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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.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.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 to65, 65 to75, 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.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.

Primary chylomicronemia (PCM) is a rare and intractable disease characterized by marked accumulation of chylomicrons in plasma. The levels of plasma triglycerides (TGs) typically range from 1,000 - 15,000 mg/dL or higher. PCM is caused by defects in the lipoprotein lipase (LPL) pathway due to genetic mutations, autoantibodies, or unidentified causes. The monogenic type is typically inherited as an autosomal recessive trait with loss-of-function mutations in LPL pathway genes ( LPL , LMF1 , GPIHBP1 , APOC2 , and APOA5 ). Secondary/environmental factors (diabetes, alcohol intake, pregnancy, etc.) often exacerbate hypertriglyceridemia (HTG). The signs, symptoms, and complications of chylomicronemia include eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and acute pancreatitis with onset as early as in infancy. Acute pancreatitis can be fatal and recurrent episodes of abdominal pain may lead to dietary fat intolerance and failure to thrive. The main goal of treatment is to prevent acute pancreatitis by reducing plasma TG levels to at least less than 500-1,000 mg/dL. However, current TG-lowering medications are generally ineffective for PCM. The only other treatment options are modulation of secondary/environmental factors. Most patients need strict dietary fat restriction, which is often difficult to maintain and likely affects their quality of life. Timely diagnosis is critical for the best prognosis with currently available management, but PCM is often misdiagnosed and undertreated. The aim of this review is firstly to summarize the pathogenesis, signs, symptoms, diagnosis, and management of PCM, and secondly to propose simple diagnostic criteria that can be readily translated into general clinical practice to improve the diagnostic rate of PCM. In fact, these criteria are currently used to define eligibility to receive social support from the Japanese government for PCM as a rare and intractable disease. Nevertheless, further research to unravel the molecular pathogenesis and develop effective therapeutic modalities is warranted. Nationwide registry research on PCM is currently ongoing in Japan with the aim of better understanding the disease burden as well as the unmet needs of this life-threatening disease with poor therapeutic options.

Heart rate variability (HRV), especially increased high frequency (HF), has been reported to provide clinically useful prognostic information regarding cardiovascular disease. Napping is an excellent sleep management strategy in older adults. This study was conducted to clarify the effect of napping on HRV in older adult patients with cardiovascular risk factors. The patients were divided into two groups: one group of 32 patients who reported napping (nap group) and another group of 45 patients who did not report napping (nonnap group). The HRV was calculated in terms of the HF component over 24 hr during wakefulness, sleep, and 1 hr after sleep onset. The HF in the nap group was significantly higher than that in the nonnap group during all times measured. In addition, napping was a significant predictor of increased HF. This study shows the effectiveness of napping in the daily lives of patients with cardiovascular risk factors.

Progress in computational methods and personal computing has made possible more accurate estimations for primary dissociation channels and energies. The main dissociation route is revealed to be via the 7E excited state with an energy of 12.23 eV, which is composed of transitions from the highest occupied molecular orbital with b1 symmetry to some degenerate unoccupied e molecular orbitals. The main contributing e orbitals consisted of antibonding combination of C2F4 π-bonding orbitals. This degenerate 7E state is lowered by non-adiabatic transitions through the conical interactions on the dissociating route to 2C2F4, so the energy is finally relaxed at the dissociative second lowest 1E excited state leading to 2C2F4 production. In the electron attachment process, the calculated results show that the F− ion is produced from the excited states of the D4h c-C4F8 − ion through conical interactions at the energies of 4.3 eV, 5.6 eV, and 5.0 eV, along the C–F dissociation route.

Objectives Objectively measured sedentary behavior (SB) on weekdays and weekends has been mainly assessed in white‐collar workers, while data in blue‐collar workers are sparse. Therefore, this study presented the difference in accelerometer‐measured SB levels between weekdays and weekends, stratified by white‐ and blue‐collar occupations. Methods This study was a sub‐analysis of accelerometer data from 73 workers (31 blue‐collar and 42 white‐collar) at a Japanese manufacturing plant. SB was defined as ≤1.5 metabolic equivalents estimated using an accelerometer, and compared between weekdays and weekends by using mixed models adjusted for confounders. The proportion of workers who sat for ≤8 h/day on weekdays and weekends were compared using McNemar's test. Results In white‐collar workers, SB time on weekdays was significantly longer than that on weekends (598 vs 479 min/day, P .99). Conclusions White‐collar workers were exposed to significantly longer SB time on weekdays than on weekends, which was not the case in blue‐collar workers. It may be rather challenging for white‐collar workers to limit their SB time to the level recommended by the latest guidelines for better health, especially on weekdays.

Caregivers who contribute to health care of their patients are significantly more likely to experience emotional difficulty, physical difficulty, and financial difficulty, than caregivers who do not contribute. This study aimed to examine the effects of free time on health-related quality of life among elderly caregivers of dementia patients. In the intervention group, caregivers set aside free time every 30 minutes three times a week, while continuing to care for patients. During the free time, caregivers were free to spend time at home and do whatever they wanted. The control group received only usual care. The intervention period was six months. The Vitality subscale score of the SF-36 decreased significantly in the intervention group, despite more than half (57.1%) of participants showing improvements or no change in the rank of this subscale relative to baseline, as assessed by the Wilcoxon signed-rank test (not significant). Caregivers indicated that daily caregiving resulted in an accumulation of physical fatigue, and they continued to have little mental leeway. Caregivers also had difficulty securing free time, which may have hindered improvements to their vitality. There is a need to develop a home-based program that can alleviate caregiver stress and improve their quality of life.

Background: Caregivers of dementia patients have significantly higher levels of serum IL-6 and CRP compared to non-caregivers, and the accumulation of everyday stressors reportedly promotes the induction of inflammatory markers. However, few studies have identified factors that affect catecholamine levels in caregivers who experience a combination of physical and mental stress from caregiving.Purpose: This study aimed to identify physical factors that impact catecholamine levels in caregivers of dementia patients.Methods: Participants were elderly caregivers living together with elderly Alzheimer’s-type dementia patients. We performed logistic regression analysis, with levels of adrenaline, noradrenaline, and dopamine (indicators of catecholamine) as dependent variables.Results: Caregiver BMI had a significant impact on adrenaline levels (OR: 0.792; 95%CI: 0.654-0.960) and noradrenaline levels (OR: 1.210; 95%CI: 1.009-1.451), whereas age had a significant impact on dopamine levels (OR: 1.162; 95%CI: 1.019-1.324).Discussion: While caregiver BMI significantly impacted adrenaline and noradrenaline levels, the mechanism underlying these relationships is unclear. One possibility is that obesity (BMI) and a rise in sympathetic nerve activity contributed to hypertension. Our findings suggest that chronic stress in elderly caregivers may potentially impair the dopaminergic activation system in the brain.Conclusion: There is a need to identify factors which increase BMI in caregivers. Future studies aimed at gaining a better understanding of the lifestyle habits of caregivers and intervention studies aimed at reducing their BMI are warranted.

Objectives To compare physical activity (PA) and sedentary behavior (SB) levels during work time between those who work from home (WFH) and at workplaces (no WFH), and by WFH subgroups. Methods This cross‐sectional internet‐based survey included 1239 workers (mean age [standard deviation], 44.7 [13.7] years; 59.2% men) living in the Tokyo Metropolitan Area. Time spent sitting (SB), standing (light‐intensity PA; LPA), walking, and engaging in heavy labor (moderate‐to‐vigorous PA; MVPA) during work time was measured using the Work‐related Physical Activity Questionnaire. Workers reported weekly WFH percentages (eg, 0% implies no WFH and 100% implies full WFH), and WFH percentages were categorized into no WFH (0% WFH) and WFH (1%‐100% WFH) groups. The WFH group was further subcategorized into 1%‐25%, 26%‐50%, 51%‐75%, and 76%‐100% subgroups. Results Overall, 494 workers (39.9%) worked from home. During working hours, SB time was longer in the WFH group than in the no WFH group (mean minutes [% working‐time SB]: 335.7 vs 224.7 min [74% vs 50%]). Significantly shorter LPA and MVPA times (%) were reported in the WFH group than in the no WFH group (LPA, 59.6 vs 122.9 min [14% vs 29%]; MVPA, 55.3 vs 91.9 min [13% vs 22%], all P

Familial hypercholesterolemia (FH) is an inherited disorder with retarded clearance of plasma LDL caused by mutations of the genes involved in the LDL receptor-mediated pathway and most of them exhibit autosomal dominant inheritance. Homozygotes of FH (HoFH) may have plasma LDL-C levels, which are at least twice as high as those of heterozygous FH (HeFH) and therefore four times higher than normal levels. Prevalence of HoFH had been estimated as 1 in 1,000,000 before but more recent genetic analysis surveys predict 1 in 170,000 to 300,000. Since LDL receptor activity is severely impaired, HoFH patients do not or very poorly respond to medications to enhance activity, such as statins, and have a poorer prognosis compared to HeFH. HoFH should therefore be clinically distinguished from HeFH. Thorough family studies and genetic analysis are recommended for their accurate diagnosis. Fatal cardiovascular complications could develop even in the first decade of life for HoFH, so aggressive lipid-lowering therapy should be initiated as early as possible. Direct removal of plasma LDL by lipoprotein apheresis has been the principal measure for these patients. However, this treatment alone may not achieve stable LDL-C target levels and combination with drugs should be considered. The lipid-lowering effects of statins and PCSK9 inhibitors substantially vary depending on the remaining LDL receptor activity of individual patients. On the other hand, the action an MTP inhibitor is independent of LDL receptor activity, and it is effective in most HoFH cases. This review summarizes the key clinical issues of HoFH as well as insurance coverage available under the Japanese public healthcare system.

Aim The purpose of the present study was to elucidate the relationship between high-frequency heart rate variability (HF HRV) and continuous daytime sitting time in patients with cardiovascular risk factors such as mild hypertension and/or stable angina pectoris. Background Decreased HF HRV precedes the progression and worsening of cardiovascular diseases. Continuous sitting behavior is a major risk factor for developing metabolic syndrome and is associated with cardiovascular disease, diabetes mellitus, renal failure, sarcopenia and osteoporosis. Risk factors for cardiovascular disease can be affected by continuous daytime sitting behaviors. Design The present study design was a post-hoc comparison. Methods Patients treated at two different primary care clinics from 2014 to 2018 were enrolled in this study (n = 53). We assessed HF HRV and continuous sitting time using 24-hour Holter electrocardiography and an activity meter at baseline and 6 months. HF HRV was calculated during sleep. Results Sitting time had decreased in 22 patients (decreased group) and increased in 31 patients (increased group) after 6 months. The mean patient ages were 73.1 and 72.0 years in the decreased and increased sitting time groups, respectively (p = 0.503). HF HRV during sleep had increased after 6 months in the decreased sitting time group. Compared with the increased group, the decreased group showed significantly higher HF HRV during sleep after 6 months by two-way repeated-measures ANOVA after adjustment for age, sex and change in activity (p = 0.045). Conclusion These results suggest that a decrease in sitting time might induce parasympathetic activity during sleep. Therefore, reducing continuous sitting time during the day might contribute, in part, to improving the prognosis of patients with cardiovascular risk factors not only by avoiding muscle loss but also by providing positive influences on parasympathetic tone during sleep.

Particulate metal selenides having narrow bandgaps for photocatalytic overall pure water splitting have not yet been reported due to the severe self-photooxidation of such materials. The present work demonstrates that solid solutions of zinc selenide and copper gallium selenide (ZnSe:CGSe), with absorption edges ranging from 480 to 750 nm, can be employed as H2 evolution photocatalysts in particulate photocatalyst sheets for Z-scheme pure water splitting, where CoOx/BiVO4 and Au are used as the oxygen evolution photocatalyst and electron mediator, respectively. Photogenerated holes in the metal selenide are efficiently recombined with electrons from BiVO4via the Au layer, thus avoiding self-oxidation of the selenides and leading to stable pure water splitting. Varying the ZnSe:CGSe composition demonstrates that both the p-type semiconductor character and excellent photoelectrochemical properties of selenides are vital to efficient Z-scheme water splitting. This study extends the application field of metal selenides in photocatalytic pure water splitting and creates new opportunities for selenide-based photocatalytic systems for solar fuel production.

Photoelectrochemical water splitting has attracted much attention in recent years as an alternative energy source. However, there have been several significant issues such as low efficiency, high cost and less scalability for its practical application. Here, we show that (CuGa1−yIny)1−xZn2xS2 (CGIZS)-based photocathodes fabricated with a particle transfer method exhibited a photocurrent of 4.5 mA cm−2 at 0.6 V vs. RHE along with a largely positive onset potential of 1.0 V vs. RHE under simulated sunlight (AM 1.5G) and an initial solar-to-hydrogen energy conversion efficiency of 1.1% was obtained with photoelectrochemical water splitting using a two-electrode cell composed of the CGIZS-based photocathode and a BiVO4-based photoanode. CGIZS used for the particle transfer method was obtained in a powder state with high crystallinity by a flux method using a molten-salt of LiCl–KCl, and also formed solid solutions with a chalcopyrite single phase structure in a wide range of Ga/In ratios and Zn contents, in which the absorption edges of photocatalysts were tunable up to 880 nm.

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 aim of this study was to examine the impact of the combination of physical frailty and social isolation on falling in community-dwelling older adults. A cross-sectional study of data obtained at registration in a randomized control trial. Community-based study of participants recruited from Toyota, Japan. 380 community-dwelling older adults (47.9% women, mean age = 72.3 ± 4.6 years). Participants were categorized as non-frail or pre-frail/frail based on the Fried frailty criteria (slowness, weakness, exhaustion, low activity, and weight loss). Social isolation was examined using the Lubben Social Network Scale (LSNS-6), and scores lower than 12 points indicated social isolation. Participants were divided into four groups depending on pre-frail/frail status and social isolation, and experiences of multiple falls over the past year were compared between the groups. Participants were classified into robust (n = 193), physical frailty (PF; n = 108), social isolation (SI; n = 43), and PF with SI (PF+SI; n = 36) groups. A total of 38 (10.0%) participants reported multiple falls. Logistic regression analysis showed that PF and SI groups were not independently associated with falling (PF: OR 1.64, 95% CI 0.65–4.16, SI: OR 2.25, 95% CI 0.77–6.58), while PF+SI group was significantly associated with falling compared with the robust group (OR 3.06, 95% CI 1.00–9.34, p = 0.049) after controlling for confounding factors. Our findings support the assertion that coexistence with physical frailty and social isolation were associated with falling in the older adults.

The EDRF discovered in 1986 by Furchgott was later identified as NO by Ignarro. NO was a widely noted gas with diverse functions, having arginine (L-Arg) as a substrate for the NO synthase (NOS). L-Arg and L-citrulline (L-Cit) have long been associated with the urea cycle. L-Cit was produced with NO by the reaction of L-Arg and oxygen. It was shown that administration of L-Arg in animals and humans caused vasodilation and anti-arteriosclerosis effects. Despite the arginine paradox ratio of intracellular arginine concentration to the Km value of NOS gaining widespread attention, advanced arteriosclerosis is known to reduce vascular reactivity towards L-Arg. In recent years, the anti-arteriosclerosis and anti-cell aging effects of the reactive substance citrulline (L-Cit) have been studied. L-Cit and L-Arg combination therapy are starting to be considered in various clinical applications as well.

The incidence of vascular diseases among caregivers of dementia patients is high, and one potential cause is the exacerbation of blood coagulability due to mental strain from caregiving. This study aimed to examine the effects of aerobic exercise on blood coagulability, from the perspective of improving the health of caregivers. Thirty-one healthy elderly caregivers, residing with patients suffering from Alzheimer’s-type dementia, were randomly divided into two groups. In the intervention group, moderate walking exercises (3 METs) were implemented. This group displayed a trend toward lower D–dimer levels, with no statistical significance (p = 0.05). Also, the Mini–Mental State Examination (MMSE) scores of the dementia patients remained unchanged. In the control group, the levels of von Willebrand factor antigen fell significantly (p < 0.05). However, the D–dimer levels remained unchanged and the MMSE scores of the patients significantly decreased following the observation period (p < 0.05). Our findings suggest the need to develop effective methods to maintain, promote, and advance the health of caregivers of dementia patients.

Objective We developed the Work-related Physical Activity Questionnaire (WPAQ) to measure occupational physical activity, including sedentary behavior and sedentary breaks (interruptions of prolonged sedentary behavior), during work. This study aimed to examine the WPAQ's reliability and criterion validity using an accelerometer. Methods To examine criterion validity, 97 full-time factory workers (male: 89.7%) wore a triaxial accelerometer while working and completed the WPAQ. The questionnaire inquired about participants' normal work activities and the proportion of sitting, standing, walking, and heavy labor engaged in during work. In calculating time spent in each behavior, the proportion of each occupational activity was multiplied by the total minutes of work. Duration of uninterrupted sitting time was also measured. For reliability, the same questionnaire was administered twice (median test-retest interval: 9 days) to another convenient sample of 54 participants. Spearman's ρ was used to assess validity and intraclass correlation coefficients (ICCs) and Cohen's kappa with quadratic weighing were used to assess reliability. Results The criterion validity of occupational sitting time measured by the WPAQ was moderate (Spearman's ρ for sedentary behavior: 0.69) based on comparison with accelerometer data. Significant positive correlations were found for standing (ρ = 0.66) and walking (ρ = 0.39) between the WPAQ and accelerometer data, though not for heavy labor. A moderate but significant correlation (ρ = 0.27) was found for sedentary breaks. Test-retest reliability for all items was adequate (ICC = 0.59-0.79 for occupational sedentary behavior and physical activities, and Cohen's kappa with quadratic weighting = 0.84 for sedentary breaks). Conclusions The WPAQ has acceptable properties for measuring workers' activities, including sedentary breaks. Reduced physical activity, increased time spent in sedentary behaviors, and fewer sedentary breaks during working time are all associated with adverse health outcomes. Though some occupational exposure to these activities might be unavoidable, the WPAQ may be a practical tool for assessing them.

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.

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. 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. 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). 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.

Gas chemistry has a significant impact on etch selectivity in semiconductor device fabrication, which is important for realization of atomic-scale removal and formation of high-aspect ratio features. To widen the controllable changes in the etchant composition in etching processes, our previous calculation showed the possibility of the controllable generation of CH2F and CHF2 related ions and radicals from a 1,1,2-trifluoroethane (CH2FCHF2) parent gas. The etch selectivity among silicon nitride (SiN), silicon dioxide (SiO2) and poly-Si films using CH2FCHF2 plasma mixed with O2 and Ar was investigated. The effects of the CH2FCHF2 and O2 partial pressures on the composition of CHF2+ and CH2F+ ions, which were measured with a quadrupole mass spectrometer, and on the possible reactions with respect to the CH2FCHF2 and O2 mixed gas phase were investigated using quantum chemical calculations. The etch selectivity was investigated through surface etching reactions for SiN, SiO2, and poly-Si films.

We have investigated the electronic properties of fluoromethane compounds to examine the electronic properties and the primary dissociation channels from a point of view of computational chemistry. For electron attachment process, it is very important to represent the observed negative mass spectrum as a function of electron energy that the calculation of MP2 method for negative ion and the subsequent calculation of EOMCCSD method to estimated the first excited state of the negative ion. In the case of evaluation of dissociated fragments through excitation process, it is very important that the structure change of the excited fragment (from pyramidal to planar) is taken into account. Evaluation of Jahn-Teller distortion for highly symmetrical CHF3 and CH3F is also very important to estimate the fragmentation process through the excitation.The calculated results after these treatments give the satisfactorily representation to the experimental values and moreover some prediction to experimentally unknown values.

This study aimed to examine the relationship between blood coagulability and sense of burden among caregivers of patients with senile dementia of the Alzheimer type.A cross-sectional study was carried out involving healthy older caregivers who lived with their patients with senile dementia of the Alzheimer type. We evaluated the Zarit Burden Interview score, levels of von Willebrand factor antigen, D-dimer, thrombin-antithrombin III complex, tissue plasminogen activator/plasminogen activator inhibitor type 1 complex, number of chronic diseases, body mass index and number of medications. A linear regression model was used to estimate adjusted associations.Thrombin-antithrombin III complex levels were higher in female caregivers than in male caregivers (P = 0.07). Headaches were significantly more frequent in female caregivers than in male caregivers, as assessed by a visual analog scale (P 0.01). The number of chronic diseases and body mass index were positively associated with levels of tissue plasminogen activator/plasminogen activator inhibitor type 1 complex (P 0.05). Similarly, the number of medications was positively associated with levels of D-dimer (P 0.05). However, the Zarit Burden Interview score was not associated with blood coagulability (P 0.05).The present study found that the number of chronic diseases and body mass index were associated with blood coagulability, and that female caregivers were more prone to headaches and higher blood coagulability than male caregivers. These findings highlight the essential nature of health management during caregiving. The impact of caregiver burden on blood coagulability is likely to differ depending on the long-term or short-term psychological stress associated with caregiving conditions. Geriatr Gerontol Int 2019; 19: 804-808.

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-β-galactosidase (SA-β-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-β-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-β-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.

See Article on Page 267-276 Angiotensin converting enzyme (ACE) inhibitors (ACEIs) are beneficial and are strongly recommended for patients with acute myocardial infarction (MI) associated with heart failure, left ventricular systolic dysfunction, or preserved left ventricular systolic function. A number of clinical trials have demonstrated the benefits of ACEIs in such patients [1,2]. In contrast, several clinical trials have consistently failed to demonstrate the benefits of angiotensin receptor blockers (ARBs). In addition, the proposed ARB-MI paradox led to a certain amount of caution in the use of ARBs because several meta-analyses suggested that ARBs do not prevent MI or cardiovascular death, in contrast to ACEIs [3,4]. However, this hypothesis is now considered to be misleading. Using propensity score matching, Lee et al. [5] investigated the association between treatment with ARBs and clinical outcomes in patients without left ventricular dysfunction or heart failure after acute MI who had a ventricular ejection fraction ≥ 40%. The effect of ARBs on in-hospital mortality and 12-month major adverse cardiovascular events (MACEs) was assessed using matched logistic and Cox regression models. Compared with ACEIs, ARBs significantly reduced in-hospital mortality (1.3% vs. 3.3%; hazard ratio [HR], 0.379; 95% confidence interval [CI], 0.190 to 0.756; p = 0.006) and 12-month MACEs (4.6% vs. 6.9%; HR, 0.661; 95% CI, 0.457 to 0.956; p = 0.028). However, the benefit of ARBs on 12-month mortality compared with ACEIs was marginal (4.3% vs. 6.2%; HR, 0.684; 95% CI, 0.467 to 1.002; p = 0.051). The authors concluded that ARBs are not inferior to, and may be better than, ACEIs in Korean patients with acute MI. The study is of note because it differs from the current American and European guidelines. Although Asians, including Koreans and Japanese, suffer more frequently from uncomfortable dry coughs when undergoing treatment with ACEIs in comparison to Caucasians, the significantly reduced in-hospital mortality and 12-month MACEs with ARBs must also be considered. We have several questions to ask of this study. What about other similar studies from Korea? What is the mechanism of ARBs compared to ACEIs that would lead to these different outcomes? Indeed, do the mechanisms actually differ? Or, were the results of this study caused by an unexplained bias, which has been detected in many other clinical studies, including a number of well-performed studies? Yang et al. [6] reported a study based on 53 Korean hospitals involved in the treatment of acute MI. They investigated the association between ARBs treatment and clinical outcomes in patients with ST segment elevation MI who underwent primary percutaneous coronary intervention and had a left ventricular ejection fraction ≥ 40% [6]. This study was very similar to that by Lee et al. [5] with regard to the study period and characteristics of the participants, and also because it was a prospective cohort study which used data from a nationwide large-scale registry. However, this study did not include a group of patients who had not received a rennin-angiotensin system (RAS) blocker. The study demonstrated that cardiac death or MI occurred in 21 patients (1.8%) in the ARBs group and 77 patients (1.7%) in the ACEIs group. After propensity score matching, no significant difference was identified in the rate of cardiac death or MI between the ARBs and ACEIs groups (21 [1.8%] vs. 23 [2.0%]; adjusted HR, 0.65; 95% CI, 0.30 to 1.38; p = 0.65). The RAS is involved in many of the stages in developing atherosclerosis. Endothelial dysfunction is one of the first steps in the development of overt atherosclerosis. ACE inactivates kinins produced within the endothelium. Thus, ACE inhibition could increase endothelial bradykinin levels, resulting in the stimulation of nitric oxide (NO) synthase via the activation of B2 receptors on the endothelial cell surface and also in the activation of phospholipase A2 and the release of vasodilating prostaglandins from the cell membrane (Fig. 1). In addition, ACEIs may induce cough in sensitive patients, such as Asians, by increasing the bradykinin levels. Alternatively, ACE inhibition could reduce the intracellular production of superoxide anions via the reduced activity of angiotensin II-dependent nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate oxidase systems within the endothelium [7,8]. Thus, ACEIs therapy may retard the progression and acute manifestations of atherosclerosis by increasing intravascular NO bioactivity and preventing the activation of nuclear transcription factor (NF-κB) with its potential proinflammatory consequences. In this regard, we demonstrated that quinapril therapy improves NO bioactivity with enhanced endothelium-dependent vasodilator responsiveness that is accomplished at a lower rate of NO synthesis in patients with coronary artery disease [9]. Clinical trials with ACEIs in patients with a low or preserved ejection fraction have documented a significant reduction in cardiovascular death, MI, stroke, and the need for coronary revascularization producers [10,11]. A recent meta-analysis with a pooled analysis of 20 cardiovascular morbidity-mortality trials demonstrated that ACEIs treatment was associated with a significant 10% reduction in all-cause mortality (HR, 0.90; 95% CI, 0.84 to 0.97; p = 0.004), whereas no mortality reduction could be demonstrated with ARBs treatment (HR, 0.99; 95% CI, 0.94 to 1.04; p = 0.683). This difference in treatment outcome between ACEIs and ARBs on all-cause mortality was statistically significant (with a p value for heterogeneity equal to 0.036) [12]. Figure 1. Angiotensin converting enzyme (ACE) and endothelial function. NOS, nitric oxide synthase; L-NMMA, NG-methyl-L-arginine; NO, nitric oxide; cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate. On the other hand, angiotensin II activates NF-κB induced by oxidative stress, mediated by the angiotensin II type 1 (AT1) receptor [8]. We reported the pleiotropic effects of candesartan, one of the ARBs, in addition to its anti-hypertensive effect, that significantly improved flow-mediated vasodilation and reduced the biomarkers of oxidant stress, inflammation, and hemostasis in patients with hypertension, independently of blood pressure reduction [13]. Now, patients at high risk of cardiovascular events such as MI are required to take statins as a preventative measure [14]. It is rather surprising that only 4.5% and 2.9% of patients with ARBs and ACEIs, respectively, took lipid-lowering drugs prior to an acute MI [5]. Of particular note, experimental and clinical studies demonstrated a cross-talk between hypercholesterolemia and RAS at multiple stages. Therefore, statins and ACEIs or ARBs may have the potential to exert additive/synergistic beneficial effects on both endothelial function and insulin sensitivity when compared with monotherapy in patients with cardiovascular risk factors by both distinct and interrelated mechanisms (Fig. 2) [15-19]. Recently, we observed that pravastatin combined with valsartan therapy improved flow-mediated vasodilation, reduced the level of C-reactive protein, a biomarker of inflammation, increased plasma adiponectin, lowered fasting insulin levels, and improved insulin sensitivity in an additive manner compared to monotherapy alone in an hypertensive population (Fig. 3) [18]. Figure 2. Additive/synergistic beneficial effects of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and statins on both endothelial function and insulin sensitivity. Dysregulation of the rennin-angiotensin system (RAS) contributes ... Figure 3. The synergistic effect of combination treatment with valsartan and pravastatin on insulin sensitivity. In 48 hypercholesterolemic patients, both pravastatin 40 mg and valsartan 160 mg increased plasma adiponectin levels, reduced fasting insulin levels, ... Although Lee et al. [5] reported that the beneficial effects of ARBs were comparable to, or even better than, ACEIs in Korean patients with acute MI, few studies have been reported in the literature, compared with ACEIs in such patients, especially without left ventricular dysfunction or heart failure. Furthermore, ACEIs are cheaper than ARBs, albeit not rare dry coughing. Therefore, current guidelines recommend the initial use of ACEIs in such patients, changing to ARBs when patients become intolerant of ACEIs [1,2].

Background Ezetimibe demonstrates decreasing visceral fat and improving insulin sensitivity (IS) in animals and humans. We first reported that simvastatin dose-dependently worsens insulin sensitivity. Whether ezetimibe may compensate untoward effects of simvastatin, depending on dosages of simvastatin has not been investigated in patients with hypercholesterolemia, compared with simvastatin alone. Methods This was a randomized, single-blind, placebo-controlled, parallel study. Fifty-one in each group were given placebo, ezetimibe 10mg combined with simvastatin 10mg (Vyto10), ezetimibe 10mg combined with simvastatin 20mg (Vyto20), or simvastatin 20mg alone (Simva20) daily for 2months. Results Placebo, Vyto10, Vyto20, and Simva20 improved flow-mediated dilation relative to baseline measurements. Placebo therapy did not significantly change insulin and IS and adiponectin levels and visceral fat area (VFA) and VFA/subcutaneous fat area (SFA) relative to baseline measurements. Vyto10 therapy significantly decreased CRP and insulin levels and increased adiponectin levels and IS, and reduced VFA, VFA/SFA, and blood pressure. Vyto20 therapy did not significantly change insulin levels and IS and adiponectin levels but significantly reduced CRP levels and VFA, VFA/SFA, and blood pressure. Simva20 therapy significantly decreased adiponectin levels and IS but did not significantly change VFA, VFA/SFA, and blood pressure. Of note, these different effects of each therapy were significant by ANOVA. Conclusions Vyto10, Vyto20, and Simva20 showed significant reduction of LDL cholesterol levels and improvement of flow-mediated dilation in patients with hypercholesterolemia. However, Vyto10, Vyto20, and Simva20 showed significantly differential metabolic effects, depending on dosages of simvastatin.

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 number of studies have reported that frailty is cross-sectionally associated with cognitive decline and is also a risk for future cognitive decline or dementia; however, there have been only a few studies that focus on the association between prefrailty and cognitive dysfunction. In the current study, we investigated the association between prefrailty and cognition A cross-sectional study of the data obtained at registration in a randomized control trial. Toyota, Japan. Community-dwelling older subjects (male 54.6%) who had cognitive complaints. A battery of neuropsychological and physical assessments were performed. Prefrailty was defined as exhibiting one or two of the five Fried criteria (weight loss, exhaustion, weakness, slow gait speed and low physical activity). We performed a multiple regression analysis to investigate the associations of cognitive performance with prefrailty, adjusting for the factors that were significantly different between the robust and prefrailty groups. To assess the cognitive attributes that were significantly associated with prefrailty, logistic analysis was performed to see if one specific criterion of the five frailty criteria was associated with cognitive performance. The study subjects included 183 prefrail and 264 robust individuals. The prefrail subjects with cognitive complaints were older, less educated, more depressive, and more likely to have diabetes mellitus than the robust subjects. The prefrail subjects had lower performance in a wide-range of cognitive domains, and after adjustments for age, education, depressive mood, and diabetes mellitus, prefrailty was associated with a decline in delayed memory and processing speed. Among the components of the Fried criteria, slow gait speed and loss of activity were significantly associated with slow processing speed as assessed by the digit symbol substitution test. The current results demonstrated that prefrailty was associated with worse memory and processing speed performance, but not with other cognitive domains.

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.

The aim of this study was to examine the association of the combination of physical frailty and social isolation with falling in community-dwelling older people. The study used baseline data on participants in the Toyota Prevention Intervention Cognitive decline and Sarcopenia (TOPICS). Participants in this cross-sectional study were 408 older adults (52% male, mean age = 72.3 ± 4.7 years). Physical frailty status was categorized as non-frail and pre-frail/frail based on the Fried frailty criteria (slow walking speed, muscle weakness, exhaustion, low activity, and weight loss). Social isolation was examined using the Lubben Social Network Scale (LSNS-6), and scores of less than 12 points indicated social isolation. Participants were divided into 4 groups depending on pre-frail/frail status and social isolation, and experiences of multiple falls over the past year were compared between the groups. Participants were classified into control (n = 202), physical frailty (PF; n = 122), social isolation (SI; n = 45), and PF with SI (PF+SI; n = 39) groups. A total of 46 (11.3%) participants reported multiple falls. Logistic regression analysis showed that PF and SI were not independently associated with falling (PF: OR 1.91, 95% CI 0.82–4.45, SI: OR 2.45, 95% CI 0.89–6.75), and PF+SI had a significant association with falling compared with the control group (OR 2.94, 95% CI 1.03–8.41) after controlling for confounding factors. Our findings support the assertion that physical frailty and social isolation are concurrently associated with falling.

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.

ObjectivesStudies have shown that organisational injustice (OIJ) is associated with mental disorders. However, there is little research regarding details on OIJ exposure. We examined the effect of OIJ on serious psychological distress (SPD) by considering the exposure frequency, the exposure duration and the OIJ-free period after the disappearance of exposure.MethodsWe used a prospective cohort design. OIJ exposure was assessed three times with 1-year intervals between assessments, and the subjects were grouped according to the exposure histories. The outcome assessment for SPD by scores of 13 or higher on the K6 questionnaire was carried out 3 years after the baseline scores were obtained. Participants were all full-time regular employees of one office of a manufacturing company in Japan. Participants who were being treated for mental disorders, those with SPD and those with missing data on the K6 questionnaire in the baseline survey were excluded from the prospective cohort. Self-reported questionnaire data from 1087 employees who participated in all surveys and answered all questions were analysed. Logistic regression analysis was used to explore the effect of OIJ on SPD.ResultsSPD developed in 35 participants. Frequent OIJ exposure was associated with a higher risk for SPD (p for trend=0.002). Of the 1087 participants, 319 (29.3%) experienced a change in OIJ exposure at least once, and 8.6% of subjects experienced such a change twice. These changes in OIJ exposure were more strongly related to SPD than was the frequency of OIJ exposure.ConclusionsOIJ was associated with SPD onset particularly when the workers were more frequently exposed to it. Moreover, frequent changes in the OIJ exposure were associated with a higher risk for SPD. Because OIJ exposure can change in a relatively short time, considering exposure histories may provide useful information for preventing mental disorders.

Electronic properties of fluoroethane compounds except C2H5F, C2H4F2, CH3CF3, C2H2F4, and C2F6 have not been reported. On the other hands, the physicochemical properties were reported for the usage as the alternative refrigerants. Dissociation channels in the process plasma for fluoroethane compounds were not fully discussed except 1,1,1,2-C2H2F4. Therefore we have investigated the electronic properties and primarily dissociation channels of fluoroethane compounds in the process plasma in semiconductor manufacturing, using computational chemistry. Positive and negative ionized states were investigated by density functional method and the excited states were investigated by EOMCCSD/aug-cc-pVDZ and TD-SCF CAM-B3LYP/aug-cc-pVDZ. It was generally shown through these investigations that C–C bond scission occurred by excitation and ionization and C–F bond scission occurred by excitation and electron attachment.

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) β-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 LXRβ mediates the prevention of endothelial cellular senescence, and that sterol regulatory element binding protein-1, which was up-regulated as a direct LXRβ 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 β-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.