Association between the decrease in medical visit frequency and chronic disease worsening in the early stages of COVID-19-A longitudinal study.

BACKGROUND: 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 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.

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.

Exposure to prolonged sedentary behavior on weekdays rather than weekends in white-collar workers in comparison with blue-collar workers.

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 < .001). In blue-collar workers, there was no significant difference in SB time between weekdays and weekends (462 vs 485 min/day, P = .43). The proportion of workers who achieved the recommended SB levels (≤8 h) was only 4.8% for white-collar workers on weekdays and 54.8% on weekends (P = .04), while that of blue-collar workers was 45.2% and 58.1% respectively (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.

Decreased continuous sitting time increases heart rate variability in patients with cardiovascular risk factors.

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.

Current Diagnosis and Management of Primary Chylomicronemia.

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.

Homozygous Familial Hypercholesterolemia.

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.

Associations of working from home with occupational physical activity and sedentary behavior under the COVID-19 pandemic.

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 < .001). Among the WFH subgroups, longer SB time and shorter LPA and MVPA times were observed in the highest WFH group (WFH 76%-100%) than in the WFH 1%-25% and 26%-50% subgroups. CONCLUSIONS: Workers who telecommuted were less physically active and had longer sedentary during work time than those who worked at the workplaces.

[Prevention of the progression of atherosclerosis and aging through nitric oxide (NO)].

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.

[Validity and reliability of the Work-related Physical Activity Questionnaire for assessing intensity-specific physical activity and sedentary behavior in the workplace].

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.

Exposure to organisational injustice and serious psychological distress: longitudinal analysis of details of exposure from a private Japanese company.

OBJECTIVES: Studies 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. METHODS: We 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. RESULTS: SPD 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. CONCLUSIONS: OIJ 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.

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.

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.

Relationship between blood coagulability and sense of burden among caregivers of patients with dementia.

AIM: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Napping Improves HRV in Older Patients With Cardiovascular Risk Factors.

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.

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.

Administration of L-arginine plus L-citrulline or L-citrulline alone successfully retarded endothelial senescence.

L-citrulline and L-arginine supplementation has been shown to have several beneficial effects on the cardiovascular system. Nitric oxide (NO) protects against the progression of atherosclerosis and is synthesized by nitric oxide synthase (NOS), which converts L-arginine (L-Arg) into L-citrulline (L-Cit). Our previous study revealed that chronic administration of a combination of L-Cit and L- Arg has a better therapeutic effect on high cholesterol-induced atherosclerosis in rabbits. We investigated how L-Arg and L-Cit affect endothelial function, aging and atherosclerosis. Following a 3-day stimulation of human umbilical venous endothelial cells (HUVECs) with high glucose (HG: 22 mM) and L-Arg (300 µM), L-Cit (300 µM) or L-Arg plus L-Cit (LALC: each 150 µM) supplementation, endothelial senescence and function were evaluated. These amino acids were also administered to dyslipidemic type 2 diabetic (ZDFM) rats fed a high cholesterol diet. They were fed L-Arg or L-Cit or LALC for four weeks. Aortic senescence was investigated by measuring senescence-associated ß-galactosidase (SA-ß-gal), telomerase activity, DNA damage and p16INK4a protein expression. Only L-Cit and LALC supplementation retarded the HG-induced endothelial senescence, as evaluated by SA-ß-gal activity, a widely used marker of cellular senescence, p16INK4a expression, a senescence-related protein, and DNA damage. Under HG conditions, L-Cit and LCLA restored telomerase activity to levels observed under normal glucose (NG) conditions. Under HG conditions, L-Cit decreased ROS production, as measured by CM-H2DCFDA and the expression of p67phox, a major component of NADPH oxidase. Under HG conditions, L-Cit and LALC increased NO production, as measured by DAF-2AM. Endothelial NO synthase (eNOS) and phosphorylated eNOS were decreased under HG conditions and L-Cit and LALC significantly increased these levels. Arginase 2 protein expression increased under the HG conditions, and L-Cit and LALC significantly attenuated this effect. In ZDFM rats, SA-ß-gal activity was detected on the aortic endothelial surface; however, L-Cit and LALC reduced these levels. L-Cit and LALC both decreased the proportion of senescent cells. Furthermore, treatment with LALC for 4 weeks increased plasma NO production. Therefore conclusively, L-citrulline supplementation rescued NO levels better than L-arginine supplementation by inhibiting ROS production and arginase 2 protein expression. Consequently, L-Cit and LCLA supplementation retaeded HG-induced endothelial senescence.

Combining Potent Statin Therapy with Other Drugs to Optimize Simultaneous Cardiovascular and Metabolic Benefits while Minimizing Adverse Events.

Hypercholesterolemia and hypertension are among the most important risk factors for cardiovascular (CV) disease. They are also important contributors to metabolic diseases including diabetes that further increase CV risk. Updated guidelines emphasize targeted reduction of overall CV risks but do not explicitly incorporate potential adverse metabolic outcomes that also influence CV health. Hypercholesterolemia and hypertension have synergistic deleterious effects on interrelated insulin resistance and endothelial dysfunction. Dysregulation of the renin-angiotensin system is an important pathophysiological mechanism linking insulin resistance and endothelial dysfunction to atherogenesis. Statins are the reference standard treatment to prevent CV disease in patients with hypercholesterolemia. Statins work best for secondary CV prevention. Unfortunately, most statin therapies dose-dependently cause insulin resistance, increase new onset diabetes risk and exacerbate existing type 2 diabetes mellitus. Pravastatin is often too weak to achieve target low-density lipoprotein cholesterol levels despite having beneficial metabolic actions. Renin-angiotensin system inhibitors improve both endothelial dysfunction and insulin resistance in addition to controlling blood pressure. In this regard, combined statin-based and renin-angiotensin system (RAS) inhibitor therapies demonstrate additive/synergistic beneficial effects on endothelial dysfunction, insulin resistance, and other metabolic parameters in addition to lowering both cholesterol levels and blood pressure. This combined therapy simultaneously reduces CV events when compared to either drug type used as monotherapy. This is mediated by both separate and interrelated mechanisms. Therefore, statin-based therapy combined with RAS inhibitors is important for developing optimal management strategies in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome, or obesity. This combined therapy can help prevent or treat CV disease while minimizing adverse metabolic consequences.

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.