An Inhibitor of Activated Blood Coagulation Factor X Shows Anti-Endothelial Senescence and Anti-Atherosclerotic Effects.

BACKGROUND: Coagulant factor Xa inhibitors (XaIs) are prescribed for patients with atrial fibrillation for years. METHODS: Human umbilical venous endothelial cells (HUVECs) were cultured with or without (w/wo) a XaI (rivaroxaban) under high glucose (HG: 22 mM). Endothelial senescence was investigated by assessing senescence-associated-ß-galactosidase (SA-ß-gal), p53, and telomere length. Endothelial function and atherosclerosis were examined by nitric oxide-related-products (NOx: NO2- and NO3-), O2-, endothelial NO synthase (eNOS), NADPH oxidase (p22phox), and ICAM1. PAR1 (protease-activated receptor 1) and PAR2, which were reported to regulate eNOS phosphorylation, were inhibited by small interfering RNAs (siRNAs). Thirty-two male dyslipidemic type 2 diabetic rats (ZFDM LepRfa/fa) were fed a high-cholesterol diet w/wo XaI (50 µg/day/kg) for 1-4 weeks. RESULTS: SA-ß-gal, p53, p21, and p16INK4a were increased by HG and restored by XaI (50 nM) in HUVECs. XaI restored telomerase activity and preserved telomere length. XaI suppressed O2-, p22phox, and ICAM1 and restored NOx and eNOS. XaI decreased PAR1 following elevation by HG, which was confirmed by PAR1 siRNA and PAR2 siRNA. In in vivo experiments, plasma glucose, total cholesterol, and triglycerides were increased for 4 weeks but were not changed by XaI. XaI decreased SA-ß-gal and telomerase and preserved telomere length in the aortic endothelium. XaI activated eNOS, inhibited p22phox, increased plasma NOx, and decreased O2-. CONCLUSION: Rivaroxaban prevents replicative senescence in HUVECs and aortic endothelial cells in dyslipidemic diabetic mice. It restores endothelial function and prevents the progression of atherosclerosis.

Strategies to Overcome Residual Risk During Statins Era.

At present, atherosclerosis is one of the most important field in clinical and research medicine. Because it is closely related to cardiovascular (CV) and endocrine disorders such as coronary artery disease, cardiometabolic disorders, much research on how to manage atherosclerosis has been performed. The low-density lipoprotein cholesterol (LDL-C) concentration has been established as an independent risk factor for developing atherosclerosis, and considerable effort has been committed to educating both physicians and the general public on the importance of lowering LDL-C with statins. Although statins have already significantly improved CV outcomes, patients with LDL-C target levels achieved by intense statin therapy still have significant remaining CV risk. Statins already play a central role in managing hyperlipidemia; however, residual risk with statins is an important field of managing remaining CV risk. Recent studies have suggested residual cholesterol and inflammation risks in causing CV events. In the current review, we will discuss residual risk and suggest strategies to overcome it in the statins era.

Best Treatment Strategies With Statins to Maximize the Cardiometabolic Benefits.

Statins are important for preventing adverse cardiovascular events in patients with both high and low risk of vascular disease, by reducing the levels of low-density lipoprotein cholesterol (LDL-C). However, statins dose-dependently increase adverse effects and increase the risk of type 2 diabetes. Previously, it was hypothesized this was caused by to off-target effects, but recent studies demonstrate it is caused by on-target effects. Nonetheless, the American guidelines recommend the use of high-intensity statin therapy, and extend its use to most people at risk of vascular diseases, particularly older people. In contrast, European, Korean, and Japanese committees have expressed concerns about the potential adverse effects of using high-intensity statins for lifelong periods in a large fraction of the population. Patients who have achieved LDL-C levels below currently recommended targets may still experience cardiovascular events, resulting from residual risk. Ezetimibe, PCSK9 inhibitors, inclisiran, and ANGPTL3 antisense oligonucleotides are promising alternative non-statin drugs. Of interest, cross-talk between hypercholesterolemia and the renin-angiotensin-system exists at multiple levels of insulin resistance and endothelial dysfunction. There are still unanswered questions on how to maximize the cardiometabolic benefits of statins in patients. We will discuss the results of randomized clinical trials, meta-analysis, and recent clinicopharmacogenetic studies, and propose practical guidelines to maximize the cardiometabolic benefits while reducing adverse effects and overcoming residual risk.

The effects on plasma L-arginine levels of combined oral L-citrulline and L-arginine supplementation in healthy males.

We investigated the effects of combining 1 g of l-citrulline and 1 g of l-arginine as oral supplementation on plasma l-arginine levels in healthy males. Oral l-citrulline plus l-arginine supplementation more efficiently increased plasma l-arginine levels than 2 g of l-citrulline or l-arginine, suggesting that oral l-citrulline and l-arginine increase plasma l-arginine levels more effectively in humans when combined.

Organizational justice and insomnia: a prospective cohort study examining insomnia onset and persistence.

PURPOSE: Insomnia is one of the most common health problems and causes a large social burden. Psychosocial work-related factors are reported to be associated with both insomnia onset and insomnia persistence. However, the association between organizational justice (OJ) and insomnia remains unclear. The objective of this study was to examine the effect of OJ on insomnia persistence, as well as insomnia onset. METHODS: A prospective cohort study with a 1-year observational period was conducted. Self-reported questionnaire data from 1588 employees were analyzed. OJ was measured using the Japanese version of the OJ questionnaire, which has four components (distributive, procedural, interpersonal, and informational). Insomnia was assessed with the Athens Insomnia Scale. Logistic regression analysis was used to explore the effects of OJ on insomnia. RESULTS: Among non-insomniac subjects at the baseline (n = 1236), low overall OJ was a risk of insomnia onset even after adjustment for lifestyle and work-related variables (adjusted odds ratio 0.66; 95% confidence interval 0.51-0.85). The procedural, interpersonal, and informational justice components were also associated with insomnia onset. Among insomniac subjects at the baseline (n = 352), low overall OJ, as well as the procedural and interpersonal justice components, was associated with insomnia persistence. Although these associations became insignificant after adjustment, the interpersonal justice component showed a marginally significant association with insomnia persistence (p = 0.058). CONCLUSIONS: OJ, especially interpersonal justice, was revealed as an associated factor for both insomnia onset and persistence. These findings may provide useful information for prevention of insomnia among working population.

Endothelial cellular senescence is inhibited by liver X receptor activation with an additional mechanism for its atheroprotection in diabetes.

Senescence of vascular endothelial cells leads to endothelial dysfunction and contributes to the progression of atherosclerosis. Liver X receptors (LXRs) are nuclear receptors whose activation protects against atherosclerosis by transcriptional regulation of genes important in promoting cholesterol efflux and inhibiting inflammation. Here we found that LXR activation with specific ligands reduced the increase in senescence-associated (SA) ß-gal activity, a senescence marker, and reversed the decrease in telomerase activity, a replicative senescence marker, in human endothelial cells under high glucose. This effect of LXR activation was associated with reduced reactive oxygen species and increased endothelial NO synthase activity. A series of experiments that used siRNAs indicated that LXRß mediates the prevention of endothelial cellular senescence, and that sterol regulatory element binding protein-1, which was up-regulated as a direct LXRß target gene, may act as a brake of endothelial cellular senescence. Although oral administration of the LXR ligand led to severe fatty liver in diabetic rats, concomitant therapy with metformin avoided the development of hepatic steatosis. However, the preventive effect of the LXR ligand on SA ß-gal-stained cells in diabetic aortic endothelium was preserved even if metformin was coadministered. Taken together, our studies demonstrate that an additional mechanism, such as the regulation of endothelial cellular senescence, is related to the antiatherogenic properties of LXRs, and concomitant treatment with metformin may provide a clinically useful therapeutic strategy to alleviate an LXR activation-mediated adverse effects on liver triglyceride metabolism.

Effects of leisure activities at home on perceived care burden and the endocrine system of caregivers of dementia patients: a randomized controlled study.

BACKGROUND: Psychological stress associated with caregiving is thought to underlie the high incidence of hypertension, ischemic heart disease, and mortality, as well as reduced immune function, among caregivers of dementia patients. Here, we examined the effects of periodic leisure activities performed by caregivers of dementia patients with care recipients at home on perceived care burden and levels of stress hormones. METHODS: Participants were 42 caregivers aged ≥ 65 years of patients diagnosed with Alzheimer's dementia. They were randomly assigned to intervention and non-intervention groups. The intervention group underwent a leisure activity program (30 min/3 times/week for 24 weeks) with the care recipient, and the control group underwent normal care activities. RESULTS: The Zarit Burden Interview (ZBI) score, a subjective indicator of care burden, significantly decreased after intervention in the intervention group (p < 0.05), whereas no difference was observed in the control group. No significant changes were observed in adrenaline, noradrenaline, dopamine, and cortisol levels in both groups. CONCLUSIONS: The lack of changes in stress hormone levels despite a decrease in subjective care burden in the intervention group might be explained by the effects of the chosen leisure activity on the neuroendocrine system. Our findings suggest that periodic leisure activities can reduce perceived care burden among caregivers of dementia patients. However, in order to evaluate accurately the effects of leisure activities of the present study, long-term follow-up of both caregivers and care recipients is necessary. The Nagoya University Department of Medicine Ethics Committee Clinical Trials Registry Number is 1290.

A cross-sectional study of the association between city scale and daily steps in Japan: Data from the National Health and Nutrition Survey Japan (NHNS-J) 2006-2010.

Objective There is little evidence showing that inhabitants of urban areas engage in more physical activity than do rural ones, although accumulating evidence concerning the best neighborhood environments conducive to physical activity supports the idea. This study sought to fill the research gap by examining the association between city scale and daily steps using data from Japan's National Health and Nutrition Survey (NHNS).Methods We analyzed data from 15,763 men and 18,479 women aged 20 years and older who participated in a one-day pedometer measurement during any part of the NHNS between 2006 and 2010. The data obtained for these years were combined into a single data set. City scale was categorized into 5 groups based on population: 1) 12 large cities and 23 wards, 2) population greater than 150,000, 3) population 50,000-150,000, 4) population less than 50,000, and 5) towns and villages. Differences in daily steps among city scale groups were analyzed using an ANCOVA, adjusting for age by gender. The Bonferroni method was employed for multiple comparisons, and linear regression was used to test for linear trends. Subgroup analyses were performed by age (20-39, 40-64, older than 64), and job status. The study was approved by the Tokyo Medical University ethics committee, and use of these data complied with the Statistics Act of Japan.Results The steps per day for men after adjusting for age were Group 1 : 7,494±4,429 (mean±SD), Group 2 : 7,407±4,428, Group 3 : 7,206±4,428, Group 4 : 6,911±4,428, and Group 5 : 6,715±4,429. Women's daily steps according to city scale group were 6,767±3,648, 6,386±3,647, 6,062±3,646, 6,069±3,649, and 6,070±3,649 for Groups 1 through 5, respectively. There were overall statistically significant differences (ANCOVA, P<0.001) between both genders. The larger the city scale, the more mean daily steps that were taken by both men and women (P values for both trends <0.001). Subgroup analyses revealed significant differences in the mean daily steps by city scale, regardless of age or job status for both genders. There were no significant differences among Groups 3, 4, or 5 among unemployed men, men older than 64, or overall women, which differed from the results for men with jobs, who took fewer steps in smaller cities.Conclusions Our study showed that men and women living in larger cities took more steps compared to those living in smaller cities. Subgroup analyses further revealed that the associations between city scale and physical activity differed according to gender, age, and job status.

Evaluation of the difference in the rate coefficients of F2 + NOx (x = 1 or 2) → F + FNOx by the stereochemical arrangement using the density functional theory.

The rate coefficient of F2 + NO → F + FNO is 2 to 5 orders of magnitude higher than that of F2 + NO2 → F + FNO2 even though bond energies of FNO and FNO2 only differ by ∼0.2 eV. To understand the cause of having different rate coefficients of these two reactions, the change in total energies was calculated by varying the stereochemical arrangement of F2 with respect to NOx (x = 1 or 2) by the density functional theory (DFT), using CAM-B3LYP/6-311 G+(d) in the Gaussian program. The permitted approaching angle between the x-axis and the plane consisting of O, N, F, and ϕ plays a key role to restrict the reaction of NO2 and F2 compared to the reaction of NO and F2. This restriction in the reaction space is considered to be the main cause of different rate coefficients depending on the selection of x = 1 or 2 of the reaction of F2 + NOx → F + FNOx, which was also confirmed by the difference in Si etch rate using the F formed by those reactions.

Oral supplementation with a combination of L-citrulline and L-arginine rapidly increases plasma L-arginine concentration and enhances NO bioavailability.

BACKGROUND: Chronic supplementation with L-citrulline plus L-arginine has been shown to exhibit anti-atherosclerotic effects. However, the short-term action of this combination on the nitric oxide (NO)-cGMP pathway remains to be elucidated. The objective of the present study was to investigate the acute effects of a combination of oral L-citrulline and L-arginine on plasma L-arginine and NO levels, as well as on blood circulation. METHODS: Rats or New Zealand white rabbits were treated orally with L-citrulline, or L-arginine, or a combination of each at half dosage. Following supplementation, plasma levels of L-arginine, NOx, cGMP and changes in blood circulation were determined sequentially. RESULTS: L-Citrulline plus L-arginine supplementation caused a more rapid increase in plasma L-arginine levels and marked enhancement of NO bioavailability, including plasma cGMP concentrations, than with dosage with the single amino acids. Blood flow in the central ear artery in rabbits was also significantly increased by L-citrulline plus L-arginine administration as compared with the control. CONCLUSION: Our data show for the first time that a combination of oral L-citrulline and L-arginine effectively and rapidly augments NO-dependent responses at the acute stage. This approach may have clinical utility for the regulation of cardiovascular function in humans.

Association between the Decrease in Medical Visit Frequency and Chronic Disease Worsening in the Early Stages of COVID-19 - A Longitudinal Study.

Objective This longitudinal study aimed to clarify the changes in the medical treatment behavior of Japanese patients with chronic diseases during the early phase of the coronavirus disease 2019 (COVID-19) pandemic and examine the factors associated with disease worsening. Methods Subjects with chronic diseases were selected from a panel survey that started at the beginning of the COVID-19 pandemic consists of 2,400 participants recruited via the Internet. Medical treatment behaviors (decrease in medical visit frequency, inability to take regular medications, and utilization of telephone/online medical care), psychological distress, and sociodemographic factors were evaluated at baseline (May 2020) and at the follow-up survey (February 2021). A worsening of chronic diseases was defined as those who answered "yes" to the question, "Has-the-condition-of-the-chronic-disease-worsened?". The factors related to the worsening of chronic diseases at follow-up were examined. Results A total of 514 participants (mean age 61.6±12.9 years) were analyzed. The percentage of participants who reported decreasing medical visit frequency was 34% at the baseline and 16.5% at follow-up, and those who reported a worsening of chronic diseases was 5.1% and 5.1%, respectively. A worsening of chronic diseases at follow-up was significantly associated with a younger age, a decreased frequency of medical visits, unemployment, a history of smoking, and psychological distress. Conclusions A decreased frequency of medical visits was observed among one-third of the participants with chronic disease in the early stage of the pandemic, and it reduced by half at follow-up. In the early stages of an emerging infectious disease pandemic, decreased regular hospital/clinic visits can lead to a worsening of chronic diseases. Those who had psychological distress, unemployment, and a history of smoking were vulnerable to a worsening chronic disease.

Metabolic predictors of ischemic heart disease and cerebrovascular attack in elderly diabetic individuals: difference in risk by age.

BACKGROUND: High LDL-cholesterol (LDL-C) and glucose levels are risk factors for ischemic heart disease (IHD) in middle-aged diabetic individuals; however, the risk among the elderly, especially the very elderly, is not well known. The aim of this study was to identify factors that predict IHD and cerebrovascular attack (CVA) in the elderly and to investigate their differences by age. METHODS: We performed a prospective cohort study (Japan Cholesterol and Diabetes Mellitus Study) with 5.5 years of follow-up. A total of 4,014 patients with type 2 diabetes and without previous IHD or CVA (1,936 women; age 67.4 ± 9.5 years, median 70 years; <65 years old, n = 1,261; 65 to 74 years old, n = 1,731; and ≥ 75 years old, n = 1,016) were recruited on a consecutive outpatient basis from 40 hospitals throughout Japan. Lipids, glucose, and other factors related to IHD or CVA risk, such as blood pressure (BP), were investigated using the multivariate Cox hazard model. RESULTS: One hundred fifty-three cases of IHD and 104 CVAs (7.8 and 5.7/1,000 people per year, respectively) occurred over 5.5 years. Lower HDL-cholesterol (HDL-C) and female gender were correlated with IHD in patients ≥75 years old (hazard ratio (HR):0.629, P < 0.01 and 1.132, P < 0.05, respectively). In contrast, systolic BP (SBP), HbA1C, LDL-C and non-HDL-C were correlated with IHD in subjects <65 years old (P < 0.05), and the LDL-C/HDL-C ratio was correlated with IHD in all subjects. HDL-C was correlated with CVA in patients ≥75 years old (HR: 0.536, P < 0.01). Kaplan-Meier estimator curves showed that IHD occurred more frequently in patients <65 years old in the highest quartile of the LDL-C/HDL-C ratio. In patients ≥75 years old, IHD and CVA were both the most frequent among those with the lowest HDL-C levels. CONCLUSIONS: IHD and CVA in late elderly diabetic patients were predicted by HDL-C. LDL-C, HbA1C, SBP and non-HDL-C are risk factors for IHD in the non-elderly. The LDL-C/HDL-C ratio may represent the effects of both LDL-C and HDL-C. These age-dependent differences in risk are important for developing individualized strategies to prevent atherosclerotic disease. TRIAL REGISTRATION: UMIN-CTR, UMIN00000516.

CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy.

Tumor growth requires neoangiogenesis. VEGF is the most potent proangiogenic factor. Dysregulation of hypoxia-inducible factor (HIF) or cytokine stimuli such as those involving the chemokine receptor 4/stromal-derived cell factor 1 (CXCR4/SDF-1) axis are the major cause of ectopic overexpression of VEGF in tumors. Although the CXCR4/SDF-1 pathway is well characterized, the transcription factors executing the effector function of this signaling are poorly understood. The multifunctional Yin Yang 1 (YY1) protein is highly expressed in different types of cancers and may regulate some cancer-related genes. The network involving CXCR4/YY1 and neoangiogenesis could play a major role in cancer progression. In this study we have shown that YY1 forms an active complex with HIF-1alpha at VEGF gene promoters and increases VEGF transcription and expression observed by RT-PCR, ELISA, and Western blot using two different antibodies against VEGFB. Long-term treatment with T22 peptide (a CXCR4/SDF-1 inhibitor) and YY1 silencing can reduce in vivo systemic neoangiogenesis (P < 0.01 and P < 0.05 vs. control, respectively) during metastasis. Moreover, using an in vitro angiogenesis assay, we observed that YY1 silencing led to a 60% reduction in branches (P < 0.01) and tube length (P < 0.02) and a 75% reduction in tube area (P < 0.001) compared with control cells. A similar reduction was observed using T22 peptide. We demonstrated that T22 peptide determines YY1 cytoplasmic accumulation by reducing its phosphorylation via down-regulation of AKT, identifying a crosstalk mechanism involving CXCR4/YY1. Thus, YY1 may represent a crucial molecular target for antiangiogenic therapy during cancer progression.

[Macrovascular diseases-based on the data of Japanese cohort study (JCDM) including 1,016 very elderly diabetic individuals older than 75 years old].

LDL-cholesterol and glucose are risk for ischemic heart disease (IHD) in middle-aged diabetic individuals; however, the risk among elderly, especially very elderly, is not well-known. We performed a prospective cohort study (JCDM) with 5.5 years of follow-up. Four thousand fourteen type 2 diabetic patients without previous IHD or cerebrovascular attack (CVA) (1,936 women: 67.4 +/- 9.5 years, > or = 75 years, n = 1,016) were recruited. One hundred fifty-three IHDs and 104 CVAs occurred over 5.5 years. Lower HDL-cholesterol (HDL-C) was correlated with IHD in patients > or = 75 years old. In contrast, systolic BP, HbA1c, LDL-C and non-HDL-C were correlated in subjects < 65 years old, and LDL-C/HDL-C ratio was correlated in all subjects. HDL-C was correlated with CVA in patients > or = 75 years old. These age-dependent differences in risk are important for developing individualized strategies to prevent atherosclerotic disease.

Association of pulse pressure with all-cause mortality in older Japanese patients with type 2 diabetes mellitus: A observational cohort study.

AIM: Although systolic and diastolic blood pressures as well as blood glucose are monitored when nurses care for patients with type 2 diabetes, the same is not true for pulse pressure. We aimed to determine the association between pulse pressure and all-cause mortality. METHODS: We conducted a longitudinal study of outpatients with type 2 diabetes aged 65 years and older at diabetes-specialized hospitals in Japan from September 2004 to December 2016. Descriptive data, blood pressure measurements, blood analysis data, and information on life and death were obtained from medical records. Cox proportional hazards models were used to estimate the relative risks with 95% confidence intervals for all-cause mortality. RESULTS: We analyzed 357 of the 383 recruited patients (mean age, 74.9 years; 175 men and 182 women; average follow-up, 7.7 years), and 50 patients died. After adjusting for covariates, the relative risks for pulse pressures of 55 to <65, 65 to <75, and ≥75 mmHg (reference: <55 mmHg) were 1.77 (95% confidence interval: [0.59, 5.28]), 2.66 (95% confidence interval: [0.93, 7.56]), and 3.23 (95% confidence interval: [1.16, 8.99]), respectively. The relative risk for the 65 mmHg or higher group (reference: <65 mmHg) was 2.08 (95% confidence interval: [1.11, 3.92]). Neither systolic blood pressure nor diastolic blood pressure alone were significantly associated with mortality. CONCLUSIONS: In older patients with type 2 diabetes, a wide pulse pressure was associated with a higher risk of all-cause mortality. Nurses caring for older people with diabetes should also monitor pulse pressure.

Dose-dependent modulatory effects of insulin on glucose-induced endothelial senescence in vitro and in vivo: a relationship between telomeres and nitric oxide.

The elderly are prone to postprandial hyperglycemia that increases their cardiovascular risk. Although insulin therapy is necessary to treat diabetes, high plasma concentrations of insulin may cause the development of atherosclerosis and accelerate endothelial senescence. We assumed that high glucose causes stress-induced premature senescence and replicative senescence and examined the regulatory role of insulin in endothelial senescence and functions under different glucose conditions. Exposure of human endothelial cells to high glucose (22 mM) for 3 days increased senescence-associated-ß-galactosidase activity, a senescence marker, and decreased telomerase activity, a replicative senescence marker. Physiological concentrations of insulin preserved telomere length and delayed endothelial senescence under high-glucose conditions. The effect of insulin under high-glucose conditions was associated with reduced reactive oxygen species and increased nitric oxide (NO). Small interfering RNA targeting endothelial NO synthase reduced the antisenescence effects of insulin. Physiological concentrations of insulin also reversed high glucose-induced increases in p53 and vascular cell adhesion molecule-1 and decreases in senescence marker protein-30. On the other hand, when insulin was given at any concentrations under normal glucose or at high concentrations under high glucose, its ability to promote cellular senescence was unrelated to endothelial NO. Finally, streptozotocin-induced diabetes showed more senescent cells in the aortic endothelium of aged rats compared with age-matched control and insulin-treated animals. Conclusively, the regulatory effects of insulin on endothelial senescence were modulated by the glucose environment. These data may help explain insulin's complicated roles in atherosclerosis in the elderly.

Age, gender, insulin and blood glucose control status alter the risk of ischemic heart disease and stroke among elderly diabetic patients.

BACKGROUND: We analyzed the effects of insulin therapy, age and gender on the risk of ischemic heart disease (IHD) and cerebrovascular accident (CVA) according to glycemic control. METHODS AND RESULTS: We performed a prospective cohort study (Japan Cholesterol and Diabetes Mellitus Study) of type 2 diabetes patients (n = 4014) for 2 years. The primary endpoint was the onset of fatal/non-fatal IHD and/or CVA, which occurred at rates of 7.9 and 7.2 per 1000 person-years, respectively. We divided diabetic patients into four groups based on age (≤ 70 and > 70) and hemoglobin A1C levels (≤ 7.0 and > 7.0%). Multiple regression analysis revealed that IHD was associated with high systolic blood pressure and low HDL-C in patients under 70 years of age with fair glycemic control and was associated with low diastolic blood pressure in the older/fair group. Interestingly, insulin use was associated with IHD in the older/poor group (OR = 2.27, 95% CI = 1.11-5.89; p = 0.026) and was associated with CVA in the older/fair group (OR = 2.09, 95% CI = 1.06-4.25; p = 0.028). CVA was associated with lower HDL-C and longer duration of diabetes in younger/poor glycemic control group. Results by stepwise analysis were similar. Next, patients were divided into four groups based on gender and diabetic control(hemoglobinA1C < or > 7.0%). Multiple regression analysis revealed that IHD was associated with high systolic blood pressure in male/fair glycemic control group, age in male/poor control group, and short duration of diabetic history in females in both glycemic control groups. Interestingly, insulin use was associated with IHD in the male/poor group(OR = 4.11, 95% CI = 1.22-8.12; p = 0.018) and with CVA in the female/poor group(OR = 3.26, 95% CI = 1.12-6.24; p = 0.02). CVA was associated with short duration of diabetes in both female groups. CONCLUSIONS: IHD and CVA risks are affected by specific factors in diabetics, such as treatment, gender and age. Specifically, insulin use has a potential role in preventing IHD but may also be a risk factor for CVA among the diabetic elderly, thus revealing a need to develop improved treatment strategies for diabetes in elderly patients. The Japan Cholesterol and Diabetes Mellitus Study was formulated to evaluate them(Umin Clinical Trials Registry, clinical trial reg. no. UMIN00000516; http://www.umin.ac.jp/ctr/index.htm).

The effects of selective estrogen receptor modulator treatment following hormone replacement therapy on elderly postmenopausal women with osteoporosis.

OBJECTIVES: A comparison between the atheroprotective and osteoprotective effects of the selective estrogen receptor modulator (SERM) raloxifene and those of hormone replacement therapy (HRT) has not been made in elderly women. METHODS: A randomized prospective controlled trial was performed in a cohort of 32 elderly Japanese women with osteoporosis receiving HRT (estriol plus medroxyprogesterone) for more than 1 year. In 16 randomly selected subjects, HRT was changed to raloxifene therapy (60mg/day, 71.4±3.4 years, SERM group). The other 16 patients were continued on HRT (71.8±2.9 years, HRT group). As a control group, 14 subjects were enrolled, did not take any medications and were age-matched to experimental patients (72.5±3.3 years, control group). Plasma lipids, TNFα, adiponectin, NO metabolites (NOx:NO2(-) and NO3(-)), cyclicGMP and bone-mineral density (BMD) were evaluated at baseline and at 26 and 52 weeks after enrollment. RESULTS: SERM (Raloxifene) increased high-density-lipoprotein cholesterol levels and tended to decrease low-density-lipoprotein cholesterol levels (P=0.058) compared with baseline. Adiponectin, NOx and cGMP levels were significantly increased after 6 months compared with baseline or the HRT group. TNFα was decreased by raloxifene. In control subjects, no significant changes were observed in any of these markers. Bone-mineral density was higher at baseline in the raloxifene and HRT groups than in the control group, and BMD increased 12 months after baseline in the HRT and control group. CONCLUSION: SERM improved BMD and endothelial function in elderly postmenopausal women with osteoporosis who had received HRT, and these effects were comparable to or slightly stronger than those of HRT. Changes in adiponectin and TNFα may underlie the improvements in endothelial function, such as NO signaling.

[Estrogen, SERM].

Osteoporosis is uncommon before menopause and dramatically increases in prevalence thereafter. That is why estrogens provide protection against osteoporosis. Studies of women receiving estrogen replacement have demonstrated improvements in bone mineral density (BMD) as well as endothelial function. Recent randomized trials, however, have produced equivocal results and raised questions about whether combined hormonal replacement therapy (HRT) prevents later cardiovascular events. Investigations of alternatives to HRT have suggested that selective estrogen receptor modulators (SERMs) may confer cardiovascular and osteoporosis protection. Raloxifene is a second-generation SERM used for the prevention and treatment of postmenopausal osteoporosis. Raloxifene decreases the incidence of vertebral fractures by 30-50% in postmenopausal women with osteoporosis. We also studied its effect on postmenopausal elderly women with osteoporosis.