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Abstract The association between subjective walking speed and metabolic diseases has received limited attention, particularly in individuals with obesity. We aimed to clarify this association using comprehensive health checkup data of participants with obesity. In total, 8578 individuals with a body mass index ≥ 25.0 kg/m2, 9626 individuals with waist circumference ≥ 85 cm in men and ≥ 90 cm in women, and 6742 individuals who met both criteria of body mass index and waist circumference were included in this cross-sectional analysis. Subjective walking speed was investigated using the question “Is your walking speed faster than the speed of those of your age and sex?” in a health examination questionnaire. Metabolic diseases were defined according to the guidelines for each disease, and modified Poisson regression analyses were performed. In the model adjusted for age and sex, individuals with obesity based on body mass index and fast subjective walking speed showed significantly lower risk of diabetes mellitus (risk ratio [RR] 0.70; 95% CI 0.63–0.77) and dyslipidemia (RR 0.97; 95% CI 0.94–1.00). Similarly, among those with obesity based on waist circumference and both body mass index and waist circumference, fast subjective walking speed showed a significant negative association with hypertension (RR 0.94; 95% CI 0.90–0.97 and RR 0.95; 95% CI 0.92–0.99, respectively), diabetes mellitus (RR 0.70; 95% CI 0.64–0.77 and RR 0.70; 95% CI 0.63–0.77, respectively), and dyslipidemia (RR 0.96; 95% CI 0.94–0.99 and RR 0.96; 95% CI 0.94–0.99, respectively). Thus, among individuals with obesity, the odds of metabolic diseases were lower if their subjective walking speed was fast. This study contributes to earlier prevention of the cascade of diseases that begin with obesity.

Abstract Introduction Even after the peak of the COVID-19 pandemic, the number of mild cases remains high, requiring continuous control. Curcumin, owing to its anti-inflammatory properties, can suppress vital proliferation and cytokine secretion in animal models. We developed a highly absorbable curcumin, curcuRouge® (cR), which is approximately 100 times more orally bioavailable than conventional curcumin. We evaluated the effect of cR on the inhibition of disease progression in asymptomatic or mildly symptomatic COVID-19 patients. Methods This study evaluated the effect of 7-day oral intake of cR (360 mg twice daily). Patients within 5 days of COVID-19 diagnosis were randomly assigned to a placebo or cR group in a double-blind manner. Results Primary endpoint events [body temperature (BT) ≥ 37.5 °C and saturation of percutaneous oxygen (SpO2)

Abstract Background Targeting mucosal immunity of the gut, which is known to provide antigen processing, while avoiding excessive or unnecessary inflammation, was tested as a way to modulate COVID-19 severity. Methods Randomized open-label trial in 204 adults hospitalized with non-critical COVID-19 who received for 14 days in addition to standard of care (SOC) degalactosylated bovine glycoproteins formulations of either MAF capsules (MAF group) or M capsules (M group) or SOC only (control group). Results Median recovery time when patients did not require supplemental oxygen was 6 days in both study groups compared to 9 days in the control (MAF vs. control; P = 0.020 and M vs. control; P = 0.004). A greater reduction in mortality was seen in the MAF group compared to the control by day 14 (8.3% vs. 1.6%; P = 0.121) and by day 29 (15.3% vs. 3.2%; P = 0.020), and similarly in the M group by day 14 (8.3% vs. 2.9%; P = 0.276) and by day 29 (15.3% vs. 2.9%; P = 0.017). The proportion of those who had baseline absolute lymphocyte count (ALC) lower than 0.8 × 109/L was 13/63 (20.6%), 17/69 (24.6%), and 18/72 (25.0%) of patients in MAF, M, and control group respectively. Day 29 mortality among these lymphopenic patients was three times higher than for the intent-to-treat population (21% vs. 7%) and consisted in above subgroups: 2/13 (15%), 2/17 (12%), and 6/18 (33%) of patients. The decreased mortality in both study subgroups correlated with greater ALC restoration above 0.8 × 109/L level seen on day 14 in 91% (11/12) and 87.5% (14/16) of survivors in MAF and M subgroups respectively compared to 53.3% (8/15) of survivors in control subgroup. Incidences of any ALC decrease below the baseline level on day 14 occurred in 25.4% of patients in the MAF group and 29.0% of patients in the M group compared to 45.8% in control and ALC depletion by ≥ 50% from the baseline level consisted of 7.9%, 5.8%, and 15.3% of cases in these groups respectively. Conclusion This study showed that both study agents prevented ALC depletion and accelerated its restoration, which is believed to be one of the mechanisms of improved crucial clinical outcomes in hospitalized COVID-19 patients. Trial registration The trial was registered after the trial start in ClinicalTrials.gov NCT04762628, registered 21/02/2021, https://www.clinicaltrials.gov/ct2/show/NCT04762628 .

Objectives: Smoking is a significant risk factor for gingivitis and has detrimental effects on both oral health and the cardiovascular system. This study aimed to evaluate the association between cardiovascular biomarkers and gingival bleeding among smokers. Materials and Methods: This cross-sectional study comprising 60 smokers (mean age, 59.9±13.7 years) was conducted at an outpatient smoking cessation clinic. The smokers were divided into two groups based on the presence or absence of gingival bleeding, which was assessed by probing. α1-antitrypsin low-density lipoprotein complex (AT-LDL), an oxidatively modified LDL complex, causes progressive atherosclerosis. The clinical characteristics and blood markers including AT-LDL levels were measured in these patients. Results: Significantly higher (p=0.03) levels of AT-LDL, an oxidized LDL complex that promotes atherosclerosis, were observed among smokers with no gingival bleeding on probing when compared to that among smokers with gingival bleeding. The pocket depths in smokers without gingival bleeding were significantly (p=0.04) lower than those among smokers with gingival bleeding. Conclusion: The absence of gingival bleeding among smokers was associated with higher levels of AT-LDL. These findings could indicate reduced blood flow due to atherosclerosis among smokers with no gingival bleeding.

We investigated the impact of the Coronavirus disease 2019 (COVID-19) pandemic on the management of endocrine and metabolic disorders in Japan. We conducted a cross-sectional nationwide questionnaire survey targeting board-certified endocrinologists under the auspices of the Japan Endocrine Society. The questionnaire consisted of multiple-choice questions and open-ended responses. Out of approximately 2,700 specialists, 528 (19.5%) opted to participate, suggesting a high level of interest in COVID-19 management among endocrinologists. The study found that almost half of participants had encountered cases of endocrine and metabolic disorders following COVID-19 infection or vaccination. Conditions related to thyroid diseases, glucose metabolism disorders/diabetes, and hypothalamic-pituitary disorders were particularly prevalent. Diabetes and obesity were identified as having high rates of severe cases or fatalities due to COVID-19. The study also highlighted challenges in routine diagnosis and treatment, emphasizing the potential benefits of combining remote consultations with in-person visits to optimize the frequency of examinations and check-ups during infectious disease outbreak which disrupts access to healthcare providers. The insights obtained from this survey are expected to contribute to ensuring appropriate healthcare provision for patients with endocrine and metabolic disorders by using flexible consultation formats, particularly even in the conditions where medical access may be limited due to future outbreaks of emerging or re-emerging infectious diseases.

Abstract Background We investigated whether the treatment needs of patients with dementia with Lewy bodies (DLB) and their caregivers, along with their attending physicians’ perception of those treatment needs, differ according to the clinical department visited by the patients. Methods This was a subanalysis of a multicenter, cross-sectional, observational survey study. Data from the main study were classified according to the clinical department visited by the patient: psychiatric group (P-group), geriatric internal medicine group (G-group), and neurology group (N-group). The treatment needs of patients and caregivers were defined as “the symptom that causes them the most distress”, and the frequency of each answer was tabulated. Results This subanalysis included 134, 65, and 49 patient–caregiver pairs in the P-, G-, and N-groups, respectively. Statistically significant differences in patient background characteristics such as patient age; initial symptom domains; use of cholinesterase inhibitors, levodopa, antipsychotics, and Yokukansan; and total scores of the Mini-Mental State Examination, Neuropsychiatric Inventory-12, and Movement Disorder Society-Unified Parkinson’s Disease Rating Scale Parts II and III were shown among the three subgroups. While there were no differences in patients’ treatment needs among the subgroups, residual analysis showed that in the N-group, parkinsonism was more of a problem than other symptom domains (p = 0.001). There were significant differences in caregivers’ treatment needs among the three subgroups (p

The burden of caregivers of people with dementia with Lewy bodies (DLB) is high; however, factors related to their caregiving burden are not fully clarified. We herein investigated factors associated with increasing caregiver burden for caregivers of people with DLB. To explore factors associated with caregiver burden, a linear regression analysis was conducted using the J-ZBI_8 total score as the dependent variable and a total of 36 factors as independent variables. This analysis included 252 pairs of people with DLB and their caregivers. Caregivers’ mean J-ZBI_8 was 8.4, indicating that caregiver burden was generally high. First, we identified 20 factors associated with caregiver burden in univariable analysis. Finally, multivariable analysis found three significant factors: irritability (β = 0.208, p < 0.001), use of “short stay” or “small-scale, multifunctional home care” (β = 0.208, p < 0.001), and nighttime behavior (β = 0.138, p = 0.020) were significantly associated with J-ZBI_8 total scores. Irritability and nighttime behavior were found to be contributing factors to caregiver burden. High caregiver burden among caregivers of people with DLB may result in the use of social services providing overnight stays, but to what extent such services reduce caregiver burden is unknown.

Abstract Aim Body mass index and waist circumference are used for obesity diagnosis and screening of visceral fat; however, their evidence in older adults is insufficient. This study investigated the age‐specific association of body mass index and waist circumference with metabolic diseases, assessing their applicability as diagnostic criteria for individuals aged ≥65 years. Methods Analysis included 46,324 individuals aged ≥18 years, categorized into five age groups: 18–44, 45–54, 55–64, 65–74, and ≥75 years. Logistic regression analyses identified associations between obesity and metabolic diseases, stratified by age and sex. Results Men with obesity based on body mass index had a significantly high risk of hypertension, diabetes mellitus, and dyslipidemia across all age groups (all, p

ObjectiveThis study aimed to identify the amount of weight loss needed in patients with obesity to improve metabolic syndrome (MetS), a risk factor for cardiovascular disease (CVD), over a long period of time.MethodsA total of 576 patients with obesity were enrolled in this study. Effects of continuous physician-supervised weight loss on the cumulative MetS components excluding abdominal circumference (defined as obesity-related CVD risk score) were investigated during a 5-year follow-up period. The extent of weight loss required to reduce the obesity-related CVD risk components was assessed using receiver operating characteristic (ROC) curve analyses.ResultsOf the 576 participants, 266 completed 5-year follow-up, with 39.1% and 24.1% of them achieving ≥5.0% and ≥7.5% weight loss at the 5-year follow-up, respectively. The area under the ROC curve for reducing the obesity-related CVD risk components was 0.719 [0.662–0.777] at 1 year and 0.694 [0.613–0.775] at 5 years. The optimal cut-off value for weight loss was 5.0% (0.66 sensitivity and 0.69 specificity) and the value with 0.80 specificity was 7.5% (0.45 sensitivity) at 5 years. Greater reductions in weight were associated with greater improvements in the obesity-related CVD risk score at all follow-up periods (P-trend

Metabolically Healthy Obesity (MHO) is generally recognized as the absence of any metabolic disorders and cardiovascular diseases, including type 2 diabetes, dyslipidemia, and hypertension, in obese individuals; however, it is not clearly defined. Therefore, the present study investigated differences in metabolic characteristics between individuals with MHO and Metabolically Unhealthy Obesity (MUO) during weight reduction therapy. The key factors defining MHO and the importance of weight reduction therapy for MHO were also examined. Cohort data from the Japan Obesity and Metabolic Syndrome (JOMS) study were analyzed. Subjects were divided into the MHO (n = 25) and MUO (n = 120) groups. Prior to weight reduction therapy, serum adiponectin levels were significantly higher in the MHO group than in the MUO group. Serum adiponectin levels also negatively correlated with the area of subcutaneous adipose tissue (SAT) and Homeostasis model assessment (HOMA)-R in the MHO group, but not in the MUO group. Collectively, the present results suggest the importance of adiponectin for maintaining metabolic homeostasis in the MHO group. On the other hand, no significant differences were observed in inflammatory markers between the MHO and MUO groups, suggesting the presence of chronic inflammation in both groups. Furthermore, a positive correlation was noted between changes in serum cystatin C levels and waist circumference in the MHO group, which indicated that despite the absence of metabolic disorders, the MHO group exhibited anti-inflammatory responses during weight reduction therapy. These results underscore the significance of weight reduction even for individuals with MHO.

Abstract It remains unclear which adjunctive drug for Parkinson’s disease (PD) in combination with levodopa is more effective, tolerable, and safe. We aimed to compare the efficacy, tolerability, and safety among anti-PD drugs from several classes in patients with fluctuating PD who received levodopa through network meta-analysis (NMA). Twelve anti-PD drugs belonging to 4 different drug classes (dopamine agonists, monoamine oxidase type B inhibitors, catechol-O-methyl transferase inhibitors, and an adenosine A2A receptor antagonist) were selected. We systematically searched PubMed, Embase, and the Cochrane Library for eligible randomized controlled trials (RCTs) comparing placebo with anti-PD drug or among anti-PD drugs in patients with PD who experienced motor fluctuations or wearing-off and received levodopa. We included 54 RCTs in the analysis. The NMA was performed under a frequentist framework using a random-effects model. The efficacy outcome was change in daily off-time, and the tolerability outcome was discontinuation due to all causes. Safety outcomes included discontinuation due to adverse events (AEs) and the incidence of AEs, dyskinesia, hallucination, and orthostatic hypotension. According to the surface under the cumulative ranking curve (SUCRA) in the NMA, ropinirole transdermal patch (SUCRA, 0.861) ranked the highest in efficacy, followed by pramipexole (0.762), ropinirole extended release (ER) (0.750), and safinamide (0.691). In terms of tolerability, ropinirole (0.954) ranked the highest, followed by pramipexole (0.857), safinamide (0.717), and ropinirole ER (0.708). Each anti-PD drug had different SUCRA ranking profiles for the safety outcomes. These findings suggest that ropinirole, pramipexole, and safinamide are well-balanced anti-PD drugs that satisfy both efficacy and tolerability outcomes.

Background: Age, genetic, and environmental factors are noted to contribute to dementia risk. Neuroplasticity, protection from degeneration and cell death, and early intervention are desirable for preventing dementia. The linkage between neurons and microglia has been a research focus. In this study, we examined the effects of dietary modification (a reduction in advanced glycation end products [AGEs]) and macrophage-activating factor (MAF; a macrophage regulator) supplementation on cognitive function in elderly participants undergoing rehabilitation. Methods: Participants were older than 60 years of age and had been attending a daycare rehabilitation facility for at least three months without cognitive dysfunction, severe anemia, terminal cancer, or neurodegenerative diseases such as Parkinson’s disease. The exercise protocol at the rehabilitation facility was not changed during the study period. Forty-three participates were randomly divided into three groups: a control group receiving placebo, a group receiving dietary guidance, and a group receiving dietary guidance and MAF supplementation. The amyloid-β40/42 ratio, dietary AGE intake, plasma AGE levels, dietary caloric intake, and mild cognitive impairment (MCI) screen test were evaluated. Results: Four participants withdrew from the study. MCI screening scores significantly improved in the MAF supplementation group, especially after 6 months. Dietary modulation was also more effective than placebo at improving cognitive function after 12 months. Only the control group exhibited significantly increased plasma AGEs while the dietary modulation and MAF supplementation groups showed no change in plasma AGEs after 12 months. Conclusions: MAF supplementation improved cognitive function, especially after 6 months, in elderly people undergoing rehabilitation. Dietary modulation was also effective for improving cognitive function after 12 months compared to that in the control group. It was difficult to supervise meals during dietary guidance at the daycare service. However, simple guidance could show improvements in cognitive function through diet.

Abstract Background Although many clinical parameters have been identified as predictors for cardiovascular disease (CVD) development in the general population, the accurate predictor for CVD in patients with obesity is still unknown. Objective The study aimed to explore an additional risk factor and predictor for CVD in patients with overweight/obesity considering the interaction of obesity‐related pathophysiology. Methods The Japan Obesity and Metabolic Syndrome study, a multicenter prospective study, enrolled 787 outpatients, of which 318 eligible patients were analyzed. Patients with fasting plasma glucose (FPG) levels ≥6.11 and

Abstract Background Smoking and depression are closely related and form a vicious cycle. Yokukansan (YiganSan) is a polyherbal remedy that has the effect of calming neuropsychiatric symptoms such as anger and irritation. To examine the efficacy of Yokukansan during smoking cessation (SC) therapy in smokers with depressive tendencies but without major depressive disorders requiring pharmacotherapy. Methods A multicenter, double-blind, randomized, placebo-controlled, parallel-group comparison trial was conducted between June 2016 and May 2020 at 12 centers of the National Hospital Organization, Japan. This trial targeted smokers who first visited the SC outpatient clinics, did not receive any pharmacological treatment at the psychiatric or psychosomatic department, and scored 39 or more on the self-rating depression scale (SDS). Participants (n = 198) were randomly assigned to either the Yokukansan or placebo groups. The trial drug was initiated with the start of the SC treatment and continued for 12 weeks. The primary outcome was the high success rate of the SC treatment, and the secondary outcomes included changes in scores of the SDS and the Profile of Mood States (POMS) instrument. Results The success rate of the SC treatment was similar between the placebo (63%) and Yokukansan (67%) groups (P = .649). The SDS scores (placebo: mean difference [MD] = -3.5, 95% confidence interval [CI][-5.8, -1.2], d = 0.42; Yokukansan: MD = -4.6, 95%CI[-6.8, -2.3], d = 0.55), and the “tension-anxiety” POMS-subscale scores (placebo: MD = -1.6, 95%CI[-2.5, -0.7], d = 0.52; Yokukansan: MD = -1.6, 95%CI[-2.9, -0.3], d = 0.36) showed significant improvement in both groups after the SC treatment. However, “depression-dejection” improved in the Yokukansan group (MD = -1.9, 95%CI[-3.1, -0.7], d = 0.44) but not in the placebo group (MD = -0.1, 95%CI[-1.0, 0.7], d = 0.04). Significant improvement in “fatigue” was noted in the Yokukansan group (MD = -2.1, 95%CI[-3.4, -0.9], d = 0.47) but not in the placebo group (MD = -0.5, 95%CI[-1.8, 0.8], d = 0.11). The time × group interaction on the improvement in “depression-dejection” was significant (P = .019). Conclusions Yokukansan does not increase the SC treatment’s success rate but has additional positive effects on the psychological states due to the SC treatment in smokers with depressive tendencies but without apparent mental disorders. Trial registration ID: UMIN000027036. Retrospectively registered at UMIN on April 18, 2017.

Abstract Weight reduction therapy represents a fundamental strategy to prevent nonalcoholic fatty liver disease (NAFLD) in patients with obesity, which may result in liver fibrosis. Histological findings previously demonstrated that weight reduction therapy attenuated NAFLD. The FIB4 index is widely used to assess the status of NAFLD. The present study investigated whether the FIB4 index improved during weight reduction therapy. We used cohort data of the Japan Obesity and Metabolic syndrome Study and examined the correlation between body weight (BW) loss (BW loss) and changes in the FIB4 index (ΔFIB4 index) in patients who successfully reduced their BW by more than 5% from baseline BW after 3, 6, and 12 months (M) of weight reduction therapy. A negative correlation (r = −0.342, p = 0.029) was observed between BW loss and FIB4 index after 3 M, but not after 6 M, whereas a positive correlation (r = 0.298, p = 0.03) was noted after 12 M. These results revealed changes in the correlation between ΔBW loss and ΔFIB4 index during the therapy, mainly due to time-dependent changes in components of the FIB4 index formula. Thus, we concluded that the FIB4 index is useful and reliable to assess liver fibrosis until 3 M during weight reduction therapy. However, after 3 M, we should recognize that the FIB4 index may not reflect liver status. Therefore, it is important to consider this characteristic of the FIB4 index as a limitation when assessing liver fibrosis in obese patients receiving weight reduction therapy.

Type 2 diabetes mellitus (T2DM) is an epidemiological risk factor for dementia and has been implicated in multifactorial pathologies, including neuroinflammation. In the present study, we aimed to elucidate the potential anti-inflammatory effects of imeglimin, a novel antidiabetic agent, on high-glucose (HG)-stimulated microglia. Mouse microglial BV2 cells were stimulated with HG in the presence or absence of imeglimin. We examined the effects of imeglimin on the levels of proinflammatory cytokines, intracellular reactive oxygen species (ROS), mitochondrial integrity, and components related to the inflammasome or autophagy pathways in these cells. Our results showed that imeglimin suppressed the HG-induced production of interleukin-1beta (IL-1β) by reducing the intracellular ROS levels, ameliorating mitochondrial dysfunction, and inhibiting the activation of the thioredoxin-interacting protein (TXNIP)–NOD-like receptor family pyrin domain containing 3 (NLRP3) axis. Moreover, the inhibitory effects of imeglimin on the TXNIP–NLRP3 axis depended on the imeglimin-induced activation of ULK1, which also exhibited novel anti-inflammatory effects without autophagy induction. These findings suggest that imeglimin exerted novel suppressive effects on HG-stimulated microglia through the ULK1–TXNIP–NLRP3 axis, and may, thereby, contribute to the development of innovative strategies to prevent T2DM-associated cognitive impairment.

Fermented tea consumption has been reported to alleviate diabetes and dyslipidemia, inducing an antiobesity effect. Here, we investigated the effects of microbial fermented tea and microbial fermented twig tea, which are made from Camellia sinensis by fermentation with Aspergillus sp., on glucose tolerance and metabolic syndrome in prediabetic subjects in a randomized, double-blind study. They were asked to consume the tea three times a day for 12 weeks. Fasting blood glucose, HbA1c, and 2-h oral glucose tolerance test (OGTT) were measured as primary endpoints. After 12 weeks, fasting blood glucose level was significantly reduced in the microbial fermented twig tea group (n = 19) as compared with that in the microbial fermented tea group (n = 16, p = 0.017). There was no significant difference in the 2-hour OGTT and HbA1c values between the two groups. Triglyceride levels were significantly lower in the microbial fermented tea group than in the microbial fermented twig tea group at 12 weeks (p = 0.049).

Introduction Mild cognitive impairment (MCI) refers to a state in which cognitive functions, such as memory, have diminished but daily activities are largely unhampered. MCI is often overlooked but carries the risk of leading to development of dementia later. Curcumin is the main component of the natural herbal medicine turmeric. Curcumin is widely used as a health food and is an antioxidant that has anti-inflammatory and anti-amyloid actions. The current trial was designed to determine the effects of curcumin on indicators of cognitive functioning.Methods and analysis The current trial will be a single-centre randomised placebo-controlled double-blind parallel group trial. The participants will be 60 members of the general public with potential MCI, based on dementia screening using the Japanese version of the Mini Mental State Examination (MMSE-J). The investigational health food used in this trial will be a recently developed preparation for highly absorbable oral curcumin. This trial will determine the effects of the highly absorbable oral curcumin (brand name: curcuRouge) on the indicators of cognitive functioning, including the scores obtained with the MMSE-J, which is an interview-based measure of cognitive functioning, and the blood biomarkers that have been reported to be associated with dementia.Ethics and dissemination Informed written consent will be obtained from all the participants. The Ethical Review Board of the National Hospital Organization Kyoto Medical Center approved the study protocol.Trial registration number University Hospital Medical Information Network (UMIN000042471).

Type 2 diabetes mellitus is associated with an increased risk of dementia, potentially through multifactorial pathologies, including neuroinflammation. Therefore, there is a need to identify novel agents that can suppress neuroinflammation and prevent cognitive impairment in diabetes. In the present study, we demonstrated that a high-glucose (HG) environment elevates the intracellular reactive oxygen species (ROS) levels and triggers inflammatory responses in the mouse microglial cell line BV-2. We further found that thioredoxin-interacting protein (TXNIP), a ROS-responsive positive regulator of the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, was also upregulated, followed by NLRP3 inflammasome activation and subsequent interleukin-1beta (IL-1β) production in these cells. Conversely, caspase-1 was not significantly activated, suggesting the involvement of noncanonical pathways in these inflammatory responses. Moreover, our results demonstrated that taxifolin, a natural flavonoid with antioxidant and radical scavenging activities, suppressed IL-1β production by reducing the intracellular ROS levels and inhibiting the activation of the TXNIP–NLRP3 axis. These findings suggest the novel anti-inflammatory effects of taxifolin on microglia in an HG environment, which could help develop novel strategies for suppressing neuroinflammation in diabetes.

Abstract Aims/Introduction Weight reduction therapy is the primary treatment to prevent complications of obesity, such as lifestyle diseases and cardiovascular disease; however, to date, useful methods and genetic factors for predicting the outcomes of weight reduction therapy in obese patients have not been established. Protein tyrosine phosphatase 1B (PTP1B), a negative regulator for insulin and leptin signaling, potentially modulates glucose and energy homeostasis. This study aimed to investigate the contribution of PTPN1 polymorphisms on weight reduction and diabetes in obese Japanese patients. Materials and Methods PTPN1‐tagged single‐nucleotide polymorphisms (SNPs) rs3787348 and rs6067484 were genotyped in 447 obese Japanese patients from the general population. In this prospective cohort study, all obese patients underwent a 3‐month weight reduction therapy with lifestyle modifications, as recommended by guidelines. Results In obese patients (male/female 196/251, age 50 ± 15 years, body mass index [BMI] 32 ± 6 kg/m2), the minor allele appeared at a frequency of 45.5% in rs3787348 SNP of the PTPN1 gene. The T allele of rs3787348 was significantly associated with a higher BMI (P = 0.041 in the additive model). The patients with the T allele in SNP rs3787348 of PTPN1 had significantly smaller reductions in BMI, bodyweight and waist circumference levels during weight reduction therapy (BMI G/G, −1.9 ± 0.2; G/T, −1.5 ± 0.1; T/T, −1.2 ± 0.1; P = 0.001 in the additive model). Conclusions Our findings show that the SNP rs3787348 in PTPN1 was associated with the effects of weight reduction therapy on BMI and waist circumference among obese Japanese patients.

BackgroundCessation of smoking can markedly reduce the incidence of cardiovascular disease, improve health economics, and benefit society. Aromatherapy has the potential to be a novel option as an adjuvant therapy for smoking cessation that may alleviate depressive symptoms. However, research on the efficacy of aromatherapy as an adjuvant therapy for smoking cessation is scarce. ObjectiveThe aim of this study was to examine the potential effects of aromatherapy on psychological states in smokers with depressive tendencies and to determine if it is reasonable to proceed to the next step (ie, a phase III trial). MethodsThis is a pre-post single-arm clinical trial. Smokers with depression will be subjected to aromatherapy during smoking cessation treatment for 12 weeks. We will evaluate changes in scores on the Zung Self-Rating Depression Scale and the Profile of Mood States from pretreatment screening to 4 weeks and 12 weeks after the start of aromatherapy. Moreover, we will compare the group treated with aromatherapy with the group that received standard treatment in our previous randomized controlled trial (ie, the control group in that study). Furthermore, we will compare successful smoking cessation rates after 12 weeks. In addition, we will conduct an exploratory analysis of the efficacy of aromatherapy. The target sample size is 100, which is the number of subjects expected to be enrolled in this study during the 2-year study period. ResultsThis study was approved by the Kyoto Medical Center Institutional Review Board (IRB approval No. 19-016). Enrollment started on July 1, 2019. As of May 2022, 76 patients have been recruited. In the original plan, recruitment should have been finished on June 30, 2021. However, the number of subjects decreased due to the COVID-19 pandemic, and the study inclusion period was extended by 1 year (ie, until the end of June 2022) with the approval of the IRB on May 17, 2021. Analyses of the results will be completed subsequently. ConclusionsThis study has some limitations. This is not a rigorous validation study because it compares the same subjects who received standard treatment in a previous study. Moreover, the sample size and methods of statistical analysis were not fully set with prior consideration of statistical rigor. To address these limitations, we plan to conduct a phase III trial that will reflect the exploratory findings of this study. This is the first study to evaluate the psychological effects of aromatherapy during a smoking cessation program, and it may help improve the quality of treatment for smoking cessation in the future. Trial RegistrationUMIN Clinical Trials Registry UMIN000043102; https://tinyurl.com/tn3hvt9w International Registered Report Identifier (IRRID)DERR1-10.2196/38626

ObjectiveType 2 diabetes is a risk factor for dementia. We investigated whether serum levels of soluble triggering receptor expressed on myeloid cell 2 (sTREM2), a soluble form of the cell surface receptor TREM2, were predictive of cognitive impairment in type 2 diabetes without obesity.MethodsA total of 166 Japanese patients with type 2 diabetes without obesity were followed-up for 2 years. We measured clinical parameters, assessed cognitive function using the mini-mental state examination (MMSE), quantified and divided serum sTREM2 levels into quartiles, and examined the longitudinal associations.ResultsDuring the follow-up, HbA1c levels were elevated in 98 patients and decreased in 68 patients. In the HbA1c-elevated group, higher sTREM2 levels at baseline showed a significant association with a greater tendency for reduction in MMSE scores (P for trend = 0.015), whereas they were not significantly associated with other examined parameters. In the HbA1c-decreased group, there was no significant association between sTREM2 levels at baseline and changes in MMSE scores, but higher sTREM2 levels at baseline were significantly associated with a greater tendency for reduction in waist circumference (P for trend = 0.027), homeostasis model assessment of insulin resistance (P for trend = 0.039), and sTREM2 levels (P for trend = 0.023).ConclusionsGlycemic control is suggested to be important in preventing cognitive impairment in patients with type 2 diabetes without obesity. Higher serum sTREM2 levels would be a predictive marker for cognitive impairment in inadequately controlled type 2 diabetes without obesity.

Objective The need for tailoring ovarian cancer treatments to individual patients is increasing. This study aimed to evaluate the prognostic value of pretreatment laboratory test data for predicting the response and survival outcomes of platinum-based chemotherapy in ovarian cancer. Methods We enrolled 270 patients with ovarian cancer diagnosed at the Kyoto Medical Center (n=120; group A) and Kyoto University (n=150; group B). Data on 9 blood parameters (neutrophil to lymphocyte ratio [NLR], platelet to lymphocyte rate [PLR], C-reactive protein, lactate dehydrogenase [LDH], glucose, total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein, and triglyceride levels), cancer pathology, cancer stage, cytoreduction outcomes, serum cancer antigen 125 levels, platinum-free interval (PFI), disease-free survival (DFS), and overall survival were assessed retrospectively. Results NLR, PLR, LDH, and HDL were significantly different in advanced stage patients (P

Abstract Aims/Introduction Our aims were to examine the add‐on effects of a sodium–glucose cotransporter 2 inhibitor, dapagliflozin, compared with existing antidiabetes treatments, on anthropometric/metabolic parameters, the levels of an endocrine regulator, fibroblast growth factor 21 (FGF21); a skeletal muscle mass (SMM) negative regulator, myostatin; and a metabolic regulator, irisin, in patients with type 2 diabetes. Materials and Methods A total of 54 patients with type 2 diabetes were randomly divided into dapagliflozin and control groups. The dapagliflozin group received dapagliflozin 5 mg/day in addition to conventional therapy for 24 weeks. The primary outcome was the change in the level of serum FGF21 from baseline. The secondary outcomes included changes from baseline in anthropometric/metabolic parameters and serum levels of myostatin and irisin. Results Bodyweight decreased in the dapagliflozin group compared with the control group (P

Background The impact of chronic kidney disease (CKD) on the prognostic utility of cardiovascular biomarkers in high‐risk patients remains unclear. Methods and Results We performed a multicenter, prospective cohort study of 3255 patients with suspected or known coronary artery disease (CAD) to investigate whether CKD modifies the prognostic utility of cardiovascular biomarkers. Serum levels of cardiovascular and renal biomarkers, including soluble fms‐like tyrosine kinase‐1 (sFlt‐1), N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), high‐sensitivity cardiac troponin‐I (hs‐cTnI), cystatin C, and placental growth factor, were measured in 1301 CKD and 1954 patients without CKD. The urine albumin to creatinine ratio (UACR) was measured in patients with CKD. The primary outcome was 3‐point MACE (3P‐MACE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcomes were all‐cause death, cardiovascular death, and 5P‐MACE defined as a composite of 3P‐MACE, heart failure hospitalization, and coronary/peripheral artery revascularization. After adjustment for clinical confounders, sFlt‐1, NT‐proBNP, and hs‐cTnI, but not other biomarkers, were significantly associated with 3P‐MACE, all‐cause death, and cardiovascular death in the entire cohort and in patients without CKD. These associations were still significant in CKD only for NT‐proBNP and hs‐cTnI. NT‐proBNP and hs‐cTnI were also significantly associated with 5P‐MACE in CKD. The UACR was not significantly associated with any outcomes in CKD. NT‐proBNP and hs‐cTnI added incremental prognostic information for all outcomes to the model with potential clinical confounders in CKD. Conclusions NT‐proBNP and hs‐cTnI were the most powerful prognostic biomarkers in patients with suspected or known CAD and concomitant CKD.

The molecular pathogenesis of nonalcoholic steatohepatitis (NASH) includes a complex interaction of metabolic stress and inflammatory stimuli. Considering the therapeutic goals of NASH, it is important to determine whether the treatment can prevent the progression from NASH to hepatocellular carcinoma. Taxifolin, also known as dihydroquercetin, is a natural bioactive flavonoid with antioxidant and anti-inflammatory properties commonly found in various foods and health supplement products. In this study, we demonstrated that Taxifolin treatment markedly prevented the development of hepatic steatosis, chronic inflammation, and liver fibrosis in a murine model of NASH. Its mechanisms include a direct action on hepatocytes to inhibit lipid accumulation. Taxifolin also increased brown adipose tissue activity and suppressed body weight gain through at least two distinct pathways: direct action on brown adipocytes and indirect action via fibroblast growth factor 21 production in the liver. Notably, the Taxifolin treatment after NASH development could effectively prevent the development of liver tumors. Collectively, this study provides evidence that Taxifolin shows pleiotropic effects for the treatment of the NASH continuum. Our data also provide insight into the novel mechanisms of action of Taxifolin, which has been widely used as a health supplement with high safety.

Previous studies have reported that the neutrophil to lymphocyte ratio (NLR) is associated with onset and prognosis of cardiovascular disease (CVD). Smoking is a major risk factor for CVD and smoking cessation significantly reduces CVD risk. However, the effects of smoking cessation on the NLR remain unknown. Among smokers visiting our smoking cessation clinics, we examined changes in the NLR and CVD biomarkers before and after smoking cessation. A total of 389 individuals (301 men and 88 women) were enrolled in the study. The median NLR was significantly reduced after successful smoking cessation (before: 1.8, interquartile range [IQR] 1.5, 2.5; after: 1.7, IQR 1.3, 2.4). In a linear regression model adjusted for sex, percent change in NLR comparing before and after smoking cessation was significantly and positively correlated with percent changes in C-reactive protein (β = 0.260), α1-antitrypsin-low density lipoprotein (β = 0.151, p

Abstract Background Associations between X-inactive transcript (Xist)–long noncoding RNA (lncRNA) and chromatin are critical intermolecular interactions in the X-chromosome inactivation (XCI) process. Despite high-resolution analyses of the Xist RNA-binding sites, specific interaction sequences are yet to be identified. Based on elusive features of the association between Xist RNA and chromatin and the possible existence of multiple low-affinity binding sites in Xist RNA, we defined short motifs (≥5 nucleotides), termed as redundant UC/TC (r-UC/TC) or AG (r-AG) motifs, which may help in the mediation of triplex formation between the lncRNAs and duplex DNA. Results The study showed that r-UC motifs are densely dispersed throughout mouse and human Xist/XIST RNAs, whereas r-AG motifs are even more densely dispersed along opossum RNA-on-the-silent X (Rsx) RNA, and also along both full-length and truncated long interspersed nuclear elements (LINE-1s, L1s) of the three species. Predicted secondary structures of the lncRNAs showed that the length range of these sequence motifs available for forming triplexes was even shorter, mainly 5- to 9-nucleotides long. Quartz crystal microbalance (QCM) measurements and Monte Carlo (MC) simulations indicated that minimum-length motifs can reinforce the binding state by increasing the copy number of the motifs in the same RNA or DNA molecule. Further, r-AG motifs in L1s had a similar length-distribution pattern, regardless of the similarities in the length or sequence of L1s across the three species; this also applies to high-frequency mutations in r-AG motifs, which suggests convergence in L1 sequence variations. Conclusions Multiple short motifs in both RNA and duplex DNA molecules could be brought together to form triplexes with either Hoogsteen or reverse Hoogsteen hydrogen bonding, by which their associations are cooperatively enhanced. This novel triplex interaction could be involved in associations between lncRNA and chromatin in XCI, particularly at the sites of L1s. Potential binding of Xist/XIST/Rsx RNAs specifically at L1s is most likely preserved through the r-AG motifs conserved in mammalian L1s through convergence in L1 nucleotide variations and by maintaining a particular r-UC/r-AG motif ratio in each of these lncRNAs, irrespective of their poorly conserved sequences.

Background Whether circulating growth differentiation factor 15 (GDF‐15) levels differ according to smoking status and whether smoking modifies the relationship between GDF‐15 and mortality in patients with coronary artery disease are unclear. Methods and Results Using data from a multicenter, prospective cohort of 2418 patients with suspected or known coronary artery disease, we assessed the association between smoking status and GDF‐15 and the impact of smoking status on the association between GDF‐15 and all‐cause death. GDF‐15 was measured in 955 never smokers, 1035 former smokers, and 428 current smokers enrolled in the ANOX Study (Development of Novel Biomarkers Related to Angiogenesis or Oxidative Stress to Predict Cardiovascular Events). Patients were followed up during 3 years. The age of the patients ranged from 19 to 94 years; 67.2% were men. Never smokers exhibited significantly lower levels of GDF‐15 compared with former smokers and current smokers. Stepwise multiple linear regression analysis revealed that the log‐transformed GDF‐15 level was independently associated with both current smoking and former smoking. In the entire patient cohort, the GDF‐15 level was significantly associated with all‐cause death after adjusting for potential clinical confounders. This association was still significant in never smokers, former smokers, and current smokers. However, GDF‐15 provided incremental prognostic information to the model with potential clinical confounders and the established cardiovascular biomarkers in never smokers, but not in current smokers or in former smokers. Conclusions Not only current, but also former smoking was independently associated with higher levels of GDF‐15. The prognostic value of GDF‐15 on mortality was most pronounced in never smokers among patients with suspected or known coronary artery disease.

Background VEGF‐D (vascular endothelial growth factor D) and VEGF‐C are secreted glycoproteins that can induce lymphangiogenesis and angiogenesis. They exhibit structural homology but have differential receptor binding and regulatory mechanisms. We recently demonstrated that the serum VEGF‐C level is inversely and independently associated with all‐cause mortality in patients with suspected or known coronary artery disease. We investigated whether VEGF‐D had distinct relationships with mortality and cardiovascular events in those patients. Methods and Results We performed a multicenter, prospective cohort study of 2418 patients with suspected or known coronary artery disease undergoing elective coronary angiography. The serum level of VEGF‐D was measured. The primary outcome was all‐cause death. The secondary outcomes were cardiovascular death and major adverse cardiovascular events defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. During the 3‐year follow‐up, 254 patients died from any cause, 88 died from cardiovascular disease, and 165 developed major adverse cardiovascular events. After adjustment for possible clinical confounders, cardiovascular biomarkers (N‐terminal pro‐B‐type natriuretic peptide, cardiac troponin‐I, and high‐sensitivity C‐reactive protein), and VEGF‐C, the VEGF‐D level was significantly associated with all‐cause death and cardiovascular death but not with major adverse cardiovascular events.. Moreover, the addition of VEGF‐D, either alone or in combination with VEGF‐C, to the model with possible clinical confounders and cardiovascular biomarkers significantly improved the prediction of all‐cause death but not that of cardiovascular death or major adverse cardiovascular events. Consistent results were observed within patients over 75 years old. Conclusions In patients with suspected or known coronary artery disease undergoing elective coronary angiography, an elevated VEGF‐D value seems to independently predict all‐cause mortality.

Introduction Treatment using sodium-glucose cotransporter (SGLT) 2 inhibitor and low-carbohydrate diet (LCD) for obesity and type 2 diabetes are similar in terms of carbohydrate limitation. However, their mechanisms of action differ, and the effects on the body remain unclear. We investigated the effects of SGLT2 inhibitor and LCD on body composition and metabolic profile using the db/db mouse model for obesity and type 2 diabetes.Research design and methods Eight-week-old male db/db mice were divided into four groups: mice receiving normal diet and vehicle or canagliflozin (Cana) administration and mice receiving LCD and vehicle or Cana administration for 8 weeks. Consumed calories were adjusted to be equal among the groups.Results Both Cana administration and LCD feeding resulted in significant weight gain. Cana administration significantly decreased plasma glucose levels and increased plasma insulin levels with preservation of pancreatic β cells. However, LCD feeding did not improve plasma glucose levels but deteriorated insulin sensitivity. LCD feeding significantly reduced liver weight and hepatic triglyceride content; these effects were not observed with Cana administration. Combined treatment with LCD did not lead to an additive increase in blood β-ketone levels.Conclusions SGLT2 inhibitors and LCD exert differential effects on the body. Their combined use may achieve better metabolic improvements in obesity and type 2 diabetes.

Abstract Background Weight gain frequently occurs after smoking cessation (SC); the risk of new-onset diabetes mellitus increases for several years after SC. However, no large-scale, randomized controlled trials have examined the effects of nutritional guidance on post-SC cardiovascular risk. The current trial will enroll individuals who successfully quit smoking with the help of a SC clinic and who gain weight, to determine the effects of nutritional guidance on cardiovascular, glucose, and lipid metabolism biomarkers. Methods/design This is a multicenter, prospective, parallel-group, randomized controlled trial. Some 250 individuals who successfully quit smoking with the help of a SC clinic and who gain weight (an increase of ≥ 1.25% Body Mass Index (BMI) between the first and the fifth visit to the SC clinic) will be enrolled within 1 month of the final (fifth) visit to the SC clinic. These participants will be randomly assigned to an intervention group (125 individuals receiving nutritional guidance) or a control group (125 individuals not receiving nutritional guidance). A registered dietitian will provide nutritional guidance once every 3 months for a total of three sessions. The primary endpoint for this trial will be the level of adiponectin, a predictor of cardiovascular risk that reflects weight and smoking status. Secondary endpoints will be levels of cardiovascular, glucose, and lipid metabolism biomarkers, BMI, abdominal circumference, and the percentage of individuals who quit smoking for a prolonged period. Discussion This trial will determine the benefits of nutritional guidance with respect to post-SC weight gain. The findings should provide useful information for devising a quality protocol for SC education to prevent cardiovascular disease. Trial registration The study is registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN000030282). Registered on 6 December 2017.

Background: Depending on the characteristics of patients, the blood concentration of apixaban can unexpectedly increase, possibly leading to bleeding events. Anti-FXa activity reflects the apixaban blood concentration; however, measurement of this activity is both time-consuming and expensive. The current study aimed to evaluate the usefulness of routinely measured coagulation indices as future indicators of the efficacy and safety of apixaban. Methods: Eighteen nonvalvular atrial fibrillation patients administered apixaban (average, 52.5 days) were prospectively enrolled in our hospital. The prothrombin time (PT) and the activated partial thromboplastin time (APTT) were measured by using the Coagpia® Reagent kits. Results: The PT and the APTT increased significantly after the administration of apixaban (PT: p

Objective Smoking is the world’s leading preventable cause of death. Smoking causes a number of atherosclerosis vascular diseases and contributes to the progression of chronic kidney disease. Serum cystatin C has a low molecular weight of 13 kDa and is produced constantly and is not affected by a decrease in muscle mass. Serum cystatin C is useful in evaluation of early renal dysfunction and serves as a cardiovascular prognostic marker. This study aimed to determine changes in serum cystatin C level after smoking cessation. Methods and Results In this study, patients who visited the smoking cessation clinic for the first time and succeeded in smoking cessation for 1 year were enrolled. Among the entire cohort of 86 patients, body mass index (BMI, P < 0.001) and waist circumference (WC, P < 0.001) increased significantly at 3 months after smoking cessation in comparison to the baseline values. These values were further increased significantly (BMI, P < 0.001; WC, P < 0.001) from 3 months to 1 year after smoking cessation. The serum cystatin C level decreased significantly at 3 months (P = 0.045) after smoking cessation, and remained unchanged (P = 0.482) from 3 months to 1 year after smoking cessation. The percent change from the baseline to 3 months after smoking cessation in serum cystatin C was correlated with the percent change in serum MCP-1 (P = 0.047). Conclusions The present study demonstrates that serum levels of cystatin C, a sensitive marker of atherosclerotic vascular, significantly reduced at 3 months after SC. AT-LDL may lead to the marker of future cardiovascular events in smoker.

Objective COPD is primarily caused by regular smoking and is associated with a high frequency of coronary artery disease. There is growing recognition that the inflammation in COPD is not only confined to the lungs but also involves the systemic circulation and can impact nonpulmonary organs, including blood vessels. α1-antitrypsin-low-density lipoprotein (AT-LDL) complex is an oxidized LDL that accelerates atherosclerosis. Curcumin, one of the best-investigated natural products, is a powerful antioxidant. However, the effects of curcumin on AT-LDL remain unknown. We hypothesized that Theracurmin®, a highly absorptive curcumin with improved bioavailability using a drug delivery system, ameliorates the inflammatory status in subjects with COPD. Methods This is a randomized, double-blind, parallel-group study. The subjects were men or women (age, 20–85 years) who met the following criteria: 1) patients with COPD at stage 0, I, or II according to the definition by the Japanese Respiratory Society and 2) patients who have never smoked at least for the past 4 months. Subjects were randomly assigned to receive 90 mg Theracurmin® or placebo twice a day for 24 weeks, and changes in inflammatory parameters were evaluated. Results There were no differences between the Theracurmin® and placebo groups in terms of age, male/female ratio, or body mass index in 39 evaluable subjects. The percent changes in blood pressure and hemoglobin A1c and LDL-cholesterol, triglyceride, or high-density lipoprotein-cholesterol levels after treatment were similar for the two groups. However, the percent change in the AT-LDL level was significantly (P=0.020) lower in the Theracurmin® group compared with the placebo group. However, LDL-C, IL-6 and TNF-α were not changed. Conclusions Theracurmin® reduced levels of atherosclerotic AT-LDL, which may lead to the prevention of future cardiovascular events in patients with COPD.

Oxidative stress is enhanced by various mechanisms. Serum oxidized low-density lipoprotein (LDL) is a useful prognostic marker in diabetic patients with coronary artery disease. To examine the effects of Theracurmin®, a highly absorbable curcumin preparation, on glucose tolerance, adipocytokines, and oxidized LDL, we conducted a double-blind placebo-controlled parallel group randomized trial in patients with impaired glucose tolerance or non-insulin-dependent diabetes mellitus. We randomly divided the patients with impaired glucose tolerance or non-insulin-dependent diabetes mellitus and stable individuals into the placebo group and the Theracurmin® (180 mg daily for 6 months) group. Of the 33 patients analyzed, 18 (14 males and 4 females) were administered placebo and 15 (9 males and 6 females) were administered Theracurmin®. The patient characteristics did not differ between the two groups. The primary endpoint, HbA1c, did not differ significantly between the two groups. However, the level of α1-antitrypsin-low-density lipoprotein (AT-LDL), the oxidized LDL, significantly increased (p=0.024) in the placebo group from the beginning of the trial up to 6 months, although there was no such change in the Theracurmin® group. The percentage change in BMI from the beginning of the trial up to 6 months tended to be higher in the Theracurmin® group than in the placebo group. Patients in the Theracurmin® group tended to have a larger percentage change in adiponectin and LDL-C than those in the placebo group. Patients in the Theracurmin® group showed a smaller percentage change in AT-LDL than those in the placebo group. This study suggests that the highly absorbable curcumin could potentially inhibit a rise in oxidized LDL in patients with impaired glucose tolerance or non-insulin-dependent diabetes mellitus. This trial is registered with UMIN000007361.

Background The lymphatic system has been suggested to play an important role in cholesterol metabolism and cardiovascular disease. However, the relationships of vascular endothelial growth factor‐C (VEGF‐C), a central player in lymphangiogenesis, with mortality and cardiovascular events in patients with suspected or known coronary artery disease are unknown. Methods and Results We performed a multicenter, prospective cohort study of 2418 patients with suspected or known coronary artery disease undergoing elective coronary angiography. The primary predictor was serum levels of VEGF‐C. The primary outcome was all‐cause death. The secondary outcomes were cardiovascular death, and major adverse cardiovascular events defined as a composite of cardiovascular death, non‐fatal myocardial infarction, and non‐fatal stroke. During the 3‐year follow‐up, 254 patients died from any cause, 88 died from cardiovascular disease, and 165 developed major adverse cardiovascular events. After adjustment for established risk factors, VEGF‐C levels were significantly and inversely associated with all‐cause death (hazard ratio for 1‐SD increase, 0.69; 95% confidence interval, 0.60–0.80) and cardiovascular death (hazard ratio, 0.67; 95% confidence interval, 0.53–0.87), but not with major adverse cardiovascular events (hazard ratio, 0.85; 95% confidence interval, 0.72–1.01). Even after incorporation of N‐terminal pro‐brain natriuretic peptide, contemporary sensitive cardiac troponin‐I, and high‐sensitivity C‐reactive protein into a model with established risk factors, the addition of VEGF‐C levels further improved the prediction of all‐cause death, but not that of cardiovascular death or major adverse cardiovascular events. Consistent results were observed within 1717 patients with suspected coronary artery disease. Conclusions In patients with suspected or known coronary artery disease, a low VEGF‐C value may independently predict all‐cause mortality.

Objective The expression level of monocyte chemoattractant protein-1 (MCP-1) is increased in atherosclerotic regions, inducing monocyte migration to the blood vessel wall. Although the serum MCP-1 concentration is higher in patients with than without cardiovascular disease, the precise correlations between the serum MCP-1 concentration and factors associated with smoking and atherosclerosis are unknown. Methods The serum MCP-1 concentration was measured using an enzyme-linked immunosorbent assay in 207 consecutive smokers who visited our smoking cessation clinic. Results Sex-adjusted analysis of smokers revealed that the MCP-1 concentration was positively correlated with age ( β = 0.311), smoking duration ( β = 0.342), systolic blood pressure ( β = 0.225), and diastolic blood pressure ( β = 0.137) but not with the body mass index. Multivariate regression analysis showed that smoking duration and systolic blood pressure were independent determinants of the MCP-1 concentration. Conclusions The MCP-1 concentration was positively correlated with blood pressure among smokers. Long-term smokers with high blood pressure may be more susceptible to plaque rupture at atherosclerotic lesion sites.

PURPOSE:The blood levels of Adiponectin, anti-inflammatory and anti-arteriosclerotic adipocytokine, decrease due to smoking and obesity. Cigarette smokers are generally known to gain weight after smoking cessation (SC). Nevertheless, precise changes in serum adiponectin levels after SC and specific effects of abdominal obesity on those changes remain unknown. The objective of this study was to elucidate the changes in serum adiponectin levels after SC and the effects of abdominal obesity on those changes. METHODS:In 86 patients (56 males and 30 females) who had successfully quit smoking, serum adiponectin levels were measured using an enzyme-linked immunosorbent assay at baseline and 1 year after beginning SC. RESULTS:Body mass index and waist circumference (WC) were significantly increased 1 year after beginning SC. Adiponectin levels, however, did not change after SC. Using the median ΔWC (+2.8%) as the cutoff point, patients were then divided into two groups. The percent change in adiponectin levels from baseline to 1 year was significantly greater in the ΔWC < median group (-1.1%) than in the ΔWC ≥ median group (+8.1%) (p = 0.011). CONCLUSIONS:Despite weight gain and increased abdominal obesity, serum adiponectin levels did not decrease after SC. Therefore, the beneficial effect of SC may eliminate the adverse effects of subsequent weight gain. Conversely, patients with less abdominal obesity had increased adiponectin levels 1 year after SC. Therefore, in such patients, the beneficial effect of SC on adiponectin levels is apparent.

Microglia maintain brain homeostasis and modulate neuroinflammation and are implicated in the pathogenesis of various neurological diseases such as Alzheimer’s disease. In this study, we found that in lipopolysaccharide (LPS)-stimulated microglia, the endoplasmic reticulum (ER) stress-related eIF-2α–ATF4 pathway plays significant roles in TNF-α and IL-6 production, as well as in the inflammasome-mediated production of IL-1β. Furthermore, our analysis revealed that oxytocin (OT), a nonapeptide synthesized in the hypothalamus, suppressed the production of these proinflammatory cytokines by inhibiting activation of the eIF-2α–ATF4 pathway. Our findings therefore suggest a novel anti-inflammatory axis of OT in activated microglia, which would be helpful for developing the novel effective strategies for regulating microglia-associated neuroinflammation.

Cigarette smokers are generally known to gain weight after quitting smoking, and such weight gain is thought to contribute to the worsening of glucose tolerance. While smoking cessation therapy such as nicotine replacement is useful to minimize post-cessation weight gain, substantial gain occurs even during the therapy. The purpose of the present study was to identify factors associated with weight gain during smoking cessation therapy. We evaluated 186 patients(132 males and 54 females)who visited our outpatient clinic for smoking cessation, and successfully achieved smoking abstinence. We performed gender-adjusted regression analysis for the rate of BMI increase from the beginning of cessation to 3 months after initiation. Furthermore, we performed multivariate analysis to investigate factors that determine the BMI increase after smoking cessation. The mean BMI significantly (p

Objectives: Smoking is a significant risk factor for gingivitis and has detrimental effects on both oral health and the cardiovascular system. This study aimed to evaluate the association between cardiovascular biomarkers and gingival bleeding among smokers. Materials and Methods: This cross-sectional study comprising 60 smokers (mean age, 59.9±13.7 years) was conducted at an outpatient smoking cessation clinic. The smokers were divided into two groups based on the presence or absence of gingival bleeding, which was assessed by probing. α1-antitrypsin low-density lipoprotein complex (AT-LDL), an oxidatively modified LDL complex, causes progressive atherosclerosis. The clinical characteristics and blood markers including AT-LDL levels were measured in these patients. Results: Significantly higher (p=0.03) levels of AT-LDL, an oxidized LDL complex that promotes atherosclerosis, were observed among smokers with no gingival bleeding on probing when compared to that among smokers with gingival bleeding. The pocket depths in smokers without gingival bleeding were significantly (p=0.04) lower than those among smokers with gingival bleeding. Conclusion: The absence of gingival bleeding among smokers was associated with higher levels of AT-LDL. These findings could indicate reduced blood flow due to atherosclerosis among smokers with no gingival bleeding. [ABSTRACT FROM AUTHOR]