小谷 和彦

Background: High body mass index (BMI) has been reported as a risk factor for cardiovascular events in Western countries, while low BMI has been reported as a risk factor for cardiovascular death in Asian countries, including Japan. Although stroke is a major cause of death and disability in Japan, few cohort studies have examined the association between BMI and stroke incidence in Japan. This study aimed to examine the association between BMI and stroke incidence using prospective data from Japanese community residents. Methods: Data were analyzed from 12,490 participants in the Jichi Medical School Cohort Study. Participants were categorized into five BMI groups: <= 18.5, 18.6-21.9, 22.0-24.9, 25.0-29.9, and >= 30.0 kg/m(2). Multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazard model. The group with a BMI of 22.0-24.9 kg/m(2) was used as the reference category. Results: During mean follow-up of 10.8 years, 395 participants (207 men and 188 women) experienced stroke, including 249 cerebral infarctions and 92 cerebral hemorrhages. Men with a BMI <= 18.5 kg/m(2) (HR 2.11; 95% CI, 1.17-3.82) and women with a BMI >= 30.0 kg/m(2) (HR 2.25; 95% CI, 1.28-5.08) were at significantly higher risk for all-stroke. Men with a BMI <= 18.5 kg/m(2) were at significantly higher risk for cerebral infarction (HR 2.15; 95% CI, 1.07-4.33). Conclusions: The association between BMI and stroke incidence observed in this population was different than those previously reported: low BMI was a risk factor for all-stroke and cerebral infarction in men, while high BMI was a risk factor for all-stroke in women. (C) 2017 The Authors. Publishing services by Elsevier B.V. on behalf of The Japan Epidemiological Association.

BACKGROUND: For achieving equity of the accessibility to primary healthcare, measuring potential geographical accessibility is essential. The provider-to-population ratio is the most frequently used measure. However, it is difficult to be used in closer region because it does not take into consideration the people and health services beyond its boundary. In order to overcome this problem, we measured the potential access to hospital, using both distance measures and the enhanced two-step floating catchment area (E2SFCA) method. The aim of this study was to compare the number of hospitals in the neighborhood and the E2SFCA score with regard to the amount and equity for access to hospitals. METHODS: This descriptive study used publicly available data from 2010. The E2SFCA score and number of neighborhood hospitals were obtained from Tochigi province in Japan using a geographic information system. Dataset of four measures by each census tract was obtained. The measures were E2SFCA score, number of hospitals within the 5 km range, number of hospitals within the 10 km range, and number of hospitals within the 15 km range. Correlation and disparity analyses with the Lorenz curve and Gini coefficient were performed. RESULTS: The measures were obtained in a smaller area than municipality considering adjacent areas using a geographical approach. The E2SFCA score was 5.3 [3.2-7.3] hospitals/million (median [quantile range]), compared to 5.6 hospitals/million in total for the given district. The median number of hospitals within the 5 km, 10 km, and 15 km ranges were 1, 39, and 47, respectively. There was no hospital within the 5 km range in one third of the blocks. Both the number of hospitals within the 10 km range and those within the 15 km range were well correlated. Regional difference became smaller as the distance to count the number of hospitals increased. The gap between small number of hospitals and the high E2SFCA score indicated the location of community hospital in depopulated areas. CONCLUSIONS: The E2SFCA method is superior for analyzing spatial access to hospital, because it provides information in the closer sub-regions. Regional differences were hardly seen in access to hospital beyond the 10 km range. Further studies in other regions and countries are needed for precise assessment.

BACKGROUND: Limited evidence is available about the relationship of lifestyle factors with glycated hemoglobin (HbA1c) in subjects with impaired glucose tolerance. The aim of study was to identify such determinant factors of HbA1c in subjects with impaired glucose tolerance. METHODS: This cross-sectional study included 121 men and 124 women with impaired glucose tolerance, who were diagnosed based on a 75-g oral glucose tolerance test. Demographic and biochemical parameters, including the body mass index (BMI), fasting plasma glucose (FPG), 2-h post-load glucose (2-h PG), and HbA1c, were measured. The pancreatic β-cell function and insulin resistance were assessed using homeostasis model assessment (HOMA-β). Dietary intake was assessed by a food frequency questionnaire. RESULTS: The levels of FPG, 2-h PG, and carbohydrate intake were correlated with the HbA1c level in men, while the FPG and 2-h PG levels were correlated with the HbA1c level in women. In multiple regression analyses, BMI, FPG, 2-h PG, and white rice intake were associated with HbA1c levels in men, while BMI, FPG, HOMA-β, and bread intake were associated with HbA1c levels in women. CONCLUSIONS: The present findings suggest that a substantial portion of HbA1c may be composed of not only glycemic but also several lifestyle factors in men with impaired glucose tolerance. These factors can be taken into consideration as modifiable determinants in assessing the HbA1c level for the diagnosis and therapeutic monitoring of the disease course.

PURPOSE: Smartphones are prevalently used among adolescents; however, nighttime exposure to blue-enriched light, through electric devices, is known to induce delays of the circadian rhythm phases and poor morning somatic conditions. We therefore investigated whether evening smartphone use may affect sleep-wake cycle and cardiac autonomic nervous system (ANS) activity after awaking in dormitory students. METHODS: The participants were high school students, living under dormitory rules regarding the curfew, study, meals, lights-out, and wake-up times. The students were forbidden from the use of both television and personal computer in their private rooms, and only the use of a smartphone was permitted. According to prior assessment of smartphone use, we chose age-, sex-, exercise time-matched long (n = 22, >120 min) and short (n = 14, ≤60 min) groups and compared sleep-wake cycle and physiological parameters, such as cardiac ANS activity, blood pressure, and intra-aural temperature. All measurements were performed during 6:30 to 7:00 a.m. in the dormitories. RESULTS: Compared with the short group, the long group showed a significantly lower cardiac ANS activity (2727 ± 308 vs. 4455 ± 667 ms2, p = 0.030) with a tendency toward a high heart rate, in addition to later bedtimes during weekdays and more delayed wake-up times over the weekend. Blood pressure and intra-aural temperature did not differ between the groups. CONCLUSIONS: In this population, evening smartphone use may be associated with altered sleep-wake cycle and a diminished cardiac ANS activity after awakening could be affecting daytime activities.

AIM: We previously proposed the concept of caregiver daily impression (CDI) as a practical tool for emergency triage. We herein assessed how CDI varies by sex, education and career length by determining CDI scores as quantitative outcome measures. METHODS: We carried out a cross-sectional study using a self-reported questionnaire among caregivers in 20 long-term care facilities in Hyogo, Japan. A total of 10 CDI variables measured participants' previous experience of emergency transfers using a scale from 0-10. The resulting total was defined as the CDI score. We hypothetically considered that higher scores indicated greater caregiver focus. The CDI scores were compared by sex, education and career length using analysis of covariance. RESULTS: A total of 601 personal caregivers were evaluated (mean age 36.7 years; 36% men). The mean career length was 6.9 years, with the following groupings: 1-4 years (38%), 5-9 years (37%) and >10 years (24%). After adjustment for sex and education, the CDI scores for the variable, "poor eye contact," significantly differed between caregivers with ≥10 and <5 years of experience (scores of 5.0 ± 3.1 and 4.0 ± 2.7, respectively). The CDI scores for variables related to eyes tended to increase with experience, whereas other CDI scores decreased. Male caregivers focused on residents' eyes significantly more than did female caregivers. CONCLUSIONS: We found that the CDI variable, "poor eye contact," is influenced by career length. Caregivers with more experience attach more importance to their impression of residents' eyes than do those with less experience. Sex-related differences in CDI might also exist. Geriatr Gerontol Int 2016; 17: 410-415.

Kawasaki disease (KD) is an acute childhood febrile disease of unknown etiology. It exhibits not only coronary artery aneurysms in some cases but also systemic vasculitis. Whether KD is associated with accelerated atherosclerosis remains debatable. The measurement of pulse wave velocity (PWV) is useful as a simple, noninvasive measurement of arterial stiffness, an atherosclerotic manifestation. We herein present a systematic review of clinical studies that focused on PWV in patients with KD. A PubMed-based search identified 8 eligible studies published until June 2015. The PWV of patients with KD, regardless of antecedent coronary artery lesions, was high relative to controls, even though their blood pressure appeared to be similar. Although definitive conclusions cannot be made with the limited information, patients with KD may be at risk of systemic atherosclerosis in association with arterial stiffness. Further research, including longitudinal and outcome studies, is needed to determine the clinical significance of a potential increase in PWV in patients with KD.

Kawasaki disease is a febrile disease of childhood that is associated with increased inflammatory cytokines and immunoregulatory abnormalities. While the serum concentrations of soluble IL-2 receptor can change under such pathologies, the relevance of the soluble IL-2 receptor concentration in patients with Kawasaki disease has not been specified. We aimed to summarize the existing studies that reported the soluble IL-2 receptor concentrations in patients with Kawasaki disease. Original articles that were published up to July 2016 were collected using a PubMed/Medline-based search engine. A total of nine articles that reported the serum soluble IL-2 receptor concentrations in acute-phase Kawasaki disease were eligible. All of the articles described a high soluble IL-2 receptor concentration in patients with Kawasaki disease relative to the level of controls or the reference range. Two of five articles on patients with coronary artery aneurysms described a significantly higher soluble IL-2 receptor concentration in patients with coronary artery aneurysms than patients without. Two articles on patients with intravenous immunoglobulin therapy described a significant decrease of the soluble IL-2 receptor concentration after the therapy. Accordingly, the serum soluble IL-2 receptor can be a potent marker of disease activity and therapeutic effects in patients with Kawasaki disease; further studies are thus warranted for its use in the clinical setting.

Although rare, second-generation antipsychotic drugs cause severe hyperglycemia within several days after the initiation of therapy. Because glucose tolerance exhibits circadian rhythmicity, we evaluated an effect of a dosing-time on quetiapine-induced acute hyperglycemia in mice. A single intraperitoneal dose of quetiapine dosing-time-independently induced insulin resistance in fasted C57BL/6J mice. However, acute hyperglycemic effect was detected only after dosing of the drug at the beginning of an active phase. Under the conditions in which hepatic glucose production was stimulated by pyruvate administration, hyperglycemic effect of quetiapine was dosing-time-independently observed. In addition, the dosing-time-dependent hyperglycemic effect of quetiapine disappeared in the liver-specific circadian clock-disrupted mice in which circadian rhythmicity in hepatic glucose production is deranged. Furthermore, the dosing-time had little impact on the pharmacokinetics of quetiapine in normal mice. These results suggest that quetiapine acutely causes hyperglycemia only when hepatic glucose production elevates. Therefore, quetiapine therapy with once daily dosing at a rest phase might be safer than that at an active phase. Further studies are needed to confirm the hypothesis. (C) 2017 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Circulating markers relevant to the development of abdominal aortic aneurysm (AAA) are currently required. Lipoprotein(a), Lp(a), is considered a candidate marker associated with the presence of AAA. The present meta-analysis aimed to evaluate the association between circulating Lp(a) levels and the presence of AAA. The PubMed-based search was conducted up to April 30, 2015, to identify the studies focusing on Lp(a) levels in patients with AAA and controls. Quantitative data synthesis was performed using a random effects model, with standardized mean difference (SMD) and 95% confidence interval (CI) as summary statistics. Overall, 9 studies were identified. After a combined analysis, patients with AAA were found to have a significantly higher level of Lp(a) compared to the controls (SMD: 0.87, 95% CI: 0.41-1.33, P < .001). This result remained robust in the sensitivity analysis, and its significance was not influenced after omitting each of the included studies from the meta-analysis. The present meta-analysis confirmed a higher level of circulating Lp(a) in patients with AAA compared to controls. High Lp(a) levels can be associated with the presence of AAA, and Lp(a) may be a marker in screening for AAA. Further studies are needed to establish the clinical utility of measuring Lp(a) in the prevention and management of AAA.

Here, we briefly report on the workshop entitled "A new era of specialists in clinical laboratory medicine." The following items were presented in the poster session on "work-life balance among specialists in clinical laboratory medicine": routine work, troublesom issues at work, networking, and career development. Re- garding the topic of "lifelong education," participants in groups discussed the joy they derive from working in the field of clinical laboratory medicine. Many participants mentioned that they had been attracted to this field because of the wide range of academic disciplines available and the relative freedom in choosing special- ties. We believe that this workshop facilitates the sharing of information about routine work and viewpoints regarding the specialty of clinical laboratory medicine, as well as personnel networking on a nationwide level.

Rheumatoid Arthritis (RA) is a chronic inflammatory disease with a potential cardiovascular (CV) risk. Flow-Mediated Vasodilation (FMD) is an ultrasonic method to evaluate endothelial function. RA is a contributor to endothelial dysfunction, a CV risk. Relevant insights on the improvement of the CV outcomes in RA patients may be obtained by a systematic review of trials that investigated the effects of RA treatment on FMD in RA patients. This review found that treatments with antirheumatic drugs and some non-antirheumatic drugs could improve the FMD in RA patients. Treatment with anti-tumour necrosis factor (TNF)-α drugs, including infliximab, etanercept and adalimumab, improved the FMD in RA patients. Treatment with non-anti-TNF-α drugs, including rituximab, anakinra and tocilizumab, also improved the FMD. One trial showed that conventional synthetic Disease-Modifying Antirheumatic Drugs (DMARDs) improved the FMD. Regarding non-antirheumatic drugs, treatment with ramipril, spironolactone and statins/ezetimibe improved the FMD in RA patients. Treatment of advanced glycation endproducts inhibitors improved the FMD in RA patients, while treatment of pioglitazone did not. Overall, treatments for RA improved endothelial dysfunction, as evaluated by FMD, in RA patients. This information may be useful in patient management, although further studies are necessary to establish strategies in relation to endothelial dysfunction among these patients.

BACKGROUND: Previous reports have shown that lipoprotein lipase (LPL) activity significantly increases in the postprandial plasma associated with the increase of TG-rich lipoproteins. Therefore, we have reexamined those relationships using newly developed LPL assay with the different kinds of food intake. METHODS: Standard meal (n=81), 50g of fat (n=54), 75g of glucose (n=25) and cookie (25g fat and 75g carbohydrate fat) (n=28) were administered in generally healthy volunteers. Plasma LPL, HTGL and TC, TG, LDL-C, HDL-C, RLP-C and RLP-TG were determined at subsequent withdrawal after the food intake. RESULTS: Plasma TG, RLP-C and RLP-TG were significantly increased at 8PM (2h after dinner of standard meal) compared with 8AM before breakfast within the same day. Also those parameters were significantly increased in 2-6h after fat load. However, the concentrations and activities of LPL and HTGL did not significantly increase in association with an increase in the TG and remnant lipoproteins. Also LPL concentration did not significantly increase after glucose and "cookie test" within 4h. CONCLUSION: No significant increase of LPL activity was found at CM and VLDL overload after different kinds of food intake when reexamined by newly developed assay for LPL activity and concentration.

Lipoprotein(a) [Lp(a)] has been identified as a risk factor for cardiovascular disease. Lp(a) levels are also high under certain clinical conditions, including familial hypercholesterolemia and high blood low-density lipoprotein (LDL) cholesterol levels. Few effective generic therapies for modulating Lp(a) have been developed. However, new therapies involving inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) using monoclonal antibodies have markedly reduced the blood LDL levels-and the Lp(a) levels as well. Much attention has therefore been focused on this therapy and its utility. The mechanism by which PCSK9 inhibitors reduce the Lp(a) levels remains unclear. We here describe the effects of PCSK9 inhibitors on Lp(a) and discuss potential mechanisms and perspectives of this topic.

The cardio-ankle vascular index (CAVI) is used to test vascular function and is an arterial stiffness marker and potential predictor of cardiovascular events. This study aimed to analyze the relation between objective indices of diabetic polyneuropathy (DPN) and the CAVI. One hundred sixty-six patients with type 2 diabetes mellitus were included in this study. We used nerve conduction studies (NCSs) and the coefficient of variation of the R-R interval to evaluate DPN. We estimated arteriosclerosis by the CAVI. Simple and multiple linear regression analyses were performed between neuropathy indices and the CAVI. In univariate analysis, the CAVI showed significant associations with sural sensory nerve conduction velocity and median F-wave conduction velocity. Multiple linear regression analysis for the CAVI showed that sural nerve conduction velocity and median F-wave conduction velocity were significant explanatory variables second only to age. In multiple linear regression analysis for sural nerve conduction velocity among neuropathy indices, the CAVI remained the most significant explanatory variable. In multiple linear regression analysis for median nerve F-wave conduction velocity among neuropathy indices, the CAVI remained the second most significant explanatory variable following HbA1c. These results suggest a close relationship between macroangiopathy and DPN.

The 3111T/C single nucleotide polymorphism (SNP) of Circadian Locomotor Output Cycles Kaput (CLOCK) gene reportedly affects gastric motility before breakfast. It is of interest to know whether this SNP can affect the motility during the daytime. We investigated the association between the CLOCK 3111T/C SNP and several gastric motility parameters during the time period from 8:00 to 20:00 in 34 young women with scheduled meals. There were similar daytime fluctuations in gastric motility before and after the meals between the major (T/T) and minor (T/C) allele carriers. The CLOCK SNP may affect daytime gastric motility less than food stimulation.

The present article is aimed at outlining the current state of knowledge regarding the clinical value of lipoprotein(a) (Lp(a)) as a marker of cardiovascular disease (CVD) risk by summarizing the results of recent clinical studies, meta-analyses and systematic reviews. The literature supports the predictive value of Lp(a) on CVD outcomes, although the effect size is modest. Lp(a) would also appear to have an effect on cerebrovascular outcomes, however the effect appears even smaller than that for CVD outcomes. Consideration of apolipoprotein(a) (apo(a)) isoforms and LPA genetics in relation to the simple assessment of Lp(a) concentration may enhance clinical practice in vascular medicine. We also describe recent advances in Lp(a) research (including therapies) and highlight areas where further research is needed such as the measurement of Lp(a) and its involvement in additional pathophysiological processes.

OBJECTIVE: The aim of the present study was to investigate the efficacy and safety of ipragliflozin treatment on glycemic control in patients with type 2 diabetes mellitus (T2DM). METHODS: We recruited 44 patients with T2DM, treated them with 50 mg/day of ipragliflozin for 12 weeks, and assessed several diabetic variables before and after treatment. We used stepwise multiple regression analysis to evaluate response to ipragliflozin in terms of changes in hemoglobin A1c (HbA1c) levels after therapy. RESULTS: Treatment with ipragliflozin for 12 weeks significantly decreased fasting glucose, HbA1c, and blood pressure levels without severe adverse events. The baseline HbA1c (β = -0.52, p < 0.01) and alanine aminotransferase (ALT) levels (β = -0.29, p = 0.03) were independently and significantly related to a decrease in HbA1c levels. CONCLUSIONS: In patients with T2DM, ipragliflozin treatment improved glycemic control, and baseline HbA1c and ALT levels appeared to predict treatment response.

Sarcopenia is an age-related health problem in general communities. Effective exercise programs against sarcopenia remain necessary for community-dwelling older people. In order to summarize the available knowledge on this subject, we collected English articles from a MEDLINE/Pubmed database examining the effects of exercise interventions on sarcopenia-related outcome measures in community-dwelling older people. When nine articles, including eight randomized controlled trials, were reviewed, most studies demonstrated significant improvements in some outcome measures. Indeed, a significant improvement in the muscle mass in one study, muscle strength in two studies and physical performance in two studies was reported among five studies using exercise (E) alone. A significant improvement in the muscle mass in two studies, muscle strength in one study and physical performance in two studies was also reported among four studies using exercise plus nutritional supplementation (EN). Notably, the EN studies appeared to have less extensive exercise interventions than the E studies. One EN study further exhibited significant improvements in all outcome measures. Collectively, exercise could be used as anti-sarcopenic strategies and nutritional interventions when combined with exercise might play a compensated or perhaps a comprehensive role among community-dwelling older people. Limited studies exist and more studies are required for the optimum programs in the community settings.

OBJECTIVES: Much attention has been paid recently to a relationship between glucose metabolism and weather. This study investigated the temporal correlation between total solar irradiance (TSI) and glycated hemoglobin (A1C) values in patients with diabetes. METHODS: In 1531 patients with diabetes who received follow-up care between 2009 and 2013 (type 1 diabetes, 123 patients; type 2 diabetes, 1408 patients; male 53.6%; mean age, 61.2 years), A1C levels were measured a total of 58,830 times. The correlation between mean monthly TSI and mean A1C values from 1 to 4 months later was then examined. RESULTS: The mean values for TSI and A1C throughout the entire study period were 13.7 MJ/m2 and 7.7%, respectively. The correlation coefficient between TSI and mean monthly A1C values at 1 to 4 months was -0.516, -0.734, -0.726 and -0.475, respectively (all p<0.001). CONCLUSIONS: There was a highly negative correlation between TSI and mean A1C values 2 to 3 months later in this population; thus, this fact may need to be considered when using A1C levels as a glycemic control index in patients with diabetes. Further studies are warranted.

Background: Although Kawasaki disease (KD) cardiac lesions can be treated with i.v. immunoglobulin (IVIG) and are associated with age and sex, the time course of cardiac lesions remains unclear on the large scale. Methods: We used the data of the 22nd nationwide survey of KD in Japan (2011-2012). We divided the time course of cardiac lesions into eight groups according to the combination of timing (first visit to hospital, acute phase, and sequelae) and presence of cardiac lesions (E, existence of cardiac lesions; N, non-existence of cardiac lesions): EEE, EEN, ENE, NEE, ENN, NEN, NNE, and NNN. For example, EEN shows that cardiac lesions existed at first visit to hospital and in the acute phase, but did not exist as sequelae. A total of 24 952 patients were analyzed. Results: The majority (90.6%) of patients belonged to the NNN group, followed by the EEN (3.21%) and NEN (3.33%) groups. Male sex and ages &lt;= 5 months and &gt;= 5 years tended to be more prevalent. Non-response to initial IVIG therapy was the most prevalent in all groups other than NNN. Conclusions: The time course of cardiac lesions and the relationship with sex, age, and IVIG therapy have been described. KD patients who are male, aged &lt;= 5 months or &gt;= 5 years, and non-responders to initial IVIG tend to have cardiac lesions at some point in the time course of KD.

BACKGROUND: Since 1987, no study has reported the municipal-level geographical clustering of Kawasaki disease (KD) in Japan. Therefore, the aim of the present study was to identify the temporal and municipal-level geographical clustering of KD. METHODS: The annual incidence rates of KD for each municipality were calculated using nationwide data from 73 758 patients with KD (2007-2012). To determine whether temporal and municipal-level clustering existed, we calculated the correlations of the annual incidence rates for each municipality during the study years, and compared these rates with those of the adjacent municipalities. Spatial scanning analysis was used to identify the geographical clusters for each year, and the incidence rates in those clusters were compared with the rates in the surrounding region. RESULTS: The annual national incidence rate of KD, adjusted for the prefecture-specific response rate, was 322.45 patients per 100 000 children aged 0-4 years. The correlation between the annual incidence rates during 2 consecutive years was significantly positive (coefficients, 0.149-0.428). On spatial scanning analysis, the most likely clusters were in the Tokyo metropolitan area during 2007-2010 and 2012, and in Kumamoto prefecture during 2011. CONCLUSION: Kawasaki disease exhibits temporal and municipal-level clustering.

BackgroundDue to ethic differences in its serum levels, clinical applicability of high-sensitivity C-reactive protein (hsCRP) to the primary prevention of atherosclerotic events has not completely been established in Japanese people whose hsCRP levels are lower than in Western people. This study investigated the relationship between hsCRP and myocardial infarction (MI) in general Japanese people. MethodsIn relation to hsCRP, the incidence of MI was determined in a multiregional population-based prospective cohort study (n = 6,637; mean age 54.9 years; 2,513 men/4,124 women). ResultsFifty-six cases of MI were confirmed during a follow-up period of 10.7 years. The cut-off levels of hsCRP between the highest quartile (fourth quartile) and the other quartiles combined were 0.368 mg/l in men and 0.279 mg/l in women. The hazard ratio (HR) of the highest quartile for MI was significantly greater than that of the other quartiles combined (multivariate-adjusted HR: 2.07, 95% confidence interval: 1.03-4.15) in men, but not in women (1.03, 0.35-2.21). ConclusionsIn this population, serum hsCRP measurement predicted MI in men, but not in women. Under the low hsCRP level, a method of applicability of hsCRP to a risk assessment for preventing MI among Japanese people should be further explored.

Protecting against liver damage, such as non-alcoholic fatty liver disease, is currently considered to be important for the prevention of adverse conditions, such as cardiovascular and cancerous diseases. Liver damage often occurs in relation to oxidative stress with metabolic disorders, including cellular lipid accumulation. Astaxanthin (3,3'-dihydroxy-β,β-carotene-4,4'dione), a xanthophyll carotenoid, is a candidate for liver protection. Here, we briefly review astaxanthin as a potential protector against liver damage. In particular, studies have reported antioxidative effects of astaxanthin in liver tissues. Astaxanthin treatment is also reported to improve hyperlipidemia, which indirectly induces the antioxidative effects of astaxanthin on liver pathologies. Furthermore, astaxanthin may alleviate liver damage independent of its antioxidative effects. Of note, there are still insufficient human data to observe the effect of astaxanthin treatment on liver function in clinical conditions. More studies investigating the relevance of astaxanthin on liver protection are necessary.

BACKGROUND: Although a postprandial increment in triglyceride (TG) levels is considered to be a risk factor for atherogenesis, tests (e.g., fat load) to assess postprandial changes in TG levels cannot be easily applied to clinical practice. Therefore, fasting markers that predict postprandial TG states are needed to be developed. One current candidate is lipoprotein lipase (LPL) protein, a molecule that hydrides TGs. This study investigated whether fasting LPL levels could predict postprandial TG levels. METHODS: A total of 17 subjects (11 men, 6 women, mean age 52 ± 11 years) with normotriglyceridemia during fasting underwent the meal test. Several fasting parameters, including LPL, were measured for the area under the curve of postprandial TGs (AUC-TG). RESULTS: The subjects' mean fasting TG level was 1.30 mmol/l, and their mean LPL level was 41.6 ng/ml. The subjects' TG levels increased after loading (they peaked after two postprandial hours). Stepwise multiple regression analysis demonstrated that fasting TG levels were a predictor of the AUC-TG. In addition, fasting LPL mass levels were found to be a predictor of the AUC-TG (β = 0.65, P < 0.01), and this relationship was independent of fasting TG levels. CONCLUSION: Fasting LPL levels may be useful to predict postprandial TG increment in this population.

Many Mongolian people suffer from non-communicable chronic diseases. In order to plan preventive strategies against such diseases, we designed a community-based prospective cohort study of chronic diseases, called the Moncohort study, in Mongolia. This is the first nationwide large-scale cohort study of chronic diseases. This paper describes the study's rationale, design and methods with baseline data. Mongolian residents aged ⩾40years were selected nationwide from many geographic regions in 2009. Data were collected on demographics, socioeconomic status, lifestyle, and anthropometric and biochemical measurements. In total, 2280 Mongolian residents were registered in the survey. Socioeconomic, lifestyle, anthropometric and biochemical characteristics were differentiated by gender and geographical area in descriptive data. Aging, low social class, physical inactivity and infrequent fruits intake were positively associated with histories of chronic disease in men, while aging was positively associated with histories of chronic disease in women. Factors associated with chronic diseases reveal gender-oriented strategies might be needed for their prevention. Detailed prospective analyses will illustrate the impact of risk factors on chronic diseases and lead to evidence for designing programs aimed at preventing chronic diseases and related disorders in Mongolia.

BACKGROUND: Gamma-glutamyltransferase (γ-GT) is used as a marker of alcohol-related pathology, while γ-GT is recently considered to be an oxidative stress marker. AIM: The present study aimed to investigate the correlation between the oxidative status and γ-GT levels, in association with menopausal stages. METHODS: In total, 252 women, who were subjectively healthy, were divided into three groups: premenopausal, perimenopausal, and postmenopausal. The circulating oxidative status was evaluated by the diacron-reactive oxygen metabolite (d-ROM) test. In addition to serum γ-GT, routine blood investigations, including lipid, glucose, and inflammatory parameters, were performed. RESULTS: The median γ-GT level was 17 U/L and the mean d-ROM level was 335 Carr U in all subjects. On multiple regression analysis, independent significant positive correlations were observed between d-ROM and high-sensitivity CRP levels in three groups, while there was a significant positive correlation between d-ROM and γ-GT levels only in the premenopausal group but not in the perimenopausal and postmenopausal groups. DISCUSSION: The significant relationship between d-ROM and γ-GT at active estrogen stage may indicate a different oxidative stress condition by memopausal stage. The reasons of this relationship should be further explored. CONCLUSION: A positive relationship between d-ROM and γ-GT levels, both as known as oxidative stress-related markers, could exist in premenopausal women.

Specific gene polymorphisms are known to be associated with a different arterial physiology in the younger generation. The present study found that young Russians with the matrix metalloproteinase 3 6A/6A and γ-glutamyltransferase 1AA genotypes have lower levels of the cardio-ankle vascular index - a recent measure of arterial stiffness. This observation may serve as an additional tool for cardiovascular disease prevention in the young population.

The amount of monoclonal immunoglobulin (M protein) distinguishes multiple myeloma (M) from mono- clonal gammopathy of undetermined significance (MGUS) and indicates the effectiveness of treatment for MM. It should be calculated by serum total protein (g/dL) and M peak ratio (%) on the densitometry of se- rum electrophoresis. However, the ordinary method possibly overestimates the amount of M protein, be- cause this method utilizes the area from the baseline of the M peak (baseline method). For the more accu- rate measurement of M protein, in this study, we evaluated a capillary electrophoresis system that enables to extract the proper area of M peak by manual operation (peak method). Three serum samples with positive M protein were mixed with M protein negative serum at various ratio, and the measured values of M protein were compared with the theoretical values for both baseline and peak methods. All the results showed that the peak method gave the values close to the theoretical values compared with the baseline method. Espe- cially, the less M protein positive serum was mixed, the further the values by the baseline method parted from the theoretical one. In conclusion, the peak method using a capillary electrophoresis system should be introduced for the accurate quantification of M protein. [Original].

OBJECTIVE: To determine the relationship between the R577X polymorphism of the α-actinin-3 (ACTN3), which may play a role in the individual differences observed in the effects of exercise on health benefits and antiatherogenic markers (i.e., high-density lipoprotein cholesterol [HDL-C] and adiponectin) in athletes. METHODS: Seventy-six male rugby players (mean age 19.8 years) were enrolled in this study. Genomic DNA was extracted from peripheral blood samples, and restriction fragment length polymorphism-polymerase chain reactions were conducted to assess ACTN3 genotypes. Body mass index (BMI), waist circumference, serum lipids including HDL-C, and adiponectin levels were measured. Current smoking and alcohol intake habits were evaluated with a questionnaire. All of the parameters were compared between 2 groups displaying frequently observed genotypes: one group consisting of patients having either the R/R or R/X genotype and a second group with the X/X genotype. RESULTS: The frequency of the X allele was 0.55 and the distribution of the genotypes was 35.5% (n = 27) for X/X, 39.5% (n = 30) for R/X, and 25.0% (n = 19) for R/R. Serum HDL-C and adiponectin levels were significantly higher in X/X genotype compared to the R/R or R/X genotype (HDL-C 1.6 ± 0.3 [SD] vs. 1.4 ± 0.2 mmol/L; P<.01, adiponectin 8.8 ± 2.6 vs. 6.9 ± 2.3 μg/mL; P<.01), even after adjustments for confounders (P<.01). CONCLUSION: There may be a relationship between the ACTN3 genotype and HDL-C and adiponectin levels in rugby players. This may be useful information when determining the individual responses of antiatherogenic markers to exercise. ABBREVIATIONS: ACTN3 = α-actinin-3 BMI = body mass index CVD = cardiovascular disease HDL-C = high-density lipoprotein cholesterol LDL-C = low-density lipoprotein cholesterol R = arginine (R) at amino acid position 577 of the ACTN3 protein TC = total cholesterol TG = triglyceride X = truncation at amino acid position 577 of the ACTN3 protein.

The macrophage and its related cholesterol efflux are considered to be a key player in atherosclerotic formation in relation to the function of high-density lipoprotein (HDL). The HDL function can be evaluated by the reaction between lipid-loaded macrophages and lipid-acceptors in the HDL fraction from the plasma, apolipoprotein B-depleted serum, and/or whole serum/plasma. Recent studies have reported that an impaired cholesterol efflux of HDL is observed in patients with cardiometabolic diseases, such as dyslipidemia, diabetes mellitus, and chronic kidney disease. A population-based cohort study has reported an inverse association between the cholesterol efflux capacity of HDL and the incidence of atherosclerotic disease, regardless of the serum HDL-cholesterol level. Moreover, in this paper, when we summarized several clinical interventional studies of statin treatment that examined cholesterol efflux, a potential increase in the efflux in patients treated with statins was implied. However, the effect was not fully defined in the current situation because of the small sample sizes, lack of a unified protocol for measuring the efflux, and short-term intervention periods without cardiovascular outcomes in available studies. Further investigation is necessary to determine the effect of drugs on cholesterol efflux. With additional advanced studies, cholesterol efflux is a promising laboratory index to understand the HDL function.

A case of acute kidney injury (AKI) strongly suspected to be drug-induced (oxaliplatin and non-steroidal anti-inflammatory drug) is discussed regarding the mechanism of a reduced glomerular filtration rate responsible for the development of AKI. Urinary biochemical tests are useful for the differential diagnosis of pre- renal (functional) AKI and intrinsic (structural) AKI(so-called acute tubular necrosis). In this case, although a comprehensive differential diagnosis using these parameters supported intrinsic AKI, only one pa- rameter, fractional excretion of urea (FEurea), indicated the existence of prerenal AKI. As a result of treatment with the appropriate management of body fluid in addition to avoiding nephrotoxic medications, AKI rapidly improved. FEurea revealed the underlying mechanism of AKI. [Review].

The beta-3 adrenergic receptor (ADRB3), primarily expressed in adipose tissue, is involved in the regulation of energy metabolism. The present study hypothesized that ADRB3 (Trp64Arg, rs4994) polymorphisms modulate the effects of lifestyle intervention on weight and metabolic parameters in patients with impaired glucose tolerance. Data were analyzed from 112 patients with impaired glucose tolerance in the Japan Diabetes Prevention Program, a lifestyle intervention trial, randomized to either an intensive lifestyle intervention group or usual care group. Changes in weight and metabolic parameters were measured after the 6-month intervention. The ADRB3 polymorphisms were determined using the polymerase chain reaction restriction fragment length polymorphism method. Non-carriers showed a greater weight reduction compared with the carriers in both the lifestyle intervention group and usual care group, and a greater increase of high-density lipoprotein cholesterol levels than the carriers only in the lifestyle intervention group. ADRB3 polymorphisms could influence the effects of lifestyle interventions on weight and lipid parameters in impaired glucose tolerance patients.

Aims: To propose a caregiver daily impression (CDI) rating instrument for personal caregivers of residents living in long-term care facilities (LTCF) to comprehensively evaluate residents' daily health condition, and to investigate whether the CDI reflects illness latency and severity in residents transferred emergently. Methods: We carried out a retrospective review of facility care records from 20 LTCF in Hyogo, Japan. The participants were 169 LTCF residents with episodes of transfer to emergency hospitalization facilities during a 3-month period. We determined specific CDI variables by interviewing experienced LTCF caregivers, and then carried out a principal component analysis to determine the major parameter set. The generated components were incorporated into a regression model to investigate the association with hospitalization. Results: The mean age was 87.9 +/- 6.5 years, 68% were women and 28% of transfers resulted in hospitalization. The interview procedure identified 12 specific CDI variables, and the principal component analysis generated five distinct components: "change in feeding," "change in emotion," "disengaged or listless gaze," "decrease in eye reactivity" and "change in movement." By multivariate logistic regression, hospitalization was associated with "decrease in eye reactivity" (adjusted OR 1.78, 95% CI 1.07-2.97) and poor vital signs (adjusted OR 2.84, 95% CI 1.15-6.98), but not with body temperature (adjusted OR 1.29, 95% CI 0.52-3.21). Conclusions: The CDI might reflect underlying illness severity beyond quantitative physical findings. Once the CDI can be appropriately validated, quantified and linked to physical findings, it could be used by caregivers for daily resident assessments and as a practical triage tool in emergency situations.

The circulating levels of lipoprotein-associated phospholipase A₂ (Lp-PLA₂) can be a simple, but practical and useful marker of cardiovascular disease (CVD). As limited studies are available in patients with diabetes mellitus (DM), further studies are needed to establish the clinical application of Lp-PLA₂ in DM practice. The present study investigated the correlation between Lp-PLA₂ and the cardio-ankle vascular index (CAVI), a recent marker of arterial stiffness, in DM patients according to their diabetes duration. Clinical data, including the plasma Lp-PLA₂ mass and CAVI values, were collected from CVD-free type 2 DM female patients (n = 65, mean age 62 years, mean hemoglobin A1c 7.0%). The Lp-PLA₂ level of patients with a diabetes duration of <10 years (n = 40:20.2 IU/mL) was not significantly different from that of patients with a diabetes duration of ≥10 years (n = 25:20.5 IU/mL), while the CAVI level was significantly higher in patients with ≥10 years (9.0) than in those with <10 years (8.1; p < 0.05). A stepwise multiple regression analysis found a positive correlation between the Lp-PLA₂ and CAVI levels (β = 0.43, p < 0.01) in patients with a diabetes duration of ≥10 years. This correlation between Lp-PLA₂ and CVAI suggests the possible use of Lp-PLA₂ in DM patients with long-term disease. Further studies on Lp-PLA₂ are warranted in DM practice in relation to the disease duration.

Kawasaki Disease (KD) is a febrile disorder seen in infants and young children. One of the most serious complications of the disease is coronary aneurysm. Endothelial dysfunction is considered to underlie the etiopathology of coronary aneurysm. Flow-mediated dilation (FMD), as assessed ultrasonically, is used to observe the endothelial function. The current paper summarizes, by providing a systematic review, the clinical studies that have examined endothelial dysfunction by determining the FMD ultrasonically in patients with KD. A PubMed-based search found eight articles published until 2013. Six studies reported the FMD level to be significantly lower in the patients with KD compared to controls, while two studies reported no significant difference in the FMD level between those with and without KD. Although patients with KD appeared to have endothelial dysfunction in the current summary, most reports have been associated with limitations, such as a small size and no prospective design for vascular outcomes. Further studies are therefore needed to draw definite conclusions regarding whether patients with KD suffer from endothelial dysfunction as determined by the FMD and/or whether this determination can be useful for understanding and managing vascular complications in these patients.

The cardio-ankle vascular index is a measure of arterial stiffness, whereas oxidative stress underlies arterial pathology. This study aimed to investigate the association between the cardio-ankle vascular index and antioxidant-related gene polymorphisms in young Russians. A total of 89 patients (mean age, 21.6 years) were examined by the cardio-ankle vascular index and for 15 gene polymorphisms related to antioxidant enzymes including FMO3 (flavin-containing monooxygenase 3), GPX1 (glutathione peroxidase 1), and GPX4 (glutathione peroxidase 4). A higher cardio-ankle vascular index level was detected in carriers with the KK-genotype of FMO3 polymorphism rs2266782 than in those without (mean levels: 6.2 versus 5.6, respectively, p<0.05). Similarly, a higher cardio-ankle vascular index level was seen in carriers with the CC-genotype of GPX4 polymorphism rs713041 than in those without (6.0 versus 5.5, respectively, p<0.05). We did not observe significant associations between the cardio-ankle vascular index levels and the other gene polymorphisms. Although carriers with the LL-genotype of GPX1 polymorphism rs1050450 showed a higher diastolic blood pressure level than those without, the polymorphism did not affect the cardio-ankle vascular index level. This study showed a significant association between rs2266782 and rs713041 polymorphisms and arterial stiffness, as measured by the cardio-ankle vascular index, in young Russians. The pathways utilised by antioxidant enzymes may be responsible for early arterial stiffening in the Russian population.

Background: Previous studies on the association between coffee consumption and subarachnoid hemorrhage (SAH) have provided inconsistent results. We examine the risk of SAH from coffee consumption in a Japanese population. Methods: Our analyses were based on the Jichi Medical School Cohort Study, a large-scale population-based prospective cohort study. A total of 9941 participants (3868 men and 6073 women; mean age 55 years) with no history of cardiovascular disease or carcinoma were examined. Participants were asked to choose one of five options to indicate their daily coffee consumption: none, less than 1 cup a day, 1-2 cups a day, 3-4 cups a day, or 5 or more cups a day. The incidence of SAH was assessed independently by a diagnostic committee. Cox proportional hazards models were used to calculate hazard ratios (HRs) and their 95% confidence intervals (CI) after adjustment for age and sex (HR1) and for additional potential confounders (HR2). Results: During 10.7 years of follow-up, SAH occurred in 47 participants. When compared with the participants who consumed less than 1 cup of coffee a day, the HR of SAH was significantly higher in the group who consumed 5 or more cups a day in both models (HR1 4.49; 95% CI, 1.44-14.00; HR2 3.79; 95% CI, 1.19-12.05). Conclusions: The present community-based cohort study showed that heavy coffee consumption was associated with an increased incidence of SAH after adjusting for age, sex, and multiple potential cardiovascular confounders.

Hemostatic factors may be involved in bone health. The present preliminary study investigated the association between plasma fibrinogen and bone mineral density (BMD) in perimenopausal women. A significant inverse correlation between fibrinogen and BMD was observed (correlation coefficient = -0.42, p < 0.01). This correlation appeared to be more clearly observed in the subgroup with a high level of high-sensitivity C-reactive protein than in that with a low level of high-sensitivity C-reactive protein, and in the subgroup with a high level of diacron reactive oxygen metabolites (an oxidative stress marker) than in that with a low level of diacron reactive oxygen metabolites. Thus, fibrinogen may be a possible marker of BMD in this population. More studies on the associations among hemostasis, inflammation, oxidative stress, and bone metabolism are warranted in the clinical setting.

AIM: Postprandial lipid level increases induce oxidative stress, which is involved in atherogenesis. The antioxidant properties of paraoxonase 1 (PON1) have attracted attention. However, changes in postprandial PON1 levels differ across prior studies, and changes in PON1 lactonase activity, potentially relevant to PON1 physiology, after the consumption of ordinary meals are unknown. Herein we evaluated postprandial serum lipid levels and PON1 changes following mixed-meal consumption of the amounts recommended for ordinary meals. METHODS: Nine healthy male volunteers consumed three different meals in a randomized cross-over design. The test meals were as follows: S, white rice; SMF, S with fat-containing protein-rich main dishes; and SMFV: SMF with vegetable dishes. The serum lipid concentrations and PON1 lactonase and arylesterase activities were determined during a three-hour period after the consumption of these meals. RESULTS: The postprandial triglyceride levels were higher after consuming the SMF and SMFV meals than after consuming the S meal. Despite postprandial high-density lipoprotein cholesterol being unchanged, PON1 lactonase activity was decreased, while PON1 arylesterase activity was increased in the postprandial state after all test meals. Postprandial changes in lactonase and arylesterase activities did not differ among the test meals. CONCLUSIONS: Inverse changes in PON1 lactonase and arylesterase activities were observed after consuming recommended ordinary meals. This observation provides useful information for choosing PON1 species as postprandial markers.

Ischemic heart disease (IHD) is considered to be a pivotal health problem in Mongolia. To summarize the existing epidemiology of IHD in the general Mongolian population is crucial for primary prevention. The present review summarized population-based epidemiological data of IHD in Mongolia. When epidemiological studies were extracted from databases, very limited studies were available. The frequencies of IHD and IHD-attributable death rates appeared to be high and have an increased tendency in Mongolia. This could to be due to a gradually worsening state of potential IHD-related risk factors, such as smoking, hypertension, hypercholesterolemia, obesity and diabetes mellitus. This might indicate an urgent need of strategies for IHD and related risk factors. Anti-IHD strategies, such as more epidemiological studies and campaigns to increase awareness of IHD, at nationwide public health levels would be required in Mongolia for more effective prevention.

BACKGROUND: The ankle-brachial index (ABI) is an indicator of peripheral arterial damage and a low (ABI ≤ 1.0) or borderline (ABI = 1.00-1.09) value is associated with risk of cardiovascular disease events. A low ratio of serum eicosapentaenoic acid to arachidonic acid (EPA/AA) is also a risk factor for cardiovascular disease events. This study examined associations between the ABI and the EPA/AA ratio in smokers and non-smokers with type 2 diabetes mellitus (T2DM). FINDINGS: Blood data including EPA, AA, and ABI were measured in smokers and non-smokers with T2DM enrolled at Jichi Medical University (n = 116, male 86 %, mean age 59 yr). The patients were classified into two groups according to their ABI level: <1.1 (low to borderline) or ≥1.1 (high). The EPA/AA ratio in smoking patients with ABI < 1.1 (n = 26; EPA/AA = 0.25) was significantly lower than in those with ABI ≥ 1.1 (n = 32; EPA/AA = 0.34; p = 0.03), but was not significantly different in non-smoking patients. The EPA/AA ratio was independently, significantly, and positively correlated with the ABI level (β = 0.41; p < 0.01) after adjusting for multiple variables only in smoking patients with T2DM. CONCLUSIONS: The EPA/AA ratio may be associated with subclinical peripheral arterial damage in smokers with T2DM. Further studies are warranted.

High-density lipoprotein(HDL) particles play a role in anti-oxidative stress, and this action is partially involved in the anti-atherosclerotic processes. Indeed, a decreased level of anti-oxidative stress in HDL has been reported in oxidative stress-related pathologies. As typical HDL-containing protein molecules, apolipoprotein A-I (apoA-I), paraoxonase-1 (PON1), and lipoprotein-associated phospholipase A2 (Lp-PLA2) are mainly described in the present review. Numerous studies have demonstrated that a low apoA-I level and the oxidative modification of apoA-I is associated with a dysfunction of anti-oxidative stress in HDL. A low PON1 level also plays a significant role in the dysfunction of anti-oxidative stress in HDL. Several studies have shown Lp-PLA2 to have an anti-atherosclerotic ability, while there have also been clinical studies showing a positive association between the Lp-PLA2 level and atherosclerotic manifestations. There are other HDL-containing protein molecules related to the anti-oxidative stress system in HDL, and all of these should be further investigated. The treatment of oxidative stress-related pathologies can lead to an improvement or even a full recovery of the anti-oxidative stress function in HDL. Given the multiple functions of HDL particles and the limitations associated with only HDL-cholesterol measurements, a comprehensive assessment of HDL particles, which includes the role of anti-oxidative stress in HDL, is thus considered to be necessary in future practice.

PURPOSE: Depression is frequently observed in people with diabetes. The purpose of this study is to develop a tool for individuals with diabetes and depression to communicate their comorbid conditions to health-care providers. METHOD: We searched the Internet to review patient-held medical records (PHRs) of patients with diabetes and examine current levels of integration of diabetes and depression care in Japan. RESULTS: Eight sets of PHRs were found for people with diabetes. All PHRs included clinical follow-up of diabetes and multidisciplinary clinical pathways for diabetes care. No PHRs included depression monitoring and/or treatment. In terms of an integrated PHR for a patient comorbid with diabetes and depression, necessary components include hopes/preferences, educational information on diabetes complications and treatment, medical history, stress and coping, resources, and monitoring diabetes and depression. CONCLUSION: A new PHR may be suitable for comorbid patients with diabetes and depression.

OBJECTIVE: The cardio-ankle vascular index (CAVI) is an index of arterial stiffness less dependent on blood pressure and an indicator suitable for assessing the arterial dysfunction. However, it remains unclear whether CAVI can predict the outcome of cardiovascular diseases (CVD) in obese patients. METHODS: A total of 425 obese Japanese outpatients (189 men and 236 women, mean age: 51.5 years) were enrolled in a multicenter prospective cohort Japan, the Japan Obesity and Metabolic Syndrome Study (JOMS). Primary analysis regarding measurements of cardiovascular risk factors including CAVI and the occurrence of macrovascular complications was based on following the participants over a 5-year period. RESULTS: Of the eligible patients, 300 (78%) were followed into the fifth year. During the study period, 15 coronary heart disease, 7 stroke, and 6 arteriosclerosis obliterans events occurred. All events occurred in 28 patients, and CVD incidence rate was 15.8 per 1000 person-years. In the analysis of adjusted models for traditional risk factors, CAVI was a significant factor for the incidence of events. In addition, high CAVI and low HDL-cholesterol were significant factors for the incidence of events in Cox stepwise multivariate analysis when age- and sex-adjusted (CAVI [per 1]: HR = 1.44 [1.02-2.02], p = 0.037; HDL-cholesterol [per 1 mmol/L]: HR = 0.20 [0.06-0.69], p = 0.011). In addition, CAVI added value to atherosclerotic cardiovascular disease risk score in predicting the development of CVD. CONCLUSION: This study demonstrates for the first time that CAVI is an effective predictor of CVD events in obese patients.

INTRODUCTION: Circulating lipoprotein (a) (Lp(a)) is a recognized risk factor for cardiovascular disease (CVD). Tibolone, a synthetic steroid, may lower Lp(a) levels; however, evidence of the effects of tibolone on Lp(a) still remain to be defined. Therefore, we investigated the effects of tibolone treatment on circulating Lp(a) levels in postmenopausal women. METHODS: The search included PUBMED, Web of Science, Scopus, and Google Scholar (up to January 31st, 2015) to identify controlled clinical studies investigating the effects of oral tibolone treatment on Lp(a) levels in postmenopausal women. Random-effects meta-regression was performed using unrestricted maximum likelihood method for the association between calculated weighted mean difference (WMD) and potential moderators. RESULTS: Meta-analysis of data from 12 trials (16 treatment arms) suggested a significant reduction of Lp(a) levels following tibolone treatment (WMD: -25.28%, 95% confidence interval [CI]: -36.50, -14.06; p < 0.001). This result was robust in the sensitivity analysis and its significance was not influenced after omitting each of the included studies from the meta-analysis. When the studies were categorized according to the tibolone dose, there were consistent significant reductions of Lp(a) in the subsets of studies with doses <2.5 mg/day (WMD: -17.00%, 95%CI: -30.22, -3.77; p < 0.012) and 2.5 mg/day (WMD: -29.18%, 95%CI: -45.02, -13.33; p < 0.001). Likewise, there were similar reductions in the subsets of trials with follow-up either <24 months (WMD: -26.79%, 95%CI: -38.40, -15.17; p < 0.001) or ≥24 months (WMD: -23.10%, 95%CI: -40.17, -6.03; p = 0.008). CONCLUSIONS: This meta-analysis shows that oral tibolone treatment significantly lowers circulating Lp(a) levels in postmenopausal women. Further studies are warranted to explore the mechanism of this effect and the potential value and place of tibolone or its analogues in the treatment of elevated Lp(a) in individuals at risk of CVD.

The aim of the present study was to investigate the prevalence of fear of hypoglycemia, in association with severe hypoglycemia and social factors, in insulin-treated patients with type 2 diabetes mellitus. A questionnaire survey on hypoglycemia and patient-physician communication was carried out in 355 patients with insulin-treated type 2 diabetes mellitus patients at 16 hospitals and clinics. A fear of hypoglycemia was reported by 27.7% of patients. A stepwise logistic regression analysis found that severe hypoglycemia during the past 1 year was a significant determinant of fear of hypoglycemia (odds ratio 2.16, 95% confidence interval 1.06-4.41; P = 0.034), and age (odds ratio 1.02, 95% confidence interval 1.00-1.05, P = 0.038) and living alone (odds ratio 1.93, 95% confidence interval 1.00-3.73, P < 0.05) were significantly higher in patients with fear of hypoglycemia than in those without it.