Circulating nicotinamide adenine dinucleotide-ubiquinone oxidoreductase chain 6 is associated with disease activity of anti-neutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: Increased serum and urinary mitochondrial DNA have been demonstrated in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Here we investigated the significance of serum nicotinamide adenine dinucleotide-ubiquinone oxidoreductase chain 6 (ND6), which is encoded by mtDNA and can attract neutrophils, in AAV. METHODS: Thirty-seven AAV patients (32 patients with positive myeloperoxidase-ANCA and 5 patients with proteinase 3-ANCA) were enrolled. Relationship between serum ND6 and clinico-laboratory characteristics were analyzed. RESULTS: The ND6 level of patients was higher than normal people (46.56 ± 23.67 pg/mL vs. 4.95 ± 2.45 pg/mL, P < 0.001) The ND6 levels of patients who needed hemodialysis at disease onset and who had pulmonary hemorrhage (PH) were higher than that of the corresponding controls (P = 0.004 and 0.044 respectively). The ND6 level negatively correlated with the percentages of normal glomeruli in kidney biopsy. The AUC of ROC curve to diagnose hemodialysis and PH was 0.804 and 0.750 respectively. ND6 level positively correlated with Birmingham Vasculitis Activity Score in active disease, and returned to normal after remission. Patients with higher serum ND6 had higher mortality (P = 0.023). CONCLUSIONS: Serum ND6 increases in active AAV, and its level correlates with the severity of disease. High ND6 level is associated with severe organ injury and predicts poor prognosis of AAV.

The Otubain YOD1 Suppresses Aggregation and Activation of the Signaling Adaptor MAVS through Lys63-Linked Deubiquitination.

MAVS is a critical adaptor required for activating an innate antiviral immune response against viral infection. The activation of MAVS requires modification of the Lys63-linked ubiquitination and formation of prion-like aggregates. However, the molecular mechanisms regulating MAVS activity remain largely obscured. In this study, we identified a deubiquitinase YOD1, also known as a member of the ovarian tumor family, as a negative regulator of MAVS activation in both human and murine cells. YOD1 was recruited to mitochondria to interact with MAVS through its UBX and Znf domains after viral infection. Subsequently, YOD1 cleaved the K63-linked ubiquitination and abrogated the formation of prion-like aggregates of MAVS, which led to attenuation of IRF3, P65 activation, and IFN-ß production. Knockdown of YOD1 potentiated IRF3 and P65 activation, IFN-ß production, and antiviral innate immune response to RNA virus. Our findings thus provided, to our knowledge, novel insights into the regulatory cascade of the cellular antiviral response through YOD1-mediated K63-linked deubiquitination and aggregation of MAVS.

Increased prevalence of peripheral arterial disease in patients with obese sarcopenia undergoing hemodialysis.

Background peripheral arterial disease (PAD) is a common complication in patients undergoing dialysis, which reduces the quality of life and increases the risk of mortality. Recent literature has documented an association between increased visceral fat (VF) content and a proatherogenic factors in end-stage renal disease. The present study investigated the prevalence of PAD in patients undergoing hemodialysis. PAD was determined as an ankle-brachial index <0.9. Additionally, VF content was determined using multiple frequency bioelectrical impendence analysis. The nutritional status of the patients was evaluated by subjective global assessment and endothelial function was measured by ultrasonographic brachial artery flow-mediated dilatation. Patients divided into two groups (malnourished and non-malnourished) with two further subgroups in each (high VF and low VF content). The prevalence of PAD was identified to be significantly higher in patients with a high VF mass compared with a low VF mass in non-malnourished patients. PAD was significantly more common in malnourished patients compared with non-malnourished patients (P<0.01). The presence of PAD in patients undergoing hemodialysis was identified to be significantly correlated with age, diabetes mellitus (DM) status VF content, malnutrition, serum albumin level, diastolic blood pressure and log C-reactive protein levels. Furthermore, logistic regression analysis determined that age, DM, VF content and malnutrition were significant independent risk factors for PAD in patients undergoing hemodialysis. In conclusion, the results of the present study indicated that obesity and malnutrition act synergistically to increase the risk of PAD in patients undergoing dialysis.

Suicidal ideation among Chinese cancer inpatients of general hospitals: prevalence and correlates.

Cancer patients are at high risk for suicide, particularly when they are informed about the cancer diagnosis or hospitalized for cancer treatment. Therefore, oncology healthcare settings such as large general hospitals in China, may represent an ideal setting to identify and treat suicidality in cancer patients. However, the clinical epidemiology of suicidality of Chinese cancer patients remains largely unknown. This study examined the prevalence and correlates of suicidal ideation among Chinese cancer inpatients of large general hospitals. A total of 517 cancer inpatients were consecutively recruited from two tertiary general hospitals of a metropolitan city in northern China, and administered with standardized questionnaires to collect data on sociodemographics, mental health, and cancer-related clinical characteristics. Suicidal ideation and mental health were measured with a single self-report question "In the past month, did you think about ending your life?" and Hospital Anxiety and Depression Scale, respectively. The one-month prevalence of suicidal ideation was 15.3% in Chinese cancer inpatients. In multivariable Logistic regression, depression, anxiety, moderate-to-severe pain, metastatic cancer, poor performance status, surgery, and palliative care were significantly associated with suicidal ideation. Cancer inpatients of large Chinese general hospitals have high prevalence of suicidal ideation and therefore potentially at high risk for suicide. Suicide prevention efforts for cancer inpatients should include periodic evaluation of suicidality, effective pain management, psychooncological supports, and, when necessary, psychiatric treatment and crisis intervention.

Elevated THBS2, COL1A2, and SPP1 Expression Levels as Predictors of Gastric Cancer Prognosis.

BACKGROUND/AIMS: Gastric cancer (GC) is an important health problem. Classification based on molecular subtypes may help to determine the prognosis of patients with GC. Tumor invasion and metastasis are important factors affecting the prognosis of cancer. We aimed to identify genes related to tumor invasion and metastasis, which may serve as indicators of good GC prognosis. METHODS: Tumor tissues and adjacent normal tissues were collected from 105 patients with primary GC who were treated by undergoing radical surgery. Samples were used for tissue microarray analysis. Identified genes with altered expression were further analyzed using the Gene Ontology (Go) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The expression levels of THBS2, COL1A2 and SPP1 were analyzed by RT-PCR, western blot and immunohistochemistry. The overall survival curves of patients with high and low expression of each gene of interest were plotted and compared. RESULTS: Forty-three genes were identified. THBS2, COL1A2 and SPP1 were selected for further analysis. Altered expression levels of THBS2, COL1A2 and SPP1 in tumor tissues were confirmed. Patients with low THBS2 expression had a better prognosis; the expression of COL1A2 and SPP1 might not affect the prognosis of patients with GC. CONCLUSION: THBS2, but not COL1A2 and SPP1, may serve as an indicator of GC prognosis.

Evaluating the efficacy and safety of intravesical chemotherapies for non-muscle invasive bladder cancer: a network meta-analysis.

Various intravesical therapies have been introduced into clinical practices for controlling non-muscle invasive bladder cancer (NMIBC). However, evidence with respect to the efficacy and safety of those intravesical therapies is very limited. Hence, we present a network meta-analysis in order to address this limitation in the current literature. The primary outcomes were the risk of tumor recurrence (TR), tumor progression (TP) and disease-specific mortality (DM). Secondary outcomes included the risk of fever, cystitis and haematuria. Conventional pair-wise and network meta-analysis were both performed for each endpoint. The surface under the cumulative ranking curve (SUCRA) was incorporated in our analysis for ranking the corresponding intravesical instillation interventions. In total, 23 randomized clinical trials (RCTs) were finally included in our study after irrelevant papers were screened out. Results of network meta-analysis suggested that Epirubicin (EPI) was less preferable than Bacille Calmette Guerin (BCG), BCG+EPI, BCG+ Isoniazid (INH), BCG+ Mytomicin C (MMC), Gemcitabine (GEM) and MMC with respect to TR. As suggested by the corresponding ranking probabilities and SUCRA, incorporating EPI or MMC into BCG may enhance the efficacy of BCG monotherapy.

Effect of AMP-activated protein kinase activation on cardiac fibroblast proliferation induced by coxsackievirus B3.

Excessive fibroblast proliferation and collagen production are the major pathogenic mechanisms in the progression of viral myocarditis, which is most frequently associated with infection by coxsackievirus B3 (CVB3). AMP-activated protein kinase (AMPK) has been confirmed to be involved in the progression of myocardial remodeling. However, it remains unclear whether AMPK has an effect on CVB3-induced cardiac fibroblast proliferation. In the present study, the effects of AMPK on cardiac fibroblast proliferation and collagen secretion induced by CVB3 were investigated. Proliferation of neonatal cardiac fibroblasts was determined by cell counting and detection of newly synthesized DNA in cells, and the proportion of cells in the S phase was measured. Hydroxyproline ELISA was used to detect collagen secretion. Phosphorylation of AMPKα-Thr172 was evaluated by western blotting. It was found that neonatal cardiac fibroblasts were clearly proliferating markedly and secreting collagen at 24 h after CVB3 infection, and peaked at 48 h. These effects were inhibited following pretreatment of the fibroblasts with 5-aminoimidazole-4-carboxamide-ribonucleoside (AICAR), a specific AMPK activator, for 2 h prior to CVB3 infection. However, if the cells were preincubated with compound C for 30 min, the inhibitive effects of AICAR were reversed. Western blotting results indicated that AMPK α-Thr172 phosphorylation was increased by AICAR and attenuated by Compound C. The results of the present study suggest that CVB3 infection increases cardiac fibroblast proliferation and collagen secretion, and that these phenomena can be inhibited by activated AMPK. These findings contribute to our understanding of AMPK function and the future design of therapeutic approaches for the treatment of cardiac fibrosis caused by chronic viral infection, such as CVB3-induced myocarditis.

Activation of AMP-activated protein kinase reduces collagen production via p38 MAPK in cardiac fibroblasts induced by coxsackievirus B3.

Collagen deposition is the major cause of myocardial fibrosis, contributing to impaired cardiac contractile function in coxsackie virus B3 (CVB3)-infected hearts. Adenosine monophosphate-activated protein kinase (AMPK) has been considered as a cellular fuel gauge and super metabolic regulator, however, whether AMPK has an effect on collagen production in CVB3­infected heart remains to be elucidated. In the present study, the association between AMPK activation and CVB3­infected neonatal rat cardiac fibroblasts (NRCFs) was investigated. Collagen production was determined by the hydroxyproline content of the supernatant and by the expression of type I/IV collagen in the cell lysate. Rat hydroxyproline ELISA was used to detect hydroxyproline content in the supernatant. The expression of type I/IV collagen, and the phosphorylation of AMPKα­Thr172 and p38 in the cell lysate were evaluated using western blotting. As expected, it was found that the hydroxyproline content in the supernatant, and the production of collagen I/IV in the cell lysate were significantly promoted at 48 h post­CVB3­infection. However, this effect was inhibited in a dose­dependent manner when pretreated with 5­aminoimidazole­4­carboxamide­1­4­ribofuranoside (AICAR) for 2 h prior to CVB3­infection. However, if the cells were preincubated with compound C or SB203580 for 30 min prior the treatment with AICAR, the inhibitive effects of AICAR were reversed. The results of the western blotting indicated that the phosphorylation of AMPKα­Thr172 and p38 were significantly increased by AICAR in the NRCFs. However, only the phosphorylation of p38 mitogen­activated protein kinase (MAPK) was inhibited by SB203580. In conclusion, AMPK activation reduced collagen production via the p38 MAPK­dependent pathway in the cardiac fibroblasts induced by CVB3. The results of the present study may contribute to identifying an effective therapy for CVB3­induced myocarditis and CVB3-associated dilated cardiomyopathy.

Urinary kidney injury molecule-1 is related to pathologic involvement in IgA nephropathy with normotension, normal renal function and mild proteinuria.

BACKGROUND: IgA nephropathy (IgAN) may progress to renal failure for some patients without any clinical risk factors and it is not unusual to find severe pathologic damage in clinically mild IgAN. We therefore investigated whether urinary kidney injury molecule-1 (KIM-1) was related to pathologic involvement in clinically mild IgAN. METHODS: Urinary KIM-1/creatinine of 51 IgAN patients with normotension, normal renal function and proteinuria < 1.0 g/24 h were tested. Relationships between urinary KIM-1 and pathologic features were analyzed. RESULTS: Eighteen of the 51 patients had elevated urinary KIM-1. The tubular atrophy/interstitial fibrosis was more severe in patients with elevated urinary KIM-1 than that in patients with normal urinary KIM-1 (T0/T1/T2, 13/5/0 vs. 33/0/0, P = 0.004). Proportion of glomeruli containing cresecents was higher in patients with elevated urinary KIM-1 than that in patients with normal urinary KIM-1 (50% vs. 18%, P = 0.026). Urinary KIM-1 correlated with the proportion of total crescents (R = 0.303, p = 0.031) and fibrous crescents (R = 0.456, p = 0.001), but did not correlate with the proportion of cellular crescents or fibrocellular crescents. Although the proportion of vascular lesions was higher in patients with elevated urinary KIM-1 (44.4%) than that in patients with normal urinary KIM-1 (18.1%), the difference was not significant (p = 0.057). There was no difference of the response to treatment between patients with and without elevated urinary KIM-1 during a short-term follow-up. CONCLUSIONS: Urinary KIM-1 is a reflection of tubularinstitial injury. For patients with clinically mild IgAN, high urinary KIM-1 is related to relatively severe pathologic involvement on renal biopsy.

Peripheral arterial disease predicts overall and cardiovascular mortality in peritoneal dialysis patients.

BACKGROUND: Peripheral arterial disease (PAD) is an important manifestation of systemic atherosclerosis and is common among dialysis patients. Cardiovascular disease (CVD) accounts for the leading cause of mortality in dialysis patients, and PAD has been found as a predictor for cardiovascular as well as overall mortality in general population. However, the study on the role of PAD in the prognosis of peritoneal dialysis patients is rather limited. METHODS: Prevalent continuous ambulatory peritoneal dialysis patients over 60 years old were recruited in this study and were followed-up regularly to death or the end of the study. The diagnosis of PAD was based on ankle-brachial pressure index (ABI) < 0.9 or intermittent claudication. Univariate and multivariate Cox proportional hazard models were used to identify the risk factors for cardiovascular and overall mortality. Survival curves were estimated by the Kaplan-Meier method followed by log-rank test to compare the mortality rate between PAD and non-PAD patients. RESULTS: One hundred and seventy-one patients were included and 62 (36%) had PAD complication. In the follow-up of 24.4 (median 34.6) months, 36 deaths were recorded: 19 from PAD group and 17 from non-PAD group. Twenty-one patients died due to CVD: 13 from PAD group and 8 from non-PAD group. The presence of PAD and serum albumin was found independently associated with cardiovascular and overall mortality using Cox proportional hazards model. CONCLUSION: PAD is very common in aged peritoneal dialysis patients and independently associated with both cardiovascular and overall mortality.

Metabolic syndrome and its components associated with endothelial dysfunction in chronic kidney disease patients.

BACKGROUND: Cardiovascular disease is more common in patients with chronic kidney disease (CKD) than in the general population. Endothelial dysfunction is an early predictor of cardiovascular events. OBJECTIVE: We conducted a cross-sectional study in CKD patients to explore the association of metabolic syndrome (MetS) components with endothelial cell function. METHODS: We evaluated clinical and laboratory data in 161 CKD patients from stage 1 to stage 5. Endothelial function was estimated by flow-mediated dilatation (FMD) of the brachial artery and expressed as percentage change relative to baseline diameter. MetS was defined according to the National Cholesterol Education Program-Adult Treatment Panel III criteria. RESULTS: Patients were grouped into two groups according to whether or not they had MetS. FMD was significantly lower in the MetS group than in the group without MetS (P = 0.012). In a Pearson's correlation analysis, FMD was significantly negatively correlated with waist circumference in women (r = -0.223, P = 0.03) and fasting blood glucose (r = -0.186, P = 0.001). Multiple linear regression analysis showed that fasting blood glucose was an independently associated factor for FMD. CONCLUSION: MetS and some components of MetS (waist circumference in women and fasting blood glucose) are closely associated with a decreased FMD in CKD patients.

Presence of peripheral arterial disease predicts loss of residual renal function in incident CAPD patients.

BACKGROUND: Accelerated cardiovascular disease (CVD), including peripheral arterial disease (PAD), is very common in patients with end-stage renal disease. Residual renal function (RRF) is a strong predictor of patient survival that is suggested to be linked to the degree of CVD. However, the relationship between PAD and decline in RRF has not previously been measured. METHODS: We studied incident continuous ambulatory peritoneal dialysis patients from Peking University Third Hospital. An ankle brachial index of less than 0.9 was used to diagnose PAD. Residual renal function (RRF) was determined as the mean of 24-hour urea and creatinine clearances (glomerular filtration rate). The Cox proportional hazards model was used to identify factors predicting loss of RRF. RESULTS: The study included 86 patients (age: 61 ± 14 years; men: 51%), 23 of whom had PAD at baseline. Mean follow-up was 19 months (median: 18 months; range: 6 - 30 months). In univariate analysis, baseline PAD, peritonitis during follow-up, inflammation (C-reactive protein), serum uric acid, Ca×P, and serum phosphate were all significantly associated with a greater-than-50% decrease in RRF during follow-up. In multivariate analysis, only baseline PAD, Ca×P, and peritonitis were independently associated with a decline in RRF. CONCLUSIONS: Our study suggests that PAD may be a clinically important marker of CVD predicting the loss of RRF. It remains to be determined whether interventions aimed at decreasing PAD may also improve renal vascular status and thus slow the rate of RRF decline.

Prevalence and risk factors for peripheral artery disease among patients on maintenance peritoneal dialysis.

BACKGROUND: Cardiovascular disease is common in end-stage renal disease patients and accounts for more than half of the mortalities. Peripheral artery disease (PAD) is frequently found in this population and is an independent predictor of cardiovascular mortality. However, there have been limited studies reporting the prevalence and risk factors for PAD among patients on maintenance continuous ambulatory peritoneal dialysis (CAPD) therapy. METHODS: 343 CAPD patients from our clinic were recruited, and PAD was diagnosed using a value of ankle-brachial index <0.9. Both traditional and dialysis-related factors were evaluated. RESULTS: The prevalence of PAD was 27.4% in all patients, which increased to 45% in patients aged >70 years. In age- and gender-adjusted logistic regression, diabetes mellitus (OR 2.354, 95% CI 1.288-4.3), diastolic blood pressure (OR 0.964, 95% CI 0.939-0.989), extracellular/intracellular water ratio (OR 2.504, 95% CI 1.067-5.804), and lnCRP (OR 1.251, 95% CI 1.031-1.518) were independently associated with PAD. CONCLUSION: Our study suggested that PAD is a common problem in patients on maintenance peritoneal dialysis, especially in elderly dialysis subjects. Diabetes mellitus, elevated hsCRP level, and extracellular/intracellular water ratio are all independent risk factors for PAD. It also suggested that aggressive risk factor management for PAD should be undertaken in CAPD patients.