Effect of propranolol on pharmacokinetics of clozapine in schizophrenic patients: a meta-analysis.

PURPOSE: Clozapine is the effective therapy for treatment-refractory schizophrenia. However, the use of clozapine is limited by its adverse effects. As propranolol is frequently used for the prevention and treatment of clozapine-induced tachycardia, we performed a meta-analysis to evaluate the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients. METHODS: We included 16 retrospective studies on the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients, with data from both generic and brand name treatment phases in eight clozapine bioequivalence studies conducted in a single center in China from 2018 to 2022. Review Manager 5.4 was used for meta-analysis of the included studies. RESULTS: The SMDs with 95% CIs of AUC0-12, Cmax,ss, C, and C were calculated to be 0.44 (0.23, 0.64), 0.40 (0.20, 0.61), 0.43 (0.22, 0.63), and 0.44 (0.23, 0.64), respectively. These findings proved that combination with propranolol would increase the systemic exposure of clozapine. T1/2 of clozapine was significantly longer in the presence of propranolol than in the absence of propranolol (SMD = 0.32, 95% CI [0.12, 0.52], p = 0.002). There was no statistically significant difference for T of clozapine in the presence or absence of propranolol (SMD = - 0.05, 95% CI [- 0.25, 0.15], p = 0.63). CONCLUSION: The combination with propranolol could significantly increase systemic exposure and extended T1/2 of clozapine, and thus need to be considered in prescribing decisions.

Association among abnormal glycolipids, reproductive hormones, and cognitive dysfunction in female patients with bipolar disorder.

BACKGROUND: Patients with bipolar disorder (BD) show abnormalities in glucolipid metabolism and reproductive hormone levels, which are of concern in women with BD. This study was dedicated to investigating the glucolipid and reproductive hormone levels of female patients, and to preliminarily investigating their relationships with cognition. METHODS: A total of 58 unmedicated female BD patients, 61 stable-medicated female BD patients, and 63 healthy controls (HC) were recruited in this study. Serum glycolipid indexes and reproductive hormones were measured. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Stroop Color-Word Test (Stroop test). RESULTS: Patients with BD showed significant cognitive impairment (p < 0.05), which was not affected by medication. Triglycerides (TG), luteinizing hormone (LH), and high-density lipoprotein cholesterol (HDL-c) were altered in stable-medicated BD patients. In addition, regression analysis showed that progesterone (PRGE) and prolactin (PRL) were negatively associated with cognitive performance in stable-medicated BD patients. CONCLUSIONS: Female BD patients may have cognitive deficits and abnormal levels of glycolipids and reproductive hormones. And abnormal levels of glycolipids and reproductive hormones may be associated with cognitive dysfunction in female BD patients.

Higher-order sensorimotor circuit of the whole-brain functional network involved in pruritus regulation in atopic dermatitis.

BACKGROUND: Little is known about the neural mechanisms underlying pruritus regulation in Atopic dermatitis (AD). OBJECTIVE: To investigate the functional changes of the resting-state whole brain network of AD participants and the mechanisms by which they were involved in pruritus regulation. METHOD: Based on the functional magnetic resonance imaging data from 19 AD participants and 37 healthy controls (HC), a graph-theoretical measure of degree centrality (DC) conjoined with a voxel-level seed-based functional connectivity (FC) method was used to identify abnormal higher-order nodes and the functionally relevant circuit in AD participants compared to healthy controls (HC). RESULTS: Of 64 participants screened, 19 AD participants (12M/7F, median [IQR] age, 27 [14] years) and 36 HCs (13M/23F, median [IQR] age, 20 [1] years) were enrolled. DC values of the left superior frontal gyrus (LSFG) increased in AD participants and exhibited a negative correlation with the SCORAD score (r = -0.561, p = 0.012) compared with HC. In the FC analysis with LSFG as the seed, FC values of several sensory and motor regions increased in AD participants, highly overlapping with the anatomical distribution of the inferior fronto-occipital fascicle (IFOF). AD participants with severe pruritus exhibited lower levels of DC (T = -2.316, p = 0.033) and FC between the LSFG and left insula (T = -2.203, p = 0.042) than those with mild-to- moderate pruritus. CONCLUSIONS AND RELEVANCE: LSFG was involved in pruritus regulation in AD by forming a high-order sensorimotor circuit through the IFOF, a white matter fascicle that proved to provide multimodal integration in motor control and sensory information processing. These results offer more mechanism-guided treatment targets for severe pruritus in AD.

Digestion profile, antioxidant, and antidiabetic capacity of Morchella esculenta exopolysaccharide: in vitro, in vivo and microbiota analysis.

BACKGROUND: Novel functional polysaccharides from fungi are important nutraceuticals. An exopolysaccharide, Morchella esculenta exopolysaccharide (MEP 2), was extracted and purified from the fermentation liquor of M. esculenta. The aim of this study was to investigate its digestion profile, antioxidant capacity, and effect on the microbiota composition in diabetic mice. RESULTS: The study found that MEP 2 was stable during in vitro saliva digestion but was partially degraded during gastric digestion. The digest enzymes exerted a negligible effect on the chemical structure of MEP 2. Molecular weight and atomic force microscope (AFM) images suggest that both smaller chains and larger aggregations were produced. Scanning electron microscope (SEM) images reveal that the surface morphology was much altered after intestinal digestion. After digestion, the antioxidant ability increased as revealed by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays. Both MEP 2 and its digested components showed strong α-amylase and moderate α-glucosidase inhibition activity, leading us to further investigate its ability to modulate the diabetic symptoms. The MEP 2 treatment ameliorated the inflammatory cell infiltration and increased the size of pancreas inlets. Serum concentration of HbA1c was significantly reduced. Blood glucose level during the oral glucose tolerance test (OGTT) was also slightly lower. The MEP 2 increased the diversity of the gut microbiota and modulated the abundance of several important bacteria including Alcaligenaceae, Caulobacteraceae, Prevotella, Brevundimonas, Demequina, and several Lachnospiraceae species. CONCLUSION: It was found that MEP 2 was partially degraded during in vitro digestion. Its potential antidiabetic bioactivity may be associated with its α-amylase inhibition and gut microbiome modulation ability. © 2023 Society of Chemical Industry.

Low potassium disrupt intestinal barrier and result in bacterial translocation.

BACKGROUND: Bacterial translocation was observed in critical illness and patients with chronic diseases such as liver cirrhosis and chronic kidney disease (CKD). Hypokalemia is a common complication in these diseases. Whether low potassium diet may increase intestinal permeability and result in bacterial translocation lack of evidence. The present study was aimed to investigate the potential effects of LK on intestinal permeability. METHODS: Grade 8-week-old male Bal B/C mice were randomly placed either on a normal potassium (NK) mouse chow or a low potassium (LK) diet for 28 days. Intestinal permeability and expression of tight junction proteins were compared between the two groups. RESULTS: Compared with the NK group, the mice in LK group had significantly lower serum potassium level, increased levels of plasmas endotoxin and plasma D-lactate. The bacterial translocation was higher and in occurred mainly in mesenteric lymph nodes (MLN), liver and spleen. The pathologic change of small intestine was obvious with thinner villus lamina propria, shorter crypt depth and thinner intestinal wall. Slight increases in the expression of proteins and mRNA levels of both claudin-1 and claudin-2 were observed in LK group. CONCLUSIONS: Low potassium diet could increase intestinal permeability and thereby lead to bacterial translocation, which was suspected to result from impaired intestinal epithelial barrier and biological barrier.

Abnormal subchondral trabecular bone remodeling in knee osteoarthritis under the influence of knee alignment.

OBJECTIVE: This study aimed to investigate the abnormal subchondral trabecular bone (STB) remodeling in knee osteoarthritis (OA) under the influence of knee alignment [hip-knee-ankle (HKA) angle]. DESIGN: Forty-one patients with knee OA underwent radiographic examination before total knee arthroplasty (TKA) for the measurement of HKA angle. Tibial plateau specimens obtained during TKA were used for histomorphometric analyses to assess STB remodeling and cartilage degradation. Tartrate-resistant acidic phosphatase (TRAP) staining was used to test osteoclast activity. Osterix, osteocalcin, and sclerostin expression in the STB were determined using immunohistochemistry. RESULTS: The interaction between HKA angle and side (medial vs lateral of tibial plateau) was the main significant influence factor for STB remodeling and microstructure. The STB with the deviation of the knee alignment was accompanied by obvious abnormal bone remodeling and microstructural sclerosis. Bone volume fraction (BV/TV) was the only significant influence factor for OARSI score, the larger the BV/TV of STB, the higher the OARSI score of cartilage. Moreover, the tibial plateau affected by alignment had more TRAP + osteoclasts, Osterix + osteoprogenitors, and osteocalcin + osteoblasts and fewer sclerostin + osteocytes. CONCLUSIONS: The variation of tibial plateau STB remodeling activity and microstructure was associated with HKA angle and cartilage degradation. Knee malalignment may cause abnormal STB remodeling and microstructural sclerosis, which may potentially affect load stress transmission from the cartilage to the STB, thus resulting in accelerated knee OA progression.

COVID-19 vaccination coverage among patients with psychiatric disorders in China during the pandemic: a cross-sectional study.

BACKGROUND: To investigate the Coronavirus Disease 2019 (COVID-19) vaccination coverage and the influential factors of vaccination among patients with mental disorders, we conducted a cross-sectional study in China. METHOD: The anonymous questionnaires including demographic data, vaccination status, intention to be vaccinated and its reasons were collected in the Second Xiangya Hospital, one of the biggest four psychiatric centers in China. Mental health of these participants were measured by the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorder-7 items (GAD-7). The influential factors associated with vaccination status were analyzed by Fisher exact tests and binary logistical analysis. RESULT: 1328 patients and 922 family members completed the survey. The vaccination rate of patients included was 69.4%, whereas 85.5% patients were willing to be vaccinated. Being hospitalized (aOR 0.41, 95% CI:0.27-0.60), suffering from schizophrenia (aOR 0.38, 95% CI: 0.19-0.75) and secondary school educational background (aOR 0.58, 95% CI: 0.37-0.93) were significantly associated with less likelihood to get vaccinated. Uptaking vaccines could reduce depressive (aOR 0.63, 95% CI: 0.41-0.98) or anxious symptoms (aOR 0.40, 95% CI: 0.25-0.63) in these patients for a short period. CONCLUSION: Further COVID-19 immunization programme should prioritize hospitalized psychiatric patients and schizophrenic patients since their demands for vaccination had been partly ignored during the current inoculation.

Incidence and Risk Factors Associated with Technique Failure in the First Year of Peritoneal Dialysis: A Single Center Retrospective Cohort Study in Southern China.

BACKGROUND: Technique failure is more likely to occur during the first 12 months after peritoneal dialysis (PD) initiation, which is a great challenge encountered in PD patients. The aim of this study was to investigate the incidence and risk factors associated with technique failure within the first year of PD patients in Southern China. METHODS: Incident PD patients who were followed up for at least one year at The First Affiliated Hospital of Sun Yat-sen University from January 1, 2006 to December 31, 2015 were included. Technique failure was defined as transferring to hemodialysis (HD) for more than 30 days or death within the first year after start of PD. A competitive risk regression analysis was used to explore the incidence and risk factors of the technique failure. RESULTS: Overall, 2,290 incident PD patients were included in this study, with a mean age of 48.2 ± 15.7 years, 40.9% female and 25.2% with diabetes. A total of 173 patients (7.5%) had technique failure during the first year of PD. Among them, the patient death account for 62.4% (n = 108) and transferring to HD account for 37.6% (n = 65). The main reasons for death were cardiovascular diseases (n = 32, 29.6%), infection (n = 15, 13.8%) and for conversion to HD were mechanical cause (n = 28, 43.1%), infection cause (n = 22, 33.8%). The risk factors for the technique failure included advanced age (HR 2.78, 95%CI 1.82-4.30), low body mass index (BMI < 18.5 kg/m2: HR 1.77, 95%CI 1.17-2.67), history of congestive heart failure (HR 2.81, 95%CI 1.58-4.98), or time on HD before PD ≤ 3 months (HR 1.49, 95%CI 1.05-2.10), peritonitis (HR 2.02, 95%CI 1.36-3.01);while higher serum albumin (HR 0.93, 95%CI 0.89-0.96) and using employee medical insurance to pay expenses (HR 0.47, 95%CI 0.32-0.69) were associated with reduced risk. CONCLUSIONS: Advanced age, poor nutritional status, history of HD or congestive heart failure, and peritonitis are related factors that increase the risk of technique failure in the first year of PD, while patients' type of medical insurance may also have an influence on early technique failure.

A visualized ratiometric fluorescence sensing system for copper ions based on gold nanoclusters/perovskite quantum dot@SiO2 nanocomposites.

Excessive copper ions (Cu2+) cause serious environmental pollution and even endanger the health of organisms. Fluorescence chemosensing materials are widely used in the detection of metal ions due to their simple operation and high sensitivity. In this study, SiO2-encapsulated single perovskite quantum dot (PQD@SiO2) core-shell nanostructures which show strong, stable, and green fluorescence are synthesized and composited with gold nanoclusters (AuNCs) which show Cu2+-sensitive and red light-emitting fluorescence to obtain a visualized ratiometric fluorescence sensor (AuNCs/PQD@SiO2) for the detection of Cu2+. In the visualized detection of Cu2+, the green fluorescence emitted from the ion-insensitive PQD@SiO2 component is used as a reference signal and the red fluorescence emitted by ion-sensitive AuNC component is adopted as a sensing signal. In the presence of Cu2+, the red fluorescence is quenched whereas the green fluorescence remains stable, which results in a visualized fluorescence color change from orange-red to yellow and finally to green with increasing Cu2+ concentration. The significant change in the fluorescence color of AuNCs/PQD@SiO2 in response to Cu2+ enables a rapid, sensitive, and visualized detection of Cu2+. Further accurate and sensitive ratiometric fluorescence analysis of Cu2+ can be accomplished by measuring the ratio of fluorescence intensities at 643 and 520 nm (I643/I520) at a certain Cu2+ level. The developed AuNCs/PQD@SiO2-based sensor has been validated by its satisfactory application in the detection of Cu2+ in human serum and environmental water samples.

RATIONALE 311: tislelizumab plus concurrent chemoradiotherapy for localized esophageal squamous cell carcinoma.

Definitive chemoradiotherapy is the standard of care for inoperable locoregionally advanced esophageal squamous cell carcinoma (ESCC). Immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibodies have led to a paradigm shift in advanced, metastatic ESCC treatment; however, the effect of incorporating checkpoint inhibitors in the definitive management of ESCC is unclear. Tislelizumab is an anti-PD-1 antibody specifically engineered to minimize FcÉ£R binding on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. The RATIONALE 311 study described here (BGB-A317-311; NCT03957590) is a registrational multicenter, double-blind, placebo-controlled, randomized, Phase III clinical trial designed to evaluate the efficacy and safety of tislelizumab combined with concurrent chemoradiotherapy in patients with inoperable localized ESCC.

Lay abstract Esophageal cancer is a challenging disease that seriously threatens patients' health and life. Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer. Most patients who have inoperable stage II­IV ESCC are currently treated with a sequential combination of chemotherapy and radiation therapy, with the hopes of increasing the positive effects seen from either therapy alone. Immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibodies have shown encouraging results in patients with ESCC, but it is not known if combining checkpoint inhibitors with simultaneous chemotherapy and radiation therapy will provide additional benefits. The safety and efficacy of tislelizumab, an anti-PD-1 antibody specifically engineered to limit potential resistance to anti-PD-1 therapy, is being investigated in combination with simultaneous chemotherapy and radiation therapy in patients with inoperable stage II­IV ESCC in an actively enrolling clinical trial, RATIONALE 311 (NCT03957590). Our trial in progress article explains the reason RATIONALE 311 was started and provides important enrollment information for doctors. Clinical trial registration: NCT03957590 (ClinicalTrials.gov).

Risk Factors and Clinical Outcomes of Cognitive Impairment in Diabetic Patients Undergoing Peritoneal Dialysis.

INTRODUCTION: Cognitive impairment (CI) is common in patients with CKD or diabetes mellitus (DM). However, the relevance between DM and CI in diabetic patients undergoing peritoneal dialysis (PD) has not been clearly established. This study aimed to explore the role of DM in CI, the association of glycemic control with CI, and clinical outcomes of CI in diabetic PD patients. METHODS: Continuous ambulatory PD (CAPD) patients followed up in our PD center between 2014 and 2016 were enrolled. The participants were followed until an endpoint was reached or December 2017. Demographic data and clinical characteristics were collected, and laboratory parameters were measured. The Montreal Cognitive Assessment (MoCA) was used to evaluate global cognitive function, and a score of <26 was considered to indicate CI. A propensity score matching according to age, gender, and mean arterial pressure was conducted between the DM and non-DM groups. RESULTS: A total of 913 CAPD patients were enrolled, of whom 186 (20.4%) had diabetes. After appropriate matching, 175 patients in the DM group and 270 patients in the non-DM group were included. Patients with diabetes had a higher prevalence of CI and lower scores for visuospatial/executive function, naming, language, delayed recall, and orientation. Higher HbA1c (odds ratio [OR], 1.547; 95% confidence interval [95% CI], 1.013-2.362) and cardiovascular disease (CVD; OR, 2.926; 95% CI, 1.139-7.516) significantly correlated with a risk of CI in diabetic patients. During a median of 26.0 (interquartile range 13.5-35.6) months of follow-up, diabetic patients with CI demonstrated a significantly lower survival rate than those without CI, and CI was an independent risk factor for mortality after adjustment (hazard ratio, 7.224; 95% CI, 1.694-30.806). However, they did not show worse technique survival or higher peritonitis rate than patients without CI. CONCLUSIONS: HbA1c and CVD are independent risk factors for CI in diabetic patients undergoing CAPD, and CI is independently associated with a higher risk of mortality.

Uric acid to high-density lipoprotein cholesterol ratio predicts cardiovascular mortality in patients on peritoneal dialysis.

BACKGROUND AND AIMS: Serum uric acid (UA) and high-density lipoprotein cholesterol (HDL-C) disorders are both considered as risk factors of cardiovascular mortality. The predictive value of UA to HDL-C ratio (UHR) has been validated in diabetes. However, association of UHR with cardiovascular (CV) mortality is undetermined in peritoneal dialysis (PD) patients. METHODS AND RESULTS: In this retrospective cohort study, we enrolled 1953 eligible incident patients who commenced PD treatment on our hospital from January 1, 2006 to December 31, 2015, and followed up until December 31, 2019. Of the participants, 14.9% were older than 65 years (mean age 47.3 ± 15.2 years), 24.6% were diabetics, and 59.4% were male. Patients were categorized into quartiles according to baseline UHR level. Multivariate Cox Proportional Regression analysis was applied to explore the association of UHR with mortality. Overall, 567 patients died during a median follow-up period of 61.3 months, of which 274 (48.3%) were attributed to CV death. The mean baseline UHR was 16.4 ± 6.7%. Compared to quartile 2 UHR, hazard ratios (HRs) for the highest quartile UHR were 1.35 (95% confidence interval [CI] 1.06-1.78; P = 0.017) and 1.46 (95% CI 1.00-2.12; P = 0.047) for all-cause and CV mortality, respectively. Subgroup analysis showed that association of UHR with CV mortality was remarkable among PD patients with age ≥65 years, malnutrition (albumin <35 g/L), diabetes, and CVD history. CONCLUSIONS: An elevated UHR predicted increased risk of all-cause and CV mortality in PD patients.

Evaluation of bioequivalence between generic and brand-name clozapine in Chinese schizophrenic patients: A randomized, two-period, crossover study.

OBJECTIVE: Clozapine is the most effective therapy for schizophrenia. This study compared the bioequivalence of a generic formulation of clozapine (ChangZhou Pharmaceutical Factory Co. Ltd. Jiangsu, China) to the brand name formulation (Clozaril, HLS Therapeutics, Inc., Philadelphia, PA, USA) after multiple doses in Chinese schizophrenic patients. MATERIALS AND METHODS: This was a randomized, open-label, multiple-dose, 2-way crossover study in which patients with schizophrenia received the generic clozapine or Clozaril 100 mg twice daily for 10 days before crossing over to the alternate formulation for the next 10 days. Blood samples were collected at regular intervals during each treatment period, and plasma concentration of clozapine was determined by high-performance liquid chromatography. RESULTS: 26 patients were enrolled, of whom 24 completed the study and were included in the steady-state analyses. The mean AUC0-12 was 6,003.29 h×ng/mL for generic clozapine and 6,347.53 h×ng/mL for Clozaril. The mean Cmax,ss was 698.52 ng/mL for generic clozapine and 739.75 ng/mL for Clozaril. The ratio of the adjusted geometric means and its 90% CI of the ratios for AUC0-12 was 96.24% (89.60 - 103.36%), and for Cmax,ss was 95.90% (88.91 - 103.44%). A total of 66 adverse events were reported by 22 (84.62%) subjects. Among them, 34 occurred in 17 (65.38%) patients during dosing of generic clozapine, and 32 occurred in 16 (61.54%) patients during dosing of brand-name clozapine. CONCLUSION: The result demonstrated that the generic clozapine was bioequivalent to brand-name clozapine (Clozaril). This would provide physicians with reassurance that patients who receive the studied generic clozapine will achieve similar plasma drug concentrations to those of brand-name clozapine (Clozaril).

Increased Global-Brain Functional Connectivity Is Associated with Dyslipidemia and Cognitive Impairment in First-Episode, Drug-Naive Patients with Bipolar Disorder.

Objectives: Previous researches have demonstrated that abnormal functional connectivity (FC) is associated with the pathophysiology of bipolar disorder (BD). However, inconsistent results were obtained due to different selections of regions of interest in previous researches. This study is aimed at examining voxel-wise brain-wide functional connectivity (FC) alterations in the first-episode, drug-naive patient with BD in an unbiased way. Methods: A total of 35 patients with BD and 37 age-, sex-, and education-matched healthy controls underwent resting-state functional magnetic resonance imaging (rs-fMRI). Global-brain FC (GFC) was applied to analyze the image data. Support vector machine (SVM) was adopted to probe whether GFC abnormalities could be used to identify the patients from the controls. Results: Patients with BD exhibited increased GFC in the left inferior frontal gyrus (LIFG), pars triangularis and left precuneus (PCu)/superior occipital gyrus (SOG). The left PCu belongs to the default mode network (DMN). Furthermore, increased GFC in the LIFG, pars triangularis was positively correlated with the triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) and negatively correlated with the scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) coding test and Stroop color. Increased GFC values in the left PCu/SOG can be applied to discriminate patients from controls with preferable sensitivity (80.00%), specificity (75.68%), and accuracy (77.78%). Conclusions: This study found increased GFC in the brain regions of DMN; LIFG, pars triangularis; and LSOG, which was associated with dyslipidemia and cognitive impairment in patients with BD. Moreover, increased GFC values in the left PCu/SOG may be utilized as a potential biomarker to differentiate patients with BD from controls.

Association of brachial-ankle pulse wave velocity with cognitive impairment in peritoneal dialysis patients.

BACKGROUND: The relationship between cognitive impairment (CI) and arterial stiffness in peritoneal dialysis (PD) patients has not been clearly clarified. The aim of this study was to examine the relationship between CI and arterial stiffness in PD patients. METHODS: This cross-sectional study enrolled PD patients who performed a vascular profiler test at a single PD center in China between January 2014 and June 2016. The cognitive function was evaluated using the Montreal cognitive assessment (MoCA). A noninvasive vascular screening device was used to assess arterial stiffness relevant indicators. RESULTS: A total of 643 PD patients with median age 45 (37-57.4) years and median duration of PD 27.8 (8.7-56.4) months were enrolled. The rate of CI was 49.9%. The mean brachial-ankle pulse wave velocity (baPWV) was 17.2 ± 5.6 m/s. Compared with normal cognitive function group, patients with CI had higher baPWV (18.6 ± 7.0 vs. 15.8 ± 3.2 m/s), systolic blood pressure (150.3 ± 21.5 vs. 144.2 ± 20.2 mmHg), and pulse pressure (59.7 ± 14.7 vs. 52.5 ± 11.6 mmHg), and lower ankle-brachial index (ABI, 1.12 ± 0.12 vs. 1.15 ± 0.09) (all p<.05). Compared with systolic blood pressure, pulse pressure, and ABI in receiver operating characteristic (ROC) analysis, baPWV had better performance in predicting CI (area under curve: 0.68, 95% confidence interval: 0.64-0.72). BaPWV was independently associated with MoCA score (B per SD, -0.42 [95% confidence interval, -0.71 to -0.12]; p = .006) and CI (OR per SD, 1.55 [95% confidence interval, 1.11-2.17]; p = .011) in PD patients after adjustment for confounders. CONCLUSIONS: Higher baPWV was independently associated with CI in PD patients.

The Association between Serum Uric Acid and Appendicular Skeletal Muscle Mass and the Effect of Their Interaction on Mortality in Patients on Peritoneal Dialysis.

BACKGROUND: Serum uric acid (SUA) has been revealed to be positively associated with the body composition parameters in hemodialysis patients, but few studies have investigated that in patients on peritoneal dialysis (PD). The aim of this study was to identify the relationship between SUA and appendicular skeletal muscle mass (ASM) and the effect of their interaction on mortality in PD patients. METHODS: This was a single-center retrospective cohort study. Patients who underwent multifrequency bioelectrical impedance analysis between January 1, 2013, and December 31, 2016, and had data on SUA values were enrolled. All patients were followed up until December 31, 2019. RESULTS: In total, 802 prevalent PD patients (57.9% male), with mean age of 46.2 ± 14.2 years were enrolled. The average SUA and ASM were 6.8 ± 1.3 mg/dL and 21.2 ± 4.9 kg. According to multiple linear regression models, SUA was positively associated with relative ASM in middle-aged and older PD patients (standardized coefficients [ß] 0.117; 95% confidence interval [CI] 0.027, 0.200; p = 0.010). Further sex-stratified analysis showed that the association existed only in males (ß 0.161; 95% CI 0.017, 0.227; p = 0.023). Moreover, the presence of hyperuricemia was found to predict lower risk of all-cause mortality (hazard ratio [HR] 0.514, 95% CI 0.272, 0.970; p = 0.040) only in patients with lower relative ASM. And, the adjusted HR of every 1 mg/dL elevated SUA level was 0.770 (95% CI 0.609, 0.972; p = 0.028) for all-cause mortality in the lower relative ASM subgroup. CONCLUSIONS: There exists a positive association between the SUA and ASM, and the ASM significantly affected the association between SUA and all-cause PD mortality.

Roles of peritoneal clearance and residual kidney removal in control of uric acid in patients on peritoneal dialysis.

BACKGROUND: There have been few systematic studies regarding clearance of uric acid (UA) in patients undergoing peritoneal dialysis (PD). This study investigated peritoneal UA removal and its influencing factors in patients undergoing PD. METHODS: This cross-sectional study enrolled patients who underwent peritoneal equilibration test and assessment of Kt/V from April 1, 2018 to August 31, 2019. Demographic data and clinical and laboratory parameters were collected, including UA levels in dialysate, blood, and urine. RESULTS: In total, 180 prevalent patients undergoing PD (52.8% men) were included. Compared with the normal serum UA (SUA) group, the hyperuricemia group showed significantly lower peritoneal UA clearance (39.1 ± 6.2 vs. 42.0 ± 8.0 L/week/1.73m2; P = 0.008). Furthermore, higher transporters (high or high-average) exhibited greater peritoneal UA clearance, compared with lower transporters (low or low-average) (42.0 ± 7.0 vs. 36.4 ± 5.6 L/week/1.73 m2; P < 0.001). Among widely used solute removal indicators, peritoneal creatinine clearance showed the best performance for prediction of higher peritoneal UA clearance in receiver operating characteristic curve analysis [area under curve (AUC) 0.96; 95% confidence interval [CI], 0.93-0.99]. Peritoneal UA clearance was independently associated with continuous SUA [standardized coefficient (ß), - 0.32; 95% CI, - 6.42 to - 0.75] and hyperuricemia [odds ratio (OR), 0.86; 95% CI, 0.76-0.98] status, only in patients with lower (≤2.74 mL/min/1.73 m2) measured glomerular filtration rate (mGFR). In those patients with lower mGFR, lower albumin level (ß - 0.24; 95%CI - 7.26 to - 0.99), lower body mass index (ß - 0.29; 95%CI - 0.98 to - 0.24), higher transporter status (ß 0.24; 95%CI 0.72-5.88) and greater dialysis dose (ß 0.24; 95%CI 0.26-3.12) were independently associated with continuous peritoneal UA clearance. Furthermore, each 1 kg/m2 decrease in body mass index (OR 0.79; 95% CI 0.63-0.99), each 1 g/dL decrease in albumin level (OR 0.08; 95%CI 0.01-0.47), and each 0.1% increase in average glucose concentration in dialysate (OR 1.56; 95%CI 1.11-2.19) were associated with greater peritoneal UA clearance (> 39.8 L/week/1.73m2). CONCLUSIONS: For patients undergoing PD who exhibited worse residual kidney function, peritoneal clearance dominated in SUA balance. Increasing dialysis dose or average glucose concentration may aid in controlling hyperuricemia in lower transporters.

Hsa_circ_0000231 knockdown inhibits the glycolysis and progression of colorectal cancer cells by regulating miR-502-5p/MYO6 axis.

BACKGROUND: Colorectal cancer (CRC) poses a heavy threat to human health owing to its high incidence and mortality. Circular RNAs (circRNAs) were investigated to participate in the progression of CRC, whereas there was no revenant data on the CRC process regulated by hsa_circ_0000231. This study aimed to explore the effects of hsa_circ_0000231 on CRC progression and underneath regulatory mechanism. METHODS: The expression levels of hsa_circ_0000231, miR-502-5p, and Myosin VI (MYO6) mRNA were detected by quantitative real time polymerase chain reaction (qRT-PCR). Western blot was employed to determine the protein expression levels of MYO6 and proliferating cell nuclear antigen (PCNA). The effects of hsa_circ_0000231 on cell proliferation, apoptosis, migration, and invasive in CRC were determined by cell counting kit-8 proliferation (CCK-8) and colony formation assays, flow cytometry analysis, wound-healing assay, and transwell invasion assay, respectively. Glucose uptake and lactate production were severally illustrated by glucose assay kit and lactate assay kit. The relationship between miR-502-5p and hsa_circ_0000231 or MYO6 was predicted by circular RNA interactome or targetScan online databases, and identified by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. In vivo tumor formation assay was carried out to determine the effects of hsa_circ_0000231 knockdown on tumor growth in vivo. RESULTS: Hsa_circ_0000231 expression was dramatically upregulated while miR-502-5p was obviously downregulated in CRC tissues and cells compared with control groups. Hsa_circ_0000231 knockdown repressed the expression levels of MYO6 and PCNA protein. Functionally, hsa_circ_0000231 knockdown repressed cell glycolysis, proliferation, migration and invasion, and induced cell apoptosis, whereas these effects were decreased by miR-502-5p inhibitor. Mechanistically, hsa_circ_0000231 acted as a sponge of miR-502-5p and miR-502-5p bound to MYO6. Furthermore, hsa_circ_0000231 knockdown decreased tumor volume and weight of CRC in vivo. CONCLUSION: Hsa_circ_0000231 knockdown inhibited CRC progression and glycolysis by downregulating MYO6 expression through sponging miR-502-5p, which might provide a theoretical basis in further studying circ_0000231-directed therapy in CRC.

Lower Phase Angle Measured by Bioelectrical Impedance Analysis Is a Marker for Increased Mortality in Incident Continuous Ambulatory Peritoneal Dialysis Patients.

OBJECTIVE: Phase angle (PA) determined by bioelectrical impedance analysis has been suggested to be a predictor of death in a variety of disease conditions, but its associations with outcomes have not yet been assessed in a large continuous ambulatory peritoneal dialysis (CAPD) patient cohort. The aim of the present study was to examine the association of PA with risks for all-cause and cardiovascular death in patients treated with CAPD. METHODS: Incident CAPD patients were enrolled from January 1, 2010 to December 31, 2015 and were followed until December 31, 2017. Multifrequency bioelectrical impedance analysis was conducted in the morning with patients in a fasting state. Multivariable linear regression analyses were performed to study the relationships between PA and other variables. Cox proportional hazard models were used to evaluate the association between PA and mortality. RESULTS: A total of 760 incident CAPD patients were enrolled in this study. Patients have a median PA value of 4.59° ranging from 2.30° to 7.22°. Aging, presence of diabetes mellitus, and fluid overload were independently associated with lower PA, whereas male sex, higher body mass index, higher serum levels of albumin and creatinine, and better residual renal function were independently associated with higher PA in a multivariable linear regression model. A total of 125 (16.4%) patients died during a median follow-up of 42 months. In the Cox model with adjustment for confounders, PA was significantly associated with all-cause and cardiovascular mortality in incident CAPD patients (hazard ratio, 0.584; 95% confidence interval, 0.403 to 0.844, P = .004; hazard ratio, 0.597; 95% confidence interval, 0.359 to 0.993, P = .047, respectively). CONCLUSIONS: PA reflected a combined dimension of the illness including deranged hydration status and nutritional status. Lower PA was associated with both all-cause and cardiovascular death in patients with CAPD.

The protective role of Nrf2 against aristolochic acid-induced renal tubular epithelial cell injury.

Aristolochic acid nephropathy is a rapidly progressive tubulointerstitial disease induced by aristolochic acid (AA) and effective treatment is lacking. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been proven to be protective in acute kidney injury and chronic kidney disease progression. But its role in AA-induced renal tubular epithelial cell injury has not been determined. This study aimed to investigate the role of Nrf2 in AA-induced renal tubular epithelial cell injury in vitro. NRK-52E cells were incubated with 5-50 µM AA to evaluate cell viability, reactive oxygen species (ROS) production, cell apoptosis/necrosis, and Nrf2 signaling pathway protein levels. We found that AA reduced cell viability and induced cell apoptosis in a time-dependent manner, accompanied by increased production of intracellular ROS. Meanwhile, the expression of Nrf2 signaling pathway proteins was significantly decreased. Downregulation of Nrf2 by Nrf2 siRNA decreased its downstream antioxidant proteins HO-1 and NQO1 and resulted in increased AA-induced ROS production and cell death. On the contrary, overexpression of Nrf2 increased HO-1 and NQO1 expression and resulted in decreased cell death. In conclusion, Nrf2 plays an important role in AA-induced injury. Enhanced Nrf2 signaling pathway could ameliorate AA-induced renal tubular epithelial cell injury, while downregulation of Nrf2 signaling exacerbated the injury.