation of serum remnant lipoprotein concentration is an emerging risk factor for coronary artery disease. An immunoseparation procedure for remnant-like particle cholesterol(RLP-C) has been evaluated extensively in recent years. In addition, a new detergent-based method has been developed and applied to automated analyzer as "MetaboLead RemL-C" (RemL-C, KYOWA MEDEX CO., LTD.). Then, we compared the concentrations of remnant lipoproteins as RemL-C with those as RLP-C in various conditions. RemL-C assay was intra-assay-reproducible (n=20, CVs: 0.6-2.2%), and reproducible for 2 days in the refrigeration and for 8 hours in room temperature. This assay was also inter-assay-reproducible (during 5 days in the deep freezing, CVs: 1.6-3.0%). The available range for RemL-C assay was between 0.09 and 121.1 mg/dl. There were no detectable interferences from hemoglobin, free/conjugated bilirubin, chyle, and Intrafat. However, heparin influenced the titer of RemL-C concentrations. Correlation of values between RLP-C and RemL-C in 123 samples was excellent (r=0.924, p<0.001). However, different responses to intermediate lipoprotein fraction derived from a patients with type III hyperlipidemia were observed. In conclusion, RemL-C and RLP-C measurements may have a similar clinical significance. Differences in sensitivity for intermediate lipoprotein fraction between both methods may exist.

Lack of association between tyrosine kinase 2 (TYK2) gene polymorphisms and susceptibility to SLE in a Japanese population

Kyogoku Chieko, Morinobu Akio, Nishimura Kunihiro, Sugiyama Daisuke, Hashimoto Hiroshi, Tokano Yoshiaki, Mimori Tsuneyo, Terao Chikashi, Matsuda Fumihiko, Kuno Takayoshi, Kumagai Shunichi

Modern Rheumatology 19 （ 4 ） 401 - 406 2009年

ISSN 1439-7595

Tyrosine kinase 2 (TYK2) is a type I interferon (IFN) signaling pathway gene and was previously reported to be a risk factor for systemic lupus erythematosus (SLE) in Caucasian populations. In order to test for its genetic association with SLE in a Japanese population, TYK2 single nucleotide polymorphisms (SNPs), rs2304256, rs12720270 and rs280519, were genotyped. A case - control association study was performed in a total of 411 Japanese SLE patients and 467 healthy controls. Linkage disequilibrium (LD) among TYK2 SNPs was examined. According to the data from 94 healthy controls, non-synonymous rs2304256 resulting in Val → Phe substitution was revealed to be in a LD with rs12720270 and rs280519. Therefore, we further genotyped rs2304256 as a tag SNP in the full sample sets. As a result, no differences in genotype distribution and allelic frequencies of rs2304256 were found between SLE patients and healthy controls. In conclusion, TYK2 is not a genetic risk factor for SLE in a Japanese population. Our result suggests that there is an ethnic difference in the susceptibility genes for SLE.

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Usefulness of the formula for predicting creatinine clearance from serum cystatin C

Oyabu Chinami, Hayashi Nobuhide, Sugiyama Daisuke, Umezu Michio, Kinoshita Shouhiro, Hayashi Hiroki, Kawano Seiji, Kumagai Shunichi

Rinsho byori. The Japanese journal of clinical pathology 56 （ 12 ） 1093 - 1099 2008年12月

ISSN 0047-1860

Estimation of Glomerular filtration rate (GFR) is crucial for the detection of renal insufficiency. In clinical practice, GFR is generally estimated from Ccr by some prediction formulas including the serum creatinine concentration and some variables: age, sex, body size. It has been suggested that serum cystatin C is less influenced by sex, body size, muscular mass or inflammation. In several studies, serum cystatin C performed better than serum creatinine did as a marker to detect GFR reduction. We developed the formula for predicting creatinine clearance (Ccr) from serum cystatin C, serum creatinine and serum beta 2-microgroburin by multiple regression analysis. In this study, we analysed 24-hour Ccr and variables (sex, age and BMI) in 82 subjects with renal diseases to develop suitable formulas. Our serum cystatin C formula is as follows: Ccr (ml/min/1.73m2) = (12.14-0.03 x age-1.72 x serum cystatin C) 2. Correlation between measured 24-hour Ccr and predicted Ccr by our serum cystatin C formula was higher (r=0.852) than our serum creatinine formula (r=0.755), serum beta 2-microgroburin formula (r=0.793), Cockcroft-Gault formula (r=0.836) and Horio formula (r=0.825). Accuracy within 15% was higher (39.0%) than other formulas (25.6-30.5%). Our formula using serum cystatin C for predicting Ccr is a useful and precise marker for Ccr than other commonly used formulas using serum creatinine.

Importance of skin perfusion pressure in treatment of critical limb ischemiai

Tsuji Yoriko, Hiroto Terashi, Kitano Ikuro, Tahara Shinya, Sugiyama Daisuke

Wounds 20 （ 4 ） 95 - 100 2008年04月

ISSN 1044-7946

The authors studied whether skin perfusion pressure (SPP) measurements can be used to accurately predict wound healing in critical limb ischemia (CLI) and to select peripheral arterial reconstructive procedures. Methods. Forty-seven patients (33 men and 14 women, age 36ĝ€"83 years) with 69 ischemic limbs with foot ulcers or gangrene were studied retrospectively. Skin perfusion pressure was compared to the treatment outcomes (ulcers healed and ulcers that failed to heal). As a diagnostic test for CLI, the sensitivity, specificity, and the positive and the negative predictive values (PPV, NPV) of SPP measurement were calculated; the data was then analyzed by the receiver operation characteristic (ROC) curve. Results. According to the ROC curve, the best SPP measurement performance was at 35 mmHg. Conclusion. Wound healing at the appropriate amputation level must be predicted to minimize invasive debridement. Skin perfusion pressure measurement is useful for predicting wound healing in the presence of CLI. Skin perfusion pressure ĝ‰¥ 35 mmHg is requisite for wound healing; at SPP

Prevalence of disease-specific antinuclear antibodies in general population

Hayashi Nobuhide, Koshiba Masahiro, Nishimura Kunihiro, Sugiyama Daisuke, Nakamura Tomoko, Morinobu Sahoko, Kawano Seiji, Kumagai Shunichi

Modern Rheumatology 18 （ 2 ） 153 - 160 2008年04月

ISSN 1439-7595

The aim of this study was to investigate the types and prevalence of disease-specific antinuclear antibodies (ANAs) and their relationship to rheumatic diseases in the general Japanese population. An immunofluorescence (IF) method was used for the first screening of ANA levels in serum samples obtained from 2181 residents of a small Japanese town. Individuals positive for IF-ANA were then further tested for disease-specific ANAs using eight enzyme immunoassays. Physical status and the presence of illness were determined by means of questionnaires and medical examinations. Based on the result of the IF-ANA assay, the rates of positive samples at 1:40 and 1:160 dilutions were 26.0 and 9.5%, respectively, with females have significantly higher positivity rates than males (P < 0.0001). Among 566 IF-ANA-positive individuals, 100 individuals were found to have 114 disease-specific ANAs. Anti-SSA/ Ro, anti-centromere, and anti-U1RNP antibodies were detected in 58, 30, and 11 individuals, respectively, but anti-Sm, anti-Scl-70, and anti-Jo-1 antibodies were undetectable. Questionnaires and medical examinations revealed that among 60 disease-specific ANA-positive individuals that were available for testing, six had Sjögren's syndrome (SS), five were suspected of having SS, and five had rheumatoid arthritis. Surprisingly, 34 (57%) of the disease-specific ANA-positive individuals were clinically healthy. Anti-SSA/Ro, anti-centromere, and anti-U1RNP antibodies were quite frequent among clinically healthy Japanese subjects, although anti-Sm, anti-Scl-70, and anti-Jo-1 antibodies were not. Of the 60 individuals who tested positive for disease-specific ANAs, 30% (18/60) actually manifested systemic rheumatic diseases, while 50% showed no detectable signs or symptoms of rheumatic diseases.

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Diagnostic accuracy of serum procalcitonin concentrations for detecting systemic bacterial infection in patients with systemic autoimmune diseases

Tamaki Kenichiro, Kogata Yoshinori, Sugiyama Daisuke, Nakazawa Takashi, Hatachi Saori, Kageyama Gohichi, Nishimura Kunihiro, Morinobu Akio, Kumagai Shunichi

Journal of Rheumatology 35 （ 1 ） 114 - 119 2008年01月

ISSN 0315-162X

Objective. To examine whether serum procalcitonin (PCT) concentrations are useful for distinguishing bacterial infections from disease flares in patients with systemic autoimmune diseases. Methods. Patients with systemic autoimmune diseases who were admitted to our hospitals due to either a suspected deterioration of their primary diseases or an infectious disease were enrolled. Serum PCT levels were measured in 99 serum samples of 98 patients who had elevated serum C-reactive protein (CRP) levels; 29 samples were obtained from patients with bacterial infections, and 70 samples were obtained from patients with disease deterioration without a detectable infection. The diagnostic accuracy, sensitivity, and specificity for identifying a bacterial infection were estimated using the receiver-operating characteristic curve. Multiple logistic regression analysis was also done with PCT level, age, sex, steroid dose, and use of immunosuppressive agents. Results. Serum PCT levels were higher in the bacterial infection group than in the disease flare group (mean ± SD, 4.539 ± 9.677 vs 0.116 ± 0.127; p < 0.0001). The diagnostic accuracy of PCT for bacterial infection was 0.797, sensitivity 53.3%, and specificity 97.1%. On multivariate analysis, the odds ratio of a PCT ≥ 0.5 ng/ml was significant (OR 59.085, 95% CI 7.705-453.088, p < 0.0001) for identifying bacterial infection. Conclusion. Elevated serum PCT levels have a good specificity for diagnosing bacterial infection in patients with systemic autoimmune diseases regardless of their dosage of oral corticosteroids and immunosuppressive agents.

Overestimation of serum levels of rheumatoid factor caused by the presence of an incorrect calibrator in the Dade Behring kit

Hayashi Nobuhide, Kawano Seiji, Sugiyama Daisuke, Nishimura Kunihiro, Nakazawa Takashi, Morinobu Akio, Kumagai Shunichi

Modern Rheumatology 17 （ 5 ） 447 - 449 2007年10月

ISSN 1439-7595

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Thioredoxin may exert a protective effect against tissue damage caused by oxidative stress in salivary glands of patients with Sjögren's syndrome

Kurimoto Chiyo, Kawano Seiji, Tsuji Goh, Hatachi Saori, Jikimoto Takumi, Sugiyama Daisuke, Kasagi Shimpei, Komori Takahide, Nakamura Hajime, Yodoi Junji, Kumagai Shunichi

Journal of Rheumatology 34 （ 10 ） 2035 - 2043 2007年10月

ISSN 0315-162X

Objective. To demonstrate the existence of oxidative stress and the role of the antioxidant thioredoxin (TRX) in Sjögren's syndrome (SS). Methods. Labial biopsy specimens from patients with SS were analyzed immunohistochemically to detect 8-hydroxy-2′-deoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal (4-HNE), nitrotyrosine, and TRX. Levels of TRX in saliva and plasma were quantified by ELISA. To analyze the effect of TRX on human salivary gland (HSG) cells, recombinant TRX (rTRX)-treated HSG cells were stimulated by interferon-γ (IFN-γ) for detecting interleukin 6 (IL-6) with ELISA and RT-PCR, or stimulated with IFN-γ and anti-Fas antibody for analyzing Fas-induced apoptosis with PI/annexin V staining. Results. Large amounts of 8-OHdG, 4-HNE, nitrotyrosine, and TRX were produced in salivary duct cells of SS patients, whether there was periductal lymphocytic infiltration or not. Strong TRX expression was detected in acinar cells from 13 of 19 SS specimens. Levels of salivary TRX were significantly higher in SS patients than in controls (p < 0.05), and were inversely related to the salivary flow rates in SS patients. Patients who showed acinar TRX expression had higher salivary TRX levels than those who did not (p < 0.05). Interferon-γ-induced expression of IL-6 and Fas-mediated apoptosis in HSG cells were significantly suppressed by pretreating cells with rTRX. Conclusion. Parallel production of oxidative stress markers together with massive secretion of TRX suggests that oxidative stress induces TRX in the salivary gland. Moreover, suppression of IL-6 production and apoptosis by rTRX in HSG cells suggests TRX acts to protect the salivary glands of SS patients from tissue damage.

Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis.

Nishimura Kunihiro, Sugiyama Daisuke, Kogata Yoshinori, Tsuji Goh, Nakazawa Takashi, Kawano Seiji, Saigo Katsuyasu, Morinobu Akio, Koshiba Masahiro, Kuntz Karen M., Kamae Isao, Kumagai Shunichi

Annals of Internal Medicine 146 （ 11 ） 797 - 808 2007年06月

ISSN 0003-4819

Background: Rheumatoid factor (RF) and autoantibodies against cyclic citrullinated peptide (CCP) are markers that might help physicians diagnose rheumatoid arthritis. Purpose: To determine whether anti-CCP antibody more accurately identifies patients with rheumatoid arthritis and better predicts radiographic progression than does RF. Data Sources: MEDLINE through September 2006 and reference lists of retrieved studies and review articles. Study Selection: Studies in any language that enrolled at least 10 participants and that examined the role of anti-CCP antibody and RF in the diagnosis or prognosis of known or suspected rheumatoid arthritis. Data Extraction: Two authors independently evaluated studies for inclusion, rated methodological quality, and abstracted relevant data. Data Synthesis: The DerSimonian-Laird random-effects method was used to summarize sensitivities, specificities, and positive and negative likelihood ratios from 37 studies of anti-CCP antibody and 50 studies of RF. The pooled sensitivity, specificity, and positive and negative likelihood ratios for anti-CCP antibody were 67% (95% CI, 62% to 72%), 95% (CI, 94% to 97%), 12.46 (CI, 9.72 to 15.98), and 0.36 (CI, 0.31 to 0.42), respectively. For IgM RF, the values were 69% (CI, 65% to 73%), 85% (CI, 82% to 88%), 4.86 (CI, 3.95 to 5.97), and 0.38 (CI, 0.33 to 0.44). Likelihood ratios among IgM RF, IgG RF, and IgA RF seemed to be similar. Results from studies of patients with early rheumatoid arthritis were similar to those from all studies. Three of 4 studies found that risk for radiographic progression was greater with anti-CCP antibody positivity than with IgM RF positivity. Limitations: Many studies had methodological limitations. Studies of RF were heterogeneous and had wide ranges of sensitivity and specificity. Conclusions: Anti-CCP antibodies are more specific than RF for diagnosing rheumatoid arthritis and may better predict erosive disease.

Is SS-A/Ro52 a hydrogen peroxide-sensitive signaling molecule?

Nobuhara Yumiko, Kawano Seiji, Kageyama Goichi, Sugiyama Daisuke, Saegusa Jun, Kumagai Shunichi

Antioxidants and Redox Signaling 9 （ 3 ） 385 - 391 2007年03月

ISSN 1523-0864

SS-A/Ro52 (Ro52) protein is one of the targets of autoantibodies in Sjogren's syndrome and systemic lupus erythematosus. Ro52 structurally belongs to the RING-B-box/coiled-coil family, which appears to carry out diverse functions, but the physiological function of Ro52 remains largely unknown. Here, the authors demonstrate that hydrogen peroxide but not other oxidative stressors induced translocation of Ro52 protein from the cytoplasm to the nucleus and this phenomenon was attenuated by inhibition of MAP kinases, ERK in particular. These findings raise the possibility that SS-A/Ro52 may function as a hydrogen peroxide-selective, oxidative stress-sensitive signaling molecule that is activated via the MAP kinase pathway.

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Usefulness of serum cystatin C for the diagnosis of impaired renal function

Oyabu Chinami, Hayashi Nobuhide, Sugiyama Daisuke, Umezu Mitio, Mukai Masahiko, Kawano Seiji, Kumagai Shunichi

Rinsho byori. The Japanese journal of clinical pathology 54 （ 12 ） 1204 - 1208 2006年12月

ISSN 0047-1860

Creatinine clearance (Ccr) is generally used as a halmark of glomerular filtration rate (GFR) in clinical medicine. Recently, it has been suggested that serum cystatin C measurement in serum reflects GFR. We compared serum cystatin C, serum creatinine, and serum beta2-microgrobrin in 70 patients with renal diseases in reference to creatinine clearance. The correlation between Ccr and 1/cystatin C was higher (r = 0.830) than that between Ccr and 1/serum creatinine (r = 0.789) or 1/serum beta2-microgroburin (r = 0.732). The levels of serum cystatin C in patients with Ccr ranging from 51 to 70 ml/min were significantly higher than those in patients with Ccr ranging more than 91 ml/min. Receiver-operated characteristic (ROC) analysis revealed that serum cystatin C showed the highest area under the curve among the three when Ccr = 90 ml/min was used as the cutoff point. We conclude that serum cystatin C is more useful than serum creatinine to detect early renal dysfunction.

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