Urinary 8-OxoGsn as a Potential Indicator of Mild Cognitive Impairment in Frail Patients With Cardiovascular Disease.

Oxidative RNA damage has been found to be associated with age-related diseases and 8-oxo-7,8-dihydroguanosine (8-oxoGsn) is a typical marker of oxidative modification of RNA. Urine tests are a feasible non-invasive diagnostic modality. The present study aimed to assess whether the measurement of urinary 8-oxoGsn could represent a potential early maker in mild cognitive impairment (MCI) of frail patients with cardiovascular disease (CVD). In this cross-sectional study performed in China from September 2018 to February 2019. Urinary 8-oxoGsn was measured in frail (Fried phenotype: 3-5) in patients with CVD and was adjusted by urinary creatinine (Cre) levels. Cognitive function was assessed by the Chinese version of the Mini-Mental State Examination (MMSE) and participants were classified into non-MCI (≥24) and MCI (<24) groups. Univariate and multivariate logistic regression models were used to determine the relationship between 8-oxoGsn/Cre and MCI. Receiver operating characteristic (ROC) curve analysis was used to assess the 8-oxoGsn/Cre ratio in relation to MCI in frail patients with CVD. A total of 106 elderly patients were enrolled in this study. The mean age of participants was 77.9 ± 6.8 years, the overall prevalence of MCI was 22.6% (24/106), and 57.5% (61/106) of participants were women. In the multivariate logistic regression analysis, urinary 8-oxoGsn/Cre was independently associated with MCI (odds ratio [OR] = 1.769, 95% confidence interval [CI] = 1.234-2.536, P = 0.002), after adjusting for age, sex, education level, marital status, and serum prealbumin levels. The area under the ROC curve was 0.786 (0.679-0.893) (P < 0.001), and the optimal cut-off value was 4.22 µmol/mol. The urinary 8-oxoGsn/Cre ratio showed a sensitivity of 87.5% and a specificity of 69.5%. The present study suggests the urinary 8-oxoGsn/Cre ratio may be a useful indicator for the early screening of MCI in frail patients with CVD. CLINICAL TRIAL REGISTRATION: ChiCTR1800017204; date of registration: 07/18/2018. URL: http://www.chictr.org.cn/showproj.aspx?proj=28931.

Prevalence and Prognostic Value of Heart Failure Stages: An Elderly Inpatient Based Cohort Study.

Background: The prevalence and prognostic value of heart failure (HF) stages among elderly hospitalized patients is unclear. Methods: We conducted a prospective, observational, multi-center, cohort study, including hospitalized patients with the sample size of 1,068; patients were age 65 years or more, able to cooperate with the assessment and to complete the echocardiogram. Two cardiologists classified all participants in various HF stages according to 2013 ACC/AHA HF staging guidelines. The outcome was rate of 1-year major adverse cardiovascular events (MACE). The Kaplan-Meier method and Cox proportional hazards models were used for survival analyses. Survival classification and regression tree analysis were used to determine the optimal cutoff of N-terminal pro-brain natriuretic peptide (NT-proBNP) to predict MACE. Results: Participants' mean age was 75.3 ± 6.88 years. Of them, 4.7% were healthy and without HF risk factors, 21.0% were stage A, 58.7% were stage B, and 15.6% were stage C/D. HF stages were associated with worsening 1-year survival without MACE (log-rank χ2 = 69.62, P < 0.001). Deterioration from stage B to C/D was related to significant increases in HR (3.636, 95% CI, 2.174-6.098, P < 0.001). Patients with NT-proBNP levels over 280.45 pg/mL in stage B (HR 2; 95% CI 1.112-3.597; P = 0.021) and 11,111.5 pg/ml in stage C/D (HR 2.603, 95% CI 1.014-6.682; P = 0.047) experienced a high incidence of MACE adjusted for age, sex, and glomerular filtration rate. Conclusions : HF stage B, rather than stage A, was most common in elderly inpatients. NT-proBNP may help predict MACE in stage B. Trial Registration: ChiCTR1800017204; 07/18/2018.

Frailty related all-cause mortality or hospital readmission among adults aged 65 and older with stage-B heart failure inpatients.

BACKGROUND: Frailty increases the adverse outcomes of clinical heart failure; however, the relationship between frailty and stage-B heart failure (SBHF) remains unknown. We aimed to explore the epidemiology and predictive value of frailty in older adults with SBHF. METHODS: A prospective cohort of SBHF inpatients aged 65 years or older who were hospitalized between September 2018 and February 2019 and were followed up for 6 months were included. SBHF was defined as systolic abnormality, structural abnormality (left ventricular enlargement, left ventricular hypertrophy, wall motion abnormalities, valvular heart disease), or prior myocardial infarction. Frailty was assessed by the Fried frailty phenotype. Multivariable Cox proportional hazards regression was used to explore the independent risk and prognostic factors. RESULTS: Data of 443 participants (age: 76.1 ± 6.79 years, LVEF: 62.8 ± 4.92%, men: 225 [50.8%], frailty: 109 [24.6%]) were analyzed. During the 6-month follow-up, 83 (18.7%) older SBHF inpatients experienced all-cause mortality or readmission, and 29 (6.5%) of them developed clinical HF. Frail individuals had a 1.78-fold (95%CI: 1.02-3.10, P = 0.041) higher risk of 6-month mortality or readmission and a 2.83-fold (95%CI 1.24-6.47, P = 0.014) higher risk of developing clinical HF, independent of age, sex, left ventricular ejection fraction, and N-terminal pro-B-type natriuretic peptide level. CONCLUSIONS: Frailty is common in older SBHF inpatients and should be considered to help identify individuals with an increased risk of mortality or readmission, and developing clinical HF. TRIAL REGISTRATION: ChiCTR1800017204 .

Adding high-sensitivity C-reactive protein to frailty assessment to predict mortality and cardiovascular events in elderly inpatients with cardiovascular disease.

OBJECTIVE: Chronic inflammation is associated with major adverse cardiovascular events (MACEs), mortality, and frailty. Our aim was to add high-sensitivity C-reactive protein (hsCRP) to the frailty assessment to predict its association with prognosis of older adults with cardiovascular disease (CVD). METHODS: A comprehensive geriatric assessment was conducted at baseline in 720 in-patients aged ≥65 years with CVD. We divided the population into frailty and non-frailty groups according to the Fried phenotype, and hsCRP was further combined with frailty to stratify all patients into c-frailty and non-c-frailty groups. Predictive validity was tested using Cox proportional hazards regression model analysis and the discriminative ability was evaluated by receiver operating characteristic (ROC) curves. RESULTS: Of all the subjects enrolled, 51.0% were male and the mean age was 75.32 ± 6.52 years. The all-cause death and MACE rate was 6.4% at the 1-year follow-up. Frailty and c-frailty were independent predictors of all-cause death and MACE (hazard ratio [HR]: 2.55, 95% confidence interval [CI]: 1.35-4.83, p = 0.004; HR: 3.67, 95% CI: 1.83-7.39, p < 0.001). Adding hsCRP to the frailty model resulted in a significant increase in the area under the ROC curve from 0.74 (95% CI: 0.70-0.77) to 0.77 (95% CI: 0.71-0.84) (p = 0.0132) and a net reclassification index of 7.9% (95% CI: 1.96%-12.56%, p = 0.012). CONCLUSION: Adding hsCRP to the frailty assessment is helpful to identify a subgroup of older CVD patients with a higher risk of death and MACE over a period of 1 year. TRIAL REGISTRATION: ChiCTR1800017204; date of registration: 07/18/2018. URL: http://www.chictr.org.cn/showproj.aspx?proj=28931.

DL-3-n-butylphthalide ameliorates diabetes-associated cognitive decline by enhancing PI3K/Akt signaling and suppressing oxidative stress.

DL-3-n-Butylphthalide (DL-NBP), a small molecular compound extracted from the seeds of Apium graveolens Linn (Chinese celery), has been shown to exert neuroprotective effects due to its anti-inflammatory, anti-oxidative and anti-apoptotic activities. DL-NBP not only protects against ischemic cerebral injury, but also ameliorates vascular cognitive impairment in dementia patients including AD and PD. In the current study, we investigated whether and how DL-NBP exerted a neuroprotective effect against diabetes-associated cognitive decline (DACD) in db/db mice, a model of type-2 diabetes. db/db mice were orally administered DL-NBP (20, 60, 120 mg· kg-1· d-1) for 8 weeks. Then the mice were subjected to behavioral test, their brain tissue was collected for morphological and biochemical analyses. We showed that oral administration of DL-NBP significantly ameliorated the cognitive decline with improved learning and memory function in Morris water maze testing. Furthermore, DL-NBP administration attenuated diabetes-induced morphological alterations and increased neuronal survival and restored the levels of synaptic protein PSD95, synaptophysin and synapsin-1 as well as dendritic density in the hippocampus, especially at a dose of 60 mg/kg. Moreover, we revealed that DL-NBP administration suppressed oxidative stress by upregulating Nrf2/HO-1 signaling, and increased brain-derived neurotrophic factor (BDNF) expression by activating PI3K/Akt/CREB signaling in the hippocampus. These beneficial effects of DL-NBP were observed in high glucose-treated PC12 cells. Our results suggest that DL-NBP may be a potential pharmacologic agent for the treatment of DACD.

Prevalence and Prognostic Significance of Frailty in Gerontal Inpatients With Pre-clinical Heart Failure: A Subgroup Analysis of a Prospective Observational Cohort Study in China.

Objective: To evaluate the prognostic value of frailty in gerontal pre-clinical heart failure (stage B heart failure, SBHF) inpatients. Background: The association between frailty and SBHF remains unknown. Methods: We conducted a subgroup analysis of a prospective observational cohort study on frailty. The previous study recruited 1,000 elderly inpatients who were consecutively admitted to a tertiary referral hospital in Beijing, China, from September 2018 to February 2019. The outcomes were all-cause death or readmission at 1-year follow-up. SBHF was diagnosed for asymptomatic cardiac structural or functional abnormalities. Frailty was assessed using the Comprehensive Geriatric Assessment-Frailty Index (CGA-FI). Results: Overall, 531 inpatients aged ≥65 years were deemed to have SBHF and followed up for 1 year. Of them, 34.5% exhibited frailty. During the follow-up period, all-cause death or readmission occurred in 157 (29.5%) participants. Of these participants, 36.6% (67/183) and 25.9% (90/348) belonged to the frail and non-frail groups, respectively (χ2 = 6.655, P = 0.010). Frailty, defined by the CGA-FI, rather than Fried frailty phenotype, could independently predict 1-year all-cause death or readmission (hazard ratio, 1.56; 95% confidence interval, 1.03-2.35; P = 0.034) and was more suitable for predicting all-cause death or readmission than N-terminal pro-B-type natriuretic peptide in female SBHF inpatients aged 80 years or over(AUCCGA-FI vs. AUCNT-proBNP 0.654 vs. 0.575, P = 0.017). Conclusions: Frailty is highly prevalent even among SBHF inpatients aged ≥65 years. The CGA-FI can independently predict 1-year all-cause death or readmission, rather than Fried frailty phenotype. Frailty in gerontal SBHF inpatients deserves more attention. Clinical Trial registration: ChiCTR1800017204; date of registration: 07/18/2018.

Evaluating the Effects of Different Sleep Supplement Modes in Attenuating Metabolic Consequences of Night Shift Work Using Rat Model.

PURPOSE: To study the effects of chronic-simulated night shift work using the rat model and examines if a particular sleep supplement mode could be better in alleviating the effects. METHODS: The male Wistar rats were randomly divided into the control (CTL: 8 rats) and night shift work (NW: 24 rats) groups of rats. Based on the sleep supplement strategy, the NW group was further segregated into three subgroups (8 rats each); late sleep supplement group (LSS), early sleep supplement group (ESS), and intermittent sleep supplement group (ISS). Sleep deprivation was achieved using the standard small-platform-over water method. Parameters such as animal body weight and food intake were measured daily. The intraperitoneal glucose tolerance test, fasting plasma insulin concentration, insulin resistance index and insulin sensitivity were measured twice, in the 4th and 8th weeks of the study. Plasma corticosterone concentration and pathological changes in islets (insulitis) were measured at the end of the 8th week. RESULTS: In NW group, night work resulted in a gain of body weight and albeit lower than that of the CTL group. NW rats also had higher food intake, showed impaired glucose metabolism and higher plasma corticosterone concentration. The sleep supplement experiments suggested that compared to the other modes, intermittent sleep supplement had significantly low changes in the body weight, glucose metabolism and the islet cells. CONCLUSION: Similar to previous studies, we also found that night shift work adversely impacts the body weight and glucose metabolism in rats. However, upon evaluating different sleep supplement strategies, we found the intermittent sleep supplement strategy to be most effective.

Trimethylamine N-Oxide, a Gut Microbiota-Dependent Metabolite, is Associated with Frailty in Older Adults with Cardiovascular Disease.

OBJECTIVE: Our study aimed to explore the association between trimethylamine N-oxide and frailty in older adults with cardiovascular disease. PATIENTS AND METHODS: This cross-sectional study analyzed a total of 451 people aged 65 years or older who underwent comprehensive geriatric assessments. Frailty status was determined using a frailty index constructed with 48 variables according to the cumulative deficits model. Physical frailty and cognitive frailty were also assessed in detail. Fasting plasma TMAO was measured by mass spectrometry. RESULTS: The proportion of frail subjects was 29.9% (135/451). Plasma TMAO levels were significantly higher in frail patients than in nonfrail individuals (4.04 [2.84-7.01] vs 3.21 [2.13-5.03] µM; p<0.001). Elevated plasma TMAO levels were independently associated with the likelihood of frailty (OR 2.12, 95% CI 1.01-4.38, p=0.046). Dose-response analysis revealed a linear association between the TMAO concentration and the OR for frailty. A 2-unit increase in TMAO was independently correlated with physical frailty (OR 1.23, 95% CI 1.08-1.41, p for trend 0.002) and cognitive frailty (OR 1.21, 95% CI 1.01-1.45, p for trend 0.04). CONCLUSION: Elevated circulating TMAO levels are independently associated with frailty among older adults with cardiovascular disease.

Predicting non-elective hospital readmission or death using a composite assessment of cognitive and physical frailty in elderly inpatients with cardiovascular disease.

BACKGROUND: We aimed to assess the utility of the combination of the mini-mental state examination (MMSE) + clock drawing test (CDT) and the Fried phenotype for predicting non-elective hospital readmission or death within 6 months in elderly inpatients with cardiovascular disease (CVD). METHODS: A single-center prospective cohort was conducted from September 2018 to February 2019. Inpatients ≥65 years old were recruited. Predictive validity was tested using a Cox proportional hazards regression model analysis, and the discriminative ability was evaluated by the receiver operating characteristic (ROC) curve. RESULTS: A total of 542 patients were included. Overall, 12% (64/542) screened positive for cognitive impairment, 16% (86/542) were physically frail and 8% (44/542) had cognitive impairment combined with physical frailty, showing an older age (P < 0.001) and a lower education level (P < 0.001) than physically frail patients. A total of 113 patients (20.9%) died or were readmitted at 6 months. Frail participants with a normal (hazard ratio [HR]: 1.73, 95% confidence interval [CI]: 1.06-2.82, P = 0.028) or impaired cognition (HR: 2.50, 95% CI: 1.27-4.91, P = 0.008) had a higher risk of non-elective hospital readmission or death than robust patients after adjusting for the age, sex, education level, marital status, the presence of diabetes mellitus, heart failure, and history of stroke. The area under the ROC curve (AUC) showed that the discriminative ability in relation to 6 months readmission and death for the MMSE + CDT + Fried phenotype was 0.65 (95% CI: 0.60-0.71), and the AUC for men was 0.71 (95% CI: 0.63-0.78), while that for women was 0.60 (95% CI: 0.51-0.69). CONCLUSIONS: Accounting for cognitive impairment in the frailty phenotype may allow for the better prediction of non-elective hospital readmission or death in elderly inpatients with CVD in the short term. TRIAL REGISTRATION: ChiCTR1800017204; date of registration: 07/18/2018.

Urinary 8-oxo-7,8-dihydroguanosine as a potential biomarker of frailty for elderly patients with cardiovascular disease.

The diagnosis of frailty is usually subjective, which calls for objective biomarkers in clinical medicine. 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGsn) and 8-oxo-7, 8-dihydroguanosine (8-oxoGsn) in urine are two aging biomarkers that have not been explored deeply in cases of frailty. A total of 508 elderly patients with cardiovascular disease (mean age 75.0 ± 6.5 years, 50.8% males) were enrolled consecutively. Frailty was assessed by the Fried phenotype (robust: 0 score; pre-frail: 1-2 scores; frail: 3-5 scores). The concentrations of 8-oxoGsn and 8-oxodGsn in urine were measured by improved ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Urinary creatinine (Cre) was tested to correct the 8-oxoGsn and 8-oxodGsn levels. According to the Fried phenotype score, the proportions of robust, pre-frail, and frail subjects were 20.5% (104/508), 53.9% (274/508), and 25.6% (130/508), respectively. The urinary 8-oxoGsn/Cre (P < 0.001) differed significantly among these 3 groups, but the urinary 8-oxodGsn/Cre (P = 0.600) showed no marked difference. Univariate and multivariate logistic regression showed that the age (odds ratio [OR] = 1.090, P < 0.001), systolic blood pressure (OR = 0.981, P = 0.008), 8-oxoGsn/Cre (OR = 1.203, P = 0.007), hemoglobin (OR = 0.980, P = 0.007), and sodium (OR = 0.915, P = 0.044) were independently associated with frailty. The sensitivity and specificity to identify frailty were 53.08% and 71.96%, respectively, for 8-oxoGsn/Cre at the optimal cut-off value of 3.879 µmol/mol according to the maximal Youden index. Urinary 8-oxoGsn, as a recognized biomarker of RNA oxidation, is independently associated with frailty in elderly patients with cardiovascular disease. However, the urinary 8-oxodGsn shows no obvious correlation with frailty. To obtain a better diagnostic performance for frailty, more biomarkers from different pathophysiological pathways should be explored in the future.

DHA inhibits protein degradation more efficiently than EPA by regulating the PPARγ/NFκB pathway in C2C12 myotubes.

This study was conducted to evaluate the mechanism by which n-3 PUFA regulated the protein degradation in C2C12 myotubes. Compared with the BSA control, EPA at concentrations from 400 to 600 µM decreased total protein degradation (P < 0.01). However, the total protein degradation was decreased when the concentrations of DHA ranged from 300 µM to 700 µM (P < 0.01). DHA (400 µM, 24 h) more efficiently decreased the I κ B α phosphorylation and increased in the I κ B α protein level than 400 µM EPA (P < 0.01). Compared with BSA, 400 µM EPA and DHA resulted in a 47% or 68% induction of the NF κ B DNA binding activity, respectively (P < 0.01). Meanwhile, 400 µM EPA and DHA resulted in a 1.3-fold and 2.0-fold induction of the PPAR γ expression, respectively (P < 0.01). In C2C12 myotubes for PPAR γ knockdown, neither 400 µM EPA nor DHA affected the levels of p-I κ B α , total I κ B α or NF κ B DNA binding activity compared with BSA (P > 0.05). Interestingly, EPA and DHA both still decreased the total protein degradation, although PPAR γ knockdown attenuated the suppressive effects of EPA and DHA on the total protein degradation (P < 0.01). These results revealed that DHA inhibits protein degradation more efficiently than EPA by regulating the PPAR γ /NF- κ B pathway in C2C12 myotubes.

Cdc42 activation couples spindle positioning to first polar body formation in oocyte maturation.

During vertebrate egg maturation, cytokinesis initiates after one pole of the bipolar metaphase I spindle attaches to the oocyte cortex, resulting in the formation of a polar body and the mature egg. It is not known what signal couples the spindle pole positioning to polar body formation. We approached this question by drawing an analogy to mitotic exit in budding yeast, as asymmetric spindle attachment to the appropriate cortical region is the common regulatory cue. In budding yeast, the small G protein Cdc42 plays an important role in mitotic exit following the spindle pole attachment . We show here that inhibition of Cdc42 activation blocks polar body formation. The oocytes initiate anaphase but fail to properly form and direct a contractile ring. Endogenous Cdc42 is activated at the spindle pole-cortical contact site immediately prior to polar body formation. The cortical Cdc42 activity zone, which directly overlays the spindle pole, is circumscribed by a cortical RhoA activity zone; the latter defines the cytokinetic contractile furrow . As the RhoA ring contracts during cytokinesis, the Cdc42 zone expands, maintaining its complementary relationship with the RhoA ring. Cdc42 signaling may thus be an evolutionarily conserved mechanism that couples spindle positioning to asymmetric cytokinesis.