Altered CD226/TIGIT expressions were associated with NK phenotypes in primary antiphospholipid syndrome and affected by IL-4/JAK pathway.

Natural killer (NK) cells were reported to be involved in the pathogenesis of primary antiphospholipid syndrome (pAPS). Immunosuppressive receptor T-cell immunoreceptor with Ig and ITIM domains (TIGIT) and activating receptor cluster of differentiation 226 (CD226) are specifically expressed on NK cells with competitive functions. This study aims to investigate the expression diversities of CD226/TIGIT on NK subsets and their associations with NK subsets activation phenotypes and potential clinical significance, furthermore, to explore potential cause for CD226/TIGIT expression diversities in pAPS. We comparatively assessed the changes of CD56brightNK, CD56dimNK, and NK-like cells in 70 pAPS patients compared with control groups, including systemic lupus erythematosus, asymptomatic antiphospholipid antibodies carriers (asymp-aPLs carriers), and healthy controls and their expression diversities of CD226/TIGIT by flow cytometry. CD25, CD69, CD107α expression, and interferon gamma (IFN-γ) secretion levels of NK subsets were detected to determine the potential association of CD226/TIGIT expression with NK subsets phenotypes. CD226/TIGIT expression levels were compared among different subgroups divided by aPLs status. Moreover, in vitro cultures were conducted to explore the potential mechanisms of CD226/TIGIT expression imbalance. CD56brightNK and CD3+CD56+NK-like cells were significantly increased while CD56dimNK cells were obviously decreased in pAPS, and CD56brightNK and NK-like cells exhibited significantly higher CD226 but lower TIGIT expressions. CD226+CD56brightNK and TIGIT-CD56brightNK cells show higher CD69 expression and IFN-γ secretion capacity, and CD226+NK-like and TIGIT-NK-like cells showed higher expressions of CD25 and CD69 but lower apoptosis rate than CD226- and TIGIT+CD56brightNK/NK-like cells, respectively. The imbalanced CD226/TIGIT expressions were most significant in aPLs triple-positive group. Imbalanced expressions of CD226/TIGIT on CD56brightNK and NK-like cells were aggravated after interleukin-4 (IL-4) stimulation and recovered after tofacitinib blocking. Our data revealed significant imbalanced CD226/TIGIT expressions on NK subsets in pAPS, which closely associated with NK subsets phenotypes and more complicated autoantibody status. CD226/TIGIT imbalanced may be affected by IL-4/Janus Kinase (JAK) pathway activation.

25-Hydroxy vitamin D deficiency is an inferior predictor of peripheral T-cell lymphomas.

The aim of the study was to explore the significance and prognostic value of 25-hydroxy vitamin D (25-(OH) D) deficiency in peripheral T-cell lymphomas (PTCLs). One hundred fifty-six patients of newly diagnosed PTCLs were enrolled in the study. Univariate and multivariate regression analyses were performed to determine independent risk factors for progression-free survival (PFS) and overall survival (OS). Receiver operating characteristic (ROC) curves were plotted, and corresponding areas under the curve (AUC) were calculated to estimate the accuracy of International Prognostic Index (IPI) plus 25-(OH) D deficiency and Prognostic Index for T-cell lymphoma (PIT) plus 25-(OH) D deficiency respectively in PTCL risk stratification. Our results showed that the 25-(OH) D deficiency was an independent inferior prognostic factor for both PFS (P = 0.0019) and OS (P = 0.005) for PTCLs, especially for AITL and PTCL-not otherwise specified (PTCL-NOS). Additionally, adding 25-(OH) D deficiency to PIT indeed has a superior prognostic significance than PIT alone for PFS (P = 0.043) and OS (P = 0.036). Multivariate COX regression analysis revealed that PIT 2‒4, albumin (ALB) ≤ 35 g/L, and 25-(OH) D deficiency were regarded as independent risk factors of PFS and OS. Our results showed that 25-(OH) D deficiency was associated with inferior survival outcome of PTCLs, especially for AITL and PTCL-NOS. PIT plus 25-(OH) D deficiency could better indicate the prognosis for PFS and OS of PTCLs than PIT.

Genome-Wide Association Studies for Albuminuria of Nondiabetic Taiwanese Population.

INTRODUCTION: Chronic kidney disease, which is defined by a reduced estimated glomerular filtration rate and albuminuria, imposes a large health burden worldwide. Ethnicity-specific associations are frequently observed in genome-wide association studies (GWAS). This study conducts a GWAS of albuminuria in the nondiabetic population of Taiwan. METHODS: Nondiabetic individuals aged 30-70 years without a history of cancer were enrolled from the Taiwan Biobank. A total of 6,768 subjects were subjected to a spot urine examination. After quality control using PLINK and imputation using SHAPEIT and IMPUTE2, a total of 3,638,350 single-nucleotide polymorphisms (SNPs) remained for testing. SNPs with a minor allele frequency of less than 0.1% were excluded. Linear regression was used to determine the relationship between SNPs and log urine albumin-to-creatinine ratio. RESULTS: Six suggestive loci are identified in or near the FCRL3 (p = 2.56 × 10-6), TMEM161 (p = 4.43 × 10-6), EFCAB1 (p = 2.03 × 10-6), ELMOD1 (p = 2.97 × 10-6), RYR3 (p = 1.34 × 10-6), and PIEZO2 (p = 2.19 × 10-7). Genetic variants in the FCRL3 gene that encode a secretory IgA receptor are found to be associated with IgA nephropathy, which can manifest as proteinuria. The PIEZO2 gene encodes a sensor for mechanical forces in mesangial cells and renin-producing cells. Five SNPs with a p-value between 5 × 10-6 and 5 × 10-5 are also identified in five genes that may have a biological role in the development of albuminuria. CONCLUSION: Five new loci and one known suggestive locus for albuminuria are identified in the nondiabetic Taiwanese population.

ER ribosomal-binding protein 1 regulates blood pressure and potassium homeostasis by modulating intracellular renin trafficking.

BACKGROUND: Genome-wide association studies (GWASs) have linked RRBP1 (ribosomal-binding protein 1) genetic variants to atherosclerotic cardiovascular diseases and serum lipoprotein levels. However, how RRBP1 regulates blood pressure is unknown. METHODS: To identify genetic variants associated with blood pressure, we performed a genome-wide linkage analysis with regional fine mapping in the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) cohort. We further investigated the role of the RRBP1 gene using a transgenic mouse model and a human cell model. RESULTS: In the SAPPHIRe cohort, we discovered that genetic variants of the RRBP1 gene were associated with blood pressure variation, which was confirmed by other GWASs for blood pressure. Rrbp1- knockout (KO) mice had lower blood pressure and were more likely to die suddenly from severe hyperkalemia caused by phenotypically hyporeninemic hypoaldosteronism than wild-type controls. The survival of Rrbp1-KO mice significantly decreased under high potassium intake due to lethal hyperkalemia-induced arrhythmia and persistent hypoaldosteronism, which could be rescued by fludrocortisone. An immunohistochemical study revealed renin accumulation in the juxtaglomerular cells of Rrbp1-KO mice. In the RRBP1-knockdown Calu-6 cells, a human renin-producing cell line, transmission electron and confocal microscopy revealed that renin was primarily retained in the endoplasmic reticulum and was unable to efficiently target the Golgi apparatus for secretion. CONCLUSIONS: RRBP1 deficiency in mice caused hyporeninemic hypoaldosteronism, resulting in lower blood pressure, severe hyperkalemia, and sudden cardiac death. In juxtaglomerular cells, deficiency of RRBP1 reduced renin intracellular trafficking from ER to Golgi apparatus. RRBP1 is a brand-new regulator of blood pressure and potassium homeostasis discovered in this study.

Renin-angiotensin-aldosterone system inhibition decreased contrast-associated acute kidney injury in chronic kidney disease patients.

BACKGROUND/PURPOSE: Chronic kidney disease (CKD) is a risk factor for contrast associated acute kidney injury (CA-AKI). The risk of renin-angiotensin-aldosterone system inhibitor (RASi) use in patients with CKD before the administration of contrast is not clear. METHODS: In this nested case-control study, 8668 patients received contrast computed tomography (CT) from 2013 to 2018 during index administration in a multicenter hospital cohort. The identification of AKI is based on the Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria within 48 h after contrast medium used. RESULTS: Finally, 986 patients (age, 63.36 ± 12.22; men, 72.92%) with CKD (estimated glomerular filtration rate (eGFR) = 35.0 ± 19.8 mL/min/1.73 m2) were eligible for analysis. After the index date, RASi users (n = 315) were less likely to develop CA-AKI (13.65% vs 30.4%, p < 0.001), and had a lower hospital mortality (8.25% vs 19.23%, p < 0.001) compared with non-users. The pre-contrast use of RASi decrease the risk of AKI (OR, 0.342, p < 0.001) and hospital mortality (OR, 0.602, p = 0.045). Even a few defined daily doses (DDDs) of RASi treatment, more than 0.02 prior to contrast CT could attenuate CA-AKI. The hospital mortality was higher in RASi non-users if their eGFR value was more than 17.9 mL/min/1.73 m2. CONCLUSION: RASi use in patients with CKD prior to contrast CT has the potential to mitigate the incidence of AKI and hospital mortality. Even a low dose of RASi will noticeably decrease the risk of AKI and will not increase the risk of hyperkalemia.

Mobile Health App With Social Media to Support Self-Management for Patients With Chronic Kidney Disease: Prospective Randomized Controlled Study.

BACKGROUND: Chronic kidney disease (CKD) is a global health burden. Self-management plays a key role in improving modifiable risk factors. OBJECTIVE: The aim of this study was to evaluate the effectiveness of wearable devices, a health management platform, and social media at improving the self-management of CKD, with the goal of establishing a new self-management intervention model. METHODS: In a 90-day prospective experimental study, a total of 60 people with CKD at stages 1-4 were enrolled in the intervention group (n=30) and control group (n=30). All participants were provided with wearable devices that collected exercise-related data. All participants maintained dietary diaries using a smartphone app. All dietary and exercise information was then uploaded to a health management platform. Suggestions about diet and exercise were provided to the intervention group only, and a social media group was created to inspire the participants in the intervention group. Participants' self-efficacy and self-management questionnaire scores, Kidney Disease Quality of Life scores, body composition, and laboratory examinations before and after the intervention were compared between the intervention and control groups. RESULTS: A total of 49 participants completed the study (25 in the intervention group and 24 in the control group); 74% of the participants were men and the mean age was 51.22 years. There were no differences in measured baseline characteristics between the groups except for educational background. After the intervention, the intervention group showed significantly higher scores for self-efficacy (mean 171.28, SD 22.92 vs mean 142.21, SD 26.36; P<.001) and self-management (mean 54.16, SD 6.71 vs mean 47.58, SD 6.42; P=.001). Kidney Disease Quality of Life scores were also higher in the intervention group (mean 293.16, SD 34.21 vs mean 276.37, SD 32.21; P=.02). The number of steps per day increased in the intervention group (9768.56 in week 1 and 11,389.12 in week 12). The estimated glomerular filtration rate (eGFR) of the intervention group was higher than that of the control group (mean 72.47, SD 24.28 vs mean 59.69, SD 22.25 mL/min/1.73m2; P=.03) and the decline in eGFR was significantly slower in the intervention group (-0.56 vs -4.58 mL/min/1.73m2). There were no differences in body composition between groups postintervention. CONCLUSIONS: The use of wearable devices, a health management platform, and social media support not only strengthened self-efficacy and self-management but also improved quality of life and a slower eGFR decline in people with CKD at stages 1-4. These results outline a new self-management model to promote healthy lifestyle behaviors for patients with CKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04617431; https://www.clinicaltrials.gov/ct2/show/NCT04617431.

Pioglitazone improves hepatic mitochondrial function in a mouse model of nonalcoholic steatohepatitis.

Pioglitazone is effective in improving insulin resistance and liver histology in patients with nonalcoholic steatohepatitis (NASH). Because dysfunctional mitochondrial metabolism is a central feature of NASH, we hypothesized that an important target of pioglitazone would be alleviating mitochondrial oxidative dysfunction. To this end, we studied hepatic mitochondrial metabolism in mice fed high-fructose high-transfat diet (TFD) supplemented with pioglitazone for 20 wk, using nuclear magnetic resonance-based 13C isotopomer analysis. Pioglitazone improved whole body and adipose insulin sensitivity in TFD-fed mice. Furthermore, pioglitazone reduced intrahepatic triglyceride content and fed plasma ketones and hepatic TCA cycle flux, anaplerosis, and pyruvate cycling in mice with NASH. This was associated with a marked reduction in most intrahepatic diacylglycerol classes and, to a lesser extent, some ceramide species (C22:1, C23:0). Considering the cross-talk between mitochondrial function and branched-chain amino acid (BCAA) metabolism, pioglitazone's impact on plasma BCAA profile was determined in a cohort of human subjects. Pioglitazone improved the plasma BCAA concentration profile in patients with NASH. This appeared to be related to an improvement in BCAA degradation in multiple tissues. These results provide evidence that pioglitazone-induced changes in NASH are related to improvements in hepatic mitochondrial oxidative dysfunction and changes in whole body BCAA metabolism.

Comparison of outcomes between emergent-start and planned-start peritoneal dialysis in incident ESRD patients: a prospective observational study.

BACKGROUND: The clinical consequences of starting chronic peritoneal dialysis (PD) after emergent dialysis via a temporary hemodialysis (HD) catheter has rarely been evaluated within a full spectrum of treated end-stage renal disease (ESRD). We investigated the longer-term outcomes of patients undergoing emergent-start PD in comparison with that of other practices of PD or HD in a prospective cohort of new-onset ESRD. METHODS: This was a 2-year prospective observational study. We enrolled 507 incident ESRD patients, among them 111 chose PD (43 planned-start, 68 emergent-start) and 396 chose HD (116 planned-start, 280 emergent-start) as the long-term dialysis modality. The logistic regression model was used to identify variables associated with emergent-start dialysis. The Kaplan-Meier survival analysis was used to determine patient survival and technique failure. The propensity score-adjusted Cox regression model was used to identify factors associated with patient outcomes. RESULTS: During the 2-year follow-up, we observed 5 (4.5%) deaths, 15 (13.5%) death-censored technique failures (transfer to HD) and 3 (2.7%) renal transplantations occurring in the PD population. Lack of predialysis education, lower predialysis estimated glomerular filtration rate and serum albumin were predictors of being assigned to emergent dialysis initiation. The emergent starters of PD displayed similar risks of patient survival, technique failure and overall hospitalization, compared with the planned-start counterparts. By contrast, the concurrent planned-start and emergent-start HD patients with an arteriovenous fistula or graft were protected from early overall death and access infection-related mortality, compared with the emergent HD starters using a central venous catheter. CONCLUSIONS: In late-referred chronic kidney disease patients who have initiated emergent dialysis via a temporary HD catheter, post-initiation PD can be a safe and effective long-term treatment option. Nevertheless, due to the potential complications and cost concerns, such practice of PD initiation would better be replaced with a planned-start mode by employing more effective predialysis therapeutic education and timely catheter placement.

[Chemical Constituents from the Roots of Lindera glauca and Their Antitumor Activity on Four Different Cancer Cell Lines].

Objective: To study the chemical constitutes from the roots of Lindera glauca and the alkaloids influence on proliferation of HT-29,SGC-7901,SMMC-7721 and A549 cell lines. Methods: The constituents were isolated by column chromatography such as RP-18,Sephadex LH-20 and silica gel,and their structures were elucidated by spectroscopic data analysis and compared with literature data. The antitumor activity was determined by MTT assay. Results: Ten compounds had been isolated and identified as(-)-magnocurarine( 1),N-methyl-laurotetanine( 2),laurotetanine( 3),( +)-boldine( 4),(-)-norisoboldine( 5),( +)-norisocorydine( 6),pmethane-3,8-trans-diol( 7),p-methane-3,8-cis-diol( 8),eudesm-4( 15)-ene-7,11-diol( 9) and 4ß,6ß-dihydroxy-1α,5ß( H)-guai-9-ene( 10). Compounds 2 ~ 4 showed significant inhibitory activities against HT-29,SGC-7901,SMMC-7721 and A549 cells. Conclusion: Compound 1,9 and 10 are isolated from this plant for the first time. The IC50 value of compound 2 against HT-29 and SGC-7901 cell lines is even lower than VP-16.

Digital health interventions to promote healthy lifestyle in hemodialysis patients: an interventional pilot study.

Low physical activity has been associated with poor prognosis in hemodialysis (HD) patients. Interventions to maintain healthy lifestyle in this population are important to reduce mortality. This study aimed to evaluate the effectiveness of digital health interventions (DHIs) for improving the physical activity and health-related quality of life (HRQoL) in HD patients. The 24-week prospective study enrolled 31 clinically stable HD patients. All participants were assigned home exercises and provided with wearable devices. Dietary and exercise information was uploaded to a health management platform. Suggestions about diet and exercise were provided, and a social media group was created. Physical performance testing was performed at baseline and during weeks 4, 8, 12, 16 and 24. HRQoL and nutritional status were evaluated. A total of 25 participants completed the study. After the interventions, the daily step count increased 1658 steps. The 10-time-repeated sit-to-stand test reduced by 4.4 s, the sit-to-stand transfers in 60 s increased 12 repetitions, the distance of six-minute walk test (6MWT) increased by 55.4 m. The mental health components and burden of kidney disease of the Kidney Disease Quality of Life survey, and subjective global assessment (SGA) scores improved. By Spearman correlation, the monthly step count correlated positively with 6MWT and SGA. DHIs that combined wearable devices, a health management platform, and social media could strengthen physical activity and improve the HRQoL and nutrition of maintenance HD patients. The results outline a new model to promote healthy lifestyle behaviors in HD patients.

[Promoting effects and mechanisms of prostaglandin E1 on proliferation and migration of endothelial cells].

OBJECTIVE: To investigate the mechanism(s) that prostaglandin E1 (PGE1) promotes human umbilical vein endothelial cell (HUVEC)proliferation and migration. METHODS: Western blot, enzyme linked immunosorbent assay, cell proliferation and cell migration tests, and tube formation were used for analyzing the roles and mechanisms of PGE1 on HUVEC; Western blot was used for analyzing the effects of PGE1 on the expression of vascular endothelial growth factor (VEGF) in rat aortic vascular smooth muscle cells (VSMC). RESULTS: PGE1 significantly increased VEGF expression of HUVEC in time and a dose dependent manner with concomitantly increased HUVEC proliferation; treatment of HUVEC with Bevacizumab apparently suppressed PGE1-stimulated VEGF expression, which led to decreased tube formation, reduced cell proliferation and migration by 41% and 38%, respectively, compared with PGE1 treatment alone; PGE1 time-dependently induced both phosphorylation of ERK and p38 in HUVEC, whereas ERK inhibitor, PD98059, or p38 inhibitor, SB203580, blocked PGE1-induced VEGF expression of HUVEC, resulting in dramatically suppression of HUVEC proliferation and migration compared with PGE1 treatment alone (60% and 55% by PD98059, 62% and 51% by SB203580, respectively); in addition, cAMP-dependent protein kinase A inhibitor, H89 or Rp-cAMP blocked PGE1-induced VEGF expression in VSMC. CONCLUSION: PGE1 promotion of proliferation, migration and tube formation of HUVEC via VEGF further provides a novel theoretical support in efficacy of PGE1 treatment of critical limb ischemia and other related diseases.

Roux-en-Y and One-Anastomosis Gastric Bypass Surgery Are Superior to Sleeve Gastrectomy in Lowering Glucose and Cholesterol Levels Independent of Weight Loss: a Propensity-Score Weighting Analysis.

BACKGROUND: The superior effects of gastric bypass surgery in preventing cardiovascular diseases compared with sleeve gastrectomy are well-established. However, whether these effects are independent of weight loss is not known. METHODS: In this retrospective cohort study, we compared the change in cardiometabolic risks of 1073 diabetic patients undergoing Roux-en-Y gastric bypass (RYGB) (n = 265), one-anastomosis gastric bypass (OAGB) (n = 619), and sleeve gastrectomy (SG) (n = 189) with equivalent weight loss from the Min-Shen General Hospital. Propensity score-weighting, multivariate regression, and matching were performed to adjust for baseline differences. RESULTS: After 12 months, OAGB and, to a lesser extent, RYGB exhibited superior effects on glycemic control compared with SG in patients with equivalent weight loss. The effect was significant in patients with mild-to-modest BMI reduction but diminished in patients with severe BMI reduction. RYGB and OAGB had significantly greater effects in lowering total and low-density lipoprotein cholesterol than SG, regardless of weight loss. The results of matching patients with equivalent weight loss yielded similar results. The longer length of bypassed biliopancreatic (BP) limbs was correlated with a greater decrease in glycemic levels, insulin resistance index, lipids, C-reactive protein (CRP) levels, and creatinine levels in patients receiving RYBG. It was correlated with greater decreases in BMI, fasting insulin, insulin resistance index, and C-reactive protein levels in patients receiving OAGB. CONCLUSION: Diabetic patients receiving OAGB and RYGB had lower glucose and cholesterol levels compared with SG independent of weight loss. Our results suggest diabetic patients with cardiovascular risk factors such as hypercholesterolemia to receive bypass surgery.

Preoperative proteinuria predicts adverse renal outcomes after coronary artery bypass grafting.

Whether preoperative proteinuria associates with adverse renal outcomes after cardiac surgery is unknown. Here, we performed a secondary analysis of a prospectively enrolled cohort of adult patients undergoing coronary artery bypass grafting (CABG) at a medical center and its two affiliate hospitals between 2003 and 2007. We excluded patients with stage 5 CKD or those who received dialysis previously. We defined proteinuria, measured with a dipstick, as mild (trace to 1+) or heavy (2+ to 4+). Among a total of 1052 patients, cardiac surgery-associated acute kidney injury (CSA-AKI) developed in 183 (17.4%) patients and required renal replacement therapy (RRT) in 50 (4.8%) patients. In a multiple logistic regression model, mild and heavy proteinuria each associated with an increased odds of CSA-AKI, independent of CKD stage and the presence of diabetes mellitus (mild: OR 1.66, 95% CI 1.09 to 2.52; heavy: OR 2.30, 95% CI 1.35 to 3.90). Heavy proteinuria also associated with increased odds of postoperative RRT (OR 7.29, 95% CI 3.00 to 17.73). In summary, these data suggest that preoperative proteinuria is a predictor of CSA-AKI among patients undergoing CABG.

Accuracy of Liver-Type Fatty Acid-Binding Protein in Predicting Acute Kidney Injury: A Meta-Analysis.

BACKGROUND: Liver-type fatty acid-binding protein (L-FABP) is a promising biomarker for the early prediction of acute kidney injury (AKI). However, the clinical utility of L-FABP in different populations or settings remains unclear. We present a meta-analysis of studies evaluating the performance of L-FABP in AKI prediction. METHODS: We performed a literature search in MEDLINE, EMBASE, and Cochrane library, using search terms "acute kidney injury" and "L-FABP." Studies investigating the performance characteristics of L-FABP for the early diagnosis of AKI were included. Data about patient characteristics, diagnostic criteria of AKI, quantitative data required for construction of a 2 × 2 table (number of participants, sensitivity, specificity, and case number), study settings, and outcomes were extracted. The bivariable model was applied to calculate the estimated sensitivity and specificity of L-FABP. A summary ROC curve was created by plotting the true-positive rate against the false-positive rate at various cutoff values from different studies. RESULTS: We found 27 studies reporting measurement of urine (n = 25 studies) or plasma (n = 2 studies) L-FABP. Overall, the estimated sensitivity was 0.74 (95% CI: 0.69-0.80) and specificity was 0.78 (95% CI: 0.71-0.83). L-FABP demonstrated a stable area under the ROC of 0.82 (95% CI: 0.79-0.85) in variable clinical settings including intensive care unit, surgery, and contrast-induced AKI. In subgroup analysis excluding pediatric and post radiocontrast exposure cohorts, L-FABP had comparative diagnostic performance with neutrophil gelatinase associated lipocalin (NGAL). CONCLUSIONS: Despite broad prevalence, L-FABP is a clinically useful marker with moderate accuracy in variable clinical settings as demonstrated in our subgroup analysis. Except for pediatric patients and those post-radiocontrast exposure, L-FABP has comparable discriminative capability as NGAL.

A genome-wide association study for melatonin secretion.

Melatonin exerts a wide range of effects among various tissues and organs. However, there is currently no study to investigate the genetic determinants of melatonin secretion. Here, we conducted a genome-wide association study (GWAS) for melatonin secretion using morning urine 6-hydroxymelatonin sulfate-to-creatinine ratio (UMCR). We initially enrolled 5000 participants from Taiwan Biobank in this study. After excluding individuals that did not have their urine collected in the morning, those who had history of neurological or psychiatric disorder, and those who failed to pass quality control, association of single nucleotide polymorphisms with log-transformed UMCR adjusted for age, sex and principal components of ancestry were analyzed. A second model additionally adjusted for estimated glomerular filtration rate (eGFR). A total of 2373 participants underwent the genome-wide analysis. Five candidate loci associated with log UMCR (P value ranging from 6.83 × 10-7 to 3.44 × 10-6) encompassing ZFHX3, GALNT15, GALNT13, LDLRAD3 and intergenic between SEPP1 and FLJ32255 were identified. Similar results were yielded with further adjustment for eGFR. Interestingly, the identified genes are associated with circadian behavior, neuronal differentiation, motor disorders, anxiety, and neurodegenerative diseases. We conducted the first GWAS for melatonin secretion and identified five candidate genetic loci associated with melatonin level. Replication and functional studies are needed in the future.

A immunosuppressive triterpenoid saponin from the stems of Epigynum griffithianum.

Chemical investigation of the stems of Epigunum griffithianum led to the isolation and identification of a new triterpenoid saponin (1) and two known compounds (epigynosides A (2) and B (3)). These structures were elucidated by means of spectroscopic analysis (1D and 2D NMR, MS, UV, IR) as well as comparison with the reported data. Compound 1 was evaluated in vitro for the immunosuppressive activities on proliferation of mice splenocyte and displayed significant immunosuppressive activities compared to the positive control (dexamethasone) with the concentration at 25 µM.[Formula: see text].

Lactate Dehydrogenase-to-Lymphocyte Ratio Represents a Powerful Prognostic Tool of Metastatic Renal Cell Carcinoma Patients Treated with Tyrosine Kinase Inhibitors.

Inflammation parameters were verified to predict clinical outcomes of metastatic renal cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors (TKIs). Here, we developed a novel marker, lactate dehydrogenase (tumor burden marker) to lymphocytes (inflammation marker) ratio (LLR), aimed to reveal the prognostic role of LLR for mRCC patients treated with TKIs. We collected clinical data of mRCC patients treated with TKIs. Receiver operating curve analysis was used to determine the optimal cut-off value. The c-index method was used to determine the best predictive marker for overall survival (OS). Clinicopathological characteristics on OS and progression-free survival (PFS) were evaluated by univariate analysis, and multivariate analyses. LLR provided the greatest improvement in the c-index, and displayed the best marker of the prognostic accuracy for OS. Univariate analysis revealed that LLR, ECOG PS and IMDC risks were significant predictors of OS and PFS. However, multivariate analysis indicated that IMDC risks failed to predict PFS, and only showed predictor of OS. We finally stratifed patients into low LLR (<150) and high LLR (≥150) group with different clinical outcomes. LLR represents a powerful prognostic tool of clinical outcome in mRCC patients treated with TKIs.

Late initiation of renal replacement therapy is associated with worse outcomes in acute kidney injury after major abdominal surgery.

INTRODUCTION: Abdominal surgery is probably associated with more likelihood to cause acute kidney injury (AKI). The aim of this study was to evaluate whether early or late start of renal replacement therapy (RRT) defined by simplified RIFLE (sRIFLE) classification in AKI patients after major abdominal surgery will affect outcome. METHODS: A multicenter prospective observational study based on the NSARF (National Taiwan University Surgical ICU Associated Renal Failure) Study Group database. 98 patients (41 female, mean age 66.4 +/- 13.9 years) who underwent acute RRT according to local indications for post-major abdominal surgery AKI between 1 January, 2002 and 31 December, 2005 were enrolled The demographic data, comorbid diseases, types of surgery and RRT, as well as the indications for RRT were documented. The patients were divided into early dialysis (sRIFLE-0 or Risk) and late dialysis (LD, sRIFLE -Injury or Failure) groups. Then we measured and recorded patients' outcome including in-hospital mortality and RRT wean-off until 30 June, 2006. RESULTS: The in-hospital mortality was compared as endpoint. Fifty-seven patients (58.2%) died during hospitalization. LD (hazard ratio (HR) 1.846; P = 0.027), old age (HR 2.090; P = 0.010), cardiac failure (HR 4.620; P < 0.001), pre-RRT SOFA score (HR 1.152; P < 0.001) were independent indicators for in-hospital mortality. CONCLUSIONS: The findings of this study support earlier initiation of acute RRT, and also underscore the importance of predicting prognoses of major abdominal surgical patients with AKI by using RIFLE classification.

A modified sequential organ failure assessment score to predict hospital mortality of postoperative acute renal failure patients requiring renal replacement therapy.

BACKGROUND: A predictive model for hospital mortality in postoperative acute renal failure (ARF) patients requiring renal replacement therapy (RRT) may aid clinicians' therapeutic decision-making and research design. METHODS: A prospective observational study of 398 postoperative ARF patients requiring RRT was conducted in four hospitals. The derivation cohort consisted of 334 patients recruited between January 2002 and December 2005. The validation cohort consisted of 64 patients recruited between January 2006 and December 2006. RESULTS: The hospital mortality rates for the derivation and validation cohorts were 65.6 and 62.5%, respectively. A modified Sequential Organ Failure Assessment (SOFA) score was constructed at the commencement of RRT by a formula of serum lactate level (mM) + 2 x (generic SOFA score) + 3 x (age per decade) + 8 (if mechanical circulatory support required) + 10 (if total parenteral nutrition required) + 11 (if status postcardiopulmonary resuscitation) + 13 (if positive sepsis sign). The area under the receiver operating characteristic curve of the model for the derivation and validation cohorts was 0.804 and 0.839, respectively. CONCLUSION: This validated score at dialysis commencement might assist clinicians in estimating hospital mortality, planning future clinical trials, and providing quantitative guidance for decision making in postoperative ARF patients requiring RRT.